The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects

Abstract

Objective: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. Design: In this retrospective multi-center study (2002( -March 2014 clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness). Results: Patients with SEDs showed similar HtSDS to patients with SHI (K2.3 and K2.6, respectively, PZ0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P!0.01) and extremities/trunk ratio 2.57 vs 2.43 (PZ0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (nZ3) was similar to the other groups. Conclusions: Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…Heterozygous deletions of the downstream and upstream enhancer of SHOX cause a similar phenotype as defects of SHOX itself (144,145,146,147,148,149), and the growth response to GH treatment is even better in children carrying a deletion of the SHOX enhancer than in carriers of a SHOX defect (150). The consequences of increased copies of SHOX are less clear (146,150,151,152,153).…”

SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature

“…SHOX downstream deletions may be associated with a broad clinical spectrum because Chen et al [2009] documented a prominent phenotype in patients with such deletions. Furthermore, Donze et al [2015] reported that patients with enhancer deletions were equally short as those with SHOX intragenic defects but were less disproportionate and showed better responses to growth hormone (GH) therapy. Benito-Sanz et al [2011] suggested that SHOX duplications are often associated with relatively mild phenotypes.…”

“…However, long-term outcomes of GH treatment need to be evaluated in future studies. Since Donze et al [2015] reported that GH treatment was more effective in patients with enhancer deletions than in those with intragenic abnormalities, patients should be classified according to their mutation types. In addition, while Ogata et al [2001b] suggested that gonadal suppression therapy may be useful to prevent the development of Madelung deformity in female patients, the outcome of this therapy remains to be investigated.…”

A SHOX géndeletio előfordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány

“…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.…”