Clinical and molecular description of 16 families with heterozygous IHH variants.

CONTEXT: Heterozygous variants in IHH have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. OBJECTIVE: To describe the genotype and phenotype of 16 probands with heterozygous variants in IHH. PATIENTS: and Methods: Targeted Next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly in which the genetic cause was unknown. RESULTS: Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands where family members were available. However, clinical heterogeneity was observed: two short-statured probands showed no hand radiological anomalies whilst another five were of normal height but had brachydactyly. CONCLUSION: Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterisation before concluding that a variant is causative.