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Endocrine Abstracts (2015) 37 S3.2 | DOI: 10.1530/endoabs.37.S3.2

1Aix-Marseille University, CNRS, CRN2M UMR 7286, Marseille, France; 2Service d’Endocrinologie, Hôpital de la Conception, APHM, Marseille, France.

Genetic causes of anterior pituitary hormone deficiencies may result in combined or isolated pituitary hormone deficiencies. These disorders represent a heterogeneous group of rare diseases leading to defective function of specific pituitary cell types. Since the first description of POU1F1 human mutations, several other genetic defects of transcription factors have been reported with variable degrees of phenotype-genotype correlations. However to date, despite the identification of a growing number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80–90%) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI…), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance).

Some patients harbour a complex phenotype including anterior pituitary hormone deficiencies in association with extra pituitary abnormalities or malformations on MRI such as pituitary stalk interruption syndrome or midline defects. The transcription factors genes involved in these phenotypes (for instance LHX3, LHX4) are early expressed in regions that determine the formation of forebrain and related midline structures such as the hypothalamus and pituitary. Mutations in these genes are therefore characterized by marked phenotypic heterogeneity. Among more recently identified forms, the DAVID syndrome, an association of a deficit in adrenocorticotrophin with recurrent infections due to variable immunodeficiency was recently associated with NFKB2 mutations. In contrast, ‘pure’ endocrine phenotypes include anterior pituitary hormone deficiencies (progressive or not) with normal hypothalamo-pituitary morphology at MRI (regardless of the size of the pituitary gland) and no extra pituitary malformation. They are due to mutations of late-acting pituitary specific transcription factors. In such a context, PROP1 gene mutations remain the most frequently reported genetic defect.

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