title: A large duplication involving the IHH locus mimics acrocallosal syndrome.
abstract: Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a ∼600-kb deletion 5' of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a ∼900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35.
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Memnune
authors.initials: M
authors.lastname: Yuksel-Apak
authors.forename: Nina
authors.initials: N
authors.lastname: Bögershausen
authors.forename: Barbara
authors.initials: B
authors.lastname: Pawlik
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Selcuk
authors.initials: S
authors.lastname: Apak
authors.forename: Oya
authors.initials: O
authors.lastname: Uyguner
authors.forename: Esther
authors.initials: E
authors.lastname: Milz
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Birsen
authors.initials: B
authors.lastname: Karaman
authors.forename: Ayan
authors.initials: A
authors.lastname: Gülgören
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Grzeschik
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D055673:Acrocallosal Syndrome / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D002648:Child; D005260:Female; D020131:Genes, Duplicate; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013576:Syndactyly / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; C509246:IHH protein, human