Pitfall in Diagnosing Growth Hormone Deficiency in a Hypochondroplastic Patient with a Delayed Puberty

Abstract

Hypochondroplasia is a clinically and genetically heterogeneous skeletal dysplasia with less obvious disproportion in childhood and a reduced pubertal growth spurt. We report on a young hypochondroplastic man who had been misdiagnosed and treated as being growth hormone (GH) deficient in the early phase of puberty. The delay of his puberty which is unusual in hypochondroplasia might have confused the results of provocative GH testing. At the age of 17 years measurement of body proportions revealed an increased upper to lower body segment ratio. Skeletal radiographs showed a lack of increase in the interpedicular distance from the first to the fifth lumbar vertebra, anteroposterior shortening of the lumbar pedicles, short femoral necks, a fibula longer than the tibia, and short tubular bones. As the clinical and radiographic features suggested the diagnosis of a skeletal dysplasia, a DNA sequence analysis of the fibroblast growth factor receptor 3 gene on chromosome 4 p16.3 was performed, which identified the missense mutation C1620 G in the tyrosine kinase domain resulting in an Asn540Lys substitution. Hypochondroplastic children with this common mutation (N540K) were previously found to respond to GH treatment with an increase in sitting height compared to leg length, which accentuated the existing disproportion.

We want to emphasise that in children with normal serum IGF-I and IGFBP-3 levels accurate measurements of body proportions and skeletal radiographs in disproportionate cases are more important than reiterative GH stimulation tests, which prepubertally and in the early phase of puberty often show subnormal responses.

Hypochondroplasia - growth hormone therapy - skeletal dysplasia - fibroblast growth factor receptor 3 - height velocity

