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Review
Overgrowth
  1. Charles F Verge1,3,
  2. David Mowat2,3
  1. 1Department of Endocrinology, Sydney Children's Hospital, Randwick, Australia
  2. 2Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia
  3. 3School of Women's and Children's Health, University of New South Wales, Sydney, Australia
  1. Correspondence to Dr Charles Verge, Department of Endocrinology, Sydney Children's Hospital, High Street, Randwick NSW 2031, Australia; c.verge{at}unsw.edu.au

Abstract

Overgrowth presenting at birth requires blood glucose monitoring while a cause is sought. Among older children presenting with tall stature, common causes such as familial tall stature and simple obesity must be distinguished from rarer endocrine and genetic causes. Several genetic overgrowth syndromes carry increased risk of malignancy and regular screening is recommended. The use of high-dose oestrogen or testosterone in an attempt to limit final stature has limited efficacy and carries a significant risk of side effects. Endocrine and genetic assessment ought to be considered for cases of unexplained overgrowth.

https://doi.org/10.1136/adc.2009.157693

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    Introduction

    Overgrowth may come to medical attention at birth, in which case attention to blood glucose monitoring and consideration of a possible syndromic diagnosis are important. Many of these conditions have normal growth parameters in adult life. Alternatively postnatal overgrowth may present as a tall child, in which case normal variants such as familial tall stature and obesity must be distinguished from much rarer entities, including endocrine and genetic causes. Overgrowth should be considered in term infants with birth weight greater than 4.5 kg, or in older children with height greater than the 99th percentile (approximately 2.33 SD above the mean) and/or growing above the midparental target height (defined below).

    Diagnosis

    Normal variants

    Familial tall stature

    Children with familial or constitutional tall stature have predicted adult height (determined from bone age and current height, with reference to the Bayley–Pinneau tables1) in keeping with their midparental height. Midparental height is calculated as the average of the parents' heights, minus 6.5 cm for girls, or plus 6.5 cm for boys2 (although in the UK ±7 cm may be used). If possible, parental heights should be measured rather than reported. Ninety-five per cent of healthy offspring have final height within 10 cm of their midparental height.2 Height velocity should be calculated from two accurate measurements, spaced at least 6 months apart. This is usually within the normal range. Dickerman et al found that height velocity in familial tall stature accelerated into the upper part of the normal range, or just above it, during early childhood, slowed after 4–5 years of age, and then tracked near the 50th percentile until age 9 years.3 Physical examination is normal. Bone age is variable in familial tall stature and is useful for final height prediction. Presentation with tall stature is uncommon in healthy boys, compared with girls, and the frequency of presentation overall has declined over the last 10 years, probably reflecting greater social acceptance of tall stature in females.

    Obesity

    With the exception of certain pathological causes (eg, Prader Willi syndrome, Albright's hereditary osteodystrophy and Cushing syndrome), obese children are commonly tall although final height is appropriate for genetic background. This may relate to the advanced bone age, earlier adrenarche4 and earlier puberty5 in obesity. Wells et al found that obese children are, on average, 0.6 SD taller than normal weight controls and have pubertal stage 0.4 more advanced on the Tanner scale.6

    Endocrine causes

    Infant of a diabetic mother and hyperinsulinism of infancy

    The possibility of maternal diabetes ought to be explored in infants born large for gestational age (greater than 4.5 kg at term). An antenatal oral glucose tolerance test may have been abnormal, or there may have been maternal glycosuria, consistent with gestational diabetes. Macrosomia is explained by the fact that insulin is an important prenatal growth factor, whereas growth hormone becomes more important in infancy. The fetus exposed to a poorly controlled diabetic pregnancy responds with increased insulin secretion. Such an infant is large for gestational age, may have organomegaly (including cardiac hypertrophy) and is at risk for postnatal hypoglycaemia until the β cells adjust to a non-diabetic environment. By age 7 years, infants of diabetic mothers are significantly heavier than normal controls but have normal height.7 They also have increased risk of developing type 2 diabetes in later life, in part explained by exposure to the diabetic environment in utero, independent of any genetic predisposition.8 Infants carrying an HNF4A gene mutation (one of at least eight genes causing maturity-onset diabetes of the young (MODY)) may paradoxically have insulin excess as neonates, with macrosomia and transient hyperinsulinaemic hypoglycaemia (even if their mother is unaffected by MODY).9 Such infants then develop relative insulin deficiency (MODY) in later life. Infants with persistent hyperinsulinaemic hypoglycaemia10 may also be large for gestational age, but usually come to medical attention because of severe hypoglycaemia in the first few days of life rather than overgrowth.

