Combined pituitary hormone deficiency (CPHD), isolated hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), and septo-optic dysplasia (SOD) are genetically related conditions caused by abnormal development of the anterior midline in the forebrain. Although mutations in the
fibroblast growth factor receptor 1 (
FGFR1) gene have been implicated in the development of IHH, KS, and SOD, the relevance of
FGFR1 abnormalities to CPHD remains to be elucidated. Here, we report a Japanese female patient with CPHD and
FGFR1 haploinsufficiency. The patient was identified through copy-number analyses and direct sequencing of
FGFR1 performed for 69 patients with CPHD. The patient presented with a combined deficiency of GH, LH and FSH, and multiple neurological abnormalities. In addition, normal TSH values along with a low free T4 level indicated the presence of central hypothyroidism. Molecular analyses identified a heterozygous ~ 8.5 Mb deletion involving 56 genes and pseudogenes. None of these genes except
FGFR1 have been associated with brain development. No
FGFR1 abnormalities were identified in the remaining 68 patients, although two patients carried nucleotide substitutions (p.V102I and p.S107L) that were assessed as benign polymorphism by
in vitro functional assays. These results indicate a possible role of
FGFR1 in anterior pituitary function and the rarity of
FGFR1 abnormalities in patients with CPHD.
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