ESPE Abstracts (2014) 82 P-D-2-1-515

High Prevalence of PROP1 Gene Defects Among Patients with Multiple Pituitary Hormone Deficiency in Lithuania

Ruta Navardauskaitea, Petra Dusatkovab, Barbora Obermannovab, Roland W Pfaefflec, Werner F Blumc, Dalia Adukauskiened, Natalija Smetaninaa, Ondrej Cinekb, Rasa Verkauskienea & Jan Leblb

aMedical Academy, Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania; b2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Department of Pediatrics, Prague, Czech Republic; cDivision of Pediatric Endocrinology, Department of Pediatrics, University of Leipzig, Leipzig, Germany; dMedical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania

Background: Mutations in PROP1 are the most common known genetic cause of congenital multiple pituitary hormone deficiency (MPHD).

Objective and hypotheses: Aim of our study was to clinically and genetically characterize a cohort of Lithuanian patients with MPHD.

Method: Seventy-six Lithuanian MPHD patients were tested for PROP1 gene by Sanger sequencing. Hormonal investigations, pituitary imaging and GH therapy were performed at a single centre in Kaunas. Ancestral origin of mutation was assessed by haplotype analysis of 21 single nucleotide polymorphisms flanking the PROP1 gene.

Results: Fifty-two subjects (28 males) including ten sibling pairs and two sibling triples from 38 unrelated families were found to carry a biallelic PROP1 gene mutation. Fifty of these were homozygous for c.296delGA and two patients were compound heterozygotes for c.296delGA/R71H and c.296delGA/c.150delA, respectively. Birth lengths/weights of PROP1 mutation carriers were normal. Height declined to SDS −1.56, −2.34, −3.43, −3.52; and −3.70 (medians) at years 1–5. Deficiencies of GH, TSH, ACTH, and FSH/LH were diagnosed in 50/52, 52/52, 21/52; and 25/52 subjects at median age of 5.5; 5.6; 13.1; and 15.0 years, respectively. Pituitary height ranged from 16.6 mm (+20.2 S.D.) to 1.4 mm (−15.5 S.D.) and declined with age (r2=0.27, P=0.001). GH therapy increased growth rates to 12.2; 9.1; 6.9; 6.8; 6.7; 5.6; and 5.7 cm/year (medians) at 1–7 years. Perinatal events attributable to hypopituitarism were not frequent, except testicular retention recorded in 28% of boys. The c.296delGA mutation carriers shared a common haplotype spanning ~1 Mb around the PROP1 gene.

Conclusion: We found the highest rate of PROP1 mutations among MPHD patients from populations studied so far (17.5 per million). High prevalence of PROP1 defects in Lithuania is caused by a presence of ancestral mutation c.296delGA.