    Precocious puberty and congenital adrenal hyperplasia

    Precocious puberty (due to early activation of the hypothalamic–pituitary–gonadal axis) and congenital adrenal hyperplasia should be considered. They can usually be excluded by physical examination and bone age. Physical examination should include Tanner pubertal staging and assessment of testicular volume in boys by comparison with an orchidometer (prepubertal size <4 ml). Late presenting congenital adrenal hyperplasia usually manifests with precocious pubic hair, tall stature and increased height velocity. Occasionally pubic hair may be absent at initial presentation, but these cases can be detected by finding markedly advanced bone age and elevated 17-OH progesterone level in blood. Without treatment, final height may be impaired due to early epiphysial fusion.

    Growth hormone excess

    Growth hormone excess is very rare in children, but is reported in the literature as a series of case reports, usually due to growth hormone secreting pituitary adenomas (reviewed in ref 11). In children, prior to epiphysial fusion, the result is pituitary gigantism, with tall stature and markedly increased height velocity. Onset in adult life presents with the coarse features of acromegaly. Adolescents may show a mixed picture of increased height velocity and some acromegalic features (such as enlargement of the jaw, hands and feet). Insulin-like growth factor 1 (IGF-1) levels are elevated, reflecting increased growth hormone secretion. IGF-1 levels must be interpreted with the caveat that normal individuals show a marked rise during puberty, and that most laboratories provide reference ranges related to age rather than to pubertal stage. In addition, children with obesity or constitutional tall stature have normal-high IGF-1 levels and increased IGF-1 response to an injection of growth hormone, compared with average-stature controls.12

    Analysis of growth hormone levels requires serial sampling every 20 min, as normal growth hormone secretion is characterised by low basal levels with intermittent peaks. Absent suppression of growth hormone during an oral glucose tolerance test does not appear to be a good discriminator in paediatrics as 31% of tall normal children and adolescents fail to suppress.13 MRI with specific pituitary views should be performed in all cases of growth hormone excess. In about half of cases the tumour also secretes prolactin, which may result in galactorrhoea. Puberty may be delayed, due to prolactin excess or to pressure effects on the pituitary gonadotropes. The presence of multiple café au lait spots in a patient with growth hormone excess suggests the McCune Albright syndrome of multiple endocrine gland hyperfunction. Final height is increased in pituitary gigantism. Of note, a discordant identical twin pair has been reported.14 The affected twin developed growth hormone excess from age 13 years and reached final height markedly greater than his unaffected co-twin, demonstrating that exposure to massively elevated growth hormone levels prior to epiphysial fusion increases final height. Treatment approaches include somatostatin analogues such as octreotide, dopamine agonists such as cabergoline, surgery and radiotherapy.

    Other endocrine causes

    Pseudoacromegaly presents a similar clinical picture to growth hormone excess, however growth hormone levels are normal and insulin or other growth factors are present in excess.15 Familial glucocorticoid deficiency (adrenocorticotropic hormone resistance causing glucocorticoid but not mineralocorticoid deficiency) presents with adrenal failure but normal electrolytes. This condition is associated with relatively tall stature that lessens on glucocorticoid treatment,16 suggesting a possible role for adrenocorticotropic hormone and its receptor in growth. Children with hyperthyroidism also have increased linear growth, although this is not a major part of the clinical picture.

    Genetic syndromes

    The presence of dysmorphic features may suggest a specific overgrowth syndrome (table 1). Tall stature is not an invariant feature of these syndromes. The final height in a number of these, such as Beckwith–Wiedemann and Sotos syndromes, may be less than predicted as puberty often has an earlier onset.

