Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

2nd Faculty of Medicine Department of Pediatrics Charles University Prague and University Hospital Motol Prague Czech Republic

Department of Endocrinology Ataturk Training and Research Hospital Izmir Turkey

Department of Endocrinology Dicle University Diyarbakir Turkey

Department of Pediatrics Leiden University Medical Center Leiden The Netherlands

Hacettepe University Faculty of Medicine Department of Pediatrics Division of Pediatric Endocrinology Ankara Turkey

Hospital for Children and Adolescents Division of Pediatric Endocrinology University of Leipzig Leipzig Germany

PAN Institute for Endocrinology and Reproductive Medicine Cologne Germany

Reinier de Graaf Gasthuis Delft The Netherlands

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Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes