MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature

in European Journal of Endocrinology
Correspondence should be addressed to A A L Jorge; Email: alexj@usp.br

Tall stature is defined as a height of more than 2 standard deviations (s.d.) above average for same sex and age. Tall individuals are usually referred to endocrinologists so that hormonal disorders leading to abnormal growth are excluded. However, the majority of these patients have familial tall stature or constitutional advance of growth (generally associated with obesity), both of which are diagnoses of exclusion. It is necessary to have familiarity with a large number of rarer overgrowth syndromes, especially because some of them may have severe complications such as aortic aneurysm, thromboembolism and tumor predisposition and demand-specific follow-up approaches. Additionally, endocrine disorders associated with tall stature have specific treatments and for this reason their recognition is mandatory. With this review, we intend to provide an up-to-date summary of the genetic conditions associated with overgrowth to emphasize a practical diagnostic approach of patients with tall stature and to discuss the limitations of current growth interruption treatment options.

Abstract

Tall stature is defined as a height of more than 2 standard deviations (s.d.) above average for same sex and age. Tall individuals are usually referred to endocrinologists so that hormonal disorders leading to abnormal growth are excluded. However, the majority of these patients have familial tall stature or constitutional advance of growth (generally associated with obesity), both of which are diagnoses of exclusion. It is necessary to have familiarity with a large number of rarer overgrowth syndromes, especially because some of them may have severe complications such as aortic aneurysm, thromboembolism and tumor predisposition and demand-specific follow-up approaches. Additionally, endocrine disorders associated with tall stature have specific treatments and for this reason their recognition is mandatory. With this review, we intend to provide an up-to-date summary of the genetic conditions associated with overgrowth to emphasize a practical diagnostic approach of patients with tall stature and to discuss the limitations of current growth interruption treatment options.

Invited Author’s profile

Alexander Augusto de Lima Jorge, MD PhD is an Associate Professor of Medicine at The University of Sao Paulo (USP), School of Medicine, Brazil. He is a clinical endocrinologist as well as a translational researcher. Dr Jorge is a principal investigator at the Developmental Endocrinology Unit and the Genetic Endocrinology Unit. He is an expert in growth disorders and responsible for molecular genetic investigation of several endocrine genetic disorders at the Hospital das Clínicas de São Paulo. His research is centered on discovering and understanding the genetic mechanisms involved in monogenic endocrine diseases, in particular those associated with growth and development disorders.

Introduction

Height is a classic example of human trait that exhibits a normal (Gaussian) distribution within each sex, age and ancestrality. Standard deviation score (SDS), or Z-score, is a well-established method used to analyze and represent height according to a specific population (1). Tall stature is usually defined as a height above 2 standard deviations (s.d.) from mean height for a specific population or also as a height above 2 s.d. from mid-parental height SDS after excluding factors that could have negatively affected the stature of the parents. Statistically, the first definition includes 2.3% of the population, but the referrals for tall stature are not as frequent as expected. This could be explained by the fact that most cases are familial and therefore do not concern physicians, parents and patients. Additionally, tall stature has a wider social acceptance than short stature. More extreme cases, with height SDS above 2.5 or 3 (which would comprise approximately 0.6 and 0.1% of the population respectively) are more often referred for clinical investigation, usually due to problems with social adjustment and/or to concerns about the increased possibility of diseases associated with growth disorder. It is interesting to consider that as height SDS is dependent on the origin of the population, a given height s.d. can differ among countries. According to World Health Organization (WHO) data, height s.d. of 2 and 2.5 in adults are equivalent to respectively, 191.1 and 194.8 cm in men and 176.2 and 179.5 cm in women (2). Height s.d. of 2 and 2.5 for different countries are described in Supplementary Table 1 (see section on supplementary data given at the end of this article).

Factors involved in global regulation of gene expression, cell cycle control and growth plate development have critical roles in linear growth (3, 4). The main endocrine factors that regulate growth are GH/IGF-1 axis and sex steroids, each one of them having more importance in a specific period of life (5). During pregnancy, fetal growth is influenced by nutritional status, insulin and IGF system. In the first years of life, nutritional status still has an important impact on growth. GH/IGF1 axis has a major role during childhood growth and sex steroids during puberty. There are far more secondary conditions that cause growth impairment than conditions that cause overgrowth. Consequently, genetic influence is expected to be proportionally higher on tall than short stature, both for syndromic and non-syndromic disorders.

Subjects with tall stature are usually referred for evaluation during childhood or adolescence, but some individuals first seek medical assistance in adulthood. Depending on the timing of clinical presentation and patient phenotype, the investigation has particularities. In this review, we will discuss the main differential diagnoses, the clinical approach and a diagnostic work-up of patients with tall stature and revise the current knowledge about growth interruption treatment.

Differential diagnosis

Tall stature results from a generalized overgrowth condition. There are disorders associated with segmental overgrowth (6), but this issue is beyond the scope of this review. The differential diagnosis of tall stature is complex given the diversity of rare conditions that can cause height above 2 s.d. and their variable presentations.

There are four main growth patterns observed in children with tall stature. The first one is seen in children who are above 2 s.d. in height and grow remaining in the same percentile (Fig. 1A) (7, 8, 9). The second pattern is seen in children who cross upwards percentiles during childhood and/or puberty (Fig. 1B) (10), reaching an adult height above 2 s.d. Another pattern is observed in children who are above 2 s.d. during childhood but have an accelerated bone maturation and reach an adult height between −2 and 2 s.d. or even a stature below −2 s.d. in adulthood (Fig. 1C) (11, 12, 13). Lastly, there are children with height between −2 and 2 s.d. during childhood, who have a prolonged growth beyond adolescence, resulting in an adult height above 2 s.d. (Fig. 1D) (14). In addition to growth patterns, patients with tall stature can also be sorted according to the presence/absence of syndromic features or according to their size at birth. Tall stature causes can be classified conforming to these characteristics (Table 1).

Figure 1
Figure 1

Representative growth chart of the main patterns observed in individuals with overgrowth conditions: (A) a patient that grows above 2 s.d. throughout childhood and reaches an adult height above 2 s.d., but consistent with his/her target height; (B) a patient that crosses through higher percentiles during childhood, reaching an adult height above 2 s.d. and above his/her target height; (C) a patient that has tall stature during childhood, but has an accelerated bone maturation and reaches a normal adult height (solid line) or even a stature below the normal range in adulthood (dashed line) and (D) a patient with normal height during childhood who has a prolonged growth beyond adolescence, resulting in an adult height above 2 s.d.

Citation: European Journal of Endocrinology 176, 6; 10.1530/EJE-16-1054

Table 1

Main conditions to consider in the differential diagnosis of tall stature.

DiagnosisLarge for gestational ageDysmorphic featuresIntellectual disabilityAdult heightMIM
Familial tall statureYesNoNoTall statureN/A
ObesityNoNoNoNormal601665
Precocious sex-steroids exposure

 Precocious puberty

 Virilizing disorders
NoNoNoShort stature*

*
Prolonged growth by delayed fusion of growth cartilageNoMildNoTall stature
 Hypogonadism

 Aromatase deficiency
*

613546
 Estrogen resistance (ESR1 mutation)615363
Supernumerary sex chromosome aneuploidies

 Klinefelter syndrome

 Triple X syndrome
NoMildVariableTall statureN/A

N/A
HomocystinuriaNoYesYesTall stature236200
Beckwith–Wiedemann syndromeYesYesNoNormal/upper limit130650
Marfan syndromeNoYesNoTall stature154700
Sotos syndromeYesYesYesNormal/upper limit117550
Weaver syndromeYesYesYesTall stature277590
Fragile X-chromosome syndromeNoYesYesNormal/short stature300624
IGF1R duplicationYesYesYesTall statureN/A
Growth hormone excessNoYesNoTall stature*
Epiphyseal chondrodysplasia, Miura type (CNP / NPR-B)YesMildNoTall stature615923
CATSHL syndrome (FGFR3)YesYesYesTall stature610474
Bannayan–Riley–Ruvacaba syndromeYesYesYesNormal153480
Simpson–Golabi–Behmel syndromeYesYesVariableTall stature312870
Lujan–Fryns syndromeNoYesYesNormal/upper limit309520
Congenital contractural arachnodactylyNoYesNoTall stature121050
SclerosteosisNoYesNoTall stature/upper limit269500

N/A: non-available.

Several entries.

As height and pubertal development are human traits with a high heritability (15, 16), it is expected that a significant proportion of tall individuals have genetic variants responsible for the observed phenotype. Consequently, it is essential for physicians who evaluate patients with tall stature to be aware of the genetic conditions associated with overgrowth (see below and Supplementary material).

