Growth hormone and gonadotropin-releasing hormone analog therapy in haploinsufficiency of SHOX

We report on GH (0.5 IU or 0.17 mg/kg/week) and GnRH analog (GnRHa, 60 mug/ kg, every 4 weeks) therapy in SHOX haploinsufficiency. Case I was a 46,XY b oy with microdeletion of the Y chromosomal pseudoautosomal region. At 7 yea rs of age, he exhibited short stature (-3.9 SD) with a reduced growth rate (3.8 cm/year), short 4th metacarpals, and mild Madelung deformity. GH thera py resulted in a marked increase in height velocity (10.7 cm/year in the fi rst year). Case 2 was a 46,XX girl with a heterozygous nonsense mutation of SHOX (C674T). At 6 years of age, she presented with short stature (-3.3 SD ) with a low height velocity (4.0 cm/year). GH therapy caused a moderate in crease in height velocity (6.6 cm/year in the first year and 6.0 cm/year in the second year) before puberty. Because of breast development, she receiv ed GnRHa from 9 8/12 years of age. At 10 10/12 years of age, she had mild s hortening and borderline curvature of radius. Case 3 was a girl with a 46,X ,der(X)t(X;2)(p22.3;p21) karyotype. She was treated with GH from 6 to 14 ye ars of age, and also with GnRHa from 12 to 15 years of age. Her height rema ined around mean - 4 SD, with no discernible alteration of height velocity. At 17 years of age, she had short stature (-4.1 SD), bilateral cubitus val gus, Madelung deformity, and full breast development. The results suggest t hat GH therapy may have variable statural effects in SHOX haploinsufficienc y as in most disorders including Turner syndrome, and that GnRHa therapy af ter pubertal entry may be insufficient to prevent the development of skelet al lesions such as Madelung deformity.