ESPE Abstracts (2014) 82 P-D-2-1-540

A Novel Mutation at a Splice Acceptor Site of WDR11 in a Patient with Combined Pituitary Hormone Deficiency

Yoko Izumia,b, Erina Suzukia, Shuichi Yatsugac, Shinichiro Sanoa, Kazuhiko Nakabayashid, Akihiro Umezawae, Kenichiro Hatad, Tsutomu Ogataf, Maki Fukamia & Yasunori Yoshimurab


aDepartment of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; bDepartment of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; cDepartment of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Fukuoka, Japan; dDepartment of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; eDepartment of Reproductive Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; fDepartment of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan


Background: WDR11 has recently been reported as one of the causative genes of hypogonadotropic hypogonadism (HH). To date, five missense mutations in WDR11 have been identified in six patients with normosmic isolated HH (nIHH) or Kallmann syndrome (KS).

Methods: We performed mutation screening of WDR11 for 46 cases with various types of HH. RT-PCR was carried out for a patient with a mutation. The protein structure of the mutant WDR11 was predicted by in silico analysis.

Results: A heterozygous mutation at a splice acceptor site of WDR11 (g.IVS3-2A>G) was identified in a male patient. RT-PCR revealed that the mutation led to an inflame deletion of the entire exon 4 of WDR11. The mutant allele was predicted to encode an aberrant protein (p.D118_L175delinsV) that disrupts the functionally-important WD40 domain.

Phenotype of the mutation-positive patient: The male patient was born at 37 weeks of gestation with 3460 g (+1.9 S.D.) and 51.0 cm (+1.8 S.D.). The pregnancy was complicated by pregnancy-induced diabetes mellitus and hypertension. He showed apparent growth failure from 1.5 years of age. Endocrine evaluation revealed impaired GH secretion and normal thyroid and adrenal function. Brain MRI showed stalk interruption and ectopic posterior lobe of the pituitary. His sense of smell was normal. GH supplementation therapy from 1.11 years of age significantly improved his growth. At 7 years of age, he presented with micropenis, descended normal sized testes, obesity (height 111.1 cm, −1.7 S.D.; weight 30.4 kg, +1.8 S.D.) and mental retardation. Blood levels of testosterone and LH were low. His mother carrying the same heterozygous mutation manifested irregular menses without delayed puberty.

Conclusion: The results indicate that WDR11 mutations can underlie not only nIHH and KS but also CPHD.