A monogenetic disorder is usually identified in patients with tall stature associated with a syndromic condition. Various genetic defects and molecular genetic mechanisms are associated with syndromic overgrowth. Chromosome imbalance can cause excessive growth due to the disruption of genes that negatively regulate growth, as observed in some cases of Sotos syndrome (12) (MIM 117550) and Beckwith–Wiedemann syndrome (17) (MIM 130650). In addition, partial trisomy can cause tall stature because of an increase in the copy number of genes that positively regulate linear growth: SHOX (18), NPPC (19) and IGF1R (20). Loss-of-function point mutations in estrogen receptor alfa (ESR1) or CYP19A1 cause estrogen resistance (MIM 615363) and aromatase deficiency (MIM 613546) (21) respectively. Both conditions are associated with delayed epiphyseal closure and prolonged growth period, resulting in tall stature. On the other hand, gain-of-function point mutations in growth promoter genes, such as natriuretic peptide receptor type B (NPR2), lead to overgrowth by upregulating mechanisms that control growth of epiphyseal cartilage (MIM 615923) (22). Additionally, there are several genetic defects extrinsic to growth plate, such as those associated with pituitary GH-secreting tumors, precocious puberty and hypogonadism, that also contribute to the genetic basis of overgrowth.

However, the majority of individuals with tall stature are healthy and non-syndromic. The height of these tall individuals can be partially explained by the combination of several common variants in a typical polygenic effect. Nevertheless, the ability to predict tall stature using several polymorphisms identified in genome-wide association studies about height is limited (12.25% of tall stature phenotype explained by 182 SNPs) (23). The area under the receiver-operating characteristic (ROC) curve for prediction of tall stature using 182 height-associated SNPs is inferior than the area obtained using the traditional approach of predicting adult height by mid-parental height (0.76 vs 0.84) (23). It is possible that taking into account the genetic interaction between SNPs and/or the addition of other genetic variants and haplotypes can improve our ability to predict non-syndromic tall stature. Alternatively, part of these patients may also have monogenic conditions, representing a milder form in the spectrum of classical disorders (24).

The main conditions associated with overgrowth will be briefly characterized below. Less common causes are described in the Supplementary material.

Familial tall stature

Familial tall stature comprises non-syndromic children who are above 2 s.d. since infancy, growing through the same percentile and reaching a tall adult height (Fig. 1A) (7). There is no abnormal growth velocity and height SDS minus target height SDS is less than 2, without dysmorphic features or pubertal disorders. Therefore, it is a diagnosis of exclusion. It is the most common diagnosis among people with tall stature (25, 26).

Endocrine causes

GH/IGF-1 excess

GH excessive production during adult life leads to acromegaly and, when it happens before epiphyseal closure, clinical presentation is pituitary gigantism (Fig. 1B). Most referrals of tall stature to endocrinologists have the objective of ruling out this diagnosis. Children with gigantism have an abnormally high growth velocity, tall stature, symptoms found in acromegaly, such as hyperhidrosis and acral enlargement and symptoms due to direct tumor effect, like headache and visual impairment (27). Serum IGF-1 is the recommended screening approach, with a lack of suppression of GH to <1 µg/L within 2 h after 75 g of oral glucose as the confirmation step (28). Patients with gigantism usually have macroadenomas, about 50% of which are invasive. The majority of them develop hypopituitarism, mainly after surgery or radiotherapy, affecting specially the gonadal axis, which may increase even more their adult height if not adequately treated (10). A recent study has shown that 46% had an identifiable genetic condition, in descending order of prevalence: AIP gene, Xq26.3 microduplications (X-linked acrogigantism), McCune–Albright syndrome, Carney complex and MEN1 gene (10).

Precocious exposure to sex steroids

Sex steroids play an important role in pubertal spurt. Estrogen not only enhances growth hormone secretion during puberty but also speeds up chondrocytes senescence in growth plate, leading to its fusion (Fig. 1C, dashed line) (29). Androgens also mediate growth spurt in part through their conversion to estrogen and also through their own action in the growth plate (5). Normal pubertal timing seems to be changing, but it is still defined as above 8 years in girls and 9 years in boys (13). Children with precocious puberty or virilizing disorders, such as congenital adrenal hyperplasia, have an increased growth velocity and height SDS compared to their peers, but at a cost of advanced bone age and short stature in adulthood if not recognized in time for appropriate treatment (13, 30).

Prolonged growth due to delayed fusion of growth plate

It comprises a heterogenous group of diseases, including hypogonadism, aromatase deficiency and estrogen resistance. As the opposite from precocious puberty, those patients do not have a growth spurt due to the absence of or resistance to sex steroids. Growth rate is slow but, as the epiphyseal plate fusion is delayed, these patients keep growing into adulthood, developing tall stature with eunuchoid proportions (increased arm span and upper-to-lower segment ratio) only later in life (Fig. 1D) (5).

Hypogonadotropic hypogonadism can be isolated or occur concurrently with other pituitary deficiencies. When it is congenital, cryptorchidism and micropenis can raise suspicion after birth. It is important to search for anosmia as a clue for Kallmann syndrome (MIM 308700), and affected relatives can present only with an impaired sense of smell (31). Aromatase deficiency (MIM 613546) is a rare autosomal recessive disorder. Affected males have no major findings but tall stature and insulin resistance, whereas females have genital ambiguity, poor breast development, multicystic ovaries and infertility (21, 32, 33). Both genders show low bone density and biochemically boys have normal testosterone levels, normal to increased FSH levels and undetectable estrogen levels. As the placenta is a tissue partially derived from the embryo, mothers can develop virilization during pregnancy of affected children because of the placental inability to convert androgens synthesized in fetal adrenal glands to estrogen (21, 32, 33). Estrogen resistance (MIM 615363) shares a similar phenotype, except for no maternal virilization during pregnancy or in affected girls (32).

Thyrotoxicosis

Hyperthyroidism is an uncommon condition during childhood. Many signs and symptoms in children are the same as in adults, like weight loss, goiter, tachycardia and ocular involvement (34). Regarding growth, an increased height velocity rate and advanced bone age are observed but, as a large number of affected children are in early-to-mid puberty, the evaluation of the isolated effect of thyroid hormone excess on height is compromised (34, 35, 36). However, in a limited number of prepubertal children, thyrotoxicosis had the same effect on growth. Rarely children are above 2 SDS for height in this condition. When adequately treated, their adult heights are within normal range, usually above 0.54 to 0.63 s.d. from target height SDS (34, 35, 36).

Obesity

Although obesity and tall stature are not related in adults, there is an important association between them during childhood. Several studies have shown that obese children are taller than their normal-weight-matched controls by a mean of 4–5 cm, and the age when this difference reaches its maximum varies between genders and among studies. Those patients show an accelerated growth with advanced bone age and early puberty in comparison with their pairs, resulting in a decreased growth velocity earlier during adolescence, and no significant difference in adult height between overweight/obese and normal-weight subjects (37, 38). Obesity probably influences growth through hormonal pathways, such as GH/IGF1/ghrelin/insulin and leptin/GnRH, but the exact mechanisms of how these neuroendocrine hormones relate to promote growth are still unknown (39).

Constitutional advance of growth (CAG)

Constitutional advance of growth is the opposite development pattern in relation to constitutional delay of growth, and it can be associated, although not exclusively, with obesity. It has been suggested that CAG could predict late onset of childhood obesity in non-obese children (40). Affected children have an abnormally high growth velocity from birth to age 4 years, when they become tall. From 5 to 9 years of age, growth velocity is maintained at 97th percentile and it drops to 50th percentile after that (7). Puberty is often earlier in those children, suggesting that CAG could be a spectrum of idiopathic precocious puberty (40). It has been shown an increase in IGF-2 levels and a higher IGFs/IGFBPs molar ratio prior to puberty, a possible mechanism of tall stature in children with CAG (41).

Syndromic causes

Supernumerary sex chromosome aneuploidies

Klinefelter syndrome: The most frequent chromosomal aneuploidy in males (1.1–1.7 cases per 1000 births), Klinefelter syndrome is associated with hypergonadotropic hypogonadism, small testes, gynecomastia, tall stature and learning disabilities (42). Beside these characteristics, patients with Klinefelter syndrome have a higher risk of developing breast cancer, metabolic syndrome and type 2 diabetes (42). Diagnosis can be easily achieved by a 47,XXY karyotype or variations. During childhood, patients present with disproportionate tall stature due to longer legs, probably because of a third copy of SHOX gene (43). This effect is nonlinear, and it has been demonstrated that males carrying 5 or more copies of sex chromosomes are actually shorter than expected (44). During adolescence, as a result of delayed bone maturation due to hypogonadism, those patients can grow even taller.

Triple X syndrome: Triple X syndrome has an incidence of 1/1000 female births and remains an underdiagnosed condition due to lack of exuberant physical findings. Affected girls can present with mild ocular hypertelorism, epicanthal folds, pes planus and 5th finger clinodactyly (45, 46, 47). Height is normal until the age of 4, and they become taller because of longer legs, reaching a stature in the upper limit of the normal range or mildly above 2 s.d. (45). Fertility is not an issue, although premature ovarian failure has been reported in some cases. Learning disabilities, especially regarding expressive language, are also present, and many girls are diagnosed during an investigation for developmental delay (47). Diagnosis is achieved by a 47,XXX karyotype with or without mosaicism. As seen in males, females carrying 4 or more copies of sex chromosomes are also shorter than expected (44).

