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.
Causes of GHD.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| GHD and potential for CPHD | ||||
| CPHD-1 (613038) | POU1F1 | GH, PRL, var. TSH def. | AR, AD | (5, 22, 23) |
| CPHD-2 (262600) | PROP1 | GH, PRL, TSH, LH, FSH, var. ACTH def. Pituitary can be enlarged. | AR | (5, 22, 23) |
| CPHD-3 (221750) | LHX3 | GH, TSH, LH, FSH, PRL def. Sensorineural hearing loss, cervical abnormalities, short stiff neck | AR | (5, 22, 23) |
| CPHD-4 (262700) | LHX4 | GH, TSH, ACTH def. | AD, AR | (5, 22, 23) |
| Septo-optic dysplasia (CPHD-5) (182230) | HESX1 | Optic nerve hypoplasia, pituitary hypoplasia, midline abnormalities of brain, absent corpus callosum and septum pellucidum | AR, AD | (5, 22, 24) |
| CPHD-6 (613986) | OTX2 | TSH, GH, LH, FSH, var. ACTH and PRL def. | AD | (5, 22, 24) |
| Axenfeld–Rieger syndrome type 1 (180500) | PITX | Coloboma, glaucoma, dental hypoplasia, protuberant umbilicus, brain abnormalities, var. pituitary def. | AD | (22) |
| Optic nerve hypoplasia and abnormalities of the central nervous system (206900) | SOX2 | Var. GHD, hypogonadism, anophthalmia, developmental delay | AD | (22, 24) |
| X-linked panhypopituitarism (312000, 300123) | SOX3dupb | GHD or CHPD, mental retardation | XLR | (5, 22, 24) |
| Dopa-responsive dystonia due to sepiapterin reductase deficiency (612716) | SPR | Diurnally fluctuating movement disorder, cognitive delay, neurologic dysfunction, GH and TSH def. | AR | (237) |
| Holoprosencephaly 9 (610829) | GLI2 | Holoprosencephaly, craniofacial abnormalities, polydactyly, single central incisor, partial agenesis corpus callosum (or hypopituitarism only) | AD | (5, 22) |
| IGSF1 deficiency syndrome (300888) | IGSF1 | TSH, var. GH and PRL def.; macroorchidism | XLR | (26) |
| Netherton syndrome (256500) | SPINK5 | Var. GH and PRL def. | AR | (27) |
| Pallister–Hall syndrome (146510) | GLI3 | Hypothalamic hamartoma, central polydactyly, visceral malformations | AD | (5) |
| FGF8 | Holoprosencephaly, septo-optic dysplasia, Moebius syndrome | AR | (5, 24) | |
| FGFR1 | Hypoplasia pituitary, corpus callosum, ocular defects | AD | (5, 238) | |
| PROKR2 | Var. hypopituitarism | AD | (238) | |
| HMGA2 | Severe GHD, ectopic posterior pituitary | AD | (239, 240) | |
| GRP161 | Pituitary 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, hypopituitarism | AR | (241) | |
| Isolated GHD or bioinactivity | ||||
| Isolated GHD, type IB (612781) | GHRHR | Low serum GH | AR | (240, 242) |
| Isolated GHD, type 1A (262400) | GH1 | No serum GH, often anti-GH ab | AR | (240, 242) |
| Isolated GHD, type IB (612781) | GH1 | Low serum GH | AR | (240, 242) |
| Isolated GHD, type II (173100) | GH1 | Var. height deficit and pituitary size; other pituitary deficits can develop | AD | (240, 242) |
| Isolated GHD, type III (307200) | BTK, SOX3 | GHD with agammaglobulinemia | XLR | (240, 242) |
| Isolated partial GHD (615925) | GHSR | Var. serum GH and IGF1 | AR, AD | (39, 41) |
| Kowarski syndrome (bioinactive GH syndrome) (262650) | GH1 | high GH; def. of IGF1, IGFBP-3, and ALS | AD | (242) |
| Almstrom syndrome (203800) | ALMS1 | 50% of cases are GHD | AR | (35) |
| RNPC3 | Severe GHD, hypoplasia anterior pituitary | AR | (33) | |
| IFT172 | Functional GHD, retinopathy, metaphyseal dysplasia, hypertension | AR | (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.
