MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

in European Journal of Endocrinology
View More View Less
  • 1 Departments of Paediatrics, Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands

Correspondence should be addressed to J M Wit; Email: j.m.wit@lumc.nl
Free access

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

Abstract

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

Invited Author's profile

Professor Jan Maarten Wit is currently Professor Emeritus and honorary staff member of the Department of Paediatrics at Leiden University Medical Centre, The Netherlands. Trained as a paediatric endocrinologist, he served as an Associate Professor of Paediatric Endocrinology in Utrecht and Full Professor/Chairman of Paediatrics in Leiden. Most of his research has been focused on the diagnosis and management of growth disorders. Shortly after his PhD thesis (Responses to growth hormone therapy), he founded the Dutch Growth Hormone Advisory Group and the Dutch Growth Hormone Research Foundation's bureau, instrumental in conducting numerous multicentre clinical trials on the efficacy and safety of growth hormone treatment. In Leiden, he led research projects on regulation of the epiphyseal growth plate and on referral criteria and diagnostic guidelines for short children, but the main subject focus over the last 10 years has been the elucidation of novel genetic causes of short and tall stature.

Introduction

The fast technological development has caused a flood of novel discoveries in genetic causes of congenital disorders, including syndromic and non-syndromic forms of short stature. In the first decade of the 21st century, the genetic toolbox was expanded by whole genome single nucleotide polymorphism (SNP) array (1) and array-comparative genomic hybridization (array-CGH) (2) for the detection of microdeletions or microduplications (copy number variants (CNVs)), the former of which is also able to detect uniparental disomy. In the second decade an even more successful tool became available – whole exome sequencing (WES) – for the detection of gene variants as possible causes of congenital disorders (3, 4, 5, 6), with a good diagnostic yield in well-selected patients (6). In general, WES is performed in an index patient and his/her parents (a ‘trio’), and (if available) affected and non-affected siblings, to limit the number of informative variants in the bioinformatic analysis.

At the same time, information about genes associated with linear growth was collected through non-clinical research, in particular through genome-wide association studies (GWAS) and animal and in vitro experiments on epiphyseal growth plate (GP) function. GWAS have shown that common SNPs at over 400 loci contribute to variation in normal adult stature, albeit with a small effect size per locus (7). Many of these genes, but also others, have appeared in gene expression studies in the various zones of the GP (8, 9).

For this review we chose to focus on discoveries made in the last 10 years (up to August 2015), against the background of earlier findings, as summarized in previous reviews by our group (10, 11, 12, 13) and others (5, 14, 15, 16, 17) (for search strategy see section at the end of the article). The tables offer the formal names of the disorders and codes according to online Mendelian inheritance in man (OMIM) (http://www.ncbi.nlm.nih.gov/omim), and we aimed at providing the most recent relevant references.

In line with a recent review paper (17), we structured this review according to a diagnostic classification centred on the GP. In the GP, chondrocytes proliferate, hypertrophy, and secrete cartilage extracellular matrix, under the influence of endocrine and paracrine factors. Thus, in this review successively hormones, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes will be discussed, followed by CNVs and imprinting disorders. Because the GP is the structure where linear growth takes place, we prefer this pathophysiologic classification above the multiple reported alternative classifications, for example proportionate vs disproportionate short stature; with or without microcephaly (18); prenatal vs postnatal onset of growth retardation (19); or growth hormone (GH) deficiency or insensitivity (20).

A complicating factor in the classification of monogenic disorders is that a variety of mutations in one gene can result in a broad phenotypic spectrum, sometimes including different clinical entities, previously defined as separate conditions (‘allelic heterogeneity’). On the other hand, one clinical disorder can be caused by mutations in different genes (‘locus heterogeneity’) (14). Furthermore, mutations in some genes not only impair GP development and/or function but also non-skeletal structures, causing associated congenital anomalies (syndromic short stature) (17).

The last decades have taught us that with time the clinical phenotype of genetic defects tends to become more variable than initially assumed. The rapid increase of the use of SNP arrays and WES in the coming years, and the expected appearance of whole genome sequencing (WGS), RNA sequencing, and methylation assays, will certainly lead to the discovery of many more novel causes of short stature, as well as a further expansion of the clinical phenotypes associated with genetic and epigenetic variants.

Genetic defects of the GH–insulin-like growth factor 1 axis

The GH––insulin-like growth factor 1 (IGF1) axis is an important pathway in the regulation of linear growth, and defects have been found in virtually all components of this cascade. Tables 1 and 2 show conditions associated with GH or IGF1 signalling, divided into three categories: i) GH deficiency (GHD); ii) GH insensitivity (GHI) and decreased expression or biologic activity of IGF1 or IGF2; and iii) IGF1 insensitivity. For various genes, a publicly available database has been established (www.growthgenetics.com) (21), and clinicians and geneticists are encouraged to upload clinical and genetic data of additional cases.

Table 1

Causes of GHD.

DisorderaGene(s)Clinical featuresInheritanceReferences
GHD and potential for CPHD
 CPHD-1 (613038)POU1F1GH, PRL, var. TSH def.AR, AD(5, 22, 23)
 CPHD-2 (262600)PROP1GH, PRL, TSH, LH, FSH, var. ACTH def. Pituitary can be enlarged.AR(5, 22, 23)
 CPHD-3 (221750)LHX3GH, TSH, LH, FSH, PRL def. Sensorineural hearing loss, cervical abnormalities, short stiff neckAR(5, 22, 23)
 CPHD-4 (262700)LHX4GH, TSH, ACTH def.AD, AR(5, 22, 23)
 Septo-optic dysplasia (CPHD-5) (182230)HESX1Optic nerve hypoplasia, pituitary hypoplasia, midline abnormalities of brain, absent corpus callosum and septum pellucidumAR, AD(5, 22, 24)
 CPHD-6 (613986)OTX2TSH, GH, LH, FSH, var. ACTH and PRL def. AD(5, 22, 24)
 Axenfeld–Rieger syndrome type 1 (180500)PITXColoboma, glaucoma, dental hypoplasia, protuberant umbilicus, brain abnormalities, var. pituitary def.AD(22)
 Optic nerve hypoplasia and abnormalities of the central nervous system (206900)SOX2Var. GHD, hypogonadism, anophthalmia, developmental delayAD(22, 24)
 X-linked panhypopituitarism (312000, 300123)SOX3dupbGHD or CHPD, mental retardationXLR(5, 22, 24)
 Dopa-responsive dystonia due to sepiapterin reductase deficiency (612716)SPRDiurnally fluctuating movement disorder, cognitive delay, neurologic dysfunction, GH and TSH def.AR(237)
 Holoprosencephaly 9 (610829)GLI2Holoprosencephaly, craniofacial abnormalities, polydactyly, single central incisor, partial agenesis corpus callosum (or hypopituitarism only)AD(5, 22)
 IGSF1 deficiency syndrome (300888)IGSF1TSH, var. GH and PRL def.; macroorchidismXLR(26)
 Netherton syndrome (256500)SPINK5Var. GH and PRL def.AR(27)
 Pallister–Hall syndrome (146510)GLI3Hypothalamic hamartoma, central polydactyly, visceral malformationsAD(5)
FGF8Holoprosencephaly, septo-optic dysplasia, Moebius syndromeAR(5, 24)
FGFR1Hypoplasia pituitary, corpus callosum, ocular defectsAD(5, 238)
PROKR2Var. hypopituitarismAD(238)
HMGA2Severe GHD, ectopic posterior pituitaryAD(239, 240)
GRP161Pituitary stalk interruption syndrome, intellectual disability, sparse hair in frontal area, hypotelorism, broad nasal root, thick alae nasi, nail hypoplasia, short fifth finger, 2–3 toe syndactyly, hypopituitarismAR(241)
Isolated GHD or bioinactivity
 Isolated GHD, type IB (612781)GHRHRLow serum GHAR(240, 242)
 Isolated GHD, type 1A (262400)GH1No serum GH, often anti-GH abAR(240, 242)
 Isolated GHD, type IB (612781)GH1Low serum GHAR(240, 242)
 Isolated GHD, type II (173100)GH1Var. height deficit and pituitary size; other pituitary deficits can developAD(240, 242)
 Isolated GHD, type III (307200)BTK, SOX3GHD with agammaglobulinemiaXLR(240, 242)
 Isolated partial GHD (615925)GHSRVar. serum GH and IGF1AR, AD(39, 41)
 Kowarski syndrome (bioinactive GH syndrome) (262650)GH1high GH; def. of IGF1, IGFBP-3, and ALSAD(242)
 Almstrom syndrome (203800)ALMS150% of cases are GHDAR(35)
RNPC3Severe GHD, hypoplasia anterior pituitaryAR(33)
IFT172Functional GHD, retinopathy, metaphyseal dysplasia, hypertensionAR(34)

AD, autosomal dominant; AR, autosomal recessive; def., deficiency; GHBP, growth hormone binding protein; GHD, growth hormone deficiency; IGF1, insulin-like growth factor 1; IGFBP-3, IGF binding protein-3; PRL, prolactin; var., variable; XLR, X-linked recessive.

Name (number) according to OMIM. For clinical and radiological features of the various conditions, see (5, 22, 23, 24).

This condition can also be caused by SOX3 polyalanine deletions and expansions.

Table 2

Causes of GH insensitivity or IGF insensitivity.

DisorderaGene(s)Clinical featuresInheritanceReferences
GH insensitivity
 Laron syndrome (262500)GHRVariable height deficit and GHBP, midfacial hypoplasia;↑GH, ↓IGF1, IGFBP-3 and ALSAR (AD)(46, 242)
 GH insensitivity with immunodeficiency (245590)STAT5BMidfacial hypoplasia, immunodeficiency; ↑GH and PRL; ↓IGF1, IGFBP-3 and ALSAR(55)
 Multisystem, infantile-onset autoimmune disease (615952)STAT3 (act)Associated with early-onset multi-organ autoimmune diseaseAD(68, 69)
 X-linked severe combined immunodeficiency (300400)IL2RGGH normal, low IGF1, non-responding to GH injectionsXLR(243, 244)
 IGF1 deficiency (608747)IGF1SGA, microcephaly, deafness; ↑GH and IGFBP-3; variable IGF1AR(13)
 Severe growth restriction with distinctive facies (616489)IGF2↓↑/nl GH, IGFBP3; nl IGF1Pat inheritance(82)
 ALS deficiency (615961)IGFALSMild height deficit; GH?,↓IGF1, IGFBP-3 and ALSAR(59)
PAPP-A2Microcephaly, skeletal abnormalities, ↑GH, IGF1, IGFBP-3, and ALSAR(84)
 Immunodeficiency 15 (615592)IKBKBImmunodeficiency; ↓IGF1 and IGFBP-3AR, AD(65)
IGF insensitivity
 Resistance to insulin-like growth factor 1IGF1RSGA, microcephaly; ↑/nl GH, IGF1, and IGFBP-3AD, AR(85)

act, activating; AD, autosomal dominant; ALS, acid-labile subunit; AR, autosomal recessive; GH, growth hormone; GHBP, growth hormone binding protein; IGF1, insulinlike growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; SGA, small for gestational age; XLR, X-linked recessive.

Name (number) according to OMIM.

GH deficiency

Table 1 shows the gene defects that have been associated with GHD. Many of the proteins encoded by these genes are associated with GHD as part of combined pituitary hormone deficiency (CPHD), and function as pituitary transcription factors (for detailed information on associated clinical features and MRI appearances see (5, 22, 23, 24)). A novel endocrine syndrome discovered by our group, immunoglobulin superfamily member 1 (IGSF1) deficiency syndrome, is primarily characterized by central hypothyroidism and macroorchidism, but can also present with hypoprolactinaemia and transient partial GHD (25, 26). The association of Netherton syndrome with GH and prolactin deficiency suggests that a defect of LEKT1 (encoded by SPINK5) may increase the degradation of these hormones in pituitary cells by human tissue kallikreins before they enter the circulation (27). Other causes of CPHD include mutations in GLI3, FGF8, FGFR1, PROKR2, HMGA2, and GRP161 (Table 1).

Isolated GHD mutations in the genes encoding GH (GH1) or GH releasing hormone receptor (GHRHR) can be found in up to 34% in familial cases (28). GH1 mutations can either lead to classical GHD (types IA, IB, and II) or bioinactive GH syndrome. While in the past the latter diagnosis was used without good experimental evidence, recent reports have shown that this is a real condition, characterized by normal or even elevated circulating GH levels, and in some cases also associated with partial GHI (28, 29, 30).

The most common cause of type IA GHD is a homozygous GH1 deletion; in most of such patients anti-GH antibodies develop with GH treatment. However, several other aberrations of GH1 have been described. The less severe type IB GHD is caused by mutations of GH1 or GHRHR, and a dominant form of GHD (type II) is usually caused by skipping of exon 3 resulting in production of a 17.5-kDa isoform of GH with a dominant negative effect (28). The X-linked type III GHD is associated with agammaglobulinaemia, and has been associated with mutations in BTK (31) and SOX3 (32).

Isolated GHD can also be caused by biallelic mutations in RNPC3, which encodes a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein (snRNP) formation and splicing of U12-type introns (33). Compound heterozygosity for a gene encoding a protein important for ciliary function (IFT172) can cause functional GHD, pituitary hypoplasia, and ectopic posterior pituitary (34), and also Alström syndrome, caused by a mutation of ALMS1 encoding a protein localized to the centrosomes and basal bodies of ciliated cells (35) is associated with GHD. GHD has also been documented in a congenital malformation syndrome associated with a paternal deletion of 6q24.2–q25.2 (36), complete generalized glucocorticoid resistance (37), and mitochondrial diseases (38).

A still insufficiently defined cause of GHD is a mutation of the gene encoding the Ghrelin receptor (GHSR) (reviewed in (39)). The variability of clinical phenotypes (GHD, idiopathic short stature (ISS) and constitutional delay of growth and puberty (CDGP)) and incomplete segregation of the mutations with the phenotype still cast doubt on the role of GHSR mutations in causing short stature, although functional studies do suggest that GHSR mutations may decrease GH secretion (40, 41, 42), implying that GHSR mutations may contribute to the genetic aetiology of children originally considered ISS (41).

