Abstract
Introduction: The SHOX gene haploinsufficiency is the main monogenic cause of short stature, being observed in 56% to 100% of patients with Leri-Weill dyschondrosthosis (LWD) and in 1% to 14% of children with idiopathic short stature (ISS). The diagnosis allows the establishment of a suitable prognosis for adult height, indication of rhGH treatment and genetic counseling. Objectives: To describe a cohort of 45 children (24 female) with molecular diagnosis of heterozygous SHOX defects, focusing on achievement of adult height. Materials and Methods: We analyzed retrospective data from 37 families in that defects in the SHOX gene were identified. The molecular study was performed by MLPA followed by gene sequencing. Results: In 64% of the families there was deletions in SHOX gene, 20% deletions in SHOX expression regulatory region and 16% point mutations. Among the 45 patients diagnosed during childhood, 14 were identified by family screening and 31 were index case. The mean age at diagnosis was 10.2 ± 3.2y, BMI SDS = 0.9 ± 0.8, height SDS of affected parent -2.4 ± 1.1 and height SDS of non-affected parent was -1.1 ± 1.2. The index cases were shorter than the children diagnosed by screening (Height SDS of -2.2 ± 1.0 vs. -1.5 ± 0.7, respectively; p 0.038). The majority (80%) of these children had disproportionate short stature (Sitting height by total height SDS = 3.5 ± 1.7), and 47% had Madelung deformity. Twenty-six patients reached adult height, 16 of them were treated with rhGH (mean duration of treatment = 4.8 ± 3.0 y, mean dose: 50 µg/kg/d). Eight patients (3 boys and 5 girls) were also treated with GnRH analog due to a low predicted adult height (mean duration of GnRHa was 3.1 ± 1.7y). At the first evaluation, treated patients were shorter than untreated ones (Height SDS = -2.3 ± 1.1 vs. -1.5 ± 0.6, respectively; p = 0.059). Mean adult height SDS was similar between treated and non-treated patients (height SDS -2.0 ± 1.2 vs. -2.6 ± 0.7, respectively, p = 0.179). Treated patients showed a slighted improvement of height SDS from the start the therapy to adult height (∆Height SDS = 0.3 ± 0.7), while untreated patients had loss of height SDS (∆Height SDS -1.2 ± 0.7 p <0.001). Of the treated patients 63% reached normal height (Height SDS >-2) whereas 75% of untreated patients had short stature at adult height (Z <-2). Conclusion: Treatment with rhGH promotes stature gain in patients with SHOX haploinsufficiency. Genetic screening in children with short stature allows the identification of new carriers of SHOX defect and precocious rhGH therapy can avoid the lost of 1 SDS of height between childhood and adult life.
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