Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants

Abstract

Context Heterozygous variants in the Indian hedgehog gene (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 The objective of this article is 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 for 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 whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly. Conclusions 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 characterization before concluding that a variant is causative.

A Japanese family with a heterozygous novel mutation in the Indian hedgehog gene exhibiting a broad spectrum of clinical features and radiological findings

“…To objectively characterize brachydactyly in this family, we performed a metacarpophalangeal pattern profile (MCPP) for the three patients, which did demonstrate not only brachymesophalangy and brachymatacarpia but brachytelephalaby, which recapitulated what Sentchordi-Montané et al reported and resembled those seen in ACFD (Figure S1). 6 In agreement with the previous report by Sentchordi-Montané et al, 5 we found that IHH heterozygous variants caused broader clinical and radiological manifestations than previously thought. The clinical manifestations of IHH heterozygous variants are variable even within the same family.…”

“…4 Recently, Sentchordi-Montané et al reported the broad spectrum of the clinical and radiological features in families with heterozygous IHH variants. 5 In addition to brachymesophalangy and short stature, affected individuals may have upper limb shortening, distal phalangeal shortening (brachytelephalangy), and metacarpal shortening (brachymetacarpia), associated with cone-shaped epiphyses. 5 Here, we describe a Japanese family with a novel heterozygous mutation in IHH.…”

“…5 In addition to brachymesophalangy and short stature, affected individuals may have upper limb shortening, distal phalangeal shortening (brachytelephalangy), and metacarpal shortening (brachymetacarpia), associated with cone-shaped epiphyses. 5 Here, we describe a Japanese family with a novel heterozygous mutation in IHH. Affected family members manifested with variable combinations of short stature, short upper limbs, and unclassifiable brachydactyly with coneshaped epiphyses.…”

SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency

“… 4 Skeletal chondrodysplasias caused by Ihh gene inactivation mutations have been reported to be among the most common forms of idiopathic short stature and are clinically characterized by variable degrees of short stature, short limbs, brachydactyly, and narrow thorax with pectus deformities. 2 , 3 , 4 , 5 Currently, there is no effective treatment for these diseases. Although human growth hormone has been used to treat these diseases, little evidence has confirmed the effectiveness of such treatments 4 , 6 due to the lack of an ideal animal model for testing the efficacy of therapeutic strategies and drugs.…”

New gene discoveries in skeletal diseases with short stature

“…Some of the patients were born small for gestational age (SGA). Recently, heterozygous pathogenic IHH variants were identified in another cohort with short stature and/or brachydactyly, including the first patient with a complete deletion of IHH , who presented with both short stature and brachydactyly ( 57 ).…”