Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort
Résumé
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.
Mots clés
ACTH deficiency
candidate gene approach
central hypothyroidism
congenital hypopituitarism
genetic screening
growth hormone deficiency
HESX1
LHX3
LHX4
PROP1
POU1F1
TBX19
OTX2
PROKR2
hypogonadotroph
hypogonadism
Next‐Generation Sequencing
ocular defect
panhypopituitarism
pituitary development
pituitary stalk interruption
transcription factor
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