CME *-*-0

Evaluating tall children

ALEXANDER K.C. LEUNG, MIBBS, FRCP(Edin) SUMMARY W LANE M. ROBSON, NID, FRCPC The causes of tall stature are numerous; genetic tall stature and constitutional tall stature are the most common. Diagnosis can usually be established from ALI SlATURE IN CHILDREN IS * precocious puberty, the history and physical defined as a * pituitary excess, examination. An estimation of arbitrarily age can help to confirm height greater than two * cerebral gigantism (), diagnosis and to determine the standard deviations above * hyperthyroidism, child's growth potential. No the mean torr- a populatlonI ot1r.l1the same * Marfan's syndrome, treatment is usually necessary. sex, age, and race.' According to this hhomocystinuria, Hormonal therapy can be definition, approximately 2.30% of chil- * Klinefelter's syndrome, considered for individuals for dren have tall stature. The most com- * XYY syndrome, whom the predicted height is mon cause of tall stature is genetic * hypogonadal syndromes, excessive if the psychosocial and medical advantages predisposition. * Beckwith-Wiedemann syndrome, outweigh the risks of treatment. Several pathologic conditions also * Weaver syndrome, present with tall stature. Excessively * Proteus syndrome, and RESUMEI I tall stature, especially of girls, can * congenital generalized lipodystrophy. ll existe de nombreuses causes cause serious psychologic problems.2 a la grande taille; les plus This article reviews the causes of tall Familial or genetic tall stature. frequentes sont les etiologies stature and suggests an approach to Familial or genetic tall stature is the genetique et constitutionnelle. management. most common cause of tall stature. l'histoire et l'examen physique These children are usually tall from permettent habituellement de preciser le diagnostic. Causes and clinical early childhood (Figure 1) and have La determination de l'age manifestations tall parents. Genetically tall children osseux peut contribuer a The causes of tall stature are: have a high normal growth rate, nor- confirmer le diagnostic et a * familial or genetic tall stature, mal results from physical examina- determiner le potentiel de * constitutional tall stature, tion, and a bone age that is croissance de l'enfant. * exogenous obesity, compatible with chronologic age. La majorite des cas ne Comparing the growth of the patient necessitent aucun traitement. Dr is Clinical Associate in the the on a chart On pourra envisager le recours Leung Professor and parents growth a I'hormonotherapie chez les Department ofPediatrics at the University of reveals that the tall stature is appro- individus a qui l'on predit une Calgary and is a Pediatric Consultant at the priate for that family. taille excessive, a la condition Alberta Children's Hospital. Dr Robson is toutefois de bien soupeser les Medical Director ofPediatric JVNephrology at the Constitutional tall stature. avantages medicaux et Children's Hospital in Greenville, SC, and is Constitutional tall stature is the second psychosociaux, ainsi que les Clinical Associate Professor in the Department of most common cause of tall stature. risques inherents au traitement. ofthe Faculy ofMedicine at the Children with constitutional tall stature Can Fam Physician 1995;41:457-468. University ofSouth Carolina in Columbia. have a normal length at birth. The

(anadian Family Plhsician VO1. 1 IOAlarc(h 199. 457 CME Evaluating tall children growth velocity accelerates in early Precocious puberty. An etiologic childhood, and the tall stature is usu- classification helps to manage preco- ally evident by the age of 3 to 4 years cious puberty.5 In affected children, (Figure 2).3 Growth velocity slows acceleration of linear growth invariably down after the child reaches 4 or 5 occurs simultaneously with signs of pre- years; thereafter the growth curve is mature sexual development or inappro- parallel to and above the normal priate virilization. Rapid growth is curve.3 Constitutionally tall children accompanied by a rate of osseous matu- have a slightly or moderately ad- ration that is greater than expected for vanced bone age. Puberty usually the chronologic age. The advanced develops in the early range of bone age results in early epiphyseal clo- .3 normal, and final adult height is in sure; consequently, the ultimate height is the upper range of normal. There is less than it would have been otherwise.5 usually a family history of a similar growth pattern. Pituitary growth hormone excess. Growth hormone hypersecre- Exogenous obesity. Children with tion in children is usually caused by a exogenous obesity are usually tall for growth hormone-producing or null- their age.4 In these children, bone age cell of the . is advanced and proportional to height Before the epiphyses close, an excess of age, and the adolescent growth spurt growth hormone produces accelerated begins and ends early. These children linear growth and results in gigantism.6 are only slightly taller than average Bone age is often advanced.7 An excess as adults.4 of growth hormone after the epiphyses

