Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

Abstract

Introduction: 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 of SHOX haploinsuf-ficiency. Methods: We analyzed 51 children with SHOX variants 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 detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. Conclusion: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.

Novel heterozygous mutation in the SHOX gene leading to familial idiopathic short stature: A case report and literature review

“…[ 16 , 17 ] Mutations in the coding and promoter sequences of the SHOX gene are more commonly found in exons 2, 3, and 4, while mutations in exon 5 account for only 6.4% of the mutations in the coding and promoter sequences of the SHOX gene. [ 18 ] Currently, there are no literature reports on the c.577G > A mutation in exon…”

Haploinsuficiência do SHOX: modificadores genéticos do fenótipo e resposta ao tratamento com hormônio de crescimento

“…This effect is more evident in individuals with defects in the SHOX regulatory region, who typically have a milder phenotype, presenting a lower degree of body disproportion and/or Madelung's deformity, when compared to alterations directly involving the SHOX coding region. 13,43,44 Deletions in SHOX regulatory regions lead to a decrease in SHOX expression 45 and are associated with low penetrance of the phenotype. 44 In our series, 27% of the families with isolated alterations in the SHOX regulatory region had a second variant.…”

“…Até o momento, não foi identificada uma correlação genótipo-fenótipo clara nas alterações envolvendo o gene SHOX. No entanto, deleções envolvendo as regiões regulatórias downstream ao SHOX são associadas a um fenótipo menos grave e menor prevalência de sinais dismórficos (cúbito valgo, encurtamento dos membros superiores e inferiores) quando comparadas a alterações envolvendo a região codificadora do gene 34,43 . No estudo de Rosilio e colaboradores 34 , deleções envolvendo a região downstream foram mais prevalentes na população com BEI (59%) do que na população com DLW (69%).…”