Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery

ABSTRACT The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clínicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe. Arch Endocrinol Metab. 2019;63(2):167-74

Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency / Análise molecular dos genes PROP1 e HESX1 em pacientes com displasia septo-ótica e/ou deficiência hormonal hipofisária

OBJECTIVE: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined - CPHD; isolated GH deficiency - GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. SUBJECTS AND METHODS: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. RESULTS: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. CONCLUSION: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process.

OBJETIVO: O presente estudo teve como objetivo avaliar os genes PROP1 e HESX1 em um grupo de pacientes com displasia septo-óptica (DSO) e deficiência hormonal hipofisária (combinada - DHHC; ou deficiência isolada de GH - DGH). Onze pacientes com apresentação clínica e bioquímica consistente com DHHC, DGH ou DSO foram avaliados. SUBJECTS AND METHODS: Em todos os pacientes, o gene HESX1 foi analisado pelo sequenciamento direto e, nos casos de DHHC, o gene PROP1 foi também sequenciado. RESULTADOS: Um polimorfismo no gene HESX1 (1772 A > G; N125S) foi identificado em um paciente com DSO. Foram encontrados três pacientes portadores da variação alélica 27 T > C; A9A e 59 A > G; N20S no éxon 1 do gene PROP1. Mutações no gene PROP1 e HESX1 não foram identificadas nesses pacientes com DGH, DHHC e DSO esporádicos. CONCLUSÃO: Alterações genéticas em um ou diversos outros genes ou mecanismos não genéticos devem estar implicados nesse processo patogênico.

De Morsier syndrome associated with periventricular nodular heterotopia: case reporte

INTRODUCTION: Septo-optic dysplasia (De Morsier syndrome) is defined as the association between optic nerve hypoplasia, midline central nervous system malformations and pituitary dysfunction. CASE REPORT: Third child born to nonconsanguineous parents, female, adequate pre-natal medical care, cesarean term delivery due to breech presentation, Apgar score 3 at the first minute and 8 at 5 minutes, symptomatic hypoglycemia at 18 hours. Neurological follow-up identified a delay in acquisition of motor and language developmental milestones. Epileptic generalized seizures began at 12 months and were controlled with phenobarbital. EEG was normal. MRI revealed agenesis of the pituitary stalk, hypoplasia of the optic chiasm and periventricular nodular heterotopia. Ophthalmologic evaluation showed bilateral optic disk hypoplasia. Endocrine function laboratory tests revealed primary hypothyroidism and hyperprolactinemia. CONCLUSION: The relevance of this case report relies on its uniqueness, since periventricular heterotopia had not been described in association with septo-optic dysplasia until 2006.

INTRODUÇÃO: Displasia septo-óptica (síndrome de De Morsier) é definida como a associação entre hipoplasia do nervo óptico, malformações de linha média do sistema nervoso central e disfunção pituitária. RELATO DE CASO: Terceiro filho, pais não consangüíneos, sexo feminino, pré-natal adequado, parto cesário a termo por apresentação pélvica, Apgar 3 no primeiro minuto e 8 no quinto minuto, hipoglicemia sintomática com 18 horas de vida. Durante o acompanhamento neurológico identificou-se atraso na aquisição dos marcos de desenvolvimento motor e linguagem. Crises epilépticas generalizadas iniciaram com 12 meses de vida sendo controladas com fenobarbital. EEG era normal. Ressonância magnética revelou agenesia de haste pituitária, hipoplasia de quiasma óptico e heterotopia nodular periventricular. Avaliação oftalmológica demonstrou hipoplasia bilateral de disco óptico. Investigação da função endócrina revelou hipotireoidismo primário e hiperprolactinemia. CONCLUSÃO: A relevância deste relato reside em seu ineditismo, já que heterotopia periventricular não havia sido descrita em associação com displasia septo-óptica até 2006.