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458 Canadian Family Physician VOL 41: March 1995 CME fuse results in , a disorder mental retardation, large elongated Evaluating tall children characterized by large hands and feet, head, large ears and jaws, high overgrowth of the mandible and supra- arched palate, prominent jaw, anti- orbital ridges, and coarse facial fea- mongoloid slant to the eyes, large tures. Pituitary tumours are associated hands and feet, and increased arm with headache, decreased visual acuity, span compared with height.9 The visual field defects (typically bitemporal bone age is often advanced and com- hemianopsia), and symptoms or signs patible with the height of the patient.9 suggesting increased intracranial pres- The serum level of growth hormone sure. Tumours are also associated with and the results of other endocrine deficiency of other pituitary hormones, studies are normal. In most patients, such as thyrotropin, corticotropin, and the lateral and third ventricles are gonadotropin. mildly dilated. Encephalograms are often abnormal.9 Most cases are spo- Cerebral gigantism (Sotos syn- radic. Familial cases are usually con- drome). Children with Sotos syn- sistent with an autosomal dominant drome are often large at birth, and mode of inheritance.9 their growth is most rapid during the first few years of life.8 Thereafter, the Hyperthyroidism. Excessive thyroid growth velocity slows, and the growth hormone in early childhood causes an curve remains parallel to and above acceleration in linear growth and pro- the normal curve. Other features portional osseous maturation. include frontal bosselation, coarse facial Craniosynostosis sometimes develops features, hypertelorism, clumsiness, when hyperthyroidism appears in very

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Canadian Family Physician VOL 41: March 1995 461 CME Evaluating tall children early life. The ultimate adult height Homocystinuna. Homocystinuria is is unaffected.'0 an autosomal recessive disorder caused by a deficiency of cystathionine Marfan's syndrome. Marfan's syn- P-synthase with resultant excretion of drome is characterized by arachno- large amounts of homocystine in the dactyly, tall stature, superior lens urine.'2 Patients with this disorder have subluxation or dislocation, and aortic a phenotypic appearance similar to or mitral regurgitation." The arm those with Marfan's syndrome (Figure 4). span is greater than height, and the Additional features of homocystinuria upper to lower body segment ratio is include mental retardation, malar flush, diminished (Figure 3). Other clinical inferior lens subluxation or dislocation, features include joint hyperextension, and an increased incidence of seizures, inguinal or femoral hernia, pectus arterial and venous thrombosis, osteo- excavatum, scoliosis, megalocornea, porosis, and vertebral collapse.'3 and myopia." Retinal detachment and aortic aneurysm and rupture are Klinefelter's syndrome. Klinefelter's the important complications. The syndrome is due to the presence of condition is inherited as an autosomal more than one X chromosome in a dominant trait. male patient."' The most common

Fzgure 3. Child with Marfan's syndrome: Figure 4. Child with homocystinuria: The disproportionatey long limbs make the arm span The thin, long limbs and sparse subcutaneous tissue exceed the height ofthepatient. are evident.

462 Canadian Family Physician VOL 41: March 1995 CME abnormal karyotype is 47 XXY. which include a small jaw, widely sepa- Evaluating tall children Affected children are tall and have rated eyes, large and dysplastic ears, eunuchoid proportions with a long arm broad forehead, long philtrum, mega- span and legs and a decreased upper to cephaly, strabismus, depressed nasal lower body segment ratio. Genital bridge, and flat occiput. 16"17 abnormalities, such as hypogonadism, cryptorchidism, and a small phallus, Proteus syndrome. Proteus syn- are sometimes present.'3 Gynecomastia drome is characterized by overgrowth is common during . Mental of various body parts, megacephaly, retardation and behavioural difficulties, multiple hyperpigmented warty nevi, such as excessive shyness, aggres- and subcutaneous vascular tumours.18'19 siveness, and antisocial behaviour, are In most individuals, the overgrowth often present. starts in the first few years of life. The overgrowth can be generalized (whole XYY syndrome. The presence of an body), unilateral (hemihypertrophy), or extra Y chromosome predisposes an localized (macrodactyly).'8 individual to tall stature. Patients with one (47, XYY) or more (48, XYYY) Congenital generalized lipodys- extra Y chromosomes achieve a trophy. Children with congenital gen- greater than average adult height. eralized lipodystrophy (Seip-Lawrence Other features include severe nodulo- syndrome) have accelerated linear and cystic acne, mental retardation, physi- muscular growth together with cal aggressiveness and violence, advanced bone age.20 Affected children impulsivity, and antisocial behaviour. have a generalized loss of subcutaneous and visceral fat. Prominent superficial Hypogonadal syndromes. Several veins, , alopecia, and acan- hypogonadal syndromes can cause tall thosis nigricans can be present. There stature and eunuchoid body propor- is an increased risk for hyperlipidemia, tions. The lack of sex hormones delays hyperinsulinism, and insulin-resistant osseous maturation and epiphyseal non-ketotic diabetes mellitus.20 fusion. This allows continued, although slow, growth to a later age. Clinical evaluation In most cases, a diagnosis can be estab- Beckwith-Wiedemann syndrome. lished from a careful history and physi- Beckwith-Wiedemann syndrome is char- cal examination. Familiarity with the acterized by macrosomia, , many diseases and syndromes associat- visceromegaly, defects of closure of the ed with tall stature is important; in abdominal wall (omphalocele, umbilical some cases, diagnosis can be estab- hernia, diastasis recti), and neonatal lished immediately. hypoglycemia.'4 Other features include The most important historical infor- facial nevus flammeus, earlobe malfor- mation in the evaluation of a child with mation, hemihypertrophy, increased risk tall stature is the family history of the for tumour formation, cardiovascular pattern of growth and the age of onset abnormalities, hypothyroidism, and thy- of puberty in parents and siblings. Any roxine-binding globulin deficiency.4"5 familial conditions associated with tall Postnatal gigantism is common. Bone stature should be noted. All previous age is advanced and is appropriate heights and weights should be obtained for height age. and plotted on a growth chart. If the growth records of the parents are avail- Weaver syndrome. Weaver syn- able, they should also be plotted for drome is characterized by accelerated comparison. linear growth, advanced bone age, A functional inquiry is important campylodactyly, mild mental retarda- and in some cases reveals the underly- tion, and characteristic facial features, ing cause of tall stature. Any medical,