Causes of GH insensitivity or IGF insensitivity.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| GH insensitivity | ||||
| Laron syndrome (262500) | GHR | Variable height deficit and GHBP, midfacial hypoplasia;↑GH, ↓IGF1, IGFBP-3 and ALS | AR (AD) | (46, 242) |
| GH insensitivity with immunodeficiency (245590) | STAT5B | Midfacial hypoplasia, immunodeficiency; ↑GH and PRL; ↓IGF1, IGFBP-3 and ALS | AR | (55) |
| Multisystem, infantile-onset autoimmune disease (615952) | STAT3 (act) | Associated with early-onset multi-organ autoimmune disease | AD | (68, 69) |
| X-linked severe combined immunodeficiency (300400) | IL2RG | GH normal, low IGF1, non-responding to GH injections | XLR | (243, 244) |
| IGF1 deficiency (608747) | IGF1 | SGA, microcephaly, deafness; ↑GH and IGFBP-3; variable IGF1 | AR | (13) |
| Severe growth restriction with distinctive facies (616489) | IGF2 | ↓↑/nl GH, IGFBP3; nl IGF1 | Pat inheritance | (82) |
| ALS deficiency (615961) | IGFALS | Mild height deficit; GH?,↓IGF1, IGFBP-3 and ALS | AR | (59) |
| PAPP-A2 | Microcephaly, skeletal abnormalities, ↑GH, IGF1, IGFBP-3, and ALS | AR | (84) | |
| Immunodeficiency 15 (615592) | IKBKB | Immunodeficiency; ↓IGF1 and IGFBP-3 | AR, AD | (65) |
| IGF insensitivity | ||||
| Resistance to insulin-like growth factor 1 | IGF1R | SGA, microcephaly; ↑/nl GH, IGF1, and IGFBP-3 | AD, 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).
Examples of genetic defects affecting paracrine factors in the growth plate.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| FGF signaling | ||||
| Pfeiffer syndrome, acrocephalosyndactyly, type V (101600) | FGFR1, FGFR2 | Craniosynostosis 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 period | AD | (9) |
| Achondroplasia (100800) | FGFR3 (act) | Rhizomelic limb shortening, frontal bossing, midface hypoplasia, exaggerated lumbar lordosis, limited elbow extension, genu varum, trident hand | AD | (9) |
| Hypochondroplasia (146000) | FGFR3 (act) | Short-limbed dwarfism, lumbar lordosis, short and broad bones, caudal narrowing of interpediculate distance of lumbar spine | AD | (9, 108, 246) |
| Short stature | FGFR3 (act) | Relative macrocephaly for height | AD | (109) |
| BMP signaling | ||||
| Brachydactyly A1 (112500) | IHH, GDF5, BMPR1B | Middle phalanges rudimentary or fused with terminal phalanges, short proximal phalanges thumbs and big toes | AD | (247) |
| Brachydactyly A2 (112600) | BMPR1B, BMP2, GDF5 | Malformations of middle phalanx of index finger, anomalies of second toe | AD | (248) |
| Brachydactyly C (113100) | GDF5, CDMP1 | Deformity of middle and proximal phalanges (II, III), hypersegmentation of proximal phalanx | AD | (249) |
| WNT signaling | ||||
| Robinow syndrome (268310) | ROR2, WNT5A | Frontal bossing, hypertelorism, broad nose, short-limbed dwarfism, vertebral segmentation, genital hypoplasia | AR, AD | (112) |
| Brachydactyly, Type B1 (113000) | ROR2 | Short middle phalanges, terminal phalanges rudimentary or absent; deformed thumbs, big toes | AD | (113) |
| PTHrP-IHH pathway | ||||
| Brachydactyly, type E2 (613382) | PTHLH | Short stature and learning difficulties | AD | (116) |