    View this table:
    Table 1

    Genetic overgrowth syndromes

    Beckwith–Wiedemann syndrome

    Beckwith–Wiedemann syndrome (BWS) has an incidence of 1 in 13 000 and often presents at birth with omphalocele or umbilical hernia, macrosomia and macroglossia (figure 1). Other associated features include hyperinsulinaemic hypoglycaemia, hemihyperplasia, organomegaly and ear pits or creases. It is caused by gene dosage abnormalities of 11p15 and increased expression of the IGF-2 gene has been implicated. In some patients there is a physical copy number excess (eg, duplication of the paternally derived 11p15 region). More commonly there is a normal physical copy number but increased expression due to imprinting anomalies (table 2). In the absence of extended periods of hypoglycaemia, mental and social development is normal compared with unaffected siblings.17 There is an increased risk of developing childhood neoplasms particularly Wilms tumour and hepatoblastoma (∼7.5%). It is recommended that abdominal ultrasound surveillance take place every 3 months until age 5 and then 4 monthly until age 8, by which time the tumour risk is similar to the population risk.18 Three monthly serum α-fetoprotein (αFP) measurement to screen for hepatoblastoma is recommended by some groups until the age of 5 years.19 Independent risk factors for tumours include nephromegaly and hemihyperplasia. The effect on tumour risk of hormone treatment to limit growth is unknown therefore caution is recommended. Molecular testing for KvDMR1 loss of methylation, and unipaternal disomy 11p is available in many centres and may help stratify the tumour risk (see table 2).

    Figure 1
    Figure 1

    Beckwith–Wiedemann syndrome. (A) Macroglossia. (B) Helical ear pits and transverse creases of the lobe. (C) Omphalocele.

    View this table:
    Table 2

    Beckwith–Wiedemann syndrome molecular subgroups and tumour risk

    Sotos syndrome

    Sotos syndrome is an overgrowth condition characterised by prenatal overgrowth, excessive growth during childhood, macrocephaly, distinctive facial gestalt, learning disability, advanced bone age and variable minor features (scoliosis, hypotonia in infancy, cardiac defects, genitourinary anomalies). Although data are limited, height may normalise after puberty in females, but probably not in males. Mutations and deletions of the NSD1 gene are responsible for over 90% of cases.20 This gene is located at chromosome 5q35 and codes for a histone methyltransferase implicated in transcription regulation. Investigations include chromosomes, multiplex ligation-dependent probe amplification looking for 5q35 deletion, followed by NSD1 sequencing. The majority of cases are sporadic, caused by de novo mutations, with rare familial cases also reported. The exact prevalence is unknown but hundreds of cases have been reported. There may be some overlap between BWS and Sotos phenotypes, leading to diagnostic errors. Baujat et al sequenced NSD1 in 52 patients previously given a clinical diagnosis of BWS and found mutations in two, one of whom had persistent hyperinsulinaemic hypoglycaemia.21 Conversely they found 11p15 anomalies in two of 20 patients previously given a clinical diagnosis of Sotos syndrome. Tumour risk is relatively low in Sotos syndrome (2.2%) based on a series of 224 cases.22 The tumours include sacrococcygeal teratoma, neuroblastoma, leukaemia and lymphoma.20 23 Specific tumour screening other than clinical assessment every year is not usually recommended.

    Perlman syndrome

    Perlman syndrome is an autosomal recessive overgrowth syndrome characterised by fetal gigantism, visceromegaly, unusual face, bilateral renal hamartomas with nephroblastomatosis and Wilms tumour. Some reported cases turned out to have 11p abnormalities and probably have BWS. Wilms tumour is the only reported malignancy, so renal ultrasound is warranted. The molecular basis of this syndrome has not been identified.

    Simpson–Golabi–Behmel syndrome

    Simpson–Golabi–Behmel (SGB) is an X linked condition caused by mutations or deletions in the glypican 3 (GPC3) gene. This gene is expressed in embryonic mesoderm where it is thought to play an important role in growth control. SGB is characterised by prenatal and postnatal overgrowth, organomegaly, coarse facies, macroglossia and variable learning disability. Adult height is often excessive. Three monthly abdominal tumour surveillance by ultrasound and urinalysis is recommended until 8 years of age in mutation positive cases.24 Serum αFP analysis is recommended three monthly until the age of 4 years.

    Bannayan–Riley–Ruvalcaba syndrome

    Bannayan–Riley–Ruvalcaba syndrome describes a clinical phenotype of macrocephaly (>98th centile), lipomatosis, haemangiomas, penile macules and intestinal hamartomas. It is caused by dominant mutations in the PTEN gene on chromosome 10. Phosphatase and tensin homolog (PTEN) plays a role in suppressing cell growth and tumourigenicity. Cowden syndrome, an adult-onset cancer syndrome, is an allelic disorder (ie, caused by mutations in the same gene). At present the tumour surveillance recommendations for mutation positive cases with Bannayan–Riley–Ruvalcaba phenotype are unclear although the same protocol as for Cowden syndrome ought to be followed. Adult final height is usually normal.25

    Weaver syndrome

    Weaver syndrome is characterised by increased prenatal and postnatal weight, accelerated growth, advanced bone age, camptodactyly, characteristic facial appearance and developmental delay.18 While Wilms tumour has been reported, ultrasound surveillance is currently not recommended. The molecular basis of this syndrome has not been identified.

