Mutation analysis of POUF‐1, PROP‐1 and HESX‐1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo‐optic dysplasia

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Abstract
Summary: Objectives  Mutations in the genes encoding the transcription factors PROP1 and POUF‐1 (Pit‐1) have been reported as common causes of combined pituitary hormone deficiency (CPHD), and HESX1 mutations have been identified in children with septo‐optic dysplasia (SOD). There are few data on UK children. We have performed mutation analysis in a large cohort of affected children within the West Midlands region to assess the feasibility of a screening strategy for molecular diagnosis in CPHD and SOD.Design and Patients  The three coding exons of PROP1, and six exons of POUF‐1 in 27 children from 26 families with CPHD, and three exons of HESX1 in 23 children from 22 families with SOD were directly sequenced from a well‐characterized regional cohort.Results  We identified a C to T transition in exon 6 of POUF‐1, resulting in a known missense mutation (R271W) in a mother and daughter from one family with CPHD. We also found a novel homozygous T to C transition in exon 6 of POUF‐1, resulting in a missense mutation (F233L) in a twin with CPHD. This mutation was excluded in 100 ethnically matched control alleles. We did not identify any mutations in the PROP1 gene or HESX1. The median maternal age at delivery for the CPHD children was 27 years, compared to 21 years for the mothers of SOD children (P = 0·04).Conclusions  Mutations in POUF‐1, PROP1 and HESX1 are rare causes of CPHD and SOD, respectively, in children from the West Midlands. In particular, we did not confirm the reported ‘hotspot’ in PROP1. A screening strategy that targets familial cases is highly likely to increase the mutation yield. The young maternal age at conception of children with SOD and potential teratogen exposure indicate the predominance of environmental factors in this condition compared with CPHD.