| Blomstrand chondro-dysplasia (215045) | PTHR1 | Short limbs, polyhydramnios, hydrops fetalis, facial anoma-lies, increased bone density, advanced skeletal maturation | AR | (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 hypophosphatemia | AD | (118) |
| Brachydactyly type A1 (112500) | IHH, GDF5, BMPR1B | Middle phalanges rudimentary or fused with terminal phalanges. Short proximal phalanges of thumbs, big toes | AD | (119) |
| Acrocapitofemoral dysplasia (607778) | IHH | Variable short stature, short limbs with brachydactyly, relatively large head circumference | AR | (119) |
| Albright hereditary osteodystrophy (103580) | GNAS | Pseudohypoparathyroidism, type Ia/c. Caused by loss of function of Gs-alpha isoform of GNAS on maternal allele. For further details see Table 8 | Imprinted | (228) |
| Acrodysostosis 1 (101800) | PRKAR1A | Severe brachydactyly, facial dysostosis, nasal hypoplasia, advanced bone age, obesity, resistance to multiple hormones | AD | (121) |
| CNP-NPR2 pathway | ||||
| Acromesomelic dysplasia, Maroteaux type (602875) | NPR2 | Disproportionate shortening of middle segments (forearms and forelegs) and distal segments (hands and feet) | AR | (124) |
| (Dis)proportionate short stature | NPR2 | Moderate short stature, short forearms and forelegs | AD | (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).
Examples of genetic defects affecting cartilage extracellular matrix.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| Acromicric dysplasia (102370) | FBN1 | Severe short stature, short hands and feet, joint limitations, skin thickening | AD | (250, 251) |
| Geleophysic dysplasia-2 (614185) | FBN1 | Severe short stature, short hands and feet, joint limitations, skin thickening, heart involvement | AD | (250, 251) |
| Brachyolmia type 4 with mild epiphyseal and metaphyseal changes (spondyloepimetaphyseal dysplasia, Pakistani type) (612847) | PAPSS2 | Short 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 bones | AR | (137, 252) |
| Hurler syndrome (607014) | IDUA | Skeletal deformities, corneal clouding, hepatosplenomegaly, psychomotor delay | AR | (253) |
| Metaphyseal chondro-dysplasia, Schmid type (156500) | COL10A1 | Short stature, widened growth plates, bowing of long bones | AD | (254) |
| Multiple epiphyseal dysplasia 1–6 | COMP, COL9A2, COL9A3, SLC26A2, MATN3, COL9A1 | Short-limbed dwarfism, joint pain and stiffness and early onset osteoarthritis | AD | (255) |
| Pseudoachondro-plasia (177170) | COMP | Disproportionate short stature, deformity of lower limbs, brachydactyly, loose joints, ligamentous laxity, vertebral anomalies, osteoarthritis | AD | (256) |
| Spondyloepiphyseal dysplasia congenita (183900) | COL2A1 | Multiple presentations | AD | (257) |
| Spondyloepimetaphy-seal dysplasia aggrecan type (612813) | ACAN | Relative 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 mesomelia | AR | (134) |
| Spondyloepiphyseal dysplasia type Kimberley (608361) | ACAN | Proportionate short stature, stocky habitus, progressive osteoarthropathy | AD | (258) |
| Short stature with advanced bone age | ACAN | Advanced bone age, premature growth cessation | AD | (135) |
| Weill–Marchesani syndrome (613195, 608328) | ADAMTS10, FBN1 | Spherophakia, lenticular myopia, ectopia lentis, joint stiffness, brachydactyly | AR | (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.
