Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects

Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects

Author Paulo, Sabrina Soares Google Scholar
Fernandes-Rosa, Fabio L. Google Scholar
Turatti, Wendy Google Scholar
Coeli-Lacchini, Fernanda Borchers Google Scholar
Martinelli, Carlos E. Google Scholar
Nakiri, Guilherme S. Google Scholar
Moreira, Ayrton C. Google Scholar
Santos, Antonio C. Google Scholar
Castro, Margaret de Google Scholar
Antonini, Sonir R. Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Abstract Context and ObjectiveSonic Hedgehog (SHH) and GLI2, an obligatory mediator of SHH signal transduction, are holoprosencephaly (HPE)-associated genes essential in pituitary formation. GLI2 variants have been found in patients with congenital hypopituitarism without complex midline cerebral defects (MCD). However, data on the occurrence of SHH mutations in these patients are limited. We screened for SHH and GLI2 mutations or copy number variations (CNV) in patients with congenital hypopituitarism without MCD or with variable degrees of MCD.Patients and MethodsDetailed data on clinical, laboratory and neuroimaging findings of 115 patients presenting with congenital hypopituitarism without MCD, septo-optic dysplasia or HPE were analysed. the SHH and GLI2 genes were directly sequenced, and the presence of gene CNV was analysed by multiplex ligation-dependent probe amplification (MLPA).ResultsAnterior pituitary deficiency was found in 74% and 53% of patients with SOD or HPE, respectively. Diabetes insipidus was common in patients with HPE (47%) but infrequent in patients with congenital hypopituitarism or SOD (7% and 8%, respectively). A single heterozygous nonsense SHH mutation (p.Tyr175Ter) was found in a patient presenting with hypopituitarism and alobar HPE. No other SHH mutations or CNV were found. Nine GLI2 variations (8 missense and 1 frameshift) including a homozygous and a compound heterozygous variation were found in patients with congenital hypopituitarism or SOD, but not in HPE patients. No GLI2 CNV were found.ConclusionSHH mutations or copy number variations are not a common cause of congenital hypopituitarism in patients without complex midline cerebral defects. GLI2 variants are found in some patients with congenital hypopituitarism without complex midline cerebral defects or septo-optic dysplasia. However, functional analyses of these variants are needed to strengthen genotype-phenotype relationship.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 10/11510-1
FAPESP: 07/59365-3
Date 2015-04-01
Published in Clinical Endocrinology. Hoboken: Wiley-Blackwell, v. 82, n. 4, p. 562-569, 2015.
ISSN 0300-0664 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 562-569
Origin http://dx.doi.org/10.1111/cen.12565
Access rights Closed access
Type Article
Web of Science ID WOS:000350982900015
URI http://repositorio.unifesp.br/handle/11600/38972

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