ESPE Abstracts (2018) 89 P-P1-186

Maternal Uniparental Disomy for Chromosome 20: Physical and Endocrinological Characteristics of Six Patients

Sayaka Kawashimaa, Akie Nakamuraa, Takanobu Inouea, Keiko Matsubaraa, Reiko Horikawab, Keiko Wakuic, Kyoko Takanoc, Yoshimitsu Fukushimac, Toshi Tatematsud, Seiji Mizunod, Junko Tsubakie, Shigeo Kuref, Yoichi Matsubarag, Tsutomu Ogatah, Keisuke Nagasakii, Maki Fukamia & Masayo Kagamia

aDepartment of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; bDivision of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan; cDepartment of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; dDepartment of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, Japan; eDepartment of Pediatrics, Japan Community Health Care Organization Hokkaido Hospital, Sapporo, Hokkaido, Japan; fDepartment of Pediatrics, Tohoku University School of Medicine, Sendai, Miyagi, Japan; gInstitute Director, National Research Institute for Child Health and Development, Tokyo, Japan; hDepartment of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; iDivision of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Context: Maternal uniparental disomy for chromosome 20 (UPD(20)mat) resulting in aberrant expression of imprinted transcripts at the GNAS locus is a poorly characterized condition. Only 10 non-mosaic cases have been studied clinically. These patients presented with pre- and post-natal growth failure and feeding difficulties. The phenotype of these cases overlapped with that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS); however, the etiological relationship between UPD(20)mat and SRS/SGA-SS remains unclear. Moreover, no report has described endocrinological assessment of UPD(20)mat patients, although paternal UPD(20), the mirror image entity of UPD(20)mat, is known to cause multiple hormone resistance reflecting reduced Gsα expression.

Methods: We screened for DNA methylation abnormalities at the GNAS locus in 59 individuals