Examples of genetic defects affecting intracellular pathways.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| SHOX aberrations | ||||
| Langer mesomelic dysplasia (249700) | SHOX | Severe limb aplasia or hypoplasia of the ulna and fibula, and a thickened and curved radius and tibia | AR | (138) |
| Leri–Weill dyschon-drosteosis (127300) | SHOX | Mesomelia, Madelung wrist deformity, or mild body disproportion | AD | (138, 149) |
| Rasopathies | ||||
| Noonan syndrome 1–8 | PTPN11, KRAS, SOS1, RAF1, NRAS, BRAF, RIT1 | Facial dysmorphism, wide spectrum of congenital heart defects | AD | (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 deafness | AD | (260) |
| Costello syndrome (218040) | HRAS | Coarse facies, distinctive hand posture and appearance, feeding difficulty, failure to thrive, cardiac anomalies, developmental delay | AD | (260) |
| Cardio-facio-cutaneous syndrome (115150) | BRAF, KRAS | Distinctive facial appearance, heart defects, mental retardation | AD | (260) |
| Neurofibromatosis-Noonan syndrome (601321) | NF1 | Features of both conditions | AD | (260) |
| Neurofibromatosis type I (162200) | NF1 | Cafe-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) | RPS6KA3 | Mental retardation, skeletal malformations, hearing deficit, paroxysmal movement disorders | XLR | (261) |
| Other syndromes | ||||
| Aarskog–Scott syndrome (faciogenital dysplasia) (305400) | FGD1 | Hypertelorism, shawl scrotum, brachydactyly | XLR | (263) |
| Alström syndrome (203800) | ALMS1 | Retinal photoreceptor degeneration, sensorineural hearing imparment, obesity, insulin resistance | AR | (35) |
| Campomelic dysplasia (114290) | SOX9 | Congenital bowing and angulation of long bones, other skeletal and extraskeletal defects | AD | (264) |
| Congenital disorders of glycosylation | Multiple genes (>76) | Multisystem disorders caused by defects in biosynthesis of glycoconjugates | AR | (168) |
| Kabuki syndrome 1 (147920) and 2 (300867) | KMT2D, KDM6A | Long 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 infancy | AD | (265) |
| Kenny–Caffey syndrome type 1 (244460) and 2 (127000) | TBCE, FAM111A | Craniofacial 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.
Examples of genetic defects in fundamental cellular processes.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| Syndromes with (usually) normal head circumference | ||||
| CHARGE syndrome (214800) | CHD7, SEMA3E | Choanal atresia, malformations of heart, inner ear and retina | AD | (267) |
| Coffin–Siris syndrome (135900) | SMARCB1, SMARCA4, SMARCA2, ARID1A, ARID1B | Developmental delay, speech impairment, coarse facial features, hypertrichosis, hypoplastic fifth fingernails or toenails, agenesis of the corpus callosum | AD | (172) |
| Floating–Harbor syndrome (136140) | SRCAP | Delayed bone age and speech, triangular face, deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lips | AD | (174, 175) |
| KBG syndrome (148050) | ANKRD11 | Macrodontia of upper central incisors, distinctive craniofacial findings, skeletal anomalies, global developmental delay, seizures, intellectual disability | AD | (176) |
| Mulibrey nanism (253250) | TRIM37 | Progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with DM2, increased risk for Wilms tumor | AR | (178) |
| SHORT syndrome (269880) | PIK3R1 | hyperextensibility of joints, inguinal hernia, ocular depression, teething delay | AD | (180) |
| Short stature, onycho-dysplasia, facial dys-morphism, hypotri-chosis (SOFT, 614813) | POC1A | Severely short long bones, peculiar facies associated with paucity of hair, triangular facies, nail anomalies, short, thickened distal phalanges. Relative macrocephaly in childhood, microcephaly in adulthood | AR | (181, 182) |
| Three-M syndrome 1 (273750), 2 (612921), 3 (614205) | CUL7, OBSL1, CCDC8 | Facial features, normal mental development, long, slender tubular bones, reduced anteroposterior diameter of vertebral bodies, delayed bone age | AR | (183, 184, 185, 186) |
