Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants

Author(s):Show less -

Sentchordi-Montane, Lucia ^{[1, 2, 3, 4]} ; Benito-Sanz, Sara ^{[5, 2]} ; Aza-Carmona, Miriam ^{[5, 2, 4]} ; Pereda, Arrate ^[6] ; Parron-Pajares, Manuel ^{[4, 7]} ; de la Torre, Carolina ^[2] ; Vasques, Gabriela A. ^{[8, 9]} ; Funari, Mariana F. A. ^[9] ; Travessa, Andre M. ^[10] ; Dias, Patricia ^[10] ; Suarez-Ortega, Larisa ^[11] ; Gonzalez-Buitrago, Jesus ^[12] ; Elizabeth Portillo-Najera, Nancy ^[13] ; Llano-Rivas, Isabel ^[14] ; Martin-Frias, Maria ^[15] ; Ramirez-Fernandez, Joaquin ^[16] ; del Pozo, Jaime Sanchez ^[17] ; Garzon-Lorenzo, Lucia ^[17] ; Martos-Moreno, Gabriel A. ^{[18, 19, 20]} ; Alfaro-Iznaola, Cristina ^[21] ; Mulero-Collantes, Ines ^[22] ; Ruiz-Ocana, Pablo ^[23] ; Casano-Sancho, Paula ^{[24, 25]} ; Portela, Ana ^[26] ; Ruiz-Perez, Lorea ^[27] ; del Pozo, Angela ^{[1, 5]} ; Vallespin, Elena ^{[1, 5]} ; Solis, Mario ^[1] ; Lerario, Antonio M. ^{[28, 8]} ; Gonzalez-Casado, Isabel ^{[4, 29]} ; Ros-Perez, Purificacion ^[30] ; Perez de Nanclares, Guiomar ^[6] ; Jorge, Alexander A. L. ^{[8, 9]} ; Heath, Karen E. ^{[5, 2, 4]}

Affiliation:Show less -

^[1] Univ Complutense Madrid, Sch Med, Dept Pediat, Madrid 28040 - Spain

^[2] Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, IdiPAZ, Madrid 28046 - Spain

^[3] Hosp Univ Infanta Leonor, Dept Pediat, Madrid 28031 - Spain

^[4] Hosp Univ La Paz, Skeletal Dysplasia Multidisciplinary Unit UMDE, Madrid 28046 - Spain

^[5] ISCIII, CIBERER, Madrid 28029 - Spain

^[6] Hosp Univ Araba Txagorritxu, BioAraba Hlth Res Inst, Mol Epi Genet Lab, Rare Dis Res Grp, Vitoria 01009, Araba - Spain

^[7] Hosp Univ La Paz, Dept Radiol, Madrid 28046 - Spain

^[8] Univ Sao Paulo, Hosp Clin, Unidades Endocrinol Genet LIM25, Fac Med, BR-01246903 Sao Paulo - Brazil

^[9] Univ Sao Paulo, Hosp Clin, Lab Hormonios & Genet Mol LIM42, Unidade Endocrinol Desenvolvimento, Fac Med, BR-05403000 Sao Paulo - Brazil

^[10] Hosp Santa Maria, Ctr Hosp Lisboa Norte, Ctr Acad Med Lisboa, Dept Pediat, Serv Genet Med, P-1649028 Lisbon - Portugal

^[11] Hosp St Joan Deu, Div Endocrinol, Barcelona 08950 - Spain

^[12] Hosp San Pedro de Alcantara, Dept Pediat, Caceres 10003 - Spain

^[13] Hosp Alto Deba, Dept Pediat, Arrasate Mondragon 20500, Guipuzkoa - Spain

^[14] Cruces Univ Hosp, Osakidetza Basque Hlth Serv, Dept Genet, Baracaldo 48903, Bizkaia - Spain

^[15] Hosp Univ Ramon y Cajal, Dept Pediat Endocrinol, Madrid 28034 - Spain

^[16] Hosp Univ Principe Asturias, Dept Pediat, Madrid 28805 - Spain

^[17] Hosp Univ Doce Octubre, Dept Pediat Endocrinol, Madrid 28041 - Spain

^[18] Hosp Infantil Univ Nino Jesus, Inst Invest Sanitaria La Princesa, Dept Endocrinol, Madrid 28009 - Spain

^[19] Univ Autonoma Madrid, Sch Med, Dept Pediat, Madrid 28029 - Spain

^[20] ISCIII, CIBEROBN, Madrid 28029 - Spain

^[21] Hosp Univ Rey Juan Carlos, Dept Pediat, Madrid 28933 - Spain

^[22] Hosp Univ Rio Hortega, Dept Pediat, Valladolid 47012 - Spain

^[23] Hosp Univ Puerta del Mar, Dept Pediat, Cadiz 11009 - Spain

^[24] Univ Barcelona, Inst Recerca Pediat, Dept Pediat Endocrinol, Hosp St Joan Deu, Barcelona 08950 - Spain

^[25] ISCIII, CIBERDEM, Madrid 28029 - Spain

^[26] Hosp Univ Nuestra Senora de Candelaria, Dept Pediat Endocrinol, Pediat Unit, Santa Cruz De Tenerif 38010 - Spain

^[27] Hosp Gen Univ Alicante, Dept Pediat Endocrinol, Alicante 03010 - Spain

^[28] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[29] Hosp Univ La Paz, Dept Pediat Endocrinol, Madrid 28046 - Spain

^[30] Hosp Univ Puerta de Hierro Majadahonda, Dept Pediat, Madrid 28222 - Spain

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 105, n. 8, p. 2654-2666, AUG 2020.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants