학술논문
Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants
CLINICAL RESEARCH ARTICLE
CLINICAL RESEARCH ARTICLE
Document Type
Academic Journal
Author
Sentchordi-Montane, Lucia; Benito-Sanz, Sara; Aza-Carmona, Miriam; Pereda, Arrate; Parron-Pajares, Manuel; de la Torre, Carolina; Vasques, Gabriela A.; Funari, Mariana F.A.; Travessa, Andre M.; Dias, Patricia; Suarez-Ortega, Larisa; Gonzalez-Buitrago, Jesus; Portillo-Najera, Nancy Elizabeth; Llano-Rivas, Isabel; Martin-Frias, Maria; Ramirez-Fernandez, Joaquin; del Pozo, Jaime Sanchez; Garzon-Lorenzo, Lucia; Martos-Moreno, Gabriel A.; Alfaro-Iznaola, Cristina; Mulero-Collantes, Ines; Ruiz-Ocana, Pablo; Casano-Sancho, Paula; Portela, Ana; Ruiz-Perez, Lorea; del Pozo, Angela; Vallespin, Elena; Solis, Mario; Lerario, Antonio M.; Gonzalez-Casado, Isabel; Ros-Perez, Purificacion; de Nanclares, Guiomar Perez; Jorge, Alexander A.L.; Heath, Karen E.
Source
Journal of Clinical Endocrinology & Metabolism. August 2020, Vol. 105 Issue 8, p1f, 13 p.
Subject
Language
English
ISSN
0021-972X
Abstract
Chondrogenesis is the fundamental biological process that drives linear growth and therefore stature in children, with heritable factors playing a paramount role in this process. Short stature is one of [...]
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. (J Clin Endocrinol Metab 105: 1-13, 2020) Freeform/Key Words: IHH, brachydactyly, short stature, NGS
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. (J Clin Endocrinol Metab 105: 1-13, 2020) Freeform/Key Words: IHH, brachydactyly, short stature, NGS