Canadian Family Physician VOL 41: March 1995 465 CME Evaluating tall children social, or psychologic problems associ- familial or genetic tall stature3 and is ated with tall stature should be noted. delayed in patients with a hypogonadal A careful and precise measurement syndrome. of the height, weight, arm span, and Other diagnostic imaging studies or upper to lower body segment ratio is laboratory tests (Table 1) should be per- necessary. The stage of puberty should formed only if suggested by the history be assessed, which can be done using or physical examination. the criteria ofMarshall and Tanner.21 22 Any dysmorphic features or other Complications abnormal physical findings should be Some tall children, especially girls, are noted. teased or ridiculed by their peers. The psychologic stress can be severe Investigations enough to cause depression and social Estimation of bone age can help to withdrawal.23 The incidence of spinal confirm the diagnosis and to deter- deformities, such as scoliosis or kypho- mine the growth potential of the child. sis, is increased in tall children.23'24 A significantly advanced bone age is Tall children can have difficulties sometimes seen in patients with true purchasing appropriate clothes. Tall precocious puberty, adrenal or gonadal girls sometimes have difficulties finding neoplasms, and congenital adrenal compatible male partners.' .5 Bone age is mildly or Other complications can be related moderately advanced in patients with to underlying disease. constitutional tall stature, exogenous obesity, pituitary growth hormone Management excess, cerebral gigantism, hyperthy- The underlying cause should be treat- roidism, Beckwith-Wiedemann syn- ed whenever possible. Children with drome, Weaver syndrome, and constitutional and familial or genetic congenital generalized lipodystrophy20 tall stature rarely require therapeutic Bone age is normal in children with intervention. Psychologic counseling Table 1. Diagnostic imaging studies and laboratory tests helpful for evaluating a child with tall stature SUSPECTED DIAGNOSIS SUGGESTED TESTS True precocious puberty Serum FSHLH, estradiol or testosterone; gonadotropin response to gonadotropin-releasing hormone; skull x-ray, or MRI ...... Ovarian or adrenal tumour Serum estradiol or testosterone; abdominal ultrasonography or CT ...... Congenital adrenal hyperplasia Serum electrolytes; plasma 1 7-hydroxyprogesterone; urinary pregnanetriol; dexamethasone suppression test ...... Pituitary growth hormone excess Serum growth hormone or somatomedin C; skull x-ray, CT, or MRI ...... Cerebral gigantism Skull x-ray, CT, or MRI; electroencephalography ...... Hyperthyroidism Serum thyroxine, triiodothyronine, and thyroid-stimulating hormone ...... Homocystinuria Plasma cystine, homocystine, and methionine; urinary homocystine ...... Klinefelter's syndrome Chromosome study ...... XYY syndrome Chromosome study

...... H Hypogonadal syndromes Serum FSH, LH, estradiol or testosterone

466 Canadian Family Physician VOL 41: March 1995 CME may be necessary if emotional stress is ty. Side effects include acne, weight Evaluating tall children associated with the tall stature. gain, edema, and a transient decrease Hormonal treatment should be consid- in testicular volume, which returns to ered for children, especially girls, who normal after therapy is stopped.33'34 have severe psychologic problems Preliminary studies on the use of a because of their height and when the analogue in a few tall predicted adult height is excessively tall. children are encouraging26'35'36 but The adult height can be calculated based require confirmation in larger prospec- on the chronologic age, sex, height, and tive studies. U bone age of the child and on the correc- tion factor published byjoss et al.25 Acknowledgment For girls, estrogen treatment can We thank Ms Kathy Campbell-Brown and reduce the final height. Estrogen acts Mrs Paula Pang for expert secretarial assis- by accelerating epiphyseal fusion and tance, Mr Sulakhan Chopra of the University suppressing somatomedin C produc- of Calgary medical libraryfor help in preparing tion." Satisfactory results can be this manuscript, and Dr Brian Lowry for pro- obtained by starting treatment when viding two ofthefigures. bone age is about 12 or 12.5 years and by using 0.1 mg of ethynyl estradiol Correspondence to: Dr Alexander K. C. daily, combined with 5 mg of medrox- Leung, Alberta Children's Hospital, 1820 yprogesterone daily for the first 5 to Richmond Rd SW, Calgary, AB T2T 5C7; 10 days of every month.27 The usual fax (403) 242-6734 duration of treatment is about 2 years. Therapy is continued until the growth References curve has levelled off and epiphyseal 1. Wettenhall HN, Cahill C, Roche AE Tall fusion is documented radiologically. girls: a survey of 15 years of management and Short-term side effects of ethynyl treatment. ] Pediatr 1975;86:602- 10. estradiol therapy are reportedly infre- 2. Kuhn N, Blunck W, Stahnke N, WiebelJ, quent and include nausea, migraine WVillig RP Estrogen treatment in tall girls. Acta headache, weight gain, increased areo- Paediatr Scand 1977;66: 161-7. lar pigmentation, leg cramps, transient 3. Dickerman Z, LoewingerJ, Laron Z. The pat- , galactorrhea, ovarian tern of growth in children with constitutional cysts, hyperlipidemia, glucose intoler- tall stature from birth to age 9 years: a longitu- ance, gallstones, thromboembolism, dinal study. Acta Paediatr Scand 1984;73:530-6. and post-therapeutic menstrual irregu- 4. Leung AK, Robson WL. Childhood obesity. larities or amenorrhea.l"28-3' Because Postgrad Med 1990;87: 123-33. the long-term effects of estrogen admin- 5. Leung AKC, McArthur RG. Recent advances istration to children are unknown, these in the treatment of isosexual precocious puber- agents should be used only if the bene- ty. Can Fam Physician 199 1;37:2597-604. fits outweigh the risks and after a thor- 6. Villee D. Excess growth. In: Avery ME, ough discussion of the potential side First LR, editors. Pediatric medicine. Baltimore: effects with the patient and parents. WVilliams & Wilkins, 1989:815-9. Treating excessively tall boys with 7. Rosenfeld RL. Somatic growth and matura- testosterone has been studied less tion. In: DeGroot LJ, Besser GM, Cahill GFJr, extensively because boys do not usually NMarshallJC, Nelson DH, Odell WD, et al, edi- complain of tall stature. Intramuscular tors. . Philadelphia: WB. Saunders injection of testosterone enanthate, Co, 1989:2242-81. 250 to 500 mg every 2 or 3 weeks for 8. WitJM, Beemer FA, Barth PG, OorthuysJW, 6 to 15 months, has been shown to be Dijkstra PF, Van den BrendaJL, et al. Cerebral effective. 13,32-34 Testosterone acts by gigantism (Sotos syndrome). Compiled data of accelerating bone maturation and epi- 22 cases: analysis of clinical features, growth physeal fusion and reduces the ultimate and plasma somatomedin. Eur§J Pediatr adult height. For most patients, therapy 1985;144:13 1-40. is initiated with the first signs of puber- Continued on page 468

