Clinical utility of PROP1 gene screening for patients with congenital hypopituitarism

The Prophet of Pit-1 ( PROP1 ) gene encodes a transcription factor restricted to anterior pituitary organogenesis, and is commonly implicated in non-syndromic combined pituitary hormone deficiency (CPHD). We aimed to evaluate the involvement of the PROP1 gene mutations in a cohort of Tunisian patients with CPHD associated or not with Turner syndrome (TS). The coding regions of the gene and their flanking introns are Sanger sequenced among twenty patients from thirteen unrelated families with variable clinical phenotypes [non-syndromic CPHD (16/20), non-syndromic CPHD associated with TS (4/20)]. Sequences analysis showed the presence of the p.Arg73Cys mutation (rs121917843), the most frequent Maghrebian defect responsible for non-syndromic CPHD, in ten patients from five unrelated pedigrees. Among them, three sisters were diagnosed with CPHD associated with TS. We also found a novel homozygous mutation c.340C>T (p.(Gln114Ter)) in one sporadic case. We confirmed by polymerase chain reaction (PCR) the absence of large exon insertions or deletions in the remaining explored patients. Mutations of PROP1 gene remain the first to be investigated in CPHD patients. The unusual association of non-syndromic CPHD with TS is explained by the high level of consanguinity and the high frequency of the mutation in the Tunisian population. The identification of the gene defects allows early treatment of anterior pituitary hormones deficiency and the prevention of their potentially consequences. On the other hand, our study highlighted the involvement of novel gene(s) in the emergence of non-syndromic CPHD.