SHOX Intragenic Microsatellite Analysis in Patients with Short Stature

Abstract

Background: SHOX haplo-insufficiency is considered the molecular basis of short stature in patients with Turner's syndrome, and gives rise to the short stature with mesomelic dysplasia and Madelung deformity of patients with Leri-Weill syndrome. Objective: Analysis of the intragenic SHOX microsatellite to define its utility in detecting SHOX haplo-insufficiency in patients with short stature. Patients and Methods: 207 patients with short stature (57 girls with Turner's syndrome [TS] [24 mosaicisms]; 73 children with isolated short stature [ISS]; 77 patients with short stature and skeletal disproportion) and 30 control subjects. DNA extraction and PCR amplification of the intragenic SHOX microsatellite, at the 5'-untranslated region. SSCP and partial sequencing of the SHOX gene in one patient with Madelung deformity and two SHOX alleles. DXS1055 (Xp) and DXS1192 (Xq) microsatellites were also analyzed, together with DXS233 and DXS234 at 0 and 2 cM of the pseudoautosomal region (PAR), in patients with one SHOX allele. Results: 1. 93% of patients with TS had a single SHOX allele, and allele unbalance was detected in the remainder. 2. Patients with ISS were not different from the normal population with respect to SHOX heterozygosity (0.92 and 0.93, respectively; ρ = 0.997). 3. Patients with short stature and skeletal disproportion showed a higher frequency of SHOX homo/hemizygosity (0.27 vs 0.08; ρ = 0.027). 4. Five patients with short stature with SHOX haplo-insufficiency were detected: three had Madelung deformity (inherited Yq;Xp translocation, de novo PAR deletion, and ST/OX microdeletion), and two had de «ovo/inherited Xp partial monosomy. Conclusions:The SHOX intragenic microsatellite might be a useful molecular marker to detect TS (including Xp distal deletions). SHOX haploinsufficiency seems not to be an important contributor to ISS, but when skeletal disproportion is associated with short stature, a significant proportion of patients is found to have a single SHOX allele. Some of these patients were found to be SHOX haplo-insufficient upon molecular, cytogenetic and radiological examination. KEY WORDSSHOX intragenic microsatellite, Turner's syndrome, Leri-Weill syndrome, isolated short stature, SHOX haplo-insufficiency

Short stature and dysmorphology associated with defects in the SHOX gene

“…Table 3 summarizes the published data in patients with SHOX haploinsufficiency treated with rhGH. 42,[66][67][68][69] The data are not complete in all cases and there was a wide range of rhGH dose. No ad- 68 demonstrated short-term benefit from rhGH therapy, with a mean improvement in height SDS of 0.8 at 12 months (n=8) and 0.6 at 24 months (n=3).…”

“…42 Clement-Jones and colleagues 15 suggested a possible involvement of SHOX-related growth impairment in the expression of other Turner stigmata such as high-arched palate, abnormal auricular development, cubitus valgus, genu valgum and short metacarpals. Other clinical investigators 39,43,44 reported that SHOX haploinsufficiency could lead to additional Turner skeletal abnormalities such as mesomelia and Madelung deformity.…”

Investigação clínica e genética em meninas com baixa estatura idiopática

“…Desde a descrição do papel do gene SHOX no crescimento e desenvolvimento ósseo e do reconhecimento que ele codifica um fator de transcrição expressado em células osteogênicas e em outros tecidos, vários trabalhos têm sido descritos associando mutações e deleções desse gene em 1 a 2,4% de crianças diagnosticadas como portadoras de baixa estatura idiopática (8,11,12,17,21,23,41).…”

“…Outros autores também têm reforçado a importância de complementar o exame clínico na busca de sinais clínicos e radiológicos achados na ST nas crianças com diagnóstico de BEI (15,19,41).…”

“…Como é conhecido que meninas com ST apresentam resposta favorável ao tratamento com hormônio de crescimento, o diagnóstico de uma anomalia numérica ou estrutural do X no grupo de baixa estatura idiopática modificaria a conduta terapêutica, permitindo que, frente a um diagnóstico precoce, pudessem ser incluídas em programas de terapia com hormônio de crescimento (9,28,41). Se existem controvérsias quanto ao ganho de estatura final em pacientes com ST, não há dúvidas que o início do GH no período escolar antecipa um ganho de estatura numa faixa etária importante para a melhora do comportamento psicossocial destas crianças (57).…”