| Microcephalic primordial dwarfism | ||||
| Cornelia de Lange syndrome 1–5 | NIPBL, SMC1A, SMC3, RAD21, HDAC8 | Low anterior hairline, arched eyebrows, synophrys, ante-verted nares, maxillary prognathism, long philtrum, thin lips, ‘carp’ mouth, upper limb anomalies. | AD | (190) |
| Meier–Gorlin syndrome 1–5 | ORC1, ORC4, ORC6, CDT1, CDC6 | Bilateral microtia, and aplasia or hypoplasia of the patellae, normal intelligence | AR | (192, 268) |
| MOPD I (210710) | U4atac | Neurologic abnormalities, including mental retardation, brain malformations, ocular/auditory sensory deficits | AR | (5, 193) |
| MOPD II (210720) | PCNT | Radiologic abnormalities, absent or mild mental retardation in comparison to Seckel syndrome, truncal obesity, diabetes, moyamoya, small loose teeth | AR | (5, 194, 269) |
| Microcephaly and chorioretinopathy, 1 (251270), 2 (616171) | TUBGCP6, PLK4 | Retinopathy. The gene encodes PLK4 kinase, a master regulator of centriole duplication. | AR | (270) |
| Rett syndrome (312750) | MECP2 | Almost 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, EP300 | Mental retardation, broad thumbs and halluces, dysmorphic facial features | AD | (272) |
| Seckel syndrome 1–8 | ATR, RBBP8, CENPJ, CEP152, CEP63, NIN, DNA2, ATRIP | Mental retardation, characteristic ‘bird-headed’ facial appearance | AR | (5, 18, 195) |
| Short stature with microcephaly and distinctive facies (615789) | CRIPT | Frontal bossing, high forehead, sparse hair and eyebrows, telecanthus, proptosis, anteverted nares, flat nasal bridge | AR | (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.
Examples of genetic defects in fundamental cellular processes: DNA repair defects.
| Disordera | Gene(s) | Clinical features | Inheritance | References |
|---|---|---|---|---|
| Bloom syndrome (210900) | RECQL3 | Sun-sensitive, telangiectatic, hypo- and hyperpigmented skin, predisposition to malignancy,chromosomal instability | AR | (274) |
| Cockayne syndrome A, B, XPG/CS (five types) | ERCC8, ERCC6, ERCC5, ERCC3, ERCC4 | Cutaneous photosensitivity, thin, dry hair, progeroid appearance, pigmentary retinopathy, sensorineural hearing loss, dental caries | AR | (272) |
| Fanconi anemia (multiple types) | FANCA and multiple genes | Heterogeneous disorder causing genomic instability, abnormalities in major organ systems, bone marrow failure, high predisposition to cancer | AR | (275, 276) |
| Hutchinson–Gilford progeria syndrome (176670) | LMNA | Low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, facial features that resemble aged persons | AD | (277) |
| Hypomorphic PCNA mutation | PCNA | Hearing loss, premature aging, telangiectasia, neurodegeneration, photosensitivity by nucleotide excision repair defect | AR | (278) |
| Immunoosseous dysplasia, Schimke type (242900) | SMARCAL1 | Spondyloepiphyseal dysplasia, numerous lentigines, slowly progressive immune defect, immune-complex nephritis | AR | (279) |
| Natural killer cell and glucocorticoid deficiency with DNA repair defect (609981) | MCM4 | Variant of familial glucocorticoid deficiency: hypocortisolemia, increased chromosomal breakage, NK cell deficiency | AR | (280, 281) |
| Nijmegen breakage syndrome (251260) | NBS1 | Microcephaly, growth retardation, immunodeficiency, predisposition to cancer | AR | (282) |
| Ovarian dysgenesis 4 | MCM9 | Hypergonadotropic hypogonadism, genomic instability | AR | (283) |
| Rothmund–Thomson syndrome | RECQL4 | Skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, premature aging | AR | (284) |
| X-linked mental retardation-hypotonic facies syndrome (309580) | ATRX | Mental retardation, dysmorphic facies, hypogonadism, deafness, renal anomalies, mild skeletal defects | XLR | (285) |
| Defective nonhomologous end-joining (NHEJ) DNA damage repair | LIG4, NHEJ1, ARTEMIS, DNA-PKCs, XRCC4, PRKDC | Radiosensitive, severe combined immunodeficiency | AR | (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.
