Holoprosencephaly, idiopathic hypogonadotropic hypogonadism, renal dysgenesis, and M. Hirschsprung: Description of a novel FGF8 mutation as a potential cause

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 596-623-Case Reports: Pediatric Endocrinology & Metabolism
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-602
Alexander Heiko Iwen*1, Sven Olaf Hiort2, Saskia Biskup3, Yorck Hellenbroich4 and Georg Brabant5
1Universität zu Lübeck, Lubeck, Germany, 2Univ of Luebeck, Luebeck, Germany, 3Center for Genomics and Transcriptomics, Tübingen, Germany, 4Universität zu Lübeck, Lübeck, Germany, 5Experimental and Clinical Endocrinology, Luebeck, Germany
Context: Holoprosencephaly (HPE) and septo-optic dysplasia have recently been analyzed in more detail and mutations of several genes have been described. We describe a novel homozygous mutation within the fibroblast growth factor 8 (FGF8) gene in a male patient suffering of this syndrome complex.

Medical history: The patient (karyotype 46, XY) was born as the first child to a consanguineous marriage (cousins). At 4 weeks of age he was diagnosed with muscular hypotonia and bilateral maldescensus testis. Constipation lead to colon surgery for M. Hirschsprung aged 8 months. At 2 years of age left nephrectomy for a dysplastic kidney and ureter and a bilateral orchidolysis and orchidopexy was performed. Due to missing thirst sensation the patient suffered of hypernatremia (155-165 mmol/l). Sensoric neuropathy with a progressive spasticity was diagnosed and cognitive function was impaired. Subsequently pseudohypoparathyroidism was detected (Ca 2,36 mmol/l, PTH 72 pg/ml, 25-OH vitamin D3 15,5 ng/ml, missing cAMP response to PTH-infusion) and hypogonadotropic hypogonadism (HH; LH 0,3 IU/l, FSH 0,6 IU/l, testosterone 0,3 ng/ml) was diagnosed. His disabilities nevertheless allow him to regularly work in a special care institution.

Results: We first performed an array CGH showing small deletions at 3p14.1(65,759,316-65,938,016)x1 and 22q11.21(21,419,630-21,464,119)x1 so far not associated with a human disease. Subsequently we used a dedicated NGS-panel to screen for mutations in the following genes: GLI2, GLI3, PTCH1, SHH, SIX3, TGIF1, CDON, ZIC2, and FGF8. A homozygous mutation of FGF8 (A169V) in a highly conserved gene region was identified. The parents were found to be heterozygous carriers of this mutation.

Summary: FGF8 mutations are recognized as a rare cause of HPE and/or hypothalamic/pituitary dysfunction including HH. The intestinal and renal disorders described in our patient suggest that FGF8 mutations may play an additional role in gut, renal and reproductive tract development in humans as shown in animal models.

Nothing to Disclose: AHI, SOH, SB, YH, GB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm