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SHOX Haploinsufficiency - Clinical Indicators« Back to Volume 23, Issue 3, November 2007 - Table of Contents Mutations in the short stature homeobox-containing gene (SHOX) are one of the more frequent genetic causes of growth retardation in individuals with short stature. SHOX is therefore an important mediator of linear growth, presenting with marked disorganization of chondrocyte proliferation. There is also a dose dependent association between the number of copies of this gene and height. In addition, SHOX deficiency includes a continuum of clinical conditions spanning from the severe Langer syndrome with no functional copy of the SHOX gene to the Leri-Weill syndrome (LWS) and isolated idiopathic short stature (ISS) without dysmorphic features and haploinsufficiency of the SHOX gene. The aim of this study was to determine the phenotypical spectrum of SHOX deficiency in a large cohort of children with short stature and to propose a scoring system to select patients who qualify for diagnostic SHOX molecular testing. A cohort of 1608 unrelated prepubertal children with short stature was studied. Investigators were requested to report the presence or absence of a number of dysmorphic signs often observed in LWS. In addition, for sake of comparison, a group of Turner syndrome patients (n=33) was included as this condition also presents one absent SHOX allele. SHOX defects were identified in 68 short stature participants (4.2%) and in 34 ISS patients (2.2%). LWS was reported in 55 participants (3.4%). For LWS patients, the presence of a SHOX defect did not induce a greater frequency of dysmorphic signs. For ISS children, a number of physical signs (shortening or bowing of the forearm, Madelung deformity [dinner fork-like deformity of the wrist], dislocation of the ulna of the elbow, high-arched palate, bowing of the tibia and appearance of muscular hypertrophy) were clinical indicators for SHOX deficiency. In addition, ISS patients presented a significantly greater BMI SDS than those without the molecular defect. They also they had disproportion and appearance of muscular hypertrophy; ISS with SHOX deficiency had a significantly greater sitting height and forearm, upper arm and upper leg circumference adjusted for standing height. The variability of the phenotype makes it difficult to decide molecular testing. Therefore various logistic regression models were developed. The diagnosis of LWS or the presence of Madelung deformity resulted in very high odds ratios. Therefore the study focused on non-syndromic ISS, and these strong indicators were excluded from the models. A scoring system was presented (Table) using rounded odds ratios as weighted score points to help identify patients who qualify for SHOX gene testing based on clinical criteria. These criteria included 3 anthropomorphic variables (arm span/height, sitting height/height, and BMI) and 5 dysmorphic signs (cubitus valgus, short forearm, bowing of forearm, appearance of muscular hypertrophy, and dislocation of the ulna at the elbow). Testing was recommended for patients having a score greater than 4 or 7 out of a total possible score of 24, a range that allows a better sensitivity.
This study provided clinical guidelines for testing of the SHOX gene. The most reliable clinical indicators of SHOX deficiency were related to disproportionate growth. The clinical findings were present in a significant number of ISS phenotype patients as well as in those with LWS. These diagnoses represent a continuum rather than discrete entities. However, there was no clear correlation between the specific SHOX gene defect and the clinical features. Rappold G, Blum WF, Shavrikova EP, et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet. 2007;44:306-13. Editor’s CommentSHOX haploinsufficiency is an important genetic cause of short stature associated with well recognized dysmorphic signs. Several studies have already reported on this clinical phenotype. The present report provided new data prospectively established from a large group of patients with short stature. This analysis should help to identify the large continuum of phenotypes related to SHOX haploinsufficiency among the various types of short stature. The gene-phenotype relationship is not a simple one, as the authors found no difference in the degree of short stature between the children with or without an identifiable SHOX defect (according to the molecular methods applied in this protocol). Furthermore, among short stature patients with a clinical diagnosis of LWS the frequency of dysmorphic signs was not different between children with a SHOX defect and those without an intragenic mutation of the SHOX gene. Other genetic defects, not investigated in this study, might have been missed: intragenic mutations located in regulatory regions of the gene, or defects at a different, but related, genetic locus. It is of interest that, for an unknown reason, BMI is increased in those patients with muscular hypertrophy. This finding is in contrast with the frequency of low to low-normal BMI values in children with ISS. A recent report1 showed that similar stimulation of growth was obtained in ISS with SHOX insufficiency and in a group of girls with Turner syndrome who received growth hormone treatment of 50 µg/kg/day. This study also showed the importance of carefully analyzed familial histories using clinical scoring and radiographic examination of the forearm and hand. Raphaël Rappaport, MD Reference - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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