Examples of contiguous gene deletion or duplication syndromes associated with short stature.
| Disordera | Location | Clinical features | References |
|---|---|---|---|
| Recurrent rearrangements of 1q21.1 | 1q21.1del | Intellectual disability, autism spectrum disorder, microcephaly, cardiac abnormalities, cataracts | (288) |
| 2p16p22 microduplication syndrome | 2p16p22dup | Delayed 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) | 4q21del | Neonatal 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 del | High-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 delay | 5q35.2q35.3dup | Microcephaly, speech delay. Reciprocal to common Sotos syndrome deletion (increased NSD1 function?) | (293) |
| Williams–Beuren syndrome (194050) | 7q11.23del | Supravalvular aortic stenosis, intellectual disability, distinctive facial features | (294) |
| Trichorhinophalangeal syndrome, type II (Langer–Giedion syndrome) (150230) | 8q21.11q24.13del | Large, 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) | 11p13del | Aniridia, hemihypertrophy, Wilms tumor, cryptorchidism. PAX6, WT1? | (296) |
| 12q14 microdeletion syndrome | 12q14del | Developmental delay, osteopoikilosis. HMGA2? | (297, 298) |
| Chromosome 13q14 deletion syndrome (613884) | 13q14del | Retinoblastoma, mental impairment, high forehead, prominent philtrum, anteverted earlobes | (299) |
| Frias syndrome (609640) | 14q22.1q22.3del | Exophthalmia, palpebral ptosis, hypertelorism, short square hands, small broad great toes. BMP4? | (300) |
| Distal 14q duplication syndrome | 14q32.2-qter | Mild developmental delay, high forehead, hypertelorism, dysplastic ear helices, short philtrum, cupid bow upper lip, broad mouth, micrognathia | (230) |
| Smith–Magenis syndrome (182290) | 17p11.2del | Brachycephaly, 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) | 17p13.3del | Lissencephaly, 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 syndrome | 17q2125dup | Developmental delay, distal arthrogryposis. GH insensitivity, disturbed STAT5B, PI3K, and NF-kappaB signaling. Role of PRKCA mRNA overexpression? | (66, 304) |
| Chromosome 18p deletion syndrome (146390) | 18p11del | Intellectual disability, round face, dysplastic ears, wide mouth, abnormalities of teeth, limbs, genitalia, brain, eyes, heart | (305) |
| Chromosome 18q deletion syndrome (601808) | 18q22.3q23del | Congenital aural atresia, GHD, intellectual disability, reduced white-matter myelination, foot deformities | (306, 307) |
| Velocardiofacial syndrome (192430) | 22q11.2del | Highly 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).
Examples of imprinting disorders.
| Disordera | Genetics | Clinical features | References |
|---|---|---|---|
| Silver–Russell syndrome (180860) | Hypomethylation of imprinting control region on paternal allele of 11p15.5 controling methylation of IGF2 and H19 | Severe 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 mellitus | Mutation in paternally imprinted gene CDKN1C | IUGR, 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 translocation | Intellectual 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 mother | Resistance to parathyroid hormone and other hormones | (228) |
| Pseudohypoparathyroidism type 1b (603233) | Both alleles have a paternal-specific imprinting pattern on both parental alleles | Resistance to PTH is present without signs of Albright hereditary osteodystrophy | |
| Pseudopseudohypopara – thyroidism (612463) | Heterozygous GNAS1 mutation inherited from father | Albright 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]).
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