Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis

Based on older analyses, the World Health Organization (WHO) recommends that cesarean delivery rates should not exceed 10 to 15 per 100 live births to optimize maternal and neonatal outcomes.

Mutations in transcription factors result in combined pituitary hormone deficiency (CPHD). A genetic screening strategy, based on endocrine and neuroradiological phenotype according to published knowledge, was applied to establish the prevalence of gene defects in each category of patients and provide a useful framework for clinicians to determine the genetic etiology and recurrence risks for individuals and families. One hundred ninety-five CPHD patients from the international GENHYPOPIT network were studied, according to their phenotype, for POU1F1, PROP1, LHX3, LHX4, and HESX1. Patients selected had two pituitary hormone deficiencies or at least one deficiency with intracerebral malformations. Total prevalence of mutations was 13.3 and 52.4% in 20 patients with familial CPHD history. No mutation of HESX1 was observed in 16 patients harboring septooptic dysplasia. A mutation of LHX4 gene, previously reported, was found in one familial case from 39 patients bearing pituitary stalk interruption syndrome. In 109 patients without extrapituitary abnormalities, 20 had PROP1 mutations, including eight patients with a family history of CPHD. Among 20 patients without pituitary stalk interruption syndrome, no LHX3 gene defect was found, even with a neck rotation deficit. One POU1F1 gene defect was found in one patient presenting the rare postpubertal association of thyrotroph (TSH deficiency) and somatotroph (GH deficiency) deficits. Mutation of PROP1 gene remains the first to be looked for, and POU1F1 mutations should be sought in GH deficiency and TSH deficiency postpubertal population without extrapituitary malformations. Identification of gene defects allows early treatment of any deficit and prevention of their potentially fatal consequences. Genotyping appears highly beneficial at an individual and familial level.

Defects in pituitary gland organogenesis are sometimes associated with congenital anomalies that affect head development. Lesions in transcription factors and signaling pathways explain some of these developmental syndromes. Basic research studies, including the characterization of genetically engineered mice, provide a mechanistic framework for understanding how mutations create the clinical characteristics observed in patients. Defects in BMP, WNT, Notch, and FGF signaling pathways affect induction and growth of the pituitary primordium and other organ systems partly by altering the balance between signaling pathways. The PITX and LHX transcription factor families influence pituitary and head development and are clinically relevant. A few later-acting transcription factors have pituitary-specific effects, including PROP1, POU1F1 (PIT1), and TPIT (TBX19), while others, such as NeuroD1 and NR5A1 (SF1), are syndromic, influencing development of other endocrine organs. We conducted a survey of genes transcribed in developing mouse pituitary to find candidates for cases of pituitary hormone deficiency of unknown etiology. We identified numerous transcription factors that are members of gene families with roles in syndromic or non-syndromic pituitary hormone deficiency. This collection is a rich source for future basic and clinical studies.