    Marfan syndrome and related disorders

    Marfan syndrome is a connective tissue disorder with skeletal manifestations that include tall stature, arachnodactyly, scoliosis and hyperextensible joints. The limbs are disproportionately long compared with the trunk, resulting in increased armspan and decreased upper to lower body segment ratio. Final height is increased, averaging 197.1 and 177.1 cm in a group of untreated males and females respectively, and 196.4 and 181.5 cm in groups treated with high-dose testosterone or oestrogen.26 Ocular features, such as lens dislocation, carry a risk of retinal detachment, glaucoma and cataract formation. Cardiovascular manifestations carry a risk of valve prolapse and aortic rupture. Detailed diagnostic criteria based on clinical findings have been proposed.27 Management involves a team including geneticist, cardiologist, ophthalmologist and orthopaedic surgeon. Inheritance is autosomal dominant with most cases explained by mutation of the fibrillin 1 gene (FBN1). This is a very large gene with more than 400 different mutations described, increasing the cost and complexity of molecular diagnosis. Exact molecular diagnosis may be helpful to define the risk of certain features developing. For example, exon 24–32 mutations have been reported to carry increased risk for severe cardiac manifestations.28

    Loeys–Dietz syndrome (also known as Marfan syndrome type II) is caused by mutations in the TGFBR1 or TGFBR2 genes (transforming growth factor β receptors 1 and 2). Affected patients share many of the features of Marfan syndrome, except for lens dislocation. Aortic root dilatation, if present, tends to progress rapidly.

    Homocystinuria has features similar to Marfan syndrome, but is differentiated by the presence of mental retardation, homocystine in the urine and predisposition to thromboembolic events. Homocystinuria is caused by mutation in the gene for cystathione synthase and has autosomal recessive inheritance.

    Beals syndrome (congenital contractural arachnodactyly) is due to autosomal dominant mutation in the FBN2 gene. The clinical features differ from Marfan syndrome in that patients have finger contractures and abnormal ‘crumpled’ ears at birth.

    Sex chromosome aneuploidies, including Klinefelter syndrome

    A karyotype should be performed if clinical features in a tall boy suggest the possibility of sex chromosome aneuploidy. These include small firm testes, pubertal failure or arrest, gynaecomastia and variable cognitive/behavioural problems with difficulties in language, problem solving and planning (reviewed in ref 29). Most are 47XXY Klinefelter syndrome (80%), but other forms include 48,XXXY, 48,XXYY, 49XXXXY and 46XY/47XXY mosaicism. The reported population prevalence of Klinefelter syndrome is between one in 500 and one in 1000. The phenotype is variable however, and many cases probably remain undiagnosed (64% according to one estimate). Aksglaede reported the median final height of 43 adults with 47XXY as 186.8 cm, with a range from 176.2 to 206.9 cm.30 The tall stature is mainly due to increased leg length, but arm span is not increased. Overdosage of the SHOX gene (short stature homeobox containing gene on X), which affects skeletal growth, may explain the tall stature in Klinefelter syndrome as well as in 47XXX females31 (while haploinsufficiency explains the short stature in Turner syndrome 45X). The germ cells in Klinefelter patients have shortened lifespan and fail to divide in the presence of the extra X chromosome, explaining the small testes and infertility. The mechanism of the androgen deficiency is unclear. Testosterone levels may increase during puberty allowing some virilisation, but pubertal progression frequently arrests and adult testosterone levels are subnormal. Follicle-stimulating hormone & luteinising hormone are elevated after the expected time of puberty, due to primary testicular failure. Although the parents of Klinefelter boys with more severe behavioural disturbance may be reluctant, testosterone replacement is usually required from the time of puberty onwards to prevent the immediate symptoms and long-term effects of androgen deficiency (including low bone density). Testosterone replacement has no effect however on infertility.

