Introduction:Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on... Show moreIntroduction:Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum ofSHOXhaploinsufficiency.Methods:We analyzed 51 children withSHOXvariants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology.Results:Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio >1 SDS or arm span >= 3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detectSHOXhaploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients.Conclusion:Novel clinical criteria for screening forSHOXhaploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions. Show less
Objective: To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS). Design and methods: Forty children with no signs of... Show moreObjective: To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS). Design and methods: Forty children with no signs of puberty, age at start 4-8 years (girls) or 4-10 years (boys), height SDS < - 2.0 SDS, and birth length > - 2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m(2) per day (equivalent to 75 mu g/kg per day at start and 64 mu g/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (S.D.) age of 20.4 (2.3) years. Results: GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2-5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (-1.3 (0.8) SDS versus -2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3-12 years, AH was -2.1 (0.7) and -1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain. Conclusion: High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls. Show less