Monogenic forms

Marfan syndrome: Marfan syndrome (MIM 154700) is a cause of disproportionate tall stature often remembered by clinicians, although height is not a criterion for diagnosis. As Marfan syndrome causes aortic root aneurysm that can lead to rupture and death, it is important to be aware of this differential diagnosis. Disease-specific growth charts were developed in the United States and South Korea and both show mean heights above the 95th percentile for general population by the age of 2–3 years (Fig. 1A) (8, 9). It is an autosomal dominant disease caused by a mutation in FBN1 gene, which encodes fibrilin-1. This protein is found in the extracellular matrix of cartilage and around 25% of affected patients harbor a de novo mutation (48). According to the revised Ghent criteria (2010), in cases with a family history of the syndrome, presence of ectopia lentis (subluxation of the lenses) or aortic root dilation (Z ≥ 2 s.d. above 20 years or Z ≥ 3 below 20 years) or a systemic score ≥7 points are sufficient for diagnosis. When there is no family history, the necessary criteria are (a) presence of ectopia lentis and a FBN1 mutation known to cause aortic root dilation or (b) presence of aortic root dilation and ectopia lentis or a systemic score ≥7 points or a FBN1 mutation. The systemic score includes phenotypic characteristics such as wrist and thumb signs, scoliosis, pectus carinatum and facial features (49) (Supplementary Table 1).

Sotos syndrome: Sotos syndrome (MIM 117550) patients have birth length above 95th percentile and birth weight often is less affected. Height continues above 2 s.d. until puberty, when there is a tendency toward the mean, which leads to adult height often in the upper limit of normal range (Fig. 1C, solid line). Approximately 75% of patients have an advanced bone age. Macrocephaly is a striking feature present since birth and is accompanied with a broad range of learning disabilities and variable abnormalities in cranial imaging (12). Facial features include frontal bossing, down-slanting palpebral fissures, pointed chin and dolichocephaly; cardiac and renal abnormalities may also occur (50). Sotos syndrome is mainly caused by haploinsufficiency of NSD1 gene. Most mutations are de novo, although there are few reports of autosomal dominant transmission. NSD1 product is suggested to be a histone methyltransferase that could positively or negatively affect the transcription in different cells (51). There are other syndromes with clinical overlap with Sotos syndrome, commonly referred as ‘Sotos-like’ or Sotos syndrome 2 and 3 (Supplementary material).

Beckwith–Wiedemann syndrome (BWS): BWS (MIM 130650) is an overgrowth syndrome in which there is an increased occurrence of embryonal tumors, such as Wilms tumor and hepatoblastoma, especially until the age of 8 years. The most common features are macroglossia, abdominal wall defects and neonatal hypoglycemia due to islet cell hyperplasia (52, 53). Newborns are macrosomic and children grow parallel or above the 95th percentile until around 8 years, with a fall in growth velocity after that. Therefore, adult height is usually in the upper limit of normal range (Fig. 1C, solid line) (11, 53). The majority of BWS cases are sporadic and associated with abnormal methylation at chromosome 11p15.5 or paternal uniparental disomy of the same region; less commonly, an autosomal dominant form of the syndrome can result from a mutation in CDKN1C gene in the maternal allele or from chromosomal deletions/duplications involving this locus (17, 53). In this chromosomal region, the maternal allele expresses CDKN1C gene, which encodes p57(KIP2), an important regulator of cell cycle progression (54). In contrast, the paternal allele expresses IGF2 gene that is positively involved in fetal growth. Case–control studies suggest an increased risk for BWS when conception is achieved by assisted reproductive technologies (55). Several score systems were developed to allow a clinical diagnosis, but no consensus was reached. Diagnosis is established by one of the clinical score systems or by the identification of alterations leading to an abnormal methylation in chromosome 11p15.5 along with clinical findings (53).

Homocystinuria: Homocystinuria caused by the deficiency of cystathionine β-synthase (MIM 236200) has clinically overlapping features with Marfan syndrome, such as ectopia lentis, pectus carinatum and scoliosis. Three main differences are an autosomal recessive inheritance, the presence of intellectual disability and thromboembolism, which is the major cause of early mortality in homocystinuria (56). Osteoporosis can also occur in these patients. Diagnosis can be established by the presence of high serum concentrations of homocysteine, total homocysteine and methionine or an increased urinary homocysteine concentration. Furthermore, the diagnosis can also be achieved by the assessment of cystathionine β-synthase enzyme activity in fibroblasts or molecular testing of CBS, which encodes cystathionine β-synthase (56).

Fragile X syndrome: Classically, fragile X syndrome (MIM 300624)-affected boys show developmental delay, intellectual disability, abnormal behavior/autism spectrum disorder, prominent forehead and jaw, large ears, macroorchidism, mitral valve prolapse, strabismus and joint laxity (57, 58). Heterozygous girls can also exhibit these features, but in a milder presentation. Most studies related to growth patterns in fragile X syndrome evaluated only boys; growth velocity was higher during prepubertal period, but it decelerated after puberty, resulting in a normal height in adulthood (59, 60). However, other studies have shown growth curves that were very similar to those seen in healthy children (61). It is a X-linked dominant syndrome caused by an expansion of CGG repeats beyond 200 in 5′UTR of o gene, leading to hypermethylation of this region and a diminished or even absent transcript (57).

Evaluation of children and adults with tall stature

Children with tall stature are usually referred to pediatric endocrinologists because of the possibility of GH excess or precocious exposure to sex steroids. Both conditions are associated with an increase in growth velocity, a height SDS that is frequently incompatible with parental height and specific clinical findings (Fig. 1B and C). Additionally, endocrinologists are also requested to evaluate adults with tall stature due to the possible association with hypogonadism (Fig. 1D). Overgrowth syndromes form a heterogeneous disease group with which it is necessary to have familiarity, especially because some of them have important implications for patients’ follow-up and genetic counseling (49, 58). However, the two most frequently observed conditions in children referred for tall stature are anticipation of growth associated with obesity and familial tall stature, both of which are diagnoses of exclusion (25, 40). In two large series of tall stature patients, with a total of 638 children evaluated, pathologic causes of overgrowth were identified in approximately 9% of cases (25, 26). In both series, Marfan syndrome was the most frequently identified disease followed by supernumerary sex chromosome aneuploidies, precocious sex steroids exposure, Sotos syndrome and Beckwith–Wiedemann syndrome. A third study assessed 132 children referred for tall stature and a pathologic cause was identified in only 2 (1.5%) patients with precocious puberty (62).

There are no evidence-based recommendations on which patients should be evaluated for pathological causes of tall stature or on which is the best strategy to investigate them. Considering that the number of diseases that may cause tall stature is smaller than the number which may be responsible for short stature, a more conservative approach is reasonable. In general, children or adults who have height SDS > 2.5 should be clinically evaluated. Additionally, we also recommend the investigation of patients with height SDS minus target height SDS > 1.5 (63) and/or with a significant positive height SDS change and/or with dysmorphic features compatible with known syndromes associated with tall stature (Fig. 2).

Figure 2
Figure 2

Suggested diagnostic flow chart for evaluation of patients referred for tall stature and the main differential diagnoses. (CAG = constitutional advance of growth; BWS = Beckwith–Wiedemann syndrome).

Citation: European Journal of Endocrinology 176, 6; 10.1530/EJE-16-1054

Clinical evaluation starts with a detailed medical and family history (Table 2). Birth weight and length should be assessed to classify tall children in two groups by the size at birth: adequate or large for gestational age (Table 1). An increased birth length is observed in several genetic conditions associated with overgrowth. Other key point is to determine if tall stature occurs in isolation or as part of a syndromic condition (Fig. 2). For this propose, medical history should focus on the presence of malformations and on neuropsychomotor development. Physical examination should be complete, including anthropometric measurements, an evaluation of facial and body dysmorphic features and a search for any other clues for one of the main causes of tall stature (Table 2).

Table 2

Main clinical findings associated with tall stature and correlated disorders.