Canadian Family Physician VOl 41: March 1995 467 CME Evaluating tall children 9. DiGeorge AM. Sotos syndrome. In: 23. Prader A, Zachmann M. Tlzreatment of Behrman RE, Kliegman RM, Nelson WE, excessively tall girls and boys with sex hor- Vaughan VC III, editors. Nelson textbook ofpedi- mones. Pediatrics 1978;62(suppl): 1202-10. atrics. Philadelphia: WB. Saunders Co, 24. Skogland LB, Steen H, Trygstad 0. Spinal 1992: 1406-7. deformities in tall girls. Acta Orthop Scand 1985; 10. MacGillivray MH. Disorders of growth 56:155-7. and development. In: Felig P, BaxterJD, 25.Joss EE, TFemperli R, Mullis PE. Adult Broadus AE, Frohman LA, editors. height in constitutionally tall stature: accuracy Endocrinology and metabolism. New York: of five different height prediction methods. McGraw-Hill Book Co, 1987:1581-628. Arch Dis Child 1992;67:1357-62. 11. McClain LG. The tall athlete and Marfan 26. Hindmarsh PC, Brook CG. Tall stature. In: syndrome. JAdolesc Health Care 1989; 10:564-6. Brook CG, Grumbach MM, editors. Clinical 12. Mudd SH, Skovby F, Levy HL, Pettigrew paediatnic endocrinology. Oxford: Blackwells KD, Wileken B, Pyeritz RE, et al. The natural Scientific Publications, 1989:128-42. history of homocystinuria due to cystathionine 27. Normann EK, Frygstad 0, Larsen S, [3-synthetase deficiency. Am]7 Hum Genet 1985; Dahl-Jorgensen K. Height reduction in 539 37:1-31. tall girls treated with three different dosages of 13. Frasier SD. Tall stature and excessive ethinyloestradiol. Arch Dis Child 1991 ;66: 1275-8. growth syndromes. In: Lifshitz F, editor. 28. Schoen EJ, Solomon IL, Warner 0, Pediatric endocrinology. New York: Marcel WingerdJ. Estrogen treatment of tall girls. Dekker, Inc, 1990:197-213. AmJDis Child 1973;125:71-4. 14. Engstrom W, Lindham S, Schofield P. 29. Werder EA, Waibel P, Sege D, Flury R. Wiedemann-Beckwith syndrome. EurJ Pediatr Severe thrombosis during oestrogen treatment 1988; 147:450-7. for tall stature. EurJ Pediatr 1990; 149:389-90. 15. Leung AK, McArthur RG, Ross SA, 30. Blomback M, Hall K, Ritzen ENI. Estrogen McMillan DD, Sauve RS. Thyroxine-binding treatment of tall girls: risk of thrombosis? globulin deficiency in Beckwith syndrome. Pediatrics 1983;72:416-9. J Pediatr 1979;95:752-4. 31. Panteon E, Loumaye E, Maes M, 16. Weaver DD, Graham B, Thomas IT, Malvaux P. Occurrence ofprolactinoma after Smith DW A new overgrowth syndrome with estrogen treatment in a girl with constitution- accelerated skeletal maturation, unusual faces, ally tall stature. 7 Pediatr 1988; 113:337-9. and camptodactyly. j Pediatr 1974;84:547-52. 32. BramswigJH, Lengerke HJ, Schmidt H, 17. Weaver DD, Ramos-Arroyo MA. Weaver Schellong G. The results of short-term syndrome. In: Buyse ML, editor. Birth defects (6 months) high-dose testosterone treatment on egclopedia. Dover, Mass: Centre for Birth bone age and adult height in boys of exces- Defects Information Services, Inc, 1990:1775-6. sively tall stature. EurJ Pediatr 1988; 148:104-6. 18. Viljoen DL, Nelson MM, dejong G, 33. BramswigJH, Nieschlag E, Schellong G. Beighton P. Proteus syndrome in Southern Pituitary-gonadal function in boys after high Africa: natural history and clinical manifesta- dose testosterone treatment for excessively tall tions in six individuals. Am 7 Med Genet 1987; stature. Acda Endocrinol 1984; 107:97-103. 27:87-97. 34. Zachmann M, Ferrandez A, Murset G, 19. Clark RD, Donnai D, RogersJ, CooperJ, Gnehm HE, Prader A. Testosterone treatment Baraister M. Proteus syndrome: an expanded of excessively tall boys. J Pediair 1976;88: 116-23. phenotype. AmJ7Med Genet 1987;27:99-117. 35. Hindmarsh PC, Pringle PJ, DiSilio L, 20. Esterly NB. Disorders ofsubcutaneous tissue. Brook CG. A preliminary report on the role of In: Behrman RE, Kliegman RM, Nelson WE, somatostatin analogue (SMS 201-995) in the Vaughan VC III, editors. Nelson textbook ofpediatrics. management of children with tall stature. Philadelphia: WB. Saunders Co, 1992:1663-4. Clin Endocrinol 1990;32:83-91. 21. Marshall WA, TannerJM. Variations in 36. Tauber MT, TauberJP, Vigoni F, pattern ofpubertal changes in girls. Arch Dis Harris AG, Rochicchioli P Effect of the long- Child 1969;44:291-301. acting somatostatin analogue SMS 201-995 22. Marshall WA, TannerJM. Variations in on growth rate and reduction ofpredicted pattern of pubertal changes in boys. Arch Ths adult height in ten tall adolescents. Child 1970;45: 13-23. Adta PaediatrScand 1990;79:176-81.

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