GHI and decreased expression or biologic activity of IGF1or IGF2

Table 2 shows the various syndromes presenting with insensitivity to GH or IGF1. The first discovered cause of GHI was Laron syndrome, usually caused by a homozygous mutation of the gene encoding the GH receptor (GHR) (43, 44, 45). Since then more than 70 mutations in >300 cases have been found with mutations in extracellular, transmembrane, and intracellular parts of the GHR (46, 47). In most cases serum GH binding protein (GHBP) is absent, except in cases with a mutation in the intracellular or transmembrane part of the protein. While the classical form causes severe growth failure, there are milder forms as well, for example caused by an intronic base change leading to the activation of a pseudoexon sequence and insertion of 36 new amino acids within the receptor extracellular domain (48, 49, 50) or by heterozygous GHR mutations causing a dominant negative effect (51, 52, 53).

In 2003 the first patient with a homozygous loss-of-function mutation of the gene encoding the main component of the intracellular GH signalling pathway (STAT5B) was found (54), and since then ten patients have been reported in seven families (55). Most have an additional immunodeficiency and pulmonary fibrosis (56). Heterozygosity for a STAT5B mutation leads to a slightly lower height (57).

Another well-defined cause of GHI is a defect in IGFALS, encoding acid-labile subunit (ALS) which forms with IGF binding protein 3 (or 5) and IGF1 (or IGF2) a ternary complex in the circulation (58, 59). Children with ALS deficiency show a mild growth failure, delayed puberty, undetectable serum ALS, low serum IGF1, and even lower IGF binding protein 3 (IGFBP-3) (59), and variable osteopenia and hyperinsulinism (60, 61, 62). Heterozygosity for IGFALS variants causes a one s.d. lower height (60, 62, 63) and may be responsible for a subset of children previously considered having ISS (64).

GHI may also be caused by a mutation in the gene encoding IκBα (IKBKB), presenting with short stature, GHI, severe immune deficiency and other features (65) or a PRKCA duplication, in a patient with a mosaic de novo duplication of 17q21–25 (66) (reviewed in (67)). Furthermore, activating STAT3 mutations may be not only associated with early-onset multi-organ autoimmune disease, but also with growth failure (68, 69).

Homozygous deletions or missense mutations of IGF1 (encoding IGF1) resulting in a complete loss-of-function (70, 71) cause a severe prenatal and postnatal growth failure, developmental delay, microcephaly, and sensorineural deafness. Patients with a homozygous hypomorphic mutation (72) or specific heterozygous mutations (73, 74) presented with less severe growth failure and normal hearing (reviewed in (75)). Heterozygous carriers of IGF1 mutations or deletions are ∼1 s.d. shorter than non-carriers (71, 73, 74, 76).

With regard to IGF2, it is assumed that in most children with Silver–Russell syndrome the pre- and post-natal growth restriction is caused by deficient expression of the paternally expressed gene encoding IGF2 (IGF2) (77, 78), usually through H19 hypomethylation. Such children can have relatively high serum IGF1 and IGFBP-3, suggesting partial IGF1 resistance (79, 80). In contrast, Silver–Russell syndrome patients carrying a maternal uniparental disomy of chromosome 7 (UPD7) usually present with low levels of IGF1 (79, 81). Very recently, the first family with a paternally inherited IGF2 mutation and growth restriction was reported, indicating that IGF2 not only is a mediator of intrauterine development but also contributes to postnatal growth (82). This confirmed an earlier observation of a patient with a paternally transmitted severe intrauterine growth retardation (IUGR) with a translocation breakpoint disrupting regulation of IGF2 (83).

Another novel finding is that a homozygous mutation of the gene encoding the protease PAPPA-2 (PAPPA2) is associated with mild short stature, presumably by insufficient availability of free IGF1 (84).

IGF1 insensitivity

Numerous cases have been reported of heterozygous mutations or deletions of the gene encoding the receptor for IGF1 (and IGF2) (IGF1R) (reviewed in (75, 85)). Clinical features include prenatal growth failure persisting after birth, microcephaly, and serum IGF1 in the upper half of, or above, the normal range. On GH treatment serum IGF1 can become very high, which may probably be accepted because of the decreased sensitivity. We estimate that IGF1R defects can be found in ∼3% of short children born small for gestational age (SGA) (86). A homozygous or compound heterozygous IGF1R mutation leads to a more severe phenotype (87, 88, 89, 90). In theory, IGF1 insensitivity may also be caused by mutations downstream of the IGF receptor, or by defective microRNA regulation of IGF1 signalling (91).

Genetic defects affecting signalling of other hormones regulating GP function

Congenital disorders of thyroid hormone signalling include primary hypothyroidism (thyroid dysgenesis or dyshormonogenesis) and thyroid hormone resistance. If undiagnosed, congenital hypothyroidism leads to very severe growth failure (92), but in most middle- and high-income countries early detection by neonatal screening will prevent this, as well as the severe consequences for mental development. Presently known genetic causes of thyroid dysgenesis and dyshormonogenesis have recently been reviewed (17, 93).

Children with thyroid hormone resistance caused by mutations of THRB (encoding the beta form of the thyroid hormone receptor (TRβ)) usually show normal growth, but in severe cases short stature has been observed (94). In contrast, all reported children with mutations in THRA (encoding TRα) are short. Further clinical features include delayed mental and bone development, constipation, and relatively low serum T4 and high serum T3 levels (elevated T3/T4 ratio) (95, 96). An opposite serum thyroid hormone profile (elevated T4 and low-normal or slightly decreased T3) is seen in a homozygous or compound heterozygous mutation of SECISBP2 (SBP2) (encoding an iodothyronine deiodinase), associated with short stature and responding to GH and T3 treatment (97).

It is well known that growth failure can be caused by excessive exposure to glucocorticoids, due to Cushing syndrome or pharmacological doses of corticosteroids. A discussion of newly discovered genetic causes of ACTH-dependent and independent Cushing syndrome is outside the scope of this paper (for recent findings, see (98, 99)). Homozygous or compound heterozygous mutations of the gene encoding the insulin receptor (INSR) cause Donohue syndrome (Leprechaunism) (100).

Genetic defects affecting paracrine factors in the GP

Paracrine regulation plays a major role in the GP, and only part of its complexity is presently understood. Most of the genetic defects of paracrine pathways result in some form of skeletal dysplasia, of which 436 conditions, caused by defects in 364 genes, have been listed in the 2015 revision of the nosology of genetic skeletal disorders (101). Disproportionate short stature is one of the main features of most of these conditions. Therefore, in the clinical assessment of the short individual, not only accurate measurements of height and head circumference have to be carried out, but also of sitting height and arm span, and the same measurements should be performed in the parents. The length of upper and lower arms and legs, and hands and feet, should be at least visually assessed, and possibly measured and compared with normative charts (a relatively short upper arm and leg is called rhizomelia, in contrast to mesomelia if forearm and lower leg are relatively short). A series of skeletal radiographs usually gives important clues for the diagnosis (15, 102, 103, 104). Most forms of skeletal dysplasia show short-limb dwarfism, in contrast to type I and II collagenopathies which are characterized by short-trunk dwarfism (14). Because a comprehensive review of these conditions is beyond the scope of this article, only a few relatively common conditions are discussed (Table 3).

Table 3

Examples of genetic defects affecting paracrine factors in the growth plate.

DisorderaGene(s)Clinical featuresInheritanceReferences
FGF signaling
 Pfeiffer syndrome, acrocephalosyndactyly, type V (101600)FGFR1, FGFR2Craniosynostosis with characteristic anomalies of the hands and feet (three types)AD(245)
 Thanatophoric dysplasia type I (187600)FGFR3 (act)Severe short-limb dwarfism syndrome usually lethal in the perinatal periodAD(9)
 Achondroplasia (100800)FGFR3 (act)Rhizomelic limb shortening, frontal bossing, midface hypoplasia, exaggerated lumbar lordosis, limited elbow extension, genu varum, trident handAD(9)
 Hypochondroplasia (146000)FGFR3 (act)Short-limbed dwarfism, lumbar lordosis, short and broad bones, caudal narrowing of interpediculate distance of lumbar spineAD(9, 108, 246)
 Short statureFGFR3 (act)Relative macrocephaly for heightAD(109)
BMP signaling
 Brachydactyly A1 (112500)IHH, GDF5, BMPR1BMiddle phalanges rudimentary or fused with terminal phalanges, short proximal phalanges thumbs and big toesAD(247)
 Brachydactyly A2 (112600)BMPR1B, BMP2, GDF5Malformations of middle phalanx of index finger, anomalies of second toeAD(248)
 Brachydactyly C (113100)GDF5, CDMP1Deformity of middle and proximal phalanges (II, III), hypersegmentation of proximal phalanxAD(249)
WNT signaling
 Robinow syndrome (268310)ROR2, WNT5AFrontal bossing, hypertelorism, broad nose, short-limbed dwarfism, vertebral segmentation, genital hypoplasiaAR, AD(112)
 Brachydactyly, Type B1 (113000)ROR2Short middle phalanges, terminal phalanges rudimentary or absent; deformed thumbs, big toesAD(113)
PTHrP-IHH pathway
 Brachydactyly, type E2 (613382)PTHLHShort stature and learning difficultiesAD(116)
 Blomstrand chondro-dysplasia (215045)PTHR1Short limbs, polyhydramnios, hydrops fetalis, facial anoma-lies, increased bone density, advanced skeletal maturationAR(117)
 Jansen type of meta-physeal chondrodys-plasia (156400)PTHR1 (act)Severe short stature, short bowed limbs, clinodactyly, prominent upper face, small mandible; hypercalcemia and hypophosphatemiaAD(118)
 Brachydactyly type A1 (112500)IHH, GDF5, BMPR1BMiddle phalanges rudimentary or fused with terminal phalanges. Short proximal phalanges of thumbs, big toesAD(119)
 Acrocapitofemoral dysplasia (607778)IHHVariable short stature, short limbs with brachydactyly, relatively large head circumferenceAR(119)
 Albright hereditary osteodystrophy (103580)GNASPseudohypoparathyroidism, type Ia/c. Caused by loss of function of Gs-alpha isoform of GNAS on maternal allele. For further details see Table 8Imprinted(228)
 Acrodysostosis 1 (101800)PRKAR1ASevere brachydactyly, facial dysostosis, nasal hypoplasia, advanced bone age, obesity, resistance to multiple hormonesAD(121)
CNP-NPR2 pathway
 Acromesomelic dysplasia, Maroteaux type (602875)NPR2Disproportionate shortening of middle segments (forearms and forelegs) and distal segments (hands and feet)AR(124)
 (Dis)proportionate short statureNPR2Moderate short stature, short forearms and forelegsAD(130)

AD, autosomal dominant; AR, autosomal recessive; act, activating.

Name (number) according to OMIM.

Fibroblast growth factor signalling

Several fibroblast growth factors (FGFs) and their receptors play a role in the GP (9, 105). Best known is the FGF receptor-3 (encoded by FGFR3), which acts as a negative regulator of GP chondrogenesis (106, 107). Consequently, heterozygous activating mutations in FGFR3 impair bone elongation and lead to a spectrum of disorders, reflecting the degree of activation of the FGFR3 mutation. The best known examples are thanatophoric dysplasia, achondroplasia, and hypochondroplasia, each associated with different locations of the mutation. The clinical presentation of hypochondroplasia is milder and more variable than achondroplasia and includes rhizomelic limb shortening, limitation of elbow extension, brachydactyly, relative macrocephaly, generalized laxity, and specific radiologic features (5, 108). We recently reported a novel activating FGFR3 mutation in a family with proportionate short stature (109).

Bone morphogenetic protein signalling

Bone morphogenetic proteins (BMPs), also known as growth and differentiation factors (GDFs), belong to the transforming growth factor-beta (TGFβ) superfamily of paracrine factors. The BMPs regulate a multitude of processes in skeletal development, including spatial regulation of proliferation and differentiation in the GP, and a BMP signalling gradient across the GP may contribute to the progressive differentiation of resting to proliferative to hypertrophic chondrocytes (9). Inactivating mutations in the genes for several BMPs, their receptors, and antagonists cause various forms of skeletal dysplasias, particularly brachydactylies.

WNT signalling

The receptor tyrosine kinase-like orphan receptor 2 (RoR2) is part of a conserved family of tyrosine kinase-like receptors that serve as receptors for noncanonical WNT ligands, participating in developmental processes like cell movement and cell polarity (110, 111). Homozygous mutations of ROR2 or heterozygous mutations of WNT5A cause Robinow syndrome (112) and dominant ROR2 mutations cause brachydactyly, Type B1 (113).

PTHrP–IHH pathway

Parathyroid hormone related peptide (PTHrP) and Indian Hedgehog (IHH) form a negative feedback loop within the GP that regulates chondrocyte hypertrophy and proliferation (114, 115). Heterozygous loss-of-function mutations in PTHLH, encoding PTHrP, and inactivating and activating mutations in PTHR1 (encoding the parathyroid hormone receptor-1) cause various short stature syndromes (116, 117, 118), as well as inactivating and activating mutations of IHH (119, 120). Heterozygous missense mutations in PRKAR1A and PDE4D cause acrodysostosis 1 and 2 respectively, with or without hormone resistance (121, 122).

CNP–NPR2 pathway

One of the most interesting breakthroughs in the field of growth genetics is the unravelling of the role of C-natriuretic peptide (CNP, encoded by NPPC) and its receptors in GP function. CNP is a local, positive regulator of GP function, and SNPs in NPPC and in the gene encoding one of its receptors (NPR3) show a significant association with adult height in GWAS (123). Homozygous inactivating mutations of NPR2 (encoding the main CNP receptor) cause a severe skeletal dysplasia, acromesomelic dysplasia, Maroteaux type (124). Initial observations that relatives heterozygous for NPR2 mutations of patients with acromesomelic dysplasia are shorter than non-carriers (125), were confirmed by recent studies (126, 127, 128, 129). The phenotype of heterozygous NPR2 mutations is similar to that of patients with SHOX haploinsufficiency (Leri–Weill syndrome), with short forearms and lower legs (mesomelia), except for the absence of Madelung deformity (130). Heterozygous NPR2 mutations may explain 2–3% of cases with assumed ISS (129) and probably more if one of the parents has a similar phenotype.

Unravelling of the role of this pathway in linear growth has led to potential therapeutic consequences for children with achondroplasia. Binding of CNP to NPR2 stimulates the receptor guanylyl cyclase activity thereby increasing synthesis of cGMP, activating the type II cGMP-dependent protein kinase (131), which in turn leads to inhibition of the MAPK pathway, thus antagonizing FGFR signalling (132). In a mouse model of achondroplasia, CNP had beneficial effects (133), and clinical trials with a long-acting CNP analogue are in progress in children with achondroplasia.