Key signs and symptomsDisorders
Presence of consanguinityHomocystinuria, sclerosteosis
Family history suggesting an autosomal dominant inheritance of tall statureFamilial tall stature, Marfan syndrome, epiphyseal chondrodysplasia and Miura type (increase of signal by CNP/NPR-B)
Developmental delay, intellectual disability and behavior problemsHomocystinuria, Sotos, CATSHL, Fragile X-chromosome, Bannayan–Riley–Ruvacaba, Weaver and Lujan-Fryns syndromes
Hearing lossSclerosteosis, CATSHL, Simpson–Golabi–Behmel and Sotos syndromes
Increased birth weight and length SDS for gestational ageSeveral syndromic tall stature conditions are associated with an increase in birth weight and/or length (Table 1)
Head circumference SDSMacrocephaly is observed in Sotos, Bannayan-Riley-Ruvalcaba, Weaver, Lujan-Fryns, Simpson-Golabi-Behmel and Fragile-X syndromes

Microcephaly is observed in CATSHL syndrome
Increased BMI SDSObesity can be associated with tall stature during infancy. Some syndromic overgrowth conditions are also characterized by obesity during infancy or adult age (like Weaver syndrome)
Sleep difficulties, hyperactivity, decrease in school performance, palpitations and weight loss

Stare and lid lag, exophthalmos, goiter, tachycardia and tremor
Thyrotoxicosis
Dysmorphic facial featuresSeveral syndromic forms of overgrowth conditions, each one with particular features (see text and supplementary material)
Presence of precocious secondary sexual characteristicsPrecocious sex steroids exposure (precocious puberty, virilizing disorders)
Signs of hypogonadism (small testes, amenorrhea, underdevelopment of breast and body hair)Several different causes; in males, mainly Klinefelter syndrome
Body disproportion (arm span that exceeds the height and/or sitting height: total height SDS < -2)Klinefelter syndrome
Marfanoid habitus (arm span that exceeds the height, arachnodactyly and hyperlaxity)Marfan, Sotos, Lujan-Fryns syndrome, Homocystinuria, Epiphyseal chondrodysplasia Miura type
Severe kyphoscoliosisCATSHL syndrome, Epiphyseal chondrodysplasia Miura type
CampodactylyCATSHL, Weaver syndrome

Complementary diagnostic tests should be individualized for each patient depending on the clinical findings and taking into account the possible differential diagnoses. An X-ray of the non-dominant hand should be used to evaluate the skeletal maturity of tall children and adolescents and is useful to predict adult height. It is important to consider that the available methods for adult height prediction are imperfect as Bayley–Pinneau method may overestimate adult height, whereas Tanner–Whitehouse Mark 1 and 2 may overestimate or underestimate it depending on bone age (64, 65). The main complementary diagnostic tests that can be useful during an investigation of a patient with tall stature are shown in Table 3.

Table 3

Complementary diagnostic tests that can be useful during investigation of a patient with tall stature.

ExamObjective
X-ray of non-dominant handBone age determination, which is important to predict adult height. Advanced bone age is often observed in patients with Sotos and Beckwith-Wiedemann syndrome, precocious sex steroids exposure, constitutional advance of growth and obesity. Delayed bone age is observed in hypogonadism conditions, aromatase deficiency and estrogen resistance.
Serum IGF-1Screening for growth hormone excess
Serum TSH, free-T4Screening for hyperthyroidism
LH, FSH, Testosterone/Estradiol levelsFor evaluation of precocious sex steroids exposure or hypogonadism
Serum homocysteineScreening for homocystinuria mainly in patients with Marfanoid habitus, consanguineous parents and intellectual disability
KaryotypeAssessment of chromosome aberrations (i.e. Klinefelter syndrome, 47 XYY, 47 XXX) or CAIS
EchocardiogramAssessment of congenital cardiac defects (i.e. Sotos syndrome) and aortic root dilation (i.e. Marfan syndrome)
Ophthalmologic evaluationAssessment of ectopia lentis (i.e. Marfan syndrome and homocystinuria)
Analysis to the trinucleotide repeat region of FMR1To confirm or exclude the diagnosis of Fragile X-chromosome syndrome
FBN1 sequenceTo confirm or exclude the diagnosis of Marfan syndrome in patients with suggestive clinical findings
Submicroscopic copy number variation analysis (SNP or CGH array)To identify submicroscopic copy number variation, mainly in patients with unexplained developmental delay/intellectual disability, autism spectrum disorders and multiple congenital anomalies
Target high throughput sequence (whole exome or gene panel sequence)To simultaneously investigate the presence of pathogenic variants in several genes associated with tall stature, especially in patients with high suspicion for genetic causes

SNP, single nucleotide polymorphism; CGH, Comparative genomic hybridization; CAIS, complete androgen insensitivity.

As several causes of tall stature have a genetic basis and molecular genetic tests are becoming more available and less expensive, it is expected that these tests will be more frequently used to assist with the diagnosis of tall stature patients. Presently, the diagnosis of genetic conditions associated with tall stature is performed based on clinical, laboratory and imaging findings. When a syndromic diagnosis is made based on the patient phenotype, genetic testing is targeted for a particular gene or genetic defect and mainly serves to confirm the diagnosis (candidate gene approach) (66) (Table 3). Genetic tests become especially important in mild or atypical cases in which the clinical diagnosis is difficult. However, the diversity of genes involved in overgrowth conditions, the rarity of these diseases and the considerable variability in phenotypes may hamper a diagnosis based only on clinical findings or on a candidate gene approach. In this scenario, a genomic approach offers an advantage in the assessment of several genes at once and has become an important tool to establish a precise diagnosis (67).

Chromosomal microarray is a well-established first-tier diagnostic test in patients with unexplained developmental delay/intellectual disability, autism spectrum disorders and multiple congenital anomalies (68). Single-nucleotide polymorphisms (SNP) or comparative genomic hybridization (CGH) arrays are also useful tools to investigate patients with syndromic overgrowth of unknown cause that have the above characteristics. Whole exome sequencing (WES) derived from targeted massively parallel sequencing allows searching for pathogenic allelic variants throughout all coding and splice-site regions in virtually all known genes. Several novel genes involved in overgrowth conditions were recently identified through WES (Supplementary Table 2) (69, 70, 71). WES was proved to be a useful and powerful tool to establish the diagnosis of complex conditions (72, 73). In the years to come, with increased access to these techniques, it is possible to expect an improvement in the establishment of the diagnosis of overgrowth patients.

Treatment

When families seek medical assistance for their children because of tall stature, their most frequent concern is that their excessive stature may cause difficulties regarding their social life. In general, families tend to worry more about tall girls than tall boys and, when treatment for overgrowth was initially proposed, intervention was recommended for girls even when their predicted height was only 10 cm above average (74). Presently, tall stature has less influence in social acceptance and treatment to cease growth is less frequently seeked (74). There are no evidence-based guidelines available on whether to treat or not and on which medication to use. Currently, the decision on whether to intervene or not to cease growth is based on the prediction of adult height. Children with a predicted adult height above 2 SDS can be considered for treatment, although a more conservative cut-off point above 2.5 or 3 SDS is preferred (75, 76, 77).

As predicted adult height is a crucial point for intervention, it is necessary to have reliable methods to assess this parameter. Equations to predict adult height were developed within groups of healthy children with normal stature, except for the Tanner–Whitehouse Mark 2, which included a group of tall girls. There are few studies assessing specifically which prediction method is the most reliable in children with tall stature. Overall, Bayley–Pinneau method usually overestimates adult height, especially when the bone age is less than 9 years, whereas Tanner–Whitehouse Mark 1 and 2 can overestimate adult height when bone age is less than 9 years, but underestimate it when bone age is higher. Generally, the prediction error is around 3 cm in boys and 2 cm in girls (75). Thus, both methods offer a reasonably accurate mean prediction and can be used in clinical practice, although major errors can occur in an individual basis (64, 65, 75, 78).

When indicated, specific treatment could lead to better height outcomes, like somatostatin analogs for GH excess, GnRH analogs for central precocious puberty and sex steroids for hypogonadism. However, in the majority of patients with tall stature, it is not available.

Sex steroids were the most studied and used off-label treatment to cease growth. The rationale is the closure of the epiphyses, caused mainly by estrogen, as seen in precocious puberty and other forms of early exposure to sex steroids. In boys, supraphysiological doses of testosterone result in an initially increased growth velocity, probably due to an increase in GH and IGF-1 levels caused by androgens (75, 79). In girls, high doses of estrogen, mostly synthetics, decrease growth velocity and were used to achieve a mean height reduction between 2.1 and 10 cm (65, 75). A recent retrospective study using 17β-estradiol has shown an adult height reduction around 1.6 ± 2.1 cm (26). Studies comparing high and low doses of ethinylestradiol have demonstrated that low doses such as 100 µg per day are sufficient to reduce adult height in girls (65, 80, 81, 82, 83). The best outcomes were achieved in girls who were treated when their bone age was equal to or below 12 years (65, 81, 82, 83, 84, 85, 86). Tables summarizing different treatment regimens studied in boys and girls are available in the Supplementary material.

Few studies assessed satisfaction with sex steroid treatment retrospectively (76, 78, 87). Although two studies showed only about 7% of dissatisfaction in treated patients, the largest one, comprising around 400 women in each treated and untreated groups, has shown that 99.1% of untreated and 57.9% of treated women were satisfied with this decision. The dissatisfaction in the treated group was mostly not related to the achieved adult height, but was instead caused by the small difference between actual and predicted adult height, by side effects during the treatment or concerns about its long-term consequences and by the lack of participation in the decision process of whether to be treated or not (87).