    Management issues

    Hypoglycaemia

    Newborn infants with birth weight >4.5 kg should have their blood glucose monitored closely and hypoglycaemia must be aggressively treated to prevent cognitive damage. Hyperinsulinaemic hypoglycaemia occurs in about 50% of infants with BWS, is usually responsive to extra feeds or intravenous dextrose, and usually resolves spontaneously during the neonatal period (reviewed in ref 32). Occasionally the hypoglycaemia persists beyond the neonatal period and in these cases may respond to treatment with diazoxide. Diazoxide acts by inhibiting the suphonylurea receptor (encoded by SUR1) on the surface of the pancreatic β cell, thereby inhibiting insulin secretion. The exact mechanism causing deranged regulation of insulin secretion in BWS remains to be fully elucidated, but islet hyperplasia has been documented.32 Analysis of pancreatic islets from one persistent case that failed to respond to diazoxide and required partial pancreatectomy found some evidence for a trafficking defect in SUR1, which is located within 11p15.33 Patients with other forms of congenital hyperinsulinism may develop diabetes mellitus in later life, but this has not been described in BWS.

    Tumour surveillance

    The aim of surveillance is to detect tumours at an early stage, allowing earlier treatment and improved prognosis as a consequence. Current recommendations for the frequency of screening are based on limited data and may be revised as more data become available. The risk of Wilms tumour development in BWS and SGB syndrome is greatest in the first 8 years of life. While the risk of Wilms tumour can be stratified according to the underlying mechanism in BWS, surveillance is still recommended for all BWS cases unless future clinical data confirm that this is not necessary. If molecular testing is available for BWS then this ought to be undertaken. Hepatoblastoma, a rare tumour with a population incidence of one in 1 000 000, has an increased frequency in the first 4 years of life in BWS and SGB syndrome. Therefore, many clinicians recommend liver ultrasound and αFP measurement (blood spot) every 3–4 months up until the age of 4 years. Whether this is justified or not remains controversial. The discussion of tumour surveillance (abdominal ultrasound ± αFP measurement) often leads to a period of parental anxiety. A six monthly clinical examination by a medical professional is recommended as this often provides extra support for the family. Physical examination by the parents at home is discouraged. In our experience most families adhere to ultrasound surveillance successfully once tumour surveillance has been raised but are less inclined for their child to have three monthly blood tests for αFP measurement. Further prospective clinical studies will hopefully provide better information to help target screening to the most ‘at risk’ population.

    Treatment aimed at limiting adult stature

    The use of high-dose oestrogen or testosterone in an attempt to limit the final height of tall children by accelerating puberty and epiphysial fusion increased after the 1950s but has now become infrequent. This may be due partly to concern about side effects, partly due to limited effectiveness, and partly because of a change in societal attitude to tall stature. Weight gain, nausea and pigmentation of the areolae are the most common short-term side effects reported with high-dose oestrogen,34 while thrombosis is uncommon but serious.35 More recently, long-term side effects have been reported in a large retrospective cohort study. Venn et al interviewed a cohort of women (mean age 40 years) who had been assessed for tall stature in adolescence. Those who had been treated with high-dose oestrogen reported higher rates of infertility and took a longer time to conceive than those who were not treated.36 Ninety-nine per cent of untreated women were glad that they had not been treated, while 42% of treated women regretted treatment, with no relationship between final height and satisfaction.37 Whether high-dose oestrogen therapy increases the rates of malignancy in oestrogen responsive tissues remains unknown. Short-term side effects of high-dose testosterone therapy in boys (given by weekly or second-weekly injections) include severe acne and gynaecomastia. Although early reports with relatively small numbers suggested that treatment may be effective, a study of 249 children treated for constitutional tall stature (159 girls and 60 boys) found no clinically significant effect.38 Treatment started at an average age of 12.7 years. The change in final height (attained final height compared with predicted adult height determined from bone age at baseline) varied from 2.4 cm reduction to 0.6 cm increase in girls, and from 0.3 cm reduction to 0.5 cm increase in boys. A similar but smaller study in Marfan syndrome26 found no significant effect in girls, but a 5.5 cm reduction in boys (95% CI, 1 to 10 cm). Recently a preliminary report from Sweden described surgical growth plate fusion, involving bilateral epiphysiodesis around the knee, without significant side effects or abnormal body proportions.39

