Beschreibung:
<jats:title>Summary</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Combined pituitary hormone deficiency (<jats:styled-content style="fixed-case">CPHD</jats:styled-content>) is characterized by deficiencies of two or more anterior pituitary hormones. Its genetic cause is unknown in the majority of cases. The Hedgehog (Hh) signalling pathway has been implicated in disorders associated with pituitary development. Mutations in Sonic Hedgehog (<jats:italic><jats:styled-content style="fixed-case">SHH</jats:styled-content></jats:italic>) have been described in patients with holoprosencephaly (with or without pituitary involvement). Hedgehog interacting protein (<jats:italic><jats:styled-content style="fixed-case">HHIP</jats:styled-content></jats:italic>) has been associated with variations in adult height in genome wide association studies. We investigated whether mutations in these two genes of the Hh pathway, <jats:italic><jats:styled-content style="fixed-case">SHH</jats:styled-content></jats:italic> and <jats:italic><jats:styled-content style="fixed-case">HHIP</jats:styled-content></jats:italic>, could result in ′idiopathic′ <jats:styled-content style="fixed-case">CPHD</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Design/Patients</jats:title><jats:p>We directly sequenced the coding regions and exon – intron boundaries of <jats:italic><jats:styled-content style="fixed-case">SHH</jats:styled-content></jats:italic> and <jats:italic><jats:styled-content style="fixed-case">HHIP</jats:styled-content></jats:italic> in 93 <jats:styled-content style="fixed-case">CPHD</jats:styled-content> patients of the Dutch <jats:styled-content style="fixed-case">HYPOPIT</jats:styled-content> study in whom mutations in the classical <jats:styled-content style="fixed-case">CPHD</jats:styled-content> genes <jats:italic><jats:styled-content style="fixed-case">PROP</jats:styled-content>1, <jats:styled-content style="fixed-case">POU</jats:styled-content>1F1, <jats:styled-content style="fixed-case">HESX</jats:styled-content>1, <jats:styled-content style="fixed-case">LHX</jats:styled-content>3</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">LHX</jats:styled-content>4</jats:italic> had been ruled out. We compared the expression of Hh genes in Hep3B transfected cells between wild‐type proteins and mutants.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified three single‐nucleotide variants (p.Ala226Thr, c.1078C>T and c.*8G>T) in <jats:italic><jats:styled-content style="fixed-case">SHH</jats:styled-content></jats:italic>. The function of the latter was severely affected in our <jats:italic>in vitro</jats:italic> assay. In <jats:italic><jats:styled-content style="fixed-case">HHIP</jats:styled-content>,</jats:italic> we detected a new activating variant c.‐1G>C, which increases <jats:styled-content style="fixed-case">HHIP</jats:styled-content>'s inhibiting function on the Hh pathway.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our results suggest involvement of the Hedgehog pathway in <jats:styled-content style="fixed-case">CPHD</jats:styled-content>. We suggest that both <jats:italic><jats:styled-content style="fixed-case">SHH</jats:styled-content></jats:italic> and <jats:italic><jats:styled-content style="fixed-case">HHIP</jats:styled-content></jats:italic> are investigated as a second screening in <jats:styled-content style="fixed-case">CPHD</jats:styled-content>, after mutations in the classical <jats:styled-content style="fixed-case">CPHD</jats:styled-content> genes have been ruled out.</jats:p></jats:sec>