Currently, sex steroids are no longer widely recommended to cease growth due to their short- and long-term consequences. In the short term, boys treated with androgens may present with myalgia, acne, gynecomastia and weight gain, whereas girls treated with high doses of estrogen may have weight gain, night cramps, galactorrhea, ovarian cysts and predisposition to thrombosis (75, 76). Long-term studies in boys have shown a slight increase in FSH levels, a significant decrease in testosterone levels, although still within normal range and a lower testicular volume, without impairment in fatherhood (76, 88, 89, 90). The long-term side effects in girls are more concerning as it was documented that in adulthood they have more fertility problems. One study showed that around 16.5% of treated women had follicular-phase FSH above 10 IU/L and decreased levels of inibin B and AMH before 40 years, revealing a diminished follicle reserve (91, 92, 93). Considering these findings along with the failure in demonstrating a better psychological wellbeing in adult women treated during childhood, sex steroids should not be routinely prescribed to halt growth in a healthy child (94).

Other treatment approaches, such as bromocriptine and pirenzepine, have been evaluated but had little effect on adult height (95, 96). Somatostatin analogs have shown to cause a modest height reduction. One promising study with long-acting lanreotide demonstrated a mean height reduction of 3.8 cm; however, this treatment is still considered experimental (97, 98). Pegvisomant, a GH receptor antagonist, has not yet been studied as a growth reduction treatment in patients with tall stature without GH excess. No new clinical therapy has been evaluated since 2009.

Percutaneous epiphysiodesis is a surgical procedure in which the epiphysis of a long bone is attached to its diaphysis to cessate growth. It can be done in distal femur and proximal tibia, promoting mean height reductions of 4 cm in girls and 6–7 cm in boys. It has been shown to be safe in the short term, but should only be considered in children with an extremely tall predicted adult height (above 3 SDS) and should be performed in a center with expertise (99, 100).

Drug strategies tested to interrupt linear growth rely either on GH/IGF-1 axis or on puberty, but not on growth plate only. Future possibilities include drugs not yet tested on humans or used for other diseases. Recently, it has been shown that estrogen promotes growth plate fusion in female mice through estrogen receptor α (ERα) (101), and the same result was demonstrated earlier in ERα knockout male mice (102). Selective estrogen receptor modulators (SERM) have been studied in vitro (tamoxifen) (103) and in animal models (raloxifene) (104), and they successfully ceased growth. In another example, retinoids are commonly used to treat cancer and skin problems, such as acne and hyperkeratotic disorders. Several reports in children exposed to retinoids have shown premature epiphyseal closure, mainly in lower limbs, with consequent development of short stature, usually around 4–5 years after a high-dose treatment (105, 106, 107). Those findings were supported by animal models of hypervitaminosis A in rats and of use of retinoids in guinea pigs, showing a direct effect in epiphyseal plate (108). However, children under retinoids treatment can develop hyperostosis, with ligament and tendon calcifications in vertebrae and other bones, limiting movement, among other severe side effects. For these reasons, retinoids have not been evaluated in children with tall stature. However, these examples could be an inspiration for the development of new therapeutic strategies that act on growth plate-exclusive pathways, like a growth plate-specific SERM, a NPR-B antagonist or a FGFR3 agonist.

Conclusion

Tall patients are commonly referred to endocrinologists to rule out GH excess or other hormonal disturbances affecting growth. Although most of these patients have an anticipation of growth or a familial trait with no major consequences, it is important to have in mind the differential diagnoses, especially those associated with medical problems, such as aortic aneurysm, thromboembolism and tumor predisposition. In recent years, our knowledge on the genetic basis of overgrowth conditions has increased considerably. Novel molecular genetic techniques, such as exome sequencing, began to be incorporated into the evaluation of syndromic conditions, including those associated with overgrowth. This is expected to improve the etiological diagnosis and to fasten medical knowledge progress, bringing medicine to a new level. Treatment options to cease growth are still limited and should be discussed thoroughly with patients and families before being used in a healthy child.

Supplementary data

This is linked to the online version of the paper at http://dx.doi.org/10.1530/EJE-16-1054.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as influencing the impartiality of the research reported.

Funding

This work was supported by grants 2013/03236-5 (to A A L J), 2016/03318-0 (to R C S) from the São Paulo Research Foundation (FAPESP) and 301871/2016-7 (to A A L J) from the National Council for Scientific and Technological Development (CNPq).

References

  • 1

    HermanussenM. Auxology: an update. Hormone Research in Paediatrics201074153164. (doi:10.1159/000317440)

  • 2

    ButteNFGarzaCde OnisM.Evaluation of the feasibility of international growth standards for school-aged children and adolescents. Journal of Nutrition2007137153157.

    • Search Google Scholar
    • Export Citation
  • 3

    BerdascoMEstellerM.Genetic syndromes caused by mutations in epigenetic genes. Human Genetics2013132359383. (doi:10.1007/s00439-013-1271-x)

    • Search Google Scholar
    • Export Citation
  • 4

    BaronJSävendahlLDe LucaFDauberAPhillipMWitJMNilssonO.Short and tall stature: a new paradigm emerges. Nature Reviews Endocrinology201511735746. (doi:10.1038/nrendo.2015.165)

    • Search Google Scholar
    • Export Citation
  • 5

    JeeYHBaronJ. The Biology of Stature. Journal of Pediatrics20161733238. (doi:10.1016/j.jpeds.2016.02.068)

  • 6

    Keppler-NoreuilKMRiosJJParkerVESempleRKLindhurstMJSappJCAlomariAEzakiMDobynsWBieseckerLG.PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. American Journal of Medical Genetics2015167A287295. (doi:10.1002/ajmg.a.36836)

    • Search Google Scholar
    • Export Citation
  • 7

    DickermanZLoewingerJLaronZ.The pattern of growth in children with constitutional tall stature from birth to age 9 years. A longitudinal study. Acta Paediatrica Scandinavica198473530536. (doi:10.1111/j.1651-2227.1984.tb09966.x)

    • Search Google Scholar
    • Export Citation
  • 8

    KwunYKimSJLeeJIsojimaTChoiDSKimDKHuhJKangISChangMChoSYDisease-specific growth charts of marfan syndrome patients in Korea. Journal of Korean Medical Science201530911916. (doi:10.3346/jkms.2015.30.7.911)

    • Search Google Scholar
    • Export Citation
  • 9

    ErkulaGJonesKBSponsellerPDDietzHCPyeritzRE.Growth and maturation in Marfan syndrome. American Journal of Medical Genetics2002109100115. (doi:10.1002/ajmg.10312)

    • Search Google Scholar
    • Export Citation
  • 10

    RostomyanLDalyAFPetrossiansPNachevELilaARLecoqALLecumberriBTrivellinGSalvatoriRMoraitisAGClinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocrine-Related Cancer201522745757. (doi:10.1530/ERC-15-0320)

    • Search Google Scholar
    • Export Citation
  • 11

    WengEYMoeschlerJBGrahamJM.Longitudinal observations on 15 children with Wiedemann-Beckwith syndrome. American Journal of Medical Genetics199556366373. (doi:10.1002/ajmg.1320560405)

    • Search Google Scholar
    • Export Citation
  • 12

    Tatton-BrownKDouglasJColemanKBaujatGColeTRDasSHornDHughesHETempleIKFaravelliFGenotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. American Journal of Human Genetics200577193204. (doi:10.1086/432082)

    • Search Google Scholar
    • Export Citation
  • 13

    LatronicoACBritoVNCarelJC.Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes & Endocrinology20164265274. (doi:10.1016/S2213-8587(15)00380-0)

    • Search Google Scholar
    • Export Citation
  • 14

    MorishimaAGrumbachMMSimpsonERFisherCQinK.Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Journal of Clinical Endocrinology and Metabolism19958036893698. (doi:10.1210/jc.80.12.3689)

    • Search Google Scholar
    • Export Citation
  • 15

    CousminerDLBerryDJTimpsonNJAngWThieringEByrneEMTaalHRHuikariVBradfieldJPKerkhofMGenome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity. Human Molecular Genetics20132227352747. (doi:10.1093/hmg/ddt104)

    • Search Google Scholar
    • Export Citation
  • 16

    WoodAREskoTYangJVedantamSPersTHGustafssonSChuAYEstradaKLuanJKutalikZDefining the role of common variation in the genomic and biological architecture of adult human height. Nature Genetics20144611731186. (doi:10.1038/ng.3097)

    • Search Google Scholar
    • Export Citation
  • 17

    EggermannKBliekJBrioudeFAlgarEBuitingKRussoSTümerZMonkDMooreGAntoniadiTEMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome. European Journal of Human Genetics20162413771387. (doi:10.1038/ejhg.2016.45)

    • Search Google Scholar
    • Export Citation
  • 18

    MarchiniAOgataTRappoldGA.A track record on SHOX: from basic research to complex models and therapy. Endocrine Reviews201637417448. (doi:10.1210/er.2016-1036)

    • Search Google Scholar
    • Export Citation
  • 19

    BocciardiRGiordaRButtgereitJGimelliSDiviziaMTBeriSGarofaloSTavellaSLeroneMZuffardiOOverexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation. Human Mutation200728724731. (doi:10.1002/humu.20511)