    References

    1. ↵
      1. Bayley N,
      2. Pinneau SR
      . Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr 1952;40: 423–41.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Larsen PR
      1. Reiter EO,
      2. Rosenfeld RG
      . Normal and aberrant growth. In: Larsen PR, ed. Williams Textbook of Endocrinology. Philadelphia, Pennsylvania, USA: Saunders, 2003:1008.
    3. ↵
      1. Dickerman Z,
      2. Loewinger J,
      3. Laron Z
      . The pattern of growth in children with constitutional tall stature from birth to age 9 years. A longitudinal study. Acta Paediatr Scand 1984;73:530–6.
      OpenUrlPubMedWeb of Science
    4. ↵
      1. Neville KA,
      2. Walker JL
      . Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity. Arch Dis Child 2005;90:258–61.
      OpenUrlAbstract/FREE Full Text
    5. ↵
      1. Kaplowitz PB,
      2. Slora EJ,
      3. Wasserman RC,
      4. et al
      . Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001;108:347–53.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Wells JC,
      2. Fewtrell MS,
      3. Williams JE,
      4. et al
      . Body composition in normal weight, overweight and obese children: matched case-control analyses of total and regional tissue masses, and body composition trends in relation to relative weight. Int J Obes (Lond) 2006;30:1506–13.
      OpenUrlCrossRefPubMed
    7. ↵
      1. Touger L,
      2. Looker HC,
      3. Krakoff J,
      4. et al
      . Early growth in offspring of diabetic mothers. Diabetes Care 2005;28:585–9.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Salbe AD,
      2. Lindsay RS,
      3. Collins CB,
      4. et al
      . Comparison of plasma insulin levels after a mixed-meal challenge in children with and without intrauterine exposure to diabetes. J Clin Endocrinol Metab 2007;92:624–8.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Pearson ER,
      2. Boj SF,
      3. Steele AM,
      4. et al
      . Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4:e118.
      OpenUrlCrossRefPubMed
    10. ↵
      1. Stanley CA
      . Advances in diagnosis and treatment of hyperinsulinism in infants and children. J Clin Endocrinol Metab 2002;87:4857–9.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Daughaday WH
      . Pituitary gigantism. Endocrinol Metab Clin North Am 1992;21:633–47.
      OpenUrlPubMedWeb of Science
    12. ↵
      1. Bouhours-Nouet N,
      2. Gatelais F,
      3. Boux de Casson F,
      4. et al
      . The insulin-like growth factor-I response to growth hormone is increased in prepubertal children with obesity and tall stature. J Clin Endocrinol Metab 2007;92:629–35.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Holl RW,
      2. Bucher P,
      3. Sorgo W,
      4. et al
      . Suppression of growth hormone by oral glucose in the evaluation of tall stature. Horm Res 1999;51:20–4.
      OpenUrlPubMedWeb of Science
    14. ↵
      1. Gagel RF,
      2. McCutcheon IE
      . Images in clinical medicine. Pituitary gigantism. N Engl J Med 1999;340:524.
      OpenUrlCrossRefPubMed
    15. ↵
      1. Srinivasan S,
      2. Waters MJ,
      3. Rowland JE,
      4. et al
      . Hyperinsulinism and overgrowth without obesity. Arch Dis Child 2003;88:332–4.
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Elias LL,
      2. Huebner A,
      3. Metherell LA,
      4. et al
      . Tall stature in familial glucocorticoid deficiency. Clin Endocrinol (Oxf) 2000;53:423–30.
      OpenUrlCrossRefPubMed
    17. ↵
      1. Weng EY,
      2. Moeschler JB,
      3. Graham JM Jr
      . Longitudinal observations on 15 children with Wiedemann-Beckwith syndrome. Am J Med Genet 1995;56:366–73.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Lapunzina P
      . Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet 2005;137C:53–71.
      OpenUrlPubMed
    19. ↵
      1. Clericuzio CL,
      2. Chen E,
      3. McNeil DE,
      4. et al
      . Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 2003;143:270–2.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Tatton-Brown K,
      2. Rahman N
      . Sotos syndrome. Eur J Hum Genet 2007;15:264–71.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Baujat G,
      2. Rio M,
      3. Rossignol S,
      4. et al
      . Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am J Hum Genet 2004;74:715–20.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Hersh JH,
      2. Cole TR,
      3. Bloom AS,
      4. et al