Genetic defects affecting cartilage extracellular matrix

A unique characteristic of chondrocytes is that they secrete an extracellular matrix containing specific collagens, non-collagenous proteins and proteoglycans, which are vital to normal GP function. This extracellular matrix not only provides the compressible, resilient structural properties of cartilage, but also interacts with signalling molecules to regulate GP chondrogenesis (17).

Mutations in several genes encoding matrix proteins and proteoglycans have been shown to lead to growth disorders (Table 4). Mutations in ACAN, encoding aggrecan, show a gene-dose effect: homozygous mutations cause a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia aggrecan type (134), while heterozygous mutations can present as a milder skeletal dysplasia, spondyloepiphyseal dysplasia type Kimberley, or as short stature without evident radiographic skeletal dysplasia (135). This latter form is associated with an advanced bone age and early cessation of growth (17, 135).

Table 4

Examples of genetic defects affecting cartilage extracellular matrix.

DisorderaGene(s)Clinical featuresInheritanceReferences
Acromicric dysplasia (102370)FBN1Severe short stature, short hands and feet, joint limitations, skin thickeningAD(250, 251)
Geleophysic dysplasia-2 (614185)FBN1Severe short stature, short hands and feet, joint limitations, skin thickening, heart involvementAD(250, 251)
Brachyolmia type 4 with mild epiphyseal and metaphyseal changes (spondyloepimetaphyseal dysplasia, Pakistani type) (612847)PAPSS2Short trunk, normal intelligence and facies; rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bonesAR(137, 252)
Hurler syndrome (607014)IDUASkeletal deformities, corneal clouding, hepatosplenomegaly, psychomotor delayAR(253)
Metaphyseal chondro-dysplasia, Schmid type (156500)COL10A1Short stature, widened growth plates, bowing of long bonesAD(254)
Multiple epiphyseal dysplasia 1–6COMP, COL9A2, COL9A3, SLC26A2, MATN3, COL9A1Short-limbed dwarfism, joint pain and stiffness and early onset osteoarthritisAD(255)
Pseudoachondro-plasia (177170)COMPDisproportionate short stature, deformity of lower limbs, brachydactyly, loose joints, ligamentous laxity, vertebral anomalies, osteoarthritisAD(256)
Spondyloepiphyseal dysplasia congenita (183900)COL2A1Multiple presentationsAD(257)
Spondyloepimetaphy-seal dysplasia aggrecan type (612813)ACANRelative macrocephaly, severe midface hypoplasia, almost absent nasal cartilage, relative prognathism, slightly low-set, posteriorly rotated ears; short neck, barrel chest, mild lumbar lordosis; rhizomelia and mesomeliaAR(134)
Spondyloepiphyseal dysplasia type Kimberley (608361)ACANProportionate short stature, stocky habitus, progressive osteoarthropathyAD(258)
Short stature with advanced bone ageACANAdvanced bone age, premature growth cessationAD(135)
Weill–Marchesani syndrome (613195, 608328)ADAMTS10, FBN1Spherophakia, lenticular myopia, ectopia lentis, joint stiffness, brachydactylyAR(259)

AD, autosomal dominant; AR, autosomal recessive.

Name (number) according to OMIM.

Some disorders, such as the genetically heterogeneous brachyolmia, tend to affect the spine more than the long bones, for example mutations in PAPSS2 encoding a sulphotransferase, required for sulphation of a variety of molecules, including cartilage glycosaminoglycans and DHEA (136, 137).

Genetic defects of intracellular pathways

Various intracellular pathways play a role in chondrocyte differentiation in the GP, and examples of disorders in such pathways are listed in Table 5.

Table 5

Examples of genetic defects affecting intracellular pathways.

DisorderaGene(s)Clinical featuresInheritanceReferences
SHOX aberrations
 Langer mesomelic dysplasia (249700)SHOXSevere limb aplasia or hypoplasia of the ulna and fibula, and a thickened and curved radius and tibiaAR(138)
 Leri–Weill dyschon-drosteosis (127300)SHOXMesomelia, Madelung wrist deformity, or mild body disproportionAD(138, 149)
Rasopathies
 Noonan syndrome 1–8PTPN11, KRAS, SOS1, RAF1, NRAS, BRAF, RIT1Facial dysmorphism, wide spectrum of congenital heart defectsAD(157, 260, 261)
 LEOPARD syndrome

1 (151100)

2 (611554)

3 (613707)


PTPN11,

RAF1,

BRAF
Multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, sensorineural deafnessAD(260)
 Costello syndrome (218040)HRASCoarse facies, distinctive hand posture and appearance, feeding difficulty, failure to thrive, cardiac anomalies, developmental delayAD(260)
 Cardio-facio-cutaneous syndrome (115150)BRAF, KRASDistinctive facial appearance, heart defects, mental retardationAD(260)
 Neurofibromatosis-Noonan syndrome (601321)NF1Features of both conditionsAD(260)
 Neurofibromatosis type I (162200)NF1Cafe-au-lait spots, Lisch nodules in eye, fibroma-tous skin tumours; short in 13%; large head circumference in 24%AD(262)
 Coffin–Lowry syndrome (303600)RPS6KA3Mental retardation, skeletal malformations, hearing deficit, paroxysmal movement disordersXLR(261)
Other syndromes
 Aarskog–Scott syndrome (faciogenital dysplasia) (305400)FGD1Hypertelorism, shawl scrotum, brachydactylyXLR(263)
 Alström syndrome (203800)ALMS1Retinal photoreceptor degeneration, sensorineural hearing imparment, obesity, insulin resistanceAR(35)
 Campomelic dysplasia (114290)SOX9Congenital bowing and angulation of long bones, other skeletal and extraskeletal defectsAD(264)
 Congenital disorders of glycosylationMultiple genes (>76)Multisystem disorders caused by defects in biosynthesis of glycoconjugatesAR(168)
 Kabuki syndrome 1 (147920) and 2 (300867)KMT2D, KDM6ALong palpebral fissures, eversion of lateral third of the lower eyelids, broad and depressed nasal tip, large prominent earlobes, cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of vertebrae, hands, and hip joints, recurrent otitis media in infancyAD(265)
 Kenny–Caffey syndrome type 1 (244460) and 2 (127000)TBCE, FAM111ACraniofacial anomalies, small hands and feet, hypocalcemia, hypoparathyroidism, cortical thickening of long bones with medullary stenosis, delayed closure of anterior fontanel, eye abnormalities, transient hypocalcemia. Gene encodes tubulin-specific chaperone E.AR

AD
(6, 266)

AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

Name (number) according to OMIM.

For the clinician, the relatively frequent aberrations of the gene encoding short stature homeobox (SHOX) (located at the tip of the X and Y chromosome, and transmitted in a pseudoautosomal fashion) are most relevant. SHOX acts as a transcriptional activator and, like in NPR2 mutations, a gene-dose effect is apparent: homozygous or compound heterozygous inactivating SHOX mutations cause Langer mesomelic dysplasia, while heterozygous mutations or deletions of SHOX cause a milder skeletal dysplasia, Leri–Weill dyschondrosteosis (with the classic Madelung deformity of the wrist) or present clinically as ISS. It is assumed that most of the growth failure characteristic for Turner syndrome is caused by heterozygous SHOX deletion. Body proportions are usually mildly affected (mesomelia) but can be within the normal range (138). Various clinical prediction rules have been proposed to select patients for testing (139, 140, 141, 142), but the high variability of the clinical presentation limits their predictive value (5). SHOX mutations account for 2–15% of individuals presenting with ISS (143). Since usually SHOX defects are transmitted from one of the parents, physical examination of the parents is essential, including height, sitting height, arm span, forearm length, and presence of Madelung deformity.

Heterozygous deletions of the downstream and upstream enhancer of SHOX cause a similar phenotype as defects of SHOX itself (144, 145, 146, 147, 148, 149), and the growth response to GH treatment is even better in children carrying a deletion of the SHOX enhancer than in carriers of a SHOX defect (150). The consequences of increased copies of SHOX are less clear (146, 150, 151, 152, 153).

A second intracellular pathway that plays a role in cellular proliferation and differentiation of GP chondrocytes is the Ras/MAPK signalling pathway, which integrates signals from several growth factors including GH, FGFs, CNP, and EGF (154, 155). Activation of this pathway results in a number of overlapping syndromes, called ‘rasopathies’, including Noonan, LEOPARD, Costello, cardio-facio-cutaneous, and neurofibromatosis–Noonan syndrome, all characterized by postnatal growth failure of varying degree (156, 157). Mutations in these genes can also cause short stature without obvious clinical features (158). Inhibition of IGF1 release via GH-induced ERK hyperactivation or EGF-induced PI3K/AKT/GSK-3β stimulation may contribute to short stature in patients with PTPN11 mutations (159, 160).

Genetic aberrations in several other intracellular pathways play a role in short stature syndromes. For example, mutations in FGD1, encoding a guanine nucleotide exchange factor of the Rho/Rac family of small GTP-binding proteins, cause the X-linked form of Aarskog–Scott syndrome (faciogenital dysplasia) (161), although in only 18% of clinically suspected cases a mutation was found (162). FGD1 activates MAP3K mixed-lineage kinase 3 (MLK3), which regulates ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, RUNX2 (163). FGD1 is involved in the regulation of the formation and function of invadopodia and podosomes, which are cellular structures devoted to degradation of the extracellular matrix in tumour and endothelial cells (164).

Inactivating mutations in SOX9 cause a severe skeletal dysplasia, campomelic dysplasia. The encoded protein and its distant relatives SOX5 and SOX6 also activate the genes for cartilage-specific extracellular matrix components (165).

Congenital disorders of glycosylation (CDG) are a rapidly expanding family of genetic diseases due to defects in the synthesis of the glycan moiety of glycoproteins and glycolipids and in their attachment to proteins and lipids. Most CDG are multisystem disorders, and many are associated with skeletal abnormalities, including short stature and microcephaly (166, 167, 168).

Genetic defects in fundamental cellular processes

Mutations in genes encoding proteins involved in fundamental cellular processes can produce severe global growth deficiencies, termed primordial dwarfisms, which affect not just the GP but multiple other tissues and typically impair both pre- and post-natal growth (17). Several of these syndromes are associated with a normal head circumference, but many are microcephalic. In some syndromes, DNA repair defects are prominent. Some examples are presented in Tables 6 and 7, classified according to head size and DNA repair.

Table 6

Examples of genetic defects in fundamental cellular processes.

DisorderaGene(s)Clinical featuresInheritanceReferences
Syndromes with (usually) normal head circumference
 CHARGE syndrome (214800)CHD7, SEMA3EChoanal atresia, malformations of heart, inner ear and retinaAD(267)
 Coffin–Siris syndrome (135900)SMARCB1, SMARCA4, SMARCA2, ARID1A, ARID1BDevelopmental delay, speech impairment, coarse facial features, hypertrichosis, hypoplastic fifth fingernails or toenails, agenesis of the corpus callosumAD(172)
 Floating–Harbor syndrome (136140)SRCAPDelayed bone age and speech, triangular face, deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lipsAD(174, 175)
 KBG syndrome (148050)ANKRD11Macrodontia of upper central incisors, distinctive craniofacial findings, skeletal anomalies, global developmental delay, seizures, intellectual disabilityAD(176)
 Mulibrey nanism (253250)TRIM37Progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with DM2, increased risk for Wilms tumorAR(178)
 SHORT syndrome (269880)PIK3R1hyperextensibility of joints, inguinal hernia, ocular depression, teething delayAD(180)
 Short stature, onycho-dysplasia, facial dys-morphism, hypotri-chosis (SOFT, 614813)POC1ASeverely short long bones, peculiar facies associated with paucity of hair, triangular facies, nail anomalies, short, thickened distal phalanges. Relative macrocephaly in childhood, microcephaly in adulthoodAR(181, 182)
 Three-M syndrome 1 (273750), 2 (612921), 3 (614205)CUL7, OBSL1, CCDC8Facial features, normal mental development, long, slender tubular bones, reduced anteroposterior diameter of vertebral bodies, delayed bone ageAR(183, 184, 185, 186)
Microcephalic primordial dwarfism
 Cornelia de Lange syndrome 1–5NIPBL, SMC1A, SMC3, RAD21, HDAC8Low anterior hairline, arched eyebrows, synophrys, ante-verted nares, maxillary prognathism, long philtrum, thin lips, ‘carp’ mouth, upper limb anomalies.AD(190)
 Meier–Gorlin syndrome 1–5ORC1, ORC4, ORC6, CDT1, CDC6Bilateral microtia, and aplasia or hypoplasia of the patellae, normal intelligenceAR(192, 268)
 MOPD I (210710)U4atacNeurologic abnormalities, including mental retardation, brain malformations, ocular/auditory sensory deficitsAR(5, 193)
 MOPD II (210720)PCNTRadiologic abnormalities, absent or mild mental retardation in comparison to Seckel syndrome, truncal obesity, diabetes, moyamoya, small loose teethAR(5, 194, 269)
 Microcephaly and chorioretinopathy, 1 (251270), 2 (616171)TUBGCP6, PLK4Retinopathy. The gene encodes PLK4 kinase, a master regulator of centriole duplication.AR(270)
 Rett syndrome (312750)MECP2Almost exclusively in females. Arrested development (6–18 months), loss of speech, stereotypic movements, microcephaly, seizures, mental retardation.XLD(271)
 Rubinstein–Taybi syndrome 1 (180849), 2 (613684)CREBBP, EP300Mental retardation, broad thumbs and halluces, dysmorphic facial featuresAD(272)
 Seckel syndrome 1–8ATR, RBBP8, CENPJ, CEP152, CEP63, NIN, DNA2, ATRIPMental retardation, characteristic ‘bird-headed’ facial appearanceAR(5, 18, 195)
 Short stature with microcephaly and distinctive facies (615789)CRIPTFrontal bossing, high forehead, sparse hair and eyebrows, telecanthus, proptosis, anteverted nares, flat nasal bridgeAR(273)

AD, autosomal dominant; AR, autosomal recessive; DM2, diabetes mellitus type 2; MOPD, microcephalic osteodysplastic primordial dwarfism; IUGR, intrauterine growth retardation; XLR, X-linked recessive.

Name (number) according to OMIM.

Table 7

Examples of genetic defects in fundamental cellular processes: DNA repair defects.