    • Search Google Scholar
    • Export Citation
  • 20

    KantSGKriekMWalenkampMJHanssonKBvan RhijnAClayton-SmithJWitJMBreuningMH.Tall stature and duplication of the insulin-like growth factor I receptor gene. European Journal of Medical Genetics200750110. (doi:10.1016/j.ejmg.2006.03.005)

    • Search Google Scholar
    • Export Citation
  • 21

    RochiraVCaraniC.Aromatase deficiency in men: a clinical perspective. Nature Reviews Endocrinology20095559568. (doi:10.1038/nrendo.2009.176)

    • Search Google Scholar
    • Export Citation
  • 22

    VasquesGAArnholdIJJorgeAA.Role of the natriuretic peptide system in normal growth and growth disorders. Hormone Research in Paediatrics201482222229. (doi:10.1159/000365049)

    • Search Google Scholar
    • Export Citation
  • 23

    LiuFHendriksAERalfABootAMBenyiESävendahlLOostraBAvan DuijnCHofmanARivadeneiraFCommon DNA variants predict tall stature in Europeans. Human Genetics2014133587597. (doi:10.1007/s00439-013-1394-0)

    • Search Google Scholar
    • Export Citation
  • 24

    HannemaSEvan DuyvenvoordeHAPremslerTYangRBMuellerTDGassnerBOberwinklerHRoelfsemaFSantenGWPrickettTAn activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities. Journal of Clinical Endocrinology and Metabolism201398E1988E1998. (doi:10.1210/jc.2013-2358)

    • Search Google Scholar
    • Export Citation
  • 25

    ThomsettMJ.Referrals for tall stature in children: a 25-year personal experience. Journal of Paediatrics and Child Health2009455863. (doi:10.1111/j.1440-1754.2008.01428.x)

    • Search Google Scholar
    • Export Citation
  • 26

    UpnersENJuulA.Evaluation and phenotypic characteristics of 293 Danish girls with tall stature: effects of oral administration of natural 17β-estradiol. Pediatric Research201680693701. (doi:10.1038/pr.2016.128)

    • Search Google Scholar
    • Export Citation
  • 27

    VilarLVilarCFLyraRNavesLA.Acromegaly: clinical features at diagnosis. Pituitary2016202232. (doi:10.1007/s11102-016-0772-8)

  • 28

    KatznelsonLLawsERMelmedSMolitchMEMuradMHUtzAWassJASocietyE. Acromegaly: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism20149939333951. (doi:10.1210/jc.2014-2700)

    • Search Google Scholar
    • Export Citation
  • 29

    NilssonOMarinoRDe LucaFPhillipMBaronJ.Endocrine regulation of the growth plate. Hormone Research200564157165. (doi:10.1159/000088791)

    • Search Google Scholar
    • Export Citation
  • 30

    BonfigW.Growth and development in children with classic congenital adrenal hyperplasia. Current Opinion in Endocrinology Diabetes and Obesity2017243942. (doi:10.1097/MED.0000000000000308)

    • Search Google Scholar
    • Export Citation
  • 31

    BoehmUBoulouxPMDattaniMTde RouxNDodéCDunkelLDwyerAAGiacobiniPHardelinJPJuulAExpert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism–pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology201511547564. (doi:10.1038/nrendo.2015.112)

    • Search Google Scholar
    • Export Citation
  • 32

    BulunSE.Aromatase and estrogen receptor α deficiency. Fertil Steril2014101323329. (doi:10.1016/j.fertnstert.2013.12.022)

  • 33

    MiedlichSUKaramoozNHammesSR.Aromatase deficiency in a male patient – case report and review of the literature. Bone201693181186. (doi:10.1016/j.bone.2016.09.024)

    • Search Google Scholar
    • Export Citation
  • 34

    BucklerJMWillgerodtHKellerE.Growth in thyrotoxicosis. Archives of Disease in Childhood198661464471. (doi:10.1136/adc.61.5.464)

  • 35

    JaruratanasirikulSSriplungH.Growth pattern of childhood thyrotoxicosis: longitudinal follow-up to final height. Journal of Medical Association of Thailand20068913961399.

    • Search Google Scholar
    • Export Citation
  • 36

    WongGWLaiJChengPS.Growth in childhood thyrotoxicosis. European Journal of Pediatrics1999158776779. (doi:10.1007/s004310051202)

  • 37

    StovitzSDDemerathEWHannanPJLytleLAHimesJH.Growing into obesity: patterns of height growth in those who become normal weight, overweight, or obese as young adults. American Journal of Human Biology201123635641. (doi:10.1002/ajhb.21191)

    • Search Google Scholar
    • Export Citation
  • 38

    JohnsonWStovitzSDChohACCzerwinskiSATowneBDemerathEW.Patterns of linear growth and skeletal maturation from birth to 18 years of age in overweight young adults. International Journal of Obesity201236535541. (doi:10.1038/ijo.2011.238)

    • Search Google Scholar
    • Export Citation
  • 39

    FennoyI.Effect of obesity on linear growth. Opinion in Endocrinology Diabetes and Obesity2013204449. (doi:10.1097/MED.0b013e32835b7f15)

    • Search Google Scholar
    • Export Citation
  • 40

    PapadimitriouANicolaidouPFretzayasAChrousosGP.Clinical review: constitutional advancement of growth, a.k.a. early growth acceleration, predicts early puberty and childhood obesity. Journal of Clinical Endocrinology and Metabolism20109545354541. (doi:10.1210/jc.2010-0895)

    • Search Google Scholar
    • Export Citation
  • 41

    GarroneSRadettiGSidotiMBozzolaMMinutoFBarrecaA. Increased insulin-like growth factor (IGF)-II and IGF/IGF-binding protein ratio in prepubertal constitutionally tall children.Journal of Clinical Endocrinology and Metabolism20028754555460. (doi:10.1210/jc.2002-020614)

    • Search Google Scholar
    • Export Citation
  • 42

    GrothKASkakkebækAHøstCGravholtCHBojesenA. Clinical review: Klinefelter syndrome – a clinical update. Journal of Clinical Endocrinology and Metabolism2013982030. (doi:10.1210/jc.2012-2382)

    • Search Google Scholar
    • Export Citation
  • 43

    WikströmAMDunkelL.Klinefelter syndrome. Best Practice & Research Clinical Endocrinology & Metabolism201125239250. (doi:10.1016/j.beem.2010.09.006)

    • Search Google Scholar
    • Export Citation
  • 44

    OttesenAMAksglaedeLGarnITartagliaNTassoneFGravholtCHBojesenASørensenKJørgensenNRajpert-De MeytsEIncreased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. American Journal of Medical Genetics2010152A12061212. (doi:10.1002/ajmg.a.33334)

    • Search Google Scholar
    • Export Citation
  • 45

    OtterMSchrander-StumpelCTCurfsLM.Triple X syndrome: a review of the literature. European Journal of Human Genetics201018265271. (doi:10.1038/ejhg.2009.109)

    • Search Google Scholar
    • Export Citation
  • 46

    TartagliaNRHowellSSutherlandAWilsonRWilsonL.A review of trisomy X (47,XXX). Orphanet Journal of Rare Diseases201058. (doi:10.1186/1750-1172-5-8)

    • Search Google Scholar
    • Export Citation
  • 47

    WigbyKD’EpagnierCHowellSReicksAWilsonRCordeiroLTartagliaN.Expanding the phenotype of Triple X syndrome: a comparison of prenatal versus postnatal diagnosis. American Journal of Medical Genetics201617028702881. (doi:10.1002/ajmg.a.37688)

    • Search Google Scholar
    • Export Citation
  • 48

    SakaiLYKeeneDRRenardMDe BackerJ.FBN1: the disease-causing gene for Marfan syndrome and other genetic disorders. Gene2016591279291. (doi:10.1016/j.gene.2016.07.033)

    • Search Google Scholar
    • Export Citation
  • 49

    LoeysBLDietzHCBravermanACCallewaertBLDe BackerJDevereuxRBHilhorst-HofsteeYJondeauGFaivreLMilewiczDMThe revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics201047476485. (doi:10.1136/jmg.2009.072785)

    • Search Google Scholar
    • Export Citation
  • 50

    Tatton-BrownKRahmanN.Sotos syndrome. European Journal of Human Genetics200715264271. (doi:10.1038/sj.ejhg.5201686)

  • 51

    KurotakiNHaradaNYoshiuraKSuganoSNiikawaNMatsumotoN.Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Gene2001279197204. (doi:10.1016/S0378-1119(01)00750-8)

    • Search Google Scholar
    • Export Citation
  • 52

    ÕunapK. Silver-Russell syndrome & Beckwith-Wiedemann syndrome: opposite phenotypes with heterogeneous molecular etiology.Molecular Syndromology20167110121. (doi:10.1159/000447413)

    • Search Google Scholar
    • Export Citation
  • 53

    ShumanCBeckwithJBWeksbergR.Beckwith-Wiedemann syndrome. In GeneReviews(R). Eds PagonRAAdamMPArdingerHHWallaceSEAmemiyaABeanLJHBirdTDFongCTMeffordHCSmithRJHStephensKSeattle, WA, USA: University of Washington, Seattle. All rights reserved. 1993.