      . Risk of malignancy in Sotos syndrome. J Pediatr 1992;120:572–4.
      OpenUrlPubMedWeb of Science
    23. ↵
      1. Martínez-Glez V,
      2. Lapunzina P
      . Sotos syndrome is associated with leukemia/lymphoma. Am J Med Genet A 2007;143A:1244–5.
      OpenUrlCrossRefPubMed
    24. ↵
      1. Scott RH,
      2. Walker L,
      3. Olsen ØE,
      4. et al
      . Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child 2006;91:995–9.
      OpenUrlAbstract/FREE Full Text
    25. ↵
      1. Lachlan KL,
      2. Lucassen AM,
      3. Bunyan D,
      4. et al
      . Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 2007;44:579–85.
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Rozendaal L,
      2. le Cessie S,
      3. Wit JM,
      4. et al
      . Growth-reductive therapy in children with marfan syndrome. J Pediatr 2005;147:674–9.
      OpenUrlCrossRefPubMed
    27. ↵
      1. De Paepe A,
      2. Devereux RB,
      3. Dietz HC,
      4. et al
      . Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417–26.
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Faivre L,
      2. Collod-Beroud G,
      3. Loeys BL,
      4. et al
      . Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007;81:454–66.
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Lanfranco F,
      2. Kamischke A,
      3. Zitzmann M,
      4. et al
      . Klinefelter's syndrome. Lancet 2004;364:273–83.
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Aksglaede L,
      2. Skakkebaek NE,
      3. Juul A
      . Abnormal sex chromosome constitution and longitudinal growth: serum levels of insulin-like growth factor (IGF)-I, IGF binding protein-3, luteinizing hormone, and testosterone in 109 males with 47,XXY, 47,XYY, or sex-determining region of the Y chromosome (SRY)-positive 46,XX karyotypes. J Clin Endocrinol Metab 2008;93:169–76.
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Ogata T,
      2. Matsuo N,
      3. Nishimura G
      . SHOX haploinsufficiency and overdosage: impact of gonadal function status. J Med Genet 2001;38:1–6.
      OpenUrlAbstract/FREE Full Text
    32. ↵
      1. Munns CF,
      2. Batch JA
      . Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed 2001;84:F67–9.
      OpenUrlFREE Full Text
    33. ↵
      1. Hussain K,
      2. Cosgrove KE,
      3. Shepherd RM,
      4. et al
      . Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels. J Clin Endocrinol Metab 2005;90:4376–82.
      OpenUrlCrossRefPubMed
    34. ↵
      1. de Waal WJ,
      2. Torn M,
      3. de Muinck Keizer-Schrama SM,
      4. et al
      . Long term sequelae of sex steroid treatment in the management of constitutionally tall stature. Arch Dis Child 1995;73:311–15.
      OpenUrlAbstract/FREE Full Text
    35. ↵
      1. Werder EA,
      2. Waibel P,
      3. Sege D,
      4. et al
      . Severe thrombosis during oestrogen treatment for tall stature. Eur J Pediatr 1990;149:389–90.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Venn A,
      2. Bruinsma F,
      3. Werther G,
      4. et al
      . Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility. Lancet 2004;364:1513–18.
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      1. Pyett P,
      2. Rayner J,
      3. Venn A,
      4. et al
      . Using hormone treatment to reduce the adult height of tall girls: are women satisfied with the decision in later years? Soc Sci Med 2005;61:1629–39.
      OpenUrlCrossRefPubMedWeb of Science
    38. ↵
      1. de Waal WJ,
      2. Greyn-Fokker MH,
      3. Stijnen T,
      4. et al
      . Accuracy of final height prediction and effect of growth-reductive therapy in 362 constitutionally tall children. J Clin Endocrinol Metab 1996;81:1206–16.
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      1. Berner M,
      2. Wehtje H,
      3. Savendahl L
      . Efficacy and safety of bilateral epiphysiodesis performed in extremely tall girls and boys. Horm Res 2008;70:113.
      OpenUrl
      1. Jones KL
      . Smith's recognizable patterns of human malformation, 6 edn. Philadelphia, Pennsylvania, USA: Elsevier Saunders, 2006.
      1. Tan TY,
      2. Amor DJ
      . Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health 2006;42:486–90.
      OpenUrlCrossRefPubMedWeb of Science
      1. Rump P,
      2. Zeegers MP,
      3. van Essen AJ
      . Tumor risk in Beckwith-Wiedemann syndrome: A review and meta-analysis. Am J Med Genet A 2005;136:95–104.
      OpenUrlPubMed

    Footnotes

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.