DisorderaGene(s)Clinical featuresInheritanceReferences
Bloom syndrome (210900)RECQL3Sun-sensitive, telangiectatic, hypo- and hyperpigmented skin, predisposition to malignancy,chromosomal instabilityAR(274)
Cockayne syndrome A, B, XPG/CS (five types)ERCC8, ERCC6, ERCC5, ERCC3, ERCC4Cutaneous photosensitivity, thin, dry hair, progeroid appearance, pigmentary retinopathy, sensorineural hearing loss, dental cariesAR(272)
Fanconi anemia (multiple types)FANCA and multiple genesHeterogeneous disorder causing genomic instability, abnormalities in major organ systems, bone marrow failure, high predisposition to cancerAR(275, 276)
Hutchinson–Gilford progeria syndrome (176670)LMNALow body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, facial features that resemble aged personsAD(277)
Hypomorphic PCNA mutationPCNAHearing loss, premature aging, telangiectasia, neurodegeneration, photosensitivity by nucleotide excision repair defectAR(278)
Immunoosseous dysplasia, Schimke type (242900)SMARCAL1Spondyloepiphyseal dysplasia, numerous lentigines, slowly progressive immune defect, immune-complex nephritisAR(279)
Natural killer cell and glucocorticoid deficiency with DNA repair defect (609981)MCM4Variant of familial glucocorticoid deficiency: hypocortisolemia, increased chromosomal breakage, NK cell deficiencyAR(280, 281)
Nijmegen breakage syndrome (251260)NBS1Microcephaly, growth retardation, immunodeficiency, predisposition to cancerAR(282)
Ovarian dysgenesis 4MCM9Hypergonadotropic hypogonadism, genomic instabilityAR(283)
Rothmund–Thomson syndromeRECQL4Skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, premature agingAR(284)
X-linked mental retardation-hypotonic facies syndrome (309580)ATRXMental retardation, dysmorphic facies, hypogonadism, deafness, renal anomalies, mild skeletal defectsXLR(285)
Defective nonhomologous end-joining (NHEJ) DNA damage repairLIG4, NHEJ1, ARTEMIS, DNA-PKCs, XRCC4, PRKDCRadiosensitive, severe combined immunodeficiencyAR(197, 198, 199, 273, 286, 287)

AD, autosomal dominant; AR, autosomal recessive; DM2, diabetes mellitus type 2; IUGR, intrauterine growth retardation; XLR, X-linked recessive; MOPD, Microcephalic osteodysplastic primordial dwarfism.

Name (number) according to OMIM.

Syndromes with (usually) normal head circumference

CHARGE syndrome is caused by heterozygous mutations in CHD7 (169) or SEMA3E (170). CHD7 is a transcriptional regulator that binds to enhancer elements in the nucleoplasm, and also functions as a positive regulator of rRNA biogenesis in the nucleolus (171).

Patients diagnosed with Coffin–Siris syndrome have a broad clinical variability, and at present mutations in six genes have been reported, all encoding components of the SWI/SNF complex (172, 173). The gene associated with Floating–Harbor syndrome (SRCAP) encodes a component of SWI/SNF chromatin remodelling complexes (174, 175).

The KBG syndrome is caused by a heterozygous mutation in ANKRD11 (176), encoding a member of a family of ankyrin repeat-containing cofactors that interacts with p160 nuclear receptor coactivators and inhibits ligand-dependent transcriptional activation (177).

Mulibrey nanism (referring to muscle, liver, brain and eye) is caused by homozygous mutations in TRIM37, which encodes a peroxisomal protein that mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression (178). In contrast to a promising short-term effect of GH treatment, the effect on adult height is modest (5 cm) (179).

SHORT syndrome is caused by mutations in PIK3R1 (p85-alpha). In addition to regulating PI3K function, p85-alpha and p85-beta regulate the function of XBP-1, a transcription factor that orchestrates the unfolded protein response following endoplasmic reticulum stress (180).

SOFT syndrome, caused by homozygous POC1A mutations, is associated with severe pre- and post-natal short stature, symmetric shortening of long bones, triangular facies, sparse hair, and short, thickened distal phalanges (181, 182).

Three-M syndrome is caused by defects in one of three genes: CUL7 (encoding a ubiquitin ligase) (183), OBSL1 (encoding a cytoskeletal adaptor) (184) or CCDC8 (encoding a protein possibly linked to CUL7 through the adaptor protein OBSL1) (185, 186). The products of these genes play a critical role in maintaining microtubule integrity with defects leading to aberrant cell division (17, 187).

Microcephalic primordial dwarfism

Microcephalic primordial dwarfism is characterized by severe pre- and post-natal growth retardation accompanied by microcephaly (18).

For Cornelia de Lange syndrome, five types have been distinguished, and the same applies to Meier–Gorlin syndrome (188, 189, 190, 191, 192). Microcephalic osteodysplastic primordial dwarfism (MOPD) type I is caused by mutations in RNU4ARAC, encoding a small nuclear RNA that is part of the minor spliceosome and necessary for proper splicing of U12-dependent introns (193). Mutations in the gene encoding pericentrin (PCNT) cause MOPD type II (5, 194). Seckel syndrome is caused by mutations in many different genes encoding proteins involved in DNA damage response or centrosomal function (reviewed in (5, 18, 195)).

DNA repair defects

Many syndromes associated with abnormal DNA repair present with short stature (Table 7). The best known example is Bloom syndrome, caused by a mutation in the gene encoding DNA helicase RecQ protein-like-3 (RECQL3). Cells of these patients show an increased frequency of chromosomal breaks, and the elevation in the rate of sister chromatid exchanges is used as a diagnostic test. Other syndromes include Cockayne syndrome, Fanconi anaemia, and Rothmund–Thomson syndrome. Fanconi anaemia is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations.

An important pathway for the repair of DNA double-stranded breaks is non-homologous end-joining (196), and mutations in several genes encoding proteins involved in this process have been discovered in short individuals, including LIG4 and XRCC4 mutations (197, 198, 199). XRCC4 mutations are also associated with hypergonadotrophic hypogonadism (199).

Chromosomal abnormalities, CNVs, and imprinting disorders associated with short stature

Chromosomal abnormalities

Most guidelines on clinical workup of children with short stature advise to perform routine karyotyping in females with unexplained short stature, to detect Turner syndrome. Indeed, it is very important to diagnose Turner syndrome, given the comorbidities (partly potentially life-threatening) and efficacy of GH treatment. However, the diagnostic yield in females with isolated short stature is low (estimated at 4% (200)), so that several clinicians have doubted if this would be cost-effective (201, 202, 203, 204). In fact, even in the presence of clear guidelines for diagnostic studies in short children, karyotyping was only performed in ∼50% of cases in a Dutch study (205). Potentially useful criteria for a cost-effective selection of short girls for this expensive test may include a large distance between height SDS and target height SDS (e.g., >2 s.d.) (206), delayed puberty and any indication of physical stigmata. Deletions of the long arm of the Y chromosome, or X/XY mosaicisms in phenotypic females or males, are associated with short stature (207, 208, 209, 210). However, in short males the diagnostic yield of karyotyping is low (3%) (200).

Besides numerical aberrations of sex chromosomes, several other chromosome abnormalities associated with short stature are detectable with routine karyotyping, e.g., Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13), and trisomy 17 mosaicism (211).

Copy number variants

As alluded to in the introduction, CNVs can be detected by array-CGH (2) or SNP arrays (1). With these methods, many new microdeletion and microduplication syndromes have been identified, and several novel genes associated with short stature as part of contiguous gene syndromes have been discovered. Examples include the observation that EPHA4 haploinsufficiency is responsible for short stature observed in children with Waardenburg syndrome caused by a chromosome 2q35q36.2 deletion (212), and a possible role of duplications of EPAS and RHOQ on chromosome 2p21 in severe short stature and delayed bone age (213). For Dubowitz syndrome, a presumed autosomal recessive disorder characterized by microcephaly, developmental delay, growth failure, and a predisposition to allergies and eczema, no unifying genetic alteration has been identified, but in a subset of individuals diagnosed with this syndrome deletions at 19q13 were found (214). Relatively frequent contiguous gene deletion (and occasionally duplication) syndromes are listed in Table 8.

Table 8

Examples of contiguous gene deletion or duplication syndromes associated with short stature.

DisorderaLocationClinical featuresReferences
Recurrent rearrangements of 1q21.11q21.1delIntellectual disability, autism spectrum disorder, microcephaly, cardiac abnormalities, cataracts(288)
2p16p22 microduplication syndrome2p16p22dupDelayed bone age, facial dysmorphism. Role of EPAS and RHOQ?(213)
Wolf–Hirschhorn syndrome (194190)4p16.3del‘Greek warrior helmet’, epicanthal folds, short philtrum, downturned corners of mouth, micrognathia, seizures. Mitochondrial defect by LETM1 haploinsufficiency(289, 290)
Chromosome 4q21 deletion syndrome (613509)4q21delNeonatal muscular hypotonia, severe psychomotor retardation, severely delayed speech, broad forehead, frontal bossing, hypertelorism, short philtrum, downturned corners of mouth(291)
Cri-du-chat syndrome (123450)5p15.2ter delHigh-pitched catlike cry, microcephaly, round face, ocular hypertelorism, micrognathia, epicanthal folds, low-set ears, hypotonia, severe psychomotor retardation. CTNND2?(292)
Short stature, microce-phaly, speech delay5q35.2q35.3dupMicrocephaly, speech delay. Reciprocal to common Sotos syndrome deletion (increased NSD1 function?)(293)
Williams–Beuren syndrome (194050)7q11.23delSupravalvular aortic stenosis, intellectual disability, distinctive facial features(294)
Trichorhinophalangeal syndrome, type II (Langer–Giedion syndrome) (150230)8q21.11q24.13delLarge, laterally protruding ears, bulbous nose, elongated upper lip, sparse scalp hair, winged scapulae, multiple cartilaginous exostoses, redundant skin, intellectual disability. TRPS1, EXT1?(295)
WAGR syndrome (194072)11p13delAniridia, hemihypertrophy, Wilms tumor, cryptorchidism. PAX6, WT1?(296)
12q14 microdeletion syndrome12q14delDevelopmental delay, osteopoikilosis. HMGA2?(297, 298)
Chromosome 13q14 deletion syndrome (613884)13q14delRetinoblastoma, mental impairment, high forehead, prominent philtrum, anteverted earlobes(299)
Frias syndrome (609640)14q22.1q22.3delExophthalmia, palpebral ptosis, hypertelorism, short square hands, small broad great toes. BMP4?(300)
Distal 14q duplication syndrome14q32.2-qterMild developmental delay, high forehead, hypertelorism, dysplastic ear helices, short philtrum, cupid bow upper lip, broad mouth, micrognathia(230)
Smith–Magenis syndrome (182290)17p11.2delBrachycephaly, midface hypoplasia, prognathism, hoarse voice, speech delay, hearing loss, psychomotor retardation, behavioral problems. RAI1? Can be associated with GHD(301)
Miller–Dieker lissencephaly syndrome (247200)17p13.3delLissencephaly, microcephaly, wrinkled skin over glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male external genitalia, seizures. CRK?(302, 303)
17q21q25 duplication syndrome17q2125dupDevelopmental delay, distal arthrogryposis. GH insensitivity, disturbed STAT5B, PI3K, and NF-kappaB signaling. Role of PRKCA mRNA overexpression?(66, 304)
Chromosome 18p deletion syndrome (146390)18p11delIntellectual disability, round face, dysplastic ears, wide mouth, abnormalities of teeth, limbs, genitalia, brain, eyes, heart(305)
Chromosome 18q deletion syndrome (601808)18q22.3q23delCongenital aural atresia, GHD, intellectual disability, reduced white-matter myelination, foot deformities(306, 307)
Velocardiofacial syndrome (192430)22q11.2delHighly variable phenotype. Central deletions: cardiac disorders, learning delays, dysmorphic facial features, hypernasal speech, velopalatal insufficiency, hypocalcemia, hypoparathyroidism, psychiatric disorders; role of TBX1? Distal: role of MAPK1?(308, 309)

GHD, growth hormone deficiency; WAGR syndrome, Wilms tumor, Aniridia, genitourinary anomalies, and mental retardation syndrome.

Name (number) according to OMIM.

Apart from these relatively well documented syndromes, there may be many more. Four recent studies (153, 215, 216, 217) showed that ∼10% of patients with ISS carry a disease-causing CNV, and in short children microdeletions (in contrast to microduplications) are significantly more frequent than in controls (218). However, for individual cases one often remains uncertain whether their growth failure is due to the encountered CNV, and which of the genes is responsible for it. Comparison with previously reported patients and databases like DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER; http://decipher.sanger.uk) and European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA; http://www.ecaruca.net) may give hints for candidate genes.

Imprinting disorders and uniparental disomy

Examples of imprinting disorders are shown in Table 9. The best known example of a growth disorder associated with an imprinting disorder is the Silver–Russell syndrome, which is most commonly caused by hypomethylation of an imprinting control region on the paternal allele of chromosome 11p15.5, controlling the methylation of the IGF2 and H19 genes (219). However, also multilocus loss-of-methylation can occur (220, 221). Other genetic causes include uniparental (maternal) disomy of chromosome 7 (UPD7) (79) and a mutation in the paternally imprinted gene CDKN1C (222). CDKN1C mutations are also associated with the IMAGe syndrome, characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (223), and a syndrome of pre and postnatal growth failure and early-onset diabetes mellitus (224). The clinical spectrum of Silver–Russell syndrome is considerably broader than thought before, and lack of intrauterine growth restriction should not automatically result in exclusion from molecular testing (225).

Table 9

Examples of imprinting disorders.