    • Search Google Scholar
    • Export Citation
  • 54

    EggermannTEggermannKSchönherrN.Growth retardation versus overgrowth: Silver-Russell syndrome is genetically opposite to Beckwith-Wiedemann syndrome. Trends in Genetics200824195204. (doi:10.1016/j.tig.2008.01.003)

    • Search Google Scholar
    • Export Citation
  • 55

    LimDBowdinSCTeeLKirbyGABlairEFryerALamWOleyCColeTBruetonLAClinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies. Human Reproduction200924741747. (doi:10.1093/humrep/den406)

    • Search Google Scholar
    • Export Citation
  • 56

    PickerJDLevyHL.Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In GeneReviews(R). Eds RA Pagon MP Adam HH Ardinger SE Wallace A Amemiya LJH Bean TD Bird CT Fong HC Mefford RJH Smith & K Stephens. Seattle WA USA: University of Washington Seattle. All rights reserved. 1993.

    • Search Google Scholar
    • Export Citation
  • 57

    SaulRATarletonJC. FMR1-Related Disorders. In GeneReviews(R). Eds PagonRAAdamMPArdingerHHWallaceSEAmemiyaABeanLJHBirdTDLedbetterNMeffordHCSmithRJHStephensKSeattle, WA, USA: University of Washington, Seattle1993.

    • Search Google Scholar
    • Export Citation
  • 58

    LozanoRAzarangAWilaisakditipakornTHagermanRJ.Fragile X syndrome: a review of clinical management. Intractable & Rare Diseases Research20165145157. (doi:10.5582/irdr.2016.01048)

    • Search Google Scholar
    • Export Citation
  • 59

    KiddSALachiewiczABarbouthDBlitzRKDelahuntyCMcBrienDVisootsakJBerry-KravisE. Fragile X syndrome: a review of associated medical problems. Pediatrics20141349951005. (doi:10.1542/peds.2013-4301)

    • Search Google Scholar
    • Export Citation
  • 60

    LoeschDZHugginsRMHoangNH.Growth in stature in fragile X families: a mixed longitudinal study. American Journal of Medical Genetics199558249256. (doi:10.1002/ajmg.1320580311)

    • Search Google Scholar
    • Export Citation
  • 61

    ButlerMGBrunschwigAMillerLKHagermanRJ.Standards for selected anthropometric measurements in males with the fragile X syndrome. Pediatrics19928910591062.

    • Search Google Scholar
    • Export Citation
  • 62

    StalmanSEPonsAWitJMKampGAPlötzFB.Diagnostic work-up and follow-up in children with tall stature: a simplified algorithm for clinical practice. Journal of Clinical Research in Pediatric Endocrinology20157260267. (doi:10.4274/jcrpe.2220)

    • Search Google Scholar
    • Export Citation
  • 63

    WrightCMCheethamTD.The strengths and limitations of parental heights as a predictor of attained height. Archives of Disease in Childhood199981257260. (doi:10.1136/adc.81.3.257)

    • Search Google Scholar
    • Export Citation
  • 64

    JossEETemperliRMullisPE.Adult height in constitutionally tall stature: accuracy of five different height prediction methods. Archives of Disease in Childhood19926713571362. (doi:10.1136/adc.67.11.1357)

    • Search Google Scholar
    • Export Citation
  • 65

    de WaalWJGreyn-FokkerMHStijnenTvan GurpEAToolensAMde Munick Keizer-SchramaSMAarsenRSDropSL.Accuracy of final height prediction and effect of growth-reductive therapy in 362 constitutionally tall children. Journal of Clinical Endocrinology and Metabolism19968112061216. (doi:10.1210/jc.81.3.1206)

    • Search Google Scholar
    • Export Citation
  • 66

    KatsanisSHKatsanisN.Molecular genetic testing and the future of clinical genomics. Nature Reviews Genetics201314415426. (doi:10.1038/nrg3493)

    • Search Google Scholar
    • Export Citation
  • 67

    de BruinCDauberA.Insights from exome sequencing for endocrine disorders. Nature Reviews Endocrinology201511455464. (doi:10.1038/nrendo.2015.72)

    • Search Google Scholar
    • Export Citation
  • 68

    MillerDTAdamMPAradhyaSBieseckerLGBrothmanARCarterNPChurchDMCrollaJAEichlerEEEpsteinCJConsensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics201086749764. (doi:10.1016/j.ajhg.2010.04.006)

    • Search Google Scholar
    • Export Citation
  • 69

    SchäfgenJCremerKBeckerJWielandTZinkAMKimSWindheuserICKreißMAretzSStromTMDe novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth. European Journal of Human Genetics20162417391745. (doi:10.1038/ejhg.2016.90)

    • Search Google Scholar
    • Export Citation
  • 70

    Thauvin-RobinetCDuplomb-JegoLLimogeFPicotDMasurelATerriatBChampilouCMinotDSt-OngeJKuentzPHomozygous FIBP nonsense variant responsible of syndromic overgrowth, with overgrowth, macrocephaly, retinal coloboma and learning disabilities. Clinical Genetics201689e1e4. (doi:10.1111/cge.12704)

    • Search Google Scholar
    • Export Citation
  • 71

    LuscanALaurendeauIMalanVFrancannetCOdentSGiulianoFLacombeDTouraineRVidaudMPasmantEMutations in SETD2 cause a novel overgrowth condition. Journal of Medical Genetics201451512517. (doi:10.1136/jmedgenet-2014-102402)

    • Search Google Scholar
    • Export Citation
  • 72

    Tarailo-GraovacMShyrCRossCJHorvathGASalvarinovaRYeXCZhangLHBhavsarAPLeeJJDrögemöllerBIExome sequencing and the management of neurometabolic disorders. New England Journal of Medicine201637422462255. (doi:10.1056/NEJMoa1515792)

    • Search Google Scholar
    • Export Citation
  • 73

    YangYMuznyDMXiaFNiuZPersonRDingYWardPBraxtonAWangMBuhayCMolecular findings among patients referred for clinical whole-exome sequencing. JAMA201431218701879. (doi:10.1001/jama.2014.14601)

    • Search Google Scholar
    • Export Citation
  • 74

    LeeJMHowellJD.Tall girls: the social shaping of a medical therapy. Archives of Pediatrics and Adolescent Medicine200616010351039. (doi:10.1001/archpedi.160.10.1035)

    • Search Google Scholar
    • Export Citation
  • 75

    DropSLDe WaalWJDe Muinck Keizer-SchramaSM.Sex steroid treatment of constitutionally tall stature. Endocrine Reviews199819540558. (doi:10.1210/er.19.5.540)

    • Search Google Scholar
    • Export Citation
  • 76

    de WaalWJTornMde Muinck Keizer-SchramaSMAarsenRSDropSL.Long term sequelae of sex steroid treatment in the management of constitutionally tall stature. Archives of Disease in Childhood199573311315. (doi:10.1136/adc.73.4.311)

    • Search Google Scholar
    • Export Citation
  • 77

    RadivojevicUThibaudESamara-BoustaniDDuflosCPolakM.Effects of growth reduction therapy using high-dose 17beta-estradiol in 26 constitutionally tall girls. Clinical Endocrinology200664423428. (doi:10.1111/j.1365-2265.2006.02485.x)

    • Search Google Scholar
    • Export Citation
  • 78

    BinderGGrauerMLWehnerAVWehnerFRankeMB.Outcome in tall stature. Final height and psychological aspects in 220 patients with and without treatment. European Journal of Pediatrics1997156905910. (doi:10.1007/s004310050740)

    • Search Google Scholar
    • Export Citation
  • 79

    DeckerRPartschCJSippellWG.Combined treatment with testosterone (T) and ethinylestradiol (EE2) in constitutionally tall boys: is treatment with T plus EE2 more effective in reducing final height in tall boys than T alone?Journal of Clinical Endocrinology and Metabolism20028716341639. (doi:10.1210/jcem.87.4.8361)

    • Search Google Scholar
    • Export Citation
  • 80

    JossEEZeunerJZurbrüggRPMullisPE.Impact of different doses of ethinyl oestradiol on reduction of final height in constitutionally tall girls. European Journal of Pediatrics1994153797801. (doi:10.1007/BF01972886)

    • Search Google Scholar
    • Export Citation
  • 81

    NormannEKTrygstadOLarsenSDahl-JørgensenK.Height reduction in 539 tall girls treated with three different dosages of ethinyloestradiol. Archives of Disease in Childhood19916612751278. (doi:10.1136/adc.66.11.1275)