References

• 1 Appan S, Laurent S, Chapman M, Hindmarsh P C, Brook C G. Growth and growth hormone therapy in hypochondroplasia.  Acta Paediatr Scand. 1990;  79 796-803
• 2 Bayley N, Pinneau S R. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards.  J Pediatr. 1952;  40 423-441
• 3 Bellus G A, McIntosh I, Smith E A, Aylsworth A S, Kaitila I, Horton W A, Greenhaw G A, Hecht J T, Francomano C A. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia.  Nat Genet. 1995;  10 357-359
• 4 Bridges N A, Brook C G. Progress report: growth hormone in skeletal dysplasia.  Hormon Res. 1994;  42 231-234
• 5 Bridges N A, Hindmarsh P C, Brook C G. Growth of children with hypochondroplasia treated with growth hormone for up to three years.  Hormon Res. 1991;  36 56-60
• 6 Cacciari E, Tassoni P, Parisi G, Pirazzoli P, Zucchini S, Mandini M, Cicognani A, Balsamo A. Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 children defined as GH deficient.  J Clin Endocrinol Metab. 1992;  74 1284-1289
• 7 Deller Jr J J, Boulis M W, Harriss W E, Hutsell T C, Garcia J F, Linfoot J A. Growth hormone response patterns to sex hormone administration in growth retardation.  Am J Med Sci. 1970;  259 292-297
• 8 Deutz-Terlouw P P, Losekoot M, Aalfs C M, Hennekam R CM, Bakker E. Asn540 Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia.  Human Mutat. 1998;  (Suppl 1) S62-S65
• 9 Eastman C J, Lazarus L, Stuart M C, Casey J H. The effect of puberty on growth hormone secretion in boys with short stature and delayed adolescence.  Aust N Z J Med. 1971;  1 154-159
• 10 Fofanova O V, Takamura N, Kinoshita E, Meerson E M, Iljina V K, Nechvolodova O L, Evgrafov O V, Peterkova V A, Yamashita S. A missense mutation of C1659 in the fibroblast growth factor receptor 3 gene in Russian patients with hypochondroplasia.  Endocr J. 1998;  45 791-795
• 11 Gourmelen M, Pham-Huu-Trung M T, Girard F. Transient partial GH deficiency in prepubertal children with delay of growth.  Pediatr Res. 1979;  13 221-224
• 12 Green H, Morikawa M, Nixon T. A dual effector theory of growth hormone action.  Differentiation. 1985;  29 195-198
• 13 Greulich W W, Pyle S I. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford; Stanford University Press 1959
• 14 Grigelioniene G, Hagenas L, Eklof O, Neumeyer L, Haereid P E, Anvret M. A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia.  Human Mutat. 1998;  11 333
• 15 Hall B D, Spranger J. Hypochondroplasia: clinical and radiological aspects in 39 cases.  Radiology. 1979;  133 95-100
• 16 Isaksson O GP, Lindahl A, Nilsson A, Isgaard J. Mechanism of stimulatory effect of growth hormone on longitudinal bone growth.  Endocrin Rev. 1987;  8 426-438
• 17 Johnson D E, Williams L T. Structural and functional diversity in the FGF receptor multigene family.  Adv Cancer Res. 1993;  60 1-40
• 18 Key L L, Gross A J. Response to growth hormone in children with chondrodysplasia.  J Pediatr. 1996;  128 S14-17
• 19 Marin G, Domene H M, Barnes K M, Blackwell B J, Cassorla F G, Cutler Jr G B. The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys.  J Clin Endocrinol Metab. 1994;  79 537-541
• 20 Martha Jr P M, Reiter E O. Pubertal growth and growth hormone secretion.  Endocrinol Metab Clin North Am. 1991;  20 165-182
• 21 Martha Jr P M, Rogol A D, Veldhuis J D, Kerrigan J R, Goodman D W, Blizzard R M. Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys.  J Clin Endocrinol Metab. 1989;  69 563-570
• 22 McKeehan W L, Wang F, Kann M. The heparan sulfate-fibroblast growth factor family: diversity of structure and function.  Progr Nucleic Acid Res Mol Biol. 1998;  59 135-176
• 23 McKusick V A. Heritable Disorders of Connective Tissue. St. Louis; Mosby 1996
• 24 Mortier G, Nuytinck L, Craen M, Renard J-P, Leroy J G, dePaepe A. Clinical and radiographic features of a family with hypochondroplasia owing to a novel Asn540Ser mutation in the fibroblast growth factor receptor 3 gene.  J Med Genet. 2000;  37 220-224
• 25 Naski M C, Wang Q, Xu J, Ornitz D M. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia.  Nat Genet. 1996;  13 233-237
• 26 Peters K, Ornitz D, Werner S, Williams L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis.  Dev Biol. 1993;  155 423-430
• 27 Prinos P, Costa T, Sommer A, Kilpatrick M W, Tsipouras P. A common FGFR 3 gene mutation in hypochondroplasia.  Hum Mol Genet. 1995;  4 2097-2101
• 28 Ramaswami U, Hindmarsh P C, Brook C GD. Growth hormone therapy in hypochondroplasia.  Acta Paediatr Suppl. 1999;  428 116-117
• 29 Ramaswami U, Rumsby G, Hindmarsh P C, Brook C G. Genotype and phenotype in hypochondroplasia.  J Pediatr. 1998;  133 99-102
• 30 Rosenfeld R G. Evaluation of growth and maturation in adolescence.  Pediatr Rev. 1982;  4 175-183
• 31 Rosenfeld R G. Growth hormone therapy in Turner's syndrome: An update on final height. Genentech National Cooperative Study Group.  Acta Pediatr. 1992;  383 (Suppl) 3-6
• 32 Shohat M, Tick D, Barakat S, Bu X, Melmed S, Rimoin D L. Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia.  J Clin Endocrinol Metab. 1996;  81 4033-4037
• 33 Wilkie A OM, Morriss-Kay G M, Jones E Y, Heath J K. Functions of fibroblast growth factors and their receptors.  Curr Biol. 1995;  5 500-507
• 34 Winterpracht A, Hilbert K, Stelzer C, Schweikardt T, Decker H, Segerer H, Spranger J, Zabel B. A novel mutation in FGFR-3 disrupts a putative N-glycosilation site and results in hypochondroplasia.  Physiol Genomics. 2000;  2 9-12