CEREBELLAR ATAXIA, PRIMARY OVARIAN INSUFFICIENCY AND HETEROZYGOUS 195.6 KB DELETION ON CHROMOSOME 6P25.1

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

Poster Board SUN-604
Michael Hauschild*, Daniele Cassatella, Danielle Martinet, Marco Belfiore, Franziska Phan Hug, Andrew A Dwyer and Nelly Pitteloud
Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
Cerebellar ataxia has been associated with either hyper or hypogonadotropic hypogonadism.  Some cases have an autosomal recessive inheritance, while others are sporadic. Interferences with common genetic pathways may explain the association of ataxia and hypogonadism.

A 17-year-old female diagnosed with congenital cerebellar ataxia presented for evaluation of slow pubertal development and primary amenorrhea. Family history was negative for ataxia or reproductive disorders. The mother has been diagnosed of vestibular schwannoma. On exam, the patient had a normal BMI (+0.95 SD), exhibited Tanner III breasts, and pubic/axillary hair, lumbar scoliosis, hypermetropism, and neurologic signs of ataxia. Hormonal evaluation revealed elevated gonadotropin levels (LH 22.6 U/L, FSH 47.9 U/L), low estradiol (0.09 nmol/L), and low Inhibin B (3.8 pg/ml), and AMH (< 3 pmol/L) levels consistent with primary ovarian insufficiency. Specific ovarian antibodies were negative. Pelvic ultrasound indicated small uterine and ovarian volumes. Cranial MRI showed a small pituitary gland (438 mm3) with cerebellar/brain stem atrophy. DEXA revealed severe osteoporosis (lumbar spine z-score: – 3.5, hip z-score: -2.7 SD) and estrogen therapy was initiated.

Karyotype was normal (46,XX) while comparative genomic hybridization (CGH) Array (agilent human genome kit 244 k) revealed a 195.6 kb heterozygous deletion on chromosome 6p25.1 also identified in her mother. At present, no RefSeq genes in this region have been described and it is considered a polymorphic region with copy number variants.  This locus harbors promoting regions for transcription factors that might regulate chromodomain protein on Y chromosome-like (CDYL), located at 241 kb from the deleted region. CDYL is required for chromatin targeting and interacts with a catalytic subunit of Polycomb Repressive Complex 2 (PRC2). CDYL is a repressor of transcription and might regulate cellular transformation (Mulligan et al; Mol Cell 2008). Quantitative Real-Time PCR to compare mRNA levels of the flanking genes in patients harboring the deletions and controls should be performed to confirm this possibility.

Conclusions: 1) A heterozygous 195kb deletion in 6p25.1 is found in a patient with ataxia and hypergonadotropic hypogonadism and her mother treated for vestibular schwannoma. 2) Although this association could be interpreted as fortuitous, the possibility of a causal phenotypic implication should be considered.

Mulligan P, et al. Mol Cell. 2008 Dec 5;32(5):718-26.

Nothing to Disclose: MH, DC, DM, MB, FP, AAD, NP

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