    • Search Google Scholar
    • Export Citation
  • 82

    GrütersAHeidemannPSchlüterHStubbePWeberBHelgeH.Effect of different oestrogen doses on final height reduction in girls with constitutional tall stature. European Journal of Pediatrics19891491113. (doi:10.1007/bf02024324)

    • Search Google Scholar
    • Export Citation
  • 83

    BartschOWeschkeBWeberB.Oestrogen treatment of constitutionally tall girls with 0.1 mg/day ethinyl oestradiol. European Journal of Pediatrics19881475963. (doi:10.1007/BF00442613)

    • Search Google Scholar
    • Export Citation
  • 84

    VennAHosmerTHosmerDBruinsmaFJonesPLumleyJPyettPRaynerJAWertherG.Oestrogen treatment for tall stature in girls: estimating the effect on height and the error in height prediction. Clinical Endocrinology200868926929. (doi:10.1111/j.1365-2265.2007.03128.x)

    • Search Google Scholar
    • Export Citation
  • 85

    WeimannEBergmannSBöhlesHJ.Oestrogen treatment of constitutional tall stature: a risk-benefit ratio. Archives of Disease in Childhood199878148151. (doi:10.1136/adc.78.2.148)

    • Search Google Scholar
    • Export Citation
  • 86

    RaskONilssonKOBerntorpE.Oestrogen treatment of constitutional tall stature in girls: is there a risk of thrombosis or bleeding?Acta Paediatrica200897342347. (doi:10.1111/j.1651-2227.2007.00635.x)

    • Search Google Scholar
    • Export Citation
  • 87

    PyettPRaynerJVennABruinsmaFWertherGLumleyJ.Using hormone treatment to reduce the adult height of tall girls: are women satisfied with the decision in later years?Social Science & Medicine20056116291639. (doi:10.1016/j.socscimed.2005.03.016)

    • Search Google Scholar
    • Export Citation
  • 88

    de WaalWJVreeburgJTBekkeringFde JongFHde Muinck Keizer-SchramaSMDropSLWeberRF.High dose testosterone therapy for reduction of final height in constitutionally tall boys: does it influence testicular function in adulthood?Clinical Endocrinology1995438795. (doi:10.1111/j.1365-2265.1995.tb01897.x)

    • Search Google Scholar
    • Export Citation
  • 89

    HendriksAEBoellaardWPvan CasterenNJRomijnJCde JongFHBootAMDropSL.Fatherhood in tall men treated with high-dose sex steroids during adolescence. Journal of Clinical Endocrinology and Metabolism20109552335240. (doi:10.1210/jc.2010-0435)

    • Search Google Scholar
    • Export Citation
  • 90

    LemckeBZentgrafJBehreHMKlieschSBramswigJHNieschlagE.Long-term effects on testicular function of high-dose testosterone treatment for excessively tall stature. Journal of Clinical Endocrinology and Metabolism199681296301. (doi:10.1210/jcem.81.1.8550767)

    • Search Google Scholar
    • Export Citation
  • 91

    HendriksAELavenJSValkenburgOFongSLFauserBCde RidderMAde JongFHVisserJAvan GinnekenAMBootAMFertility and ovarian function in high-dose estrogen-treated tall women. Journal of Clinical Endocrinology and Metabolism20119610981105. (doi:10.1210/jc.2010-2244)

    • Search Google Scholar
    • Export Citation
  • 92

    HendriksAEDropSLLavenJSBootAM.Fertility of tall girls treated with high-dose estrogen, a dose-response relationship. Journal of Clinical Endocrinology and Metabolism20129731073114. (doi:10.1210/jc.2012-1078)

    • Search Google Scholar
    • Export Citation
  • 93

    VennABruinsmaFWertherGPyettPBairdDJonesPRaynerJLumleyJ.Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility. Lancet200436415131518. (doi:10.1016/S0140-6736(04)17274-7)

    • Search Google Scholar
    • Export Citation
  • 94

    LouhialaP.On the ethics of oestrogen treatment for tall girls: an update. J Med Ethics200935713714. (doi:10.1136/jme.2009.030189)

  • 95

    HindmarshPCPringlePJBrookCG.Cholinergic muscarinic blockade produces short-term suppression of growth hormone secretion in children with tall stature. Clinical Endocrinology198829289296. (doi:10.1111/j.1365-2265.1988.tb01227.x)

    • Search Google Scholar
    • Export Citation
  • 96

    SchoenleEJTheintzGTorresaniTPraderAIlligRSizonenkoPC.Lack of bromocriptine-induced reduction of predicted height in tall adolescents. Journal of Clinical Endocrinology and Metabolism198765355358. (doi:10.1210/jcem-65-2-355)

    • Search Google Scholar
    • Export Citation
  • 97

    NoordamCvan DaalenSOttenBJ.Treatment of tall stature in boys with somatostatin analogue 201–995: effect on final height. European Journal of Endocrinology2006154253257. (doi:10.1530/eje.1.02087)

    • Search Google Scholar
    • Export Citation
  • 98

    CarelJCBlumbergJBougeard-JulienMRochiccioliPChaussainJLTauberMGroupLiTSS.Long-acting lanreotide in adolescent girls with constitutional tall stature. Hormone Research200971228236. (doi:10.1159/000201112)

    • Search Google Scholar
    • Export Citation
  • 99

    BenyiEBernerMBjernekullIBomanAChrysisDNilssonOWaehreAWehtjeHSävendahlL.Efficacy and safety of percutaneous epiphysiodesis operation around the knee to reduce adult height in extremely tall adolescent girls and boys. International Journal of Pediatric Endocrinology20102010740629. (doi:10.1186/1687-9856-2010-740629)

    • Search Google Scholar
    • Export Citation
  • 100

    OdinkRJGerverWJHeegMRouwéCWvan WaardeWMSauerPJ.Reduction of excessive height in boys by bilateral percutaneous epiphysiodesis around the knee. European Journal of Pediatrics20061655054. (doi:10.1007/s00431-005-1722-z)

    • Search Google Scholar
    • Export Citation
  • 101

    IravaniMLagerquistMOhlssonCSävendahlL.Regulation of bone growth via ligand-specific activation of estrogen receptor alpha. Journal of Endocrinology2017232403410. (doi:10.1530/JOE-16-0263)

    • Search Google Scholar
    • Export Citation
  • 102

    VidalOLindbergMKHollbergKBaylinkDJAnderssonGLubahnDBMohanSGustafssonJAOhlssonC.Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. PNAS20009754745479. (doi:10.1073/pnas.97.10.5474)

    • Search Google Scholar
    • Export Citation
  • 103

    ChaginASKarimianEZamanFTakigawaMChrysisDSävendahlL.Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones. Bone20074014151424. (doi:10.1016/j.bone.2006.12.066)

    • Search Google Scholar
    • Export Citation
  • 104

    NilssonOFalkJRitzénEMBaronJSävendahlL.Raloxifene acts as an estrogen agonist on the rabbit growth plate. Endocrinology200314414811485. (doi:10.1210/en.2002-221108)

    • Search Google Scholar
    • Export Citation
  • 105

    NishimuraGMugishimaHHiraoJYamatoM.Generalized metaphyseal modification with cone-shaped epiphyses following long-term administration of 13-cis-retinoic acid. European Journal of Pediatrics1997156432435. (doi:10.1007/s004310050631)

    • Search Google Scholar
    • Export Citation
  • 106

    PrendivilleJBinghamEABurrowsD.Premature epiphyseal closure – a complication of etretinate therapy in children. Journal of American Academy of Dermatology19861512591262. (doi:10.1016/S0190-9622(86)70300-9)

    • Search Google Scholar
    • Export Citation
  • 107

    NoyesJJLevineMABelascoJBMostoufi-MoabS.Premature epiphyseal closure of the lower extremities contributing to short stature after cis-retinoic acid therapy in medulloblastoma: a case report. Hormone Research in Paediatrics2016856973. (doi:10.1159/000441140)

    • Search Google Scholar
    • Export Citation
  • 108

    DiGiovannaJJ.Isotretinoin effects on bone. Journal of American Academy of Dermatology200145S176S182. (doi:10.1067/mjd.2001.113721)

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 2108 1918 110
PDF Downloads 1156 1127 82

Altmetrics

Figures

  • View in gallery

    Representative growth chart of the main patterns observed in individuals with overgrowth conditions: (A) a patient that grows above 2 s.d. throughout childhood and reaches an adult height above 2 s.d., but consistent with his/her target height; (B) a patient that crosses through higher percentiles during childhood, reaching an adult height above 2 s.d. and above his/her target height; (C) a patient that has tall stature during childhood, but has an accelerated bone maturation and reaches a normal adult height (solid line) or even a stature below the normal range in adulthood (dashed line) and (D) a patient with normal height during childhood who has a prolonged growth beyond adolescence, resulting in an adult height above 2 s.d.

  • View in gallery

    Suggested diagnostic flow chart for evaluation of patients referred for tall stature and the main differential diagnoses. (CAG = constitutional advance of growth; BWS = Beckwith–Wiedemann syndrome).

Cited By

PubMed

Google Scholar