DisorderaGeneticsClinical featuresReferences
Silver–Russell syndrome (180860)Hypomethylation of imprinting control region on paternal allele of 11p15.5 controling methylation of IGF2 and H19Severe IUGR, triangular shaped face, broad forehead, body asymmetry, variety of minor malformations(79, 219, 220, 229, 310)
Maternal UPD7 (SRS, 7p11.2)
Silver–Russell syndrome or IMAGe syndrome (614732) or IUGR + early-onset diabetes mellitusMutation in paternally imprinted gene CDKN1CIUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies; or only Silver–Russell syndrome; or IUGR and early-adulthood-onset diabetes with normal adrenal function(222, 224)
Prader–Willi syndrome (176270)Loss of expression of paternal copies of imprinted genes (SNRPN, NDN), and others (15q11–q13) by deletion, maternal UPD, imprinting center defect, or Robertsonian translocationIntellectual disability, seizures, poor gross and fine motor coordination, behavioral problems, sleep disturbances, high pain threshold(226)
Pseudohypoparathyroidism type 1a/c (103580)Heterozygous GNAS1 (20q13.32) mutation inherited from motherResistance to parathyroid hormone and other hormones(228)
Pseudohypoparathyroidism type 1b (603233)Both alleles have a paternal-specific imprinting pattern on both parental allelesResistance to PTH is present without signs of Albright hereditary osteodystrophy
Pseudopseudohypopara – thyroidism (612463)Heterozygous GNAS1 mutation inherited from fatherAlbright hereditary osteodystrophy without multiple hormone resistance, brachydactyly
Temple syndrome (616222)Maternal UPD14 (14q32)Low birth weight, hypotonia, motor delay, feeding problems early in life, early puberty, reduced adult height, broad forehead, short nose with wide nasal tip, small hands and feet(153, 229)

IUGR, intrauterine growth retartdation.

Name (number) according to OMIM.

Another well-known example is Prader–Willi syndrome, a contiguous gene syndrome. There are three main genetic subtypes: a paternal chromosome 15q11q13 deletion (65–75% of cases), a maternal UPD of chromosome 15 (20–30% of cases), and an imprinting defect (1–3%). It is now thought that deletion of the paternal copies of the imprinted genes SNRPN, NDN, and possibly others within the chromosome region 15q11q13, are responsible for the phenotype (226). GH secretion can be low and GH treatment has positive effects on linear growth and body composition (227).

Loss-of-function mutations of GNAS, coding for the α-subunit of the Gs protein, is associated with a spectrum of growth disorders (228). The term pseudohypoparathyroidism indicates a group of heterogeneous disorders whose common feature is represented by impaired signalling of various hormones (primarily PTH) that activate cAMP-dependent pathways via Gsα protein. The two main subtypes of PHP (types Ia and Ib) are caused by molecular alterations within or upstream of the imprinted GNAS gene, which encodes Gsα and other translated and untranslated products. Patients who inherited a GNAS mutation from their father develop Albright hereditary osteodystrophy (AHO) without multiple hormone resistance (pseudopseudohypoparathyroidism), characterized by brachydactyly and short stature. In contrast, patients who inherited the mutation from their mother, additionally develop resistance to PTH and other hormones (pseudohypoparathyroidism type 1a or 1c). This difference is caused by the tissue-specific imprinting of GNAS. In pseudohypoparathyroidism type 1b only resistance to PTH is present without signs of AHO, due to an imprinting defect of GNAS with silencing of the maternal allele, affecting mainly the renal tubules.

Besides UPD7, there is another UPD syndrome that is associated with short stature and various additional clinical features: maternal UPD14 (Temple syndrome) (229). This syndrome shares similarities with the distal 14q duplication phenotype (Table 8) (230). We showed that such diagnoses can be found using SNP array technology in children who had been considered ISS (153).

There may be many more epigenetic disorders associated with short stature. In a study on 79 patients with suspected Silver–Russell syndrome or unexplained short stature/intrauterine growth restriction, 37% showed a methylation abnormality in eleven imprinted loci. The commonest finding was a loss of methylation at H19, and a gain of methylation at IGF2R was significantly more observed than in controls (231). Another example is the epigenetic control of several parts of the IGF1 signalling pathway. The IGF1 P2 promotor is an epigenetic quantitative trait locus (QTL), and methylation of a cluster of six CGs located within the proximal part of this promoter shows a strong negative association with serum IGF1 and growth (232). In children with ISS CG-137 methylation in this promoter contributed 30% to the variance of the IGF1 response to GH in an IGF1 generation test (233).

Diagnostic approach

In agreement with Dauber et al. (5), we believe that genetic testing to identify rare monogenic causes of short stature is important for various reasons: i) it can end the diagnostic workup and the family's uncertainty about the cause of the condition; ii) it may alert the clinician to other medical comorbidities; iii) it is invaluable for genetic counselling; and iv) it may have implications for therapy (e.g., some conditions, such as Bloom syndrome, are contraindications for GH treatment (234)). With respect to the question of who should undergo genetic testing, the clinician should take several factors into consideration that increase the likelihood of a monogenic cause of short stature (5). The severity of the growth failure, presence of additional abnormalities, presence of sibling or parent with similar features, and consanguinity may be the most important indicators.

The genetic evaluation of short stature is well described in a recent review, which also presents a useful diagnostic algorithm (5) in a step-wise fashion. If a particular genetic aetiology or syndrome is suspected, based on clinical features such as birth size, head circumference, body proportions, and inheritance pattern, a single gene-based test or gene panel is usually indicated. We estimate that this applies to a limited number of patients, since in the majority short stature is probably of polygenic origin. If there is no strong suspicion on a certain genetic diagnosis, or if initial testing showed no abnormality – while a monogenic disorder appears very likely – the clinician can either accept the diagnosis ‘apparent ISS’ or proceed on a hypothesis-free approach. To arrive at this decision, various considerations apply, including the availability of DNA from other family members, informed consent, local infrastructure, and financial aspects. It is noteworthy that presently limited information is available about the sensitivity, specificity and cost-effectiveness of this approach, while it is important that the ethical aspects are properly dealt with, for example appropriate informed consent forms including information about handling incidental findings. For details we refer to recently published guidelines for diagnostic next-generation sequencing (235).

The hypothesis-free approach consists of two steps. First, an array-cGH or SNP array is carried out, to search for CNVs and uniparental disomies (with SNP-arrays) (1). Even if no CNV is found, the results are useful for the analysis of the second step, WES. For example, SNP arrays provide information about homozygous regions, which can be used in the bioinformatic analyses of the WES data, particularly if a recessive condition is suspected. If a potentially causative gene variant is found, it should be confirmed by Sanger sequencing. After confirmation, cosegregation studies in affected and non-affected relatives should be performed, and if confirmatory, functional studies are usually indicated to provide final proof.

However, we expect that in the coming years further reduction of costs of next generation sequencing technologies will render this step-wise approach superfluous, so that WES will be used as a tool to identify small mutations as well as CNVs and homozygous regions. The next step that the field will probably take is WGS which, in combination with RNA sequencing of the whole transcriptome and sequencing-based DNA methylation analysis of the whole genome, will provide additional information. It will probably lead to further novel insights in the causes of short stature, if the ability to interpret sequence variants outside the exome can be improved.

Conclusion

In the past decade, many novel gene defects have been found in association with multiple clinical disorders associated with short stature, which has enormously expanded the ability of clinicians to obtain a diagnosis in their patients. A more widespread use of currently available genetic tools will certainly lead to a further increase of clinical syndromes associated with genetic aberrations. We agree with Lu et al. (236) and Dauber et al. (5) that clinical use of sequencing data may reduce the cost of care, result in more specific treatment guidelines and avoidance of costly diagnostic and therapeutic procedures, and reduce variance in diagnosis and treatment outcomes between academic medical centres and community hospitals and clinics.

Declaration of interest

J M Wit has served as consultant for Pfizer, Biopartners, OPKO, Versartis, Teva, Merck-Serono, and Ammonett and has received speaker's honoraria from Pfizer, Versartis, Merck-Serono, Lilly and Sandoz. W Oostdijk received unrestricted grant support from Novo Nordisk, Ipsen and Ferring. The other authors have nothing to disclose.

Funding

This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Search Strategy

The search strategy started with updating information on genetic causes of short stature described in previous reviews (10, 11, 13) and others (5, 14, 15, 16, 17), through OMIM and PubMed. Novel genetic causes were found with the following search strategy (courtesy J. Schoones, Leiden):

(("body size"[Majr] OR Body Size[ti] OR "body height"[Majr] OR body height[Ti] OR "body height"[ti] OR (growth[ti] NOT ("growth factor"[ti] OR "growth factors"[ti]))) AND ("child"[MeSH Terms] OR child[Text Word] OR children[Text Word] OR "infant"[MeSH Terms] OR infant[Text Word] OR infants[Text Word] OR pediatric[tiab] OR paediatric[tiab]) NOT (obese OR obesity OR obes* OR mice[tiab] OR animal[tiab] OR animals[tiab] OR cattle[tiab] OR bovine[tiab] OR cows[tiab] OR pigs[tiab] OR birds[tiab] OR fish[tiab] OR snakes[tiab] OR squirrels[tiab] OR cow[tiab] OR pig[tiab] OR bird[tiab] OR fishes[tiab] OR snake[tiab] OR squirrel[tiab]) AND english[la] AND ("genetics"[Subheading] OR "genetics"[tw] OR "genetics"[mesh] OR "Genetic Techniques"[mesh])) AND ("2005/01/01"[PDAT]: "3000/12/31"[PDAT]) NOT ("cell growth"[tw] OR "Cell Transformation, Neoplastic"[mesh] OR "Cell Proliferation"[mesh] OR "Gene Expression Regulation, Neoplastic"[mesh] OR "Cell Movement"[mesh]).

References

  • 1

    Gijsbers AC, Ruivenkamp CA. Molecular karyotyping: from microscope to SNP arrays. Hormone Research in Pædiatrics 2011 76 208213. (doi:10.1159/000330406).

    • Search Google Scholar
    • Export Citation
  • 2

    Kharbanda M, Tolmie J, Joss S. How to use… microarray comparative genomic hybridisation to investigate developmental disorders. Archives of Disease in Childhood. Education and Practice Edition 2015 100 2429. (doi:10.1136/archdischild-2014-306022).

    • Search Google Scholar
    • Export Citation
  • 3

    Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z et al.. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. New England Journal of Medicine 2013 369 15021511. (doi:10.1056/NEJMoa1306555).

    • Search Google Scholar
    • Export Citation
  • 4

    Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. New England Journal of Medicine 2014 370 24182425. (doi:10.1056/NEJMra1312543).

    • Search Google Scholar
    • Export Citation
  • 5

    Dauber A, Rosenfeld RG, Hirschhorn JN. Genetic evaluation of short stature. Journal of Clinical Endocrinology and Metabolism 2014 99 30803092. (doi:10.1210/jc.2014-1506).

    • Search Google Scholar
    • Export Citation
  • 6

    Guo MH, Shen Y, Walvoord EC, Miller TC, Moon JE, Hirschhorn JN, Dauber A. Whole exome sequencing to identify genetic causes of short stature. Hormone Research in Pædiatrics 2014 82 4452. (doi:10.1159/000360857).

    • Search Google Scholar
    • Export Citation
  • 7

    Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z et al.. Defining the role of common variation in the genomic and biological architecture of adult human height. Nature Genetics 2014 46 11731186. (doi:10.1038/ng.3097).

    • Search Google Scholar
    • Export Citation
  • 8

    Lui JC, Nilsson O, Chan Y, Palmer CD, Andrade AC, Hirschhorn JN, Baron J. Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height. Human Molecular Genetics 2012 21 51935201. (doi:10.1093/hmg/dds347).

    • Search Google Scholar
    • Export Citation
  • 9

    Lui JC, Nilsson O, Baron J. Recent research on the growth plate: Recent insights into the regulation of the growth plate. Journal of Molecular Endocrinology 2014 53 T1T9. (doi:10.1530/JME-14-0022).

    • Search Google Scholar
    • Export Citation
  • 10

    Kant SG, Wit JM, Breuning MH. Genetic analysis of short stature. Hormone Research 2003 60 157165. (doi:10.1159/000073226).

  • 11

    Walenkamp MJ, Wit JM. Genetic disorders in the growth hormone–IGFI axis. Hormone Research 2006 66 221230. (doi:10.1159/000095161).

  • 12

    Wit JM, Ranke MB, Kelnar CJH. ESPE classification of paediatric endocrine diagnoses. Hormone Research 2007 68 (Suppl 2) 1120.

  • 13

    Wit JM, Kiess W, Mullis P. Genetic evaluation of short stature. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 117. (doi:10.1016/j.beem.2010.06.007).

    • Search Google Scholar
    • Export Citation
  • 14

    Mortier GR, Graham JM Jr & Rimoin DL. Short stature syndromes. In Growth Disorders, ch. 17, 2nd edn, pp 259–280. Eds CJH Kelnar, MO Savage, P Saenger & CT Cowell. London, UK: Hodder Arnold, 2007

  • 15

    Seaver LH, Irons M. ACMG practice guideline: genetic evaluation of short stature. Genetics in Medicine 2009 11 465470. (doi:10.1097/GIM.0b013e3181a7e8f8).

    • Search Google Scholar
    • Export Citation
  • 16

    Durand C, Rappold GA. Height matters-from monogenic disorders to normal variation. Nature Reviews. Endocrinology 2013 9 171177. (doi:10.1038/nrendo.2012.251).

    • Search Google Scholar
    • Export Citation
  • 17

    Baron J, Savendahl L, De Luca F, Dauber A, Phillip M, Wit JM, Nilsson O. Short and tall stature: a new paradigm emerges. Nature Reviews. Endocrinology 2015 11 735746. (doi:10.1038/nrendo.2015.165).

    • Search Google Scholar
    • Export Citation
  • 18

    Klingseisen A, Jackson AP. Mechanisms and pathways of growth failure in primordial dwarfism. Genes & development 2011 25 20112024. (doi:10.1101/gad.169037).

    • Search Google Scholar
    • Export Citation
  • 19

    Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. Journal of Clinical Endocrinology and Metabolism 2007 92 804810. (doi:10.1210/jc.2006-2017).

    • Search Google Scholar
    • Export Citation
  • 20

    Rosenfeld RG. The molecular basis of idiopathic short stature. Growth Hormone & IGF Research 2005 15 S3S5. (doi:10.1016/j.ghir.2005.06.014).

    • Search Google Scholar
    • Export Citation
  • 21

    Rosenfeld RG, von Stein T. A database and website for molecular defects of the GH–IGF axis: www.growthgenetics.com. Hormone Research in Pædiatrics 2013 80 443448. (doi:10.1159/000355543).

    • Search Google Scholar
    • Export Citation
  • 22

    Alatzoglou KS, Dattani MT. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Human Development 2009 85 705712. (doi:10.1016/j.earlhumdev.2009.08.057).

    • Search Google Scholar
    • Export Citation
  • 23

    Pfaffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 4360. (doi:10.1016/j.beem.2010.10.014).

    • Search Google Scholar
    • Export Citation
  • 24

    McCabe MJ, Alatzoglou KS, Dattani MT. Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 115124. (doi:10.1016/j.beem.2010.06.008).

