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Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects

Jan Lebl¹, Jan Vosáhlo¹, Roland W Pfaeffle³, Heike Stobbe³, Jana erná⁴, Dana Novotná⁵, Jiina Zapletalová⁶, Boena Kalvachová⁷, Václav Hána², Vladimír Weiss² and Werner F Blum⁸

¹ Department of Paediatrics, 3^rd Faculty of Medicine and ² 3^rd Department of Internal Medicine, 1^st Faculty of Medicine, Charles University, Prague, Czech Republic, ³ University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany, ⁴ Department of Paediatrics, University Hospital Ostrava, Ostrava, Czech Republic, ⁵ 2^nd Department of Paediatrics, University Hospital Brno, Brno, Czech Republic, ⁶ Department of Paediatrics, Faculty of Medicine, Palacky University, Olomouc, Czech Republic, ⁷ Institute of Endocrinology, Prague, Czech Republic and ⁸ Eli Lilly and Company, Bad Homburg, Germany

(Correspondence should be addressed to J Lebl; Email: lebl{at}fnkv.cz)

Objective: Multiple pituitary hormone deficiency (MPHD) may result from defects of transcription factors that govern early pituitary development. We aimed to establish the prevalence of HESX1, PROP1, and POU1F1 gene defects in a population-based cohort of patients with MPHD and to analyse the phenotype of affected individuals.

Design and methods: Genomic analysis was carried out on 74 children and adults with MPHD from the Czech Republic (including four sibling pairs). Phenotypic data were collected from medical records and referring physicians.

Results: One patient carried a heterozygous mutation of POU1F1 (71C > T), and 18 patients (including three sibling pairs) had a PROP1 mutation (genotypes 150delA/301delGA/9/, 301delGA/301-delGA/8/, or 301delGA/349T > A/1/). A detailed longitudinal phenotypic analysis was performed for patients with PROP1 mutations (n = 17). The mean ( ±S.D.) birth length SDS of these patients (0.12 ± 0.76) was lower than expected based on their mean ( ±S.D.) birth weight SDS (0.63 ± 1.27; P = 0.01). Parental heights were normal. The patients’ mean ( ±S.D.) height SDS declined to –1.5 ± 0.9, –3.6 ± 1.3 and –4.1 ± 1.2 at 1.5, 3 and 5 years of age, respectively. GH therapy, initiated at 6.8 ± 3.2 years of age (mean dose: 0.022 mg/kg per day), led to substantial growth acceleration in all patients. Mean adult height (n = 7) was normal when adjusted for mid-parental height. ACTH deficiency developed in two out of seven young adult patients.

Conclusions: PROP1 defects are a prevalent cause of MPHD. We suggest that testing for PROP1 mutations in patients with MPHD might become standard practice in order to predict risk of additional pituitary hormone deficiencies.

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