medwireNews: French researchers have characterised the associations betweena gender, genotype and phenotype in a cohort of patients with mutations affecting the SHOX (short stature homeobox gene) region.

“Our analysis confirms the higher penetrance and the different expression of SHOX rearrangements in females compared to males”, say Julie Auger (Brabois Hospital, Vandoeuvre-lès-Nancy) and study co-authors.

Their study included 205 index cases and 100 additional patients who were related to the index cases. Of note, the related cases were mainly parents of the index cases, showing “that adults with a short stature due to a SHOX defect remain undiagnosed”, note the researchers.

The average height standard deviation score was –2.3 for the index cases, at a median age of 11.7 years, and –1.7 among the related cases, who were aged a median of 38.0 years. Most patients had Léri-Weill dyschondrosteosis, identified in 91.3% of the 242 patients with available data, while 5.0% were initially diagnosed with idiopathic short stature and 3.7% had no outward sign of their mutation.

In line with other studies, the team found an increased proportion of females among their patients, especially among the index cases (70.7%).

This has been attributed in part to more severe symptoms in females, leading to detection bias. And indeed, female patients were more likely than males to have growth retardation, the Madelung deformity and mesomelic shortening. But Auger et al also found that patients more often inherited their mutations from their mothers than their fathers, at 59.1% versus 36.6%, “suggesting a favored mother-to-child transmission.”

The most common mutations were deletions; these were in the SHOX regulatory (enhancer) region only in 33.8% of patients, SHOX plus its enhancer region in 35.7% and SHOX only in 4.6%. Duplications were less frequent and found in the enhancer region alone or in combination with SHOX, at 5.9% and 2.0%, respectively.

The patients also carried 30 point mutations, including six novel missense mutations, and three novel frameshift mutations in the SHOX coding sequence.

Patients’ phenotypes varied according to the underlying mutation, with deletions generally producing a more severe phenotype than duplications. However, this also varied by gender, with the genotype–phenotype associations being evident only in females. Specifically, 61.5% of girls with deletions had Madelung deformity, compared with 8.3% of those with duplications, while 67.8% versus 33.3% had mesomelic shortening and 87.9% versus 45.4% had radiological signs of dyschondrosteosis.

This indicates a milder effect of duplications on skeletal growth, “regardless of the pathogenic mechanism”, write the researchers in Hormone Research in Paediatrics.

By Eleanor McDermid

Horm Res Paediatr 2016; Advance online publication

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