Short Stature in Isodicentric Y Chromosome and Three Copies of the SHOX Gene: Clinical Report and Review of Literature

Abstract

Short stature homeobox gene (SHOX) mutations and pseudoautosomal region 1 (PAR1) deletions encompassing SHOX are known causes of Léri-Weill dyschondrosteosis and isolated short stature, while 3 copies of SHOX in cases with triple sex chromosome constitution are responsible for tall stature. Duplications involving SHOX have been rarely reported, and they were found in individuals with short, normal and tall stature. An adopted boy with short stature, isodicentric Y chromosome and 3 copies of SHOX is described. Normal growth hormone (GH) secretion and insulin-like growth factor 1 (IGF1) increase during an IGF1 generation test were found, ruling out impaired GH-IGF1 axis. No other organic or psychiatric causes of impaired growth were found. GH treatment improved linear growth, as reported in children with SHOX haploinsufficiency. This new report and the review of literature support that SHOX duplication may cause short stature, especially in those children with duplications of the 5′SHOX regulatory elements. Chromosome analysis and detailed molecular characterization of the duplicated region should be warranted in individuals with SHOX duplications in order to investigate the presence of occult chromosome imbalance. Additional reports and follow-up till adult height are needed to give conclusions on long-term efficacy and safety of GH treatment in short children with SHOX duplication.

An Association of PTPN11 and SHOX Mutations in a Male Presenting With Syndromic Growth Failure

“…The atypical proliferation and differentiation of chondrocytes is the cause of the delayed growth of the long bones ( 17 , 18 ). There are data that indicate that GH administration can be effective in reducing short stature even in cases of SHOX duplications ( 19 , 20 ). The potential efficacy of GH administration for short stature due to both of these genetic conditions seems to be confirmed by the findings collected from our patient, for whom GH administration led to a significant increase in growth velocity that reached the highest normal values for his age.…”

A SHOX géndeletio előfordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány

“…A gént 1997-ben, egymástól függetlenül fedezte fel két kutatócsoport [4]. A 40 kb hosszúságú SHOX gén a humán genomban az X-(Xp22.3) és Y-(Zp11.3) kromoszómák pszeudoautoszomális régiójában (PAR1), a nemi kromoszómák telomerjeitől 500 kb-nyi távolságra talál-ható [5][6][7][8]. Elhelyezkedésének köszönhetően elkerüli az X-kromoszóma inaktiválódását, így a hibáihoz tartozó betegségek öröklődésmenetére a pszeudoautoszomális mód jellemző [9], ezért a gén kifejeződésének mértéke a férfi és a női szervezetben megegyezik.…”

Unbalanced X;9 translocation in an infertile male with de novo duplication Xp22.31p22.33

“…Likewise, duplications of SHOX have been described in apparently normal individuals with short, normal, or tall stature and no skeletal anomalies or neurodevelopmental delay [27][28][29]. However, there are several reports suggesting an association of microduplications at the STS and SHOX loci with skeletal dysplasias, or autism spectrum disorders [14,[30][31][32]. Esplin et al (2013) presented nine individuals from five families (five males and four females) with maternally inherited Xp22.31 duplications involving the STS gene [14].…”