    • Search Google Scholar
    • Export Citation
  • 25

    Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, Cambridge E, White JK, Le Tissier P, Gharavy SN et al.. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nature Genetics 2012 44 13751381. (doi:10.1038/ng.2453).

    • Search Google Scholar
    • Export Citation
  • 26

    Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, Beck-Peccoz P, Zhu H, Davis TM, Sun Y et al.. The IGSF1 deficiency syndrome: characteristics of male and female patients. Journal of Clinical Endocrinology and Metabolism 2013 98 49424952. (doi:10.1210/jc.2013-2743).

    • Search Google Scholar
    • Export Citation
  • 27

    Aydin BK, Bas F, Tamay Z, Kilic G, Suleyman A, Bundak R, Saka N, Ozkaya E, Guler N, Darendeliler F. Netherton syndrome associated with growth hormone deficiency. Pediatric Dermatology 2014 31 9094. (doi:10.1111/pde.12220).

    • Search Google Scholar
    • Export Citation
  • 28

    Alatzoglou KS, Turton JP, Kelberman D, Clayton PE, Mehta A, Buchanan C, Aylwin S, Crowne EC, Christesen HT, Hertel NT et al.. Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 2009 94 31913199. (doi:10.1210/jc.2008-2783).

    • Search Google Scholar
    • Export Citation
  • 29

    Petkovic V, Godi M, Pandey AV, Lochmatter D, Buchanan CR, Dattani MT, Eble A, Fluck CE, Mullis PE. Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting secretion and action. Journal of Clinical Endocrinology and Metabolism 2010 95 731739. (doi:10.1210/jc.2009-1247).

    • Search Google Scholar
    • Export Citation
  • 30

    Fritez N, Sobrier ML, Iraqi H, Vie-Luton MP, Netchine I, El Annas A, Pantel J, Collot N, Rose S, Piterboth W et al.. Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism. Clinical Endocrinology 2015 82 876884. (doi:10.1111/cen.12706).

    • Search Google Scholar
    • Export Citation
  • 31

    Duriez B, Duquesnoy P, Dastot F, Bougneres P, Amselem S, Goossens M. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Letters 1994 346 165170. (doi:10.1016/0014-5793(94)00457-9).

    • Search Google Scholar
    • Export Citation
  • 32

    Burkitt Wright EM, Perveen R, Clayton PE, Hall CM, Costa T, Procter AM, Giblin CA, Donnai D, Black GC. X-linked isolated growth hormone deficiency: expanding the phenotypic spectrum of SOX3 polyalanine tract expansions. Clinical Dysmorphology 2009 18 218221. (doi:10.1097/MCD.0b013e32832d06f0).

    • Search Google Scholar
    • Export Citation
  • 33

    Argente J, Flores R, Gutierrez-Arumi A, Verma B, Martos-Moreno GA, Cusco I, Oghabian A, Chowen JA, Frilander MJ, Perez-Jurado LA. Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency. EMBO Molecular Medicine 2014 6 299306. (doi:10.1002/emmm.201303573).

    • Search Google Scholar
    • Export Citation
  • 34

    Lucas-Herald AK, Kinning E, Iida A, Wang Z, Miyake N, Ikegawa S, McNeilly J, Ahmed SF. A case of functional growth hormone deficiency and early growth retardation in a child with IFT172 mutations. Journal of Clinical Endocrinology and Metabolism 2015 100 12211224. (doi:10.1210/jc.2014-3852).

    • Search Google Scholar
    • Export Citation
  • 35

    Romano S, Maffei P, Bettini V, Milan G, Favaretto F, Gardiman M, Marshall JD, Greggio NA, Pozzan GB, Collin GB et al.. Alstrom syndrome is associated with short stature and reduced GH reserve. Clinical Endocrinology 2013 79 529536. (doi:10.1111/cen.12180).

    • Search Google Scholar
    • Export Citation
  • 36

    Stagi S, Lapi E, Pantaleo M, Carella M, Petracca A, De Crescenzo A, Zelante L, Riccio A, de Martino M. A new case of de novo 6q24.2-q25.2 deletion on paternal chromosome 6 with growth hormone deficiency: a twelve-year follow-up and literature review. BMC Medical Genetics 2015 16 69. (doi:10.1186/s12881-015-0212-z).

    • Search Google Scholar
    • Export Citation
  • 37

    McMahon SK, Pretorius CJ, Ungerer JP, Salmon NJ, Conwell LS, Pearen MA, Batch JA. Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1). Journal of Clinical Endocrinology and Metabolism 2010 95 297302. (doi:10.1210/jc.2009-1003).

    • Search Google Scholar
    • Export Citation
  • 38

    Rocha V, Rocha D, Santos H, Marques JS. Growth hormone deficiency in a patient with mitochondrial disease. Journal of Pediatric Endocrinology & Metabolism 2015 28 10031004. (doi:10.1515/jpem-2014-0315).

    • Search Google Scholar
    • Export Citation
  • 39

    Wit JM, Oostdijk W, Losekoot M. Spectrum of insulin-like growth factor deficiency. Endocrine Development 2012 23 3041. (doi:10.1159/000341739).

    • Search Google Scholar
    • Export Citation
  • 40

    Pantel J, Legendre M, Nivot S, Morisset S, Vie-Luton MP, Le Bouc Y, Epelbaum J, Amselem S. Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. Journal of Clinical Endocrinology and Metabolism 2009 94 43344341. (doi:10.1210/jc.2009-1327).

    • Search Google Scholar
    • Export Citation
  • 41

    Inoue H, Kangawa N, Kinouchi A, Sakamoto Y, Kimura C, Horikawa R, Shigematsu Y, Itakura M, Ogata T, Fujieda K. Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature. Journal of Clinical Endocrinology and Metabolism 2011 96 E373E378. (doi:10.1210/jc.2010-1570).

    • Search Google Scholar
    • Export Citation
  • 42

    Pugliese-Pires PN, Fortin JP, Arthur T, Latronico AC, Mendonca BB, Villares SM, Arnhold IJ, Kopin AS, Jorge AA. Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty. European Journal of Endocrinology/European Federation of Endocrine Societies 2011 165 233241. (doi:10.1530/EJE-11-0168).

    • Search Google Scholar
    • Export Citation
  • 43

    Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone – a new inborn error of metabolism? Israel Journal of Medical Sciences 1966 2 152155.

    • Search Google Scholar
    • Export Citation
  • 44

    Amselem S, Duquesnoy P, Attree O, Novelli G, Bousnina S, Postel-Vinay MC, Goossens M. Laron dwarfism and mutations of the growth hormone-receptor gene. New England Journal of Medicine 1989 321 989995. (doi:10.1056/NEJM198910123211501).

    • Search Google Scholar
    • Export Citation
  • 45

    Godowski PJ, Leung DW, Meacham LR, Galgani JP, Hellmiss R, Keret R, Rotwein PS, Parks JS, Laron Z, Wood WI. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. PNAS 1989 86 80838087. (doi:10.1073/pnas.86.20.8083).

    • Search Google Scholar
    • Export Citation
  • 46

    David A, Hwa V, Metherell LA, Netchine I, Camacho-Hubner C, Clark AJ, Rosenfeld RG, Savage MO. Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endocrine Reviews 2011 32 472497. (doi:10.1210/er.2010-0023).

    • Search Google Scholar
    • Export Citation
  • 47

    Kurtoglu S, Hatipoglu N. Growth hormone insensitivity: diagnostic and therapeutic approaches. Journal of Endocrinological Investigation 2015 In press.

    • Search Google Scholar
    • Export Citation
  • 48

    Maamra M, Finidori J, Von Laue S, Simon S, Justice S, Webster J, Dower S, Ross R. Studies with a growth hormone antagonist and dual-fluorescent confocal microscopy demonstrate that the full-length human growth hormone receptor, but not the truncated isoform, is very rapidly internalized independent of Jak2-Stat5 signaling. Journal of Biological Chemistry 1999 274 1479114798. (doi:10.1074/jbc.274.21.14791).

    • Search Google Scholar
    • Export Citation
  • 49

    Metherell LA, Akker SA, Munroe PB, Rose SJ, Caulfield M, Savage MO, Chew SL, Clark AJ. Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. American Journal of Human Genetics 2001 69 641646. (doi:10.1086/323266).

    • Search Google Scholar
    • Export Citation
  • 50

    David A, Camacho-Hubner C, Bhangoo A, Rose SJ, Miraki-Moud F, Akker SA, Butler GE, Ten S, Clayton PE, Clark AJ et al.. An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes. Journal of Clinical Endocrinology and Metabolism 2007 92 655659. (doi:10.1210/jc.2006-1527).

    • Search Google Scholar
    • Export Citation
  • 51

    Ayling RM, Ross R, Towner P, Von Laue S, Finidori J, Moutoussamy S, Buchanan CR, Clayton PE, Norman MR. A dominant-negative mutation of the growth hormone receptor causes familial short stature (letter). Nature Genetics 1997 16 1314. (doi:10.1038/ng0597-13).

    • Search Google Scholar
    • Export Citation
  • 52

    Iida K, Takahashi Y, Kaji H, Nose O, Okimura Y, Abe H, Chihara K. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. Journal of Clinical Endocrinology and Metabolism 1998 83 531537.

    • Search Google Scholar
    • Export Citation
  • 53

    Aalbers AM, Chin D, Pratt KL, Little BM, Frank SJ, Hwa V, Rosenfeld RG. Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene. Hormone Research 2009 71 276284. (doi:10.1159/000208801).

    • Search Google Scholar
    • Export Citation
  • 54

    Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A et al.. Growth hormone insensitivity associated with a STAT5b mutation. New England Journal of Medicine 2003 349 11391147. (doi:10.1056/NEJMoa022926).

    • Search Google Scholar
    • Export Citation
  • 55

    Hwa V, Nadeau K, Wit JM, Rosenfeld RG. STAT5b deficiency: Lessons from STAT5b gene mutations. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 6175. (doi:10.1016/j.beem.2010.09.003).

    • Search Google Scholar
    • Export Citation
  • 56

    Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. Journal of Pediatrics 2011 158 701708. (doi:10.1016/j.jpeds.2010.12.042).

    • Search Google Scholar
    • Export Citation
  • 57

    Scalco RC, Hwa V, Domene H, Jasper HG, Belgorosky A, Marino R, Pereira AM, Tonelli C, Wit JM, Rosenfeld RG et al.. STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability. European Journal of Endocrinology 2015 173 291296. (doi:10.1530/EJE-15-0398).

    • Search Google Scholar
    • Export Citation
  • 58

    Domene HM, Bengolea SV, Martinez AS, Ropelato MS, Pennisi P, Scaglia P, Heinrich JJ, Jasper HG. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. New England Journal of Medicine 2004 350 570577. (doi:10.1056/NEJMoa013100).

    • Search Google Scholar
    • Export Citation
  • 59

    Domene HM, Hwa V, Jasper HG, Rosenfeld RG. Acid-labile subunit (ALS) deficiency. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 101113. (doi:10.1016/j.beem.2010.08.010).

    • Search Google Scholar
    • Export Citation
  • 60

    van Duyvenvoorde HA, Kempers MJ, Twickler TB, van Doorn J, Gerver WJ, Noordam C, Losekoot M, Karperien M, Wit JM, Hermus AR. Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. European Journal of Endocrinology/European Federation of Endocrine Societies 2008 159 113120. (doi:10.1530/EJE-08-0081).

    • Search Google Scholar
    • Export Citation
  • 61

    Hess O, Khayat M, Hwa V, Heath KE, Teitler A, Hritan Y, Allon-Shalev S, Tenenbaum-Rakover Y. A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1). Clinical Endocrinology 2013 79 838844. (doi:10.1111/cen.12200).

    • Search Google Scholar
    • Export Citation
  • 62

    Hogler W, Martin DD, Crabtree N, Nightingale P, Tomlinson J, Metherell L, Rosenfeld R, Hwa V, Rose S, Walker J et al.. IGFALS gene dosage effects on serum IGF-I and glucose metabolism, body composition, bone growth in length and width, and the pharmacokinetics of recombinant human IGF-I administration. Journal of Clinical Endocrinology and Metabolism 2014 99 E703E712. (doi:10.1210/jc.2013-3718).

    • Search Google Scholar
    • Export Citation
  • 63

    Fofanova-Gambetti OV, Hwa V, Wit JM, Domene HM, Argente J, Bang P, Hogler W, Kirsch S, Pihoker C, Chiu HK et al.. Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium. Journal of Clinical Endocrinology and Metabolism 2010 95 41844191. (doi:10.1210/jc.2010-0489).

    • Search Google Scholar
    • Export Citation
  • 64

    Domene HM, Scaglia PA, Martinez AS, Keselman AC, Karabatas LM, Pipman VR, Bengolea SV, Guida MC, Ropelato MG, Ballerini MG et al.. Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system. Hormone Research in Pædiatrics 2013 80 413423. (doi:10.1159/000355412).

    • Search Google Scholar
    • Export Citation
  • 65

    Wu S, Walenkamp MJ, Lankester A, Bidlingmaier M, Wit JM, De Luca F. Growth hormone and insulin-like growth factor I insensitivity of fibroblasts isolated from a patient with an IκBα mutation. Journal of Clinical Endocrinology and Metabolism 2010 95 12201228. (doi:10.1210/jc.2009-1662).

    • Search Google Scholar
    • Export Citation
  • 66

    Mul D, Wu S, de Paus RA, Oostdijk W, Lankester AC, Duyvenvoorde HA, Ruivenkamp CA, Losekoot M, Tol MJ, De Luca LF et al.. A mosaic de novo duplication of 17q21-25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NFκB activation. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 166 743752. (doi:10.1530/EJE-11-0774).

    • Search Google Scholar
    • Export Citation
  • 67

    Wit JM, De Luca F. Atypical defects resulting in growth hormone insensitivity. Growth Hormone & IGF Research 2015 In press.

  • 68

    Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Lango AH, De Franco E, McDonald TJ, Rajala H, Ramelius A, Barton J et al.. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nature Genetics 2014 46 812814. (doi:10.1038/ng.3040).

    • Search Google Scholar
    • Export Citation
  • 69

    Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N et al.. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 2015 125 591599. (doi:10.1182/blood-2014-09-602763).

    • Search Google Scholar
    • Export Citation
  • 70

    Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. New England Journal of Medicine 1996 335 13631367. (doi:10.1056/NEJM199610313351805).

    • Search Google Scholar
    • Export Citation
  • 71

    Walenkamp MJ, Karperien M, Pereira AM, Hilhorst-Hofstee Y, van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, van Duyvenvoorde HA et al.. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. Journal of Clinical Endocrinology and Metabolism 2005 90 28552864. (doi:10.1210/jc.2004-1254).

    • Search Google Scholar
    • Export Citation
  • 72

    Netchine I, Azzi S, Houang M, Seurin D, Perin L, Ricort JM, Daubas C, Legay C, Mester J, Herich R et al.. Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. Journal of Clinical Endocrinology and Metabolism 2009 94 39133921. (doi:10.1210/jc.2009-0452).

    • Search Google Scholar
    • Export Citation
  • 73

    van Duyvenvoorde HA, van Setten PA, Walenkamp MJ, van Doorn J, Koenig J, Gauguin L, Oostdijk W, Ruivenkamp CA, Losekoot M, Wade JD et al.. Short stature associated with a novel heterozygous mutation in the insulin-like growth factor 1 gene. Journal of Clinical Endocrinology and Metabolism 2010 95 E363E367. (doi:10.1210/jc.2010-0511).

    • Search Google Scholar
    • Export Citation
  • 74

    Fuqua JS, Derr M, Rosenfeld RG, Hwa V. Identification of a novel heterozygous IGF1 splicing mutation in a large kindred with familial short stature. Hormone Research in Pædiatrics 2012 78 5966. (doi:10.1159/000337249).

    • Search Google Scholar
    • Export Citation
  • 75

    Walenkamp MJ, Losekoot M, Wit JM. Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management. Endocrine Development 2013 24 128137. (doi:10.1159/000342841).

    • Search Google Scholar
    • Export Citation
  • 76

    Batey L, Moon JE, Yu Y, Wu B, Hirschhorn JN, Shen Y, Dauber A. A novel deletion of IGF1 in a patient with idiopathic short stature provides insight Into IGF1 haploinsufficiency. Journal of Clinical Endocrinology and Metabolism 2014 99 E153E159. (doi:10.1210/jc.2013-3106).

    • Search Google Scholar
    • Export Citation
  • 77

    Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le MM, Burglen L et al.. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver–Russell syndrome. Nature Genetics 2005 37 10031007. (doi:10.1038/ng1629).

    • Search Google Scholar
    • Export Citation
  • 78

    Binder G, Seidel AK, Weber K, Haase M, Wollmann HA, Ranke MB, Eggermann T. IGF-II serum levels are normal in children with Silver–Russell syndrome who frequently carry epimutations at the IGF2 locus. Journal of Clinical Endocrinology and Metabolism 2006 91 47094712. (doi:10.1210/jc.2006-1127).

    • Search Google Scholar
    • Export Citation
  • 79

    Binder G, Seidel AK, Martin DD, Schweizer R, Schwarze CP, Wollmann HA, Eggermann T, Ranke MB. The endocrine phenotype in Silver–Russell syndrome is defined by the underlying epigenetic alteration. Journal of Clinical Endocrinology and Metabolism 2008 93 14021407. (doi:10.1210/jc.2007-1897).

    • Search Google Scholar
    • Export Citation
  • 80

    Montenegro LR, Leal AC, Coutinho DC, Valassi HP, Nishi MY, Arnhold IJ, Mendonca BB, Jorge AA. Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver–Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 166 543550. (doi:10.1530/EJE-11-0964).

    • Search Google Scholar
    • Export Citation
  • 81

    Iliev DI, Kannenberg K, Weber K, Binder G. IGF-I sensitivity in Silver–Russell syndrome with IGF2/H19 hypomethylation. Growth Hormone & IGF Research 2014 24 187191. (doi:10.1016/j.ghir.2014.06.005).

    • Search Google Scholar
    • Export Citation
  • 82

    Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Buttel HM, Schweizer R, van Workum W, Binder G, Eggermann T. Paternally inherited IGF2 mutation and growth restriction. New England Journal of Medicine 2015 373 349356. (doi:10.1056/NEJMoa1415227).

    • Search Google Scholar
    • Export Citation
  • 83

    Murphy R, Baptista J, Holly J, Umpleby AM, Ellard S, Harries LW, Crolla J, Cundy T, Hattersley AT. Severe intrauterine growth retardation and atypical diabetes associated with a translocation breakpoint disrupting regulation of the insulin-like growth factor 2 gene. Journal of Clinical Endocrinology and Metabolism 2008 93 43734380. (doi:10.1210/jc.2008-0819).

    • Search Google Scholar
    • Export Citation
  • 84

    Munoz-Calvo MT, Barrios V, Pozo J, Martos-Moreno GA, Hawkings FG, Domene H, Jasper H, Yakar S, Conover CA, Kopchick.JE et al. A new syndrome of short stature, mild microcephaly, skeletal abnormalities and high circulating IGF1, IGFBP3 and ALS associated with a homozygous mutation in the gene for pregnancy-associated plasma protein A2 (PAPP-A2, pappalysin2). Endocrine Society Meeting 2015. Abstract

  • 85

    Klammt J, Kiess W, Pfaffle R. IGF1R mutations as cause of SGA. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 191206. (doi:10.1016/j.beem.2010.09.012).

    • Search Google Scholar
    • Export Citation
  • 86

    Ester WA, van Duyvenvoorde HA, de Wit CC, Broekman AJ, Ruivenkamp CA, Govaerts LC, Wit JM, Hokken-Koelega AC, Losekoot M. Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype. Journal of Clinical Endocrinology and Metabolism 2009 94 47174727. (doi:10.1210/jc.2008-1502).

    • Search Google Scholar
    • Export Citation
  • 87

    Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D et al.. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. New England Journal of Medicine 2003 349 22112222. (doi:10.1056/NEJMoa010107).

    • Search Google Scholar
    • Export Citation
  • 88

    Fang P, Cho YH, Derr MA, Rosenfeld RG, Hwa V, Cowell CT. Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). Journal of Clinical Endocrinology and Metabolism 2012 97 E243E247. (doi:10.1210/jc.2011-2142).

    • Search Google Scholar
    • Export Citation
  • 89

    Gannage-Yared MH, Klammt J, Chouery E, Corbani S, Megarbane H, Abou GJ, Choucair N, Pfaffle R, Megarbane A. Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. European Journal of Endocrinology/European Federation of Endocrine Societies 2013 168 K1K7. (doi:10.1530/EJE-12-0701).

    • Search Google Scholar
    • Export Citation
  • 90

    Prontera P, Micale L, Verrotti A, Napolioni V, Stangoni G, Merla G. A new homozygous IGF1R variant defines a clinically recognizable incomplete dominant form of SHORT syndrome. Human Mutation 2015 36 10431047. (doi:10.1002/humu.22853).

    • Search Google Scholar
    • Export Citation
  • 91

    Jung HJ, Suh Y. Regulation of IGF1 signaling by microRNAs. Frontiers in Genetics 2014 5 472. (doi:10.3389/fgene.2014.00472).

  • 92

    Boersma B, Otten BJ, Stoelinga GB, Wit JM. Catch-up growth after prolonged hypothyroidism. European Journal of Pediatrics 1996 155 362367. (doi:10.1007/BF01955262).

    • Search Google Scholar
    • Export Citation
  • 93

    Kuhnen P, Turan S, Frohler S, Guran T, Abali S, Biebermann H, Bereket A, Gruters A, Chen W, Krude H. Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis. Journal of Clinical Endocrinology and Metabolism 2014 99 E169E176. (doi:10.1210/jc.2013-2619).

    • Search Google Scholar
    • Export Citation
  • 94

    Phillips SA, Rotman-Pikielny P, Lazar J, Ando S, Hauser P, Skarulis MC, Brucker-Davis F, Yen PM. Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant. Journal of Clinical Endocrinology and Metabolism 2001 86 51425147. (doi:10.1210/jcem.86.11.8051).

    • Search Google Scholar
    • Export Citation
  • 95

    Schoenmakers N, Moran C, Peeters RP, Visser T, Gurnell M, Chatterjee K. Resistance to thyroid hormone mediated by defective thyroid hormone receptor α. Biochimica et Biophysica Acta 2013 1830 40044008. (doi:10.1016/j.bbagen.2013.03.018).

    • Search Google Scholar
    • Export Citation
  • 96

    van Mullem AA, Visser TJ, Peeters RP. Clinical consequences of mutations in thyroid hormone receptor-α1. European Thyroid Journal 2014 3 1724. (doi:10.1159/000360637).

    • Search Google Scholar
    • Export Citation
  • 97

    Hamajima T, Mushimoto Y, Kobayashi H, Saito Y, Onigata K. Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation. European Journal of Endocrinology/European Federation of Endocrine Societies 2012 166 757764. (doi:10.1530/EJE-11-0812).

    • Search Google Scholar
    • Export Citation
  • 98

    Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y et al.. Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature Genetics 2015 47 3138. (doi:10.1038/ng.3166).

    • Search Google Scholar
    • Export Citation
  • 99

    Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR et al.. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. New England Journal of Medicine 2014 370 10191028. (doi:10.1056/NEJMoa1310359).

    • Search Google Scholar
    • Export Citation
  • 100

    Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. Genetic syndromes of severe insulin resistance. Endocrine Reviews 2011 32 498514. (doi:10.1210/er.2010-0020).

    • Search Google Scholar
    • Export Citation
  • 101

    Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D et al.. Nosology and classification of genetic skeletal disorders: 2015 revision. American Journal of Medical Genetics. Part A 2015 167 28692892. (doi:10.1002/ajmg.a.37365).

    • Search Google Scholar
    • Export Citation
  • 102

    Kant SG, Grote F, de Ru MH, Oostdijk W, Zonderland HM, Breuning MH, Wit JM. Radiographic evaluation of children with growth disorders. Hormone Research 2007 68 310315. (doi:10.1159/000108399).

    • Search Google Scholar
    • Export Citation
  • 103

    Veeramani AK, Higgins P, Butler S, Donaldson M, Dougan E, Duncan R, Murday V, Ahmed SF. Diagnostic use of skeletal survey in suspected skeletal dysplasia. Journal of Clinical Research in Pediatric Endocrinology 2009 1 270274. (doi:10.4274/jcrpe.v1i6.270).

    • Search Google Scholar
    • Export Citation
  • 104

    Alanay Y, Lachman RS. A review of the principles of radiological assessment of skeletal dysplasias. Journal of Clinical Research in Pediatric Endocrinology 2011 3 163178. (doi:10.4274/jcrpe.463).

    • Search Google Scholar
    • Export Citation
  • 105

    Grunwald T, De Luca F. Role of Fibroblast Growth Factor 21 (FGF21) in the regulation of statural growth. Current Pediatric Reviews 2015 11 98105. (doi:10.2174/1573396311666150702105152).

    • Search Google Scholar
    • Export Citation
  • 106

    Foldynova-Trantirkova S, Wilcox WR, Krejci P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Human Mutation 2012 33 2941. (doi:10.1002/humu.21636).

    • Search Google Scholar
    • Export Citation
  • 107

    Krejci P. The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate. Mutation Research. Reviews in Mutation Research 2014 759 4048. (doi:10.1016/j.mrrev.2013.11.001).

    • Search Google Scholar
    • Export Citation
  • 108

    Song SH, Balce GC, Agashe MV, Lee H, Hong SJ, Park YE, Kim SG, Song HR. New proposed clinico-radiologic and molecular criteria in hypochondroplasia: FGFR 3 gene mutations are not the only cause of hypochondroplasia. American Journal of Medical Genetics. Part A 158A 2012 24562462. (doi:10.1002/ajmg.a.35564).

    • Search Google Scholar
    • Export Citation
  • 109

    Kant SG, Cervenkova I, Balek L, Trantirek L, Santen GW, de Vries MC, van Duyvenvoorde HA, van der Wielen MJ, Verkerk AJ, Uitterlinden AG et al.. A novel variant of FGFR3 causes proportionate short stature. European Journal of Endocrinology/European Federation of Endocrine Societies 2015 172 763770. (doi:10.1530/EJE-14-0945).

    • Search Google Scholar
    • Export Citation
  • 110

    Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC et al.. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes to Cells: Devoted to Molecular & Cellular Mechanisms 2003 8 645654. (doi:10.1046/j.1365-2443.2003.00662.x).

    • Search Google Scholar
    • Export Citation
  • 111

    Cerpa W, Latorre-Esteves E, Barria A. RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission. PNAS 2015 112 47974802. (doi:10.1073/pnas.1417053112).

    • Search Google Scholar
    • Export Citation
  • 112

    Roifman M, Marcelis CL, Paton T, Marshall C, Silver R, Lohr JL, Yntema HG, Venselaar H, Kayserili H, van Bon B et al.. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype. Clinical Genetics 2015 87 3441. (doi:10.1111/cge.12401).

    • Search Google Scholar
    • Export Citation
  • 113

    Habib R, Amin-ud-din M, Ahmad W. A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B. Clinical Dysmorphology 2013 22 4750. (doi:10.1097/MCD.0b013e32835c6c8c).

    • Search Google Scholar
    • Export Citation
  • 114

    van der Eerden BC, Karperien M, Gevers EF, Lowik CW, Wit JM. Expression of Indian hedgehog, parathyroid hormone-related protein, and their receptors in the postnatal growth plate of the rat: evidence for a locally acting growth restraining feedback loop after birth. Journal of Bone and Mineral Research 2000 15 10451055. (doi:10.1359/jbmr.2000.15.6.1045).

    • Search Google Scholar
    • Export Citation
  • 115

    Kronenberg HM. Developmental regulation of the growth plate. Nature 2003 423 332336. (doi:10.1038/nature01657).

  • 116

    Klopocki E, Hennig BP, Dathe K, Koll R, de Ravel T, Baten E, Blom E, Gillerot Y, Weigel JF, Kruger G et al.. Deletion and point mutations of PTHLH cause brachydactyly type E. American Journal of Human Genetics 2010 86 434439. (doi:10.1016/j.ajhg.2010.01.023).

    • Search Google Scholar
    • Export Citation
  • 117

    Hoogendam J, Farih-Sips H, Wynaendts LC, Lowik CW, Wit JM, Karperien M. Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II. Journal of Clinical Endocrinology and Metabolism 2007 92 10881095. (doi:10.1210/jc.2006-0300).

    • Search Google Scholar
    • Export Citation
  • 118

    Schipani E, Kruse K, Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 1995 268 98100. (doi:10.1126/science.7701349).

    • Search Google Scholar
    • Export Citation
  • 119

    Byrnes AM, Racacho L, Grimsey A, Hudgins L, Kwan AC, Sangalli M, Kidd A, Yaron Y, Lau YL, Nikkel SM et al.. Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog. European Journal of Human Genetics 2009 17 11121120. (doi:10.1038/ejhg.2009.18).

    • Search Google Scholar
    • Export Citation
  • 120

    Klopocki E, Lohan S, Brancati F, Koll R, Brehm A, Seemann P, Dathe K, Stricker S, Hecht J, Bosse K et al.. Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. American Journal of Human Genetics 2011 88 7075. (doi:10.1016/j.ajhg.2010.11.006).

    • Search Google Scholar
    • Export Citation
  • 121

    Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y, Cancel M, Motte E, Pinto G, Chanson P, Bougneres P et al.. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. New England Journal of Medicine 2011 364 22182226. (doi:10.1056/NEJMoa1012717).

    • Search Google Scholar
    • Export Citation
  • 122

    Lindstrand A, Grigelioniene G, Nilsson D, Pettersson M, Hofmeister W, Anderlid BM, Kant SG, Ruivenkamp CA, Gustavsson P, Valta H et al.. Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. Journal of Medical Genetics 2014 51 4554. (doi:10.1136/jmedgenet-2013-101937).

    • Search Google Scholar
    • Export Citation
  • 123

    Estrada K, Krawczak M, Schreiber S, van Duijn K, Stolk L, van Meurs JB, Liu F, Penninx BW, Smit JH, Vogelzangs N et al.. A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. Human Molecular Genetics 2009 18 35163524. (doi:10.1093/hmg/ddp296).

    • Search Google Scholar
    • Export Citation
  • 124

    Bartels CF, Bukulmez H, Padayatti P, Rhee DK, Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al Gazali LI et al.. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. American Journal of Human Genetics 2004 75 2734. (doi:10.1086/422013).

    • Search Google Scholar
    • Export Citation
  • 125

    Olney RC, Bukulmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, Warman ML. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. Journal of Clinical Endocrinology and Metabolism 2006 91 12291232. (doi:10.1210/jc.2005-1949).

    • Search Google Scholar
    • Export Citation
  • 126

    Vasques GA, Amano N, Docko AJ, Funari MF, Quedas EP, Nishi MY, Arnhold IJ, Hasegawa T, Jorge AA. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. Journal of Clinical Endocrinology and Metabolism 2013 98 E1636E1644. (doi:10.1210/jc.2013-2142).

    • Search Google Scholar
    • Export Citation
  • 127

    Amano N, Mukai T, Ito Y, Narumi S, Tanaka T, Yokoya S, Ogata T, Hasegawa T. Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. Journal of Clinical Endocrinology and Metabolism 2014 99 E713E718. (doi:10.1210/jc.2013-3525).

    • Search Google Scholar
    • Export Citation
  • 128

    Vasques GA, Arnhold IJ, Jorge AA. Role of the natriuretic peptide system in normal growth and growth disorders. Hormone Research in Pædiatrics 2014 82 222229. (doi:10.1159/000365049).

    • Search Google Scholar
    • Export Citation
  • 129

    Wang SR, Jacobsen CM, Carmichael H, Edmund AB, Robinson JW, Olney RC, Miller TC, Moon JE, Mericq V, Potter LR et al.. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Human Mutation 2015 36 474481. (doi:10.1002/humu.22773).

    • Search Google Scholar
    • Export Citation
  • 130

    Hisado-Oliva A, Garre-Vazquez AI, Santaolalla-Caballero F, Belinchon A, Barreda-Bonis AC, Vasques GA, Ramirez J, Luzuriaga C, Carlone G, Gonzalez-Casado I et al.. Heterozygous NPR2 mutations cause disproportionate short stature, similar to Leri-Weill dyschondrosteosis. Journal of Clinical Endocrinology and Metabolism 2015 100 E1133E1142. (doi:10.1210/jc.2015-1612).

    • Search Google Scholar
    • Export Citation
  • 131

    Teixeira CC, Agoston H, Beier F. Nitric oxide, C-type natriuretic peptide and cGMP as regulators of endochondral ossification. Developmental Biology 2008 319 171178. (doi:10.1016/j.ydbio.2008.04.031).

    • Search Google Scholar
    • Export Citation
  • 132

    Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M, Prats H, Wilcox WR. Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. Journal of Cell Science 2005 118 50895100. (doi:10.1242/jcs.02618).

    • Search Google Scholar
    • Export Citation
  • 133

    Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S et al.. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. American Journal of Human Genetics 2012 91 11081114. (doi:10.1016/j.ajhg.2012.10.014).

    • Search Google Scholar
    • Export Citation
  • 134

    Tompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, Nelson SF, Briggs MD, Cohn DH, Krakow D. A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. American Journal of Human Genetics 2009 84 7279. (doi:10.1016/j.ajhg.2008.12.001).

    • Search Google Scholar
    • Export Citation
  • 135

    Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, Lui JC, Hirschhorn JN, Baron J, Dauber A. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. Journal of Clinical Endocrinology and Metabolism 2014 99 E1510E1518. (doi:10.1210/jc.2014-1332).

    • Search Google Scholar
    • Export Citation
  • 136

    Ahmad M, Faiyaz Ul Haque M, Ahmad W, Abbas H, Haque S, Krakow D, Rimoin DL, Lachman RS, Cohn DH. Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred. American Journal of Medical Genetics 1998 78 468473. (doi:10.1002/(SICI)1096-8628(19980806)78:5<468::AID-AJMG13>3.0.CO;2-D).

    • Search Google Scholar
    • Export Citation
  • 137

    Oostdijk W, Idkowiak J, Mueller JW, House PJ, Taylor AE, O'Reilly MW, Hughes BA, de Vries MC, Kant SG, Santen GW et al.. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation – in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations. Journal of Clinical Endocrinology and Metabolism 2015 100 E672E680. (doi:10.1210/jc.2014-3556).

    • Search Google Scholar
    • Export Citation
  • 138

    Malaquias AC, Scalco RC, Fontenele EG, Costalonga EF, Baldin AD, Braz AF, Funari MF, Nishi MY, Guerra-Junior G, Mendonca BB et al.. The sitting height/height ratio for age in healthy and short individuals and its potential role in selecting short children for SHOX analysis. Hormone Research in Pædiatrics 2013 80 449456. (doi:10.1159/000355411).

    • Search Google Scholar
    • Export Citation
  • 139

    Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bettendorf M, Heinrich U, Vlachopapadoupoulou E, Reinehr T, Onigata K et al.. Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. Journal of Clinical Endocrinology and Metabolism 2002 87 14021406. (doi:10.1210/jcem.87.3.8328).

    • Search Google Scholar
    • Export Citation
  • 140

    Binder G, Ranke MB, Martin DD. Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in school-age children with unexplained short stature. Journal of Clinical Endocrinology and Metabolism 2003 88 48914896. (doi:10.1210/jc.2003-030136).

    • Search Google Scholar
    • Export Citation
  • 141

    Jorge AA, Arnhold IJ. Anthropometric evaluation of children with SHOX mutations can be used as indication for genetic studies in children of short stature. Journal of Medical Genetics 2007 44 e90.

    • Search Google Scholar
    • Export Citation
  • 142

    Jorge AA, Souza SC, Nishi MY, Billerbeck AE, Liborio DC, Kim CA, Arnhold IJ, Mendonca BB. SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Clinical Endocrinology 2007 66 130135.

    • Search Google Scholar
    • Export Citation
  • 143

    Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Hormone Research in Pædiatrics 2011 75 8189. (doi:10.1159/000324105).

    • Search Google Scholar
    • Export Citation
  • 144

    Chen J, Wildhardt G, Zhong Z, Roth R, Weiss B, Steinberger D, Decker J, Blum WF, Rappold G. Enhancer deletions of the SHOX gene as a frequent cause of short stature: the essential role of a 250 kb downstream regulatory domain. Journal of Medical Genetics 2009 46 834839. (doi:10.1136/jmg.2009.067785).

    • Search Google Scholar
    • Export Citation
  • 145

    Huber C, Rosilio M, Munnich A, Cormier-Daire V. High incidence of SHOX anomalies in individuals with short stature. Journal of Medical Genetics 2006 43 735739. (doi:10.1136/jmg.2006.040998).

    • Search Google Scholar
    • Export Citation
  • 146

    Benito-Sanz S, Barroso E, Heine-Suner D, Hisado-Oliva A, Romanelli V, Rosell J, Aragones A, Caimari M, Argente J, Ross JL et al.. Clinical and molecular evaluation of SHOX/PAR1 duplications in Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS). Journal of Clinical Endocrinology and Metabolism 2011 96 E404E412. (doi:10.1210/jc.2010-1689).

    • Search Google Scholar
    • Export Citation
  • 147

    Benito-Sanz S, Aza-Carmona M, Rodriguez-Estevez A, Rica-Etxebarria I, Gracia R, Campos-Barros A, Heath KE. Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature. European Journal of Human Genetics 2012 20 125127. (doi:10.1038/ejhg.2011.210).

    • Search Google Scholar
    • Export Citation
  • 148

    Rosilio M, Huber-Lequesne C, Sapin H, Carel JC, Blum WF, Cormier-Daire V. Genotypes and phenotypes of children with SHOX deficiency in France. Journal of Clinical Endocrinology and Metabolism 2012 97 E1257E1265. (doi:10.1210/jc.2011-3460).

    • Search Google Scholar
    • Export Citation
  • 149

    Kant SG, Broekman SJ, de Wit CC, Bos M, Scheltinga SA, Bakker E, Oostdijk W, van der Kamp HJ, van Zwet EW, van der Hout AH et al.. Phenotypic characterization of patients with deletions in the 3′-flanking SHOX region. PeerJ 2013 1 e35. (doi:10.7717/peerj.35).

    • Search Google Scholar
    • Export Citation
  • 150

    Donze SH, Meijer CR, Kant SG, Zandwijken GR, van der Hout AH, van Spaendonk RM, van den Ouweland AM, Wit JM, Losekoot M, Oostdijk W. The growth response to growth hormone treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects. European Journal of Endocrinology 2015 173 611621. (doi:10.1530/EJE-15-0451).

    • Search Google Scholar
    • Export Citation
  • 151

    Iughetti L, Capone L, Elsedfy H, Bertorelli R, Predieri B, Bruzzi P, Forabosco A, El Kholy M. Unexpected phenotype in a boy with trisomy of the SHOX gene. Journal of Pediatric Endocrinology & Metabolism 2010 23 159169. (doi:10.1515/JPEM.2010.23.1-2.159).

    • Search Google Scholar
    • Export Citation
  • 152

    Caliebe J, Broekman S, Boogaard M, Bosch CA, Ruivenkamp CA, Oostdijk W, Kant SG, Binder G, Ranke MB, Wit JM et al.. IGF1, IGF1R and SHOX mutation analysis in short children born small for gestational age and short children with normal birth size (idiopathic short stature). Hormone Research in Pædiatrics 2012 77 250260. (doi:10.1159/000338341).

    • Search Google Scholar
    • Export Citation
  • 153

    Wit JM, van Duyvenvoorde HA, van Klinken JB, Caliebe J, Bosch CA, Lui JC, Gijsbers AC, Bakker E, Breuning MH, Oostdijk W et al.. Copy number variants in short children born small for gestational age. Hormone Research in Pædiatrics 2014 82 310318. (doi:10.1159/000367712).

    • Search Google Scholar
    • Export Citation
  • 154

    Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M et al.. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nature Medicine 2004 10 8086. (doi:10.1038/nm971).

    • Search Google Scholar
    • Export Citation
  • 155

    Cseh B, Doma E, Baccarini M. "RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway. FEBS Letters 2014 588 23982406. (doi:10.1016/j.febslet.2014.06.025).

    • Search Google Scholar
    • Export Citation
  • 156

    Lee BH, Kim JM, Jin HY, Kim GH, Choi JH, Yoo HW. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. Journal of Pediatrics 2011 159 10291035. (doi:10.1016/j.jpeds.2011.05.024).

    • Search Google Scholar
    • Export Citation
  • 157

    Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet 2013 381 333342. (doi:10.1016/S0140-6736(12)61023-X).

  • 158

    Wang SR, Carmichael H, Andrew SF, Miller TC, Moon JE, Derr MA, Hwa V, Hirschhorn JN, Dauber A. Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature. Journal of Clinical Endocrinology and Metabolism 2013 98 E1428E1437. (doi:10.1210/jc.2013-1534).

    • Search Google Scholar
    • Export Citation
  • 159

    De Rocca Serra-Nedelec A, Edouard T, Treguer K, Tajan M, Araki T, Dance M, Mus M, Montagner A, Tauber M, Salles JP et al.. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature. PNAS 2012 109 42574262. (doi:10.1073/pnas.1119803109).

    • Search Google Scholar
    • Export Citation
  • 160

    Edouard T, Combier JP, Nedelec A, Bel-Vialar S, Metrich M, Conte-Auriol F, Lyonnet S, Parfait B, Tauber M, Salles JP et al.. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3β signaling. Molecular and Cellular Biology 2010 30 24982507. (doi:10.1128/MCB.00646-09).

    • Search Google Scholar
    • Export Citation
  • 161

    Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE, Glover TW, Wilroy RS, Gorski JL. Isolation and characterization of the faciogenital dysplasia (Aarskog–Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. Cell 1994 79 669678. (doi:10.1016/0092-8674(94)90552-5).

    • Search Google Scholar
    • Export Citation
  • 162

    Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM, Jacquemont S, Taurisano R, Arroyo Carrera I, Tarantino E et al.. Aarskog–Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene. American Journal of Medical Genetics. Part A 152A 2010 313318. (doi:10.1002/ajmg.a.33199).

    • Search Google Scholar
    • Export Citation
  • 163

    Zou W, Greenblatt MB, Shim JH, Kant S, Zhai B, Lotinun S, Brady N, Hu DZ, Gygi SP, Baron R et al.. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. Journal of Clinical Investigation 2011 121 43834392. (doi:10.1172/JCI59041).

    • Search Google Scholar
    • Export Citation
  • 164

    Genot E, Daubon T, Sorrentino V, Buccione R. FGD1 as a central regulator of extracellular matrix remodelling – lessons from faciogenital dysplasia. Journal of Cell Science 2012 125 32653270. (doi:10.1242/jcs.093419).

    • Search Google Scholar
    • Export Citation
  • 165

    Akiyama H, Lefebvre V. Unraveling the transcriptional regulatory machinery in chondrogenesis. Journal of Bone and Mineral Metabolism 2011 29 390395. (doi:10.1007/s00774-011-0273-9).