Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections.

CONTEXT: Among 22 independent patients from the GENHYPOPIT network who had ACTH deficiency and no identified mutation of TPIT, three of them (13.6%) displayed common variable immunodeficiency (CVID), characterized by defective Ig production. OBJECTIVE: Our objective was to describe an as yet unrecognized disease association. DESIGN: We considered the hypothesis of ACTH deficiency being associated with antipituitary autoimmunity or lymphocytic hypophysitis. In the context of a functional network between the immune and endocrine systems, we also tested the hypothesis of a common genetic cause using a candidate gene approach. SETTING: This was a multicentric study in three academic hospitals. PATIENTS: We report four patients from three unrelated families presenting with ACTH deficiency and CVID. MAIN OUTCOME MEASURES: Detection of antipituitary autoantibodies, and sequencing of candidate genes (LIF, IKAROS, EOS) were the main outcome measures. RESULTS: All patients including a pedigree with two affected siblings had ACTH deficit diagnosed from 5-15 yr, with symptomatic hypoglycemia, and CVID diagnosed from 2-8 yr revealed by recurrent infections. Three of the four patients had a hypoplastic pituitary. One patient had low IGF-I and subnormal GH response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients proved negative for pituitary autoantibodies and had no alteration in any of the genes tested. CONCLUSIONS: The remarkable association of two rare disorders affecting two functionally related systems in four patients from three independent pedigrees including a familial case provides strong evidence of the existence of a disease association: deficit in anterior pituitary function and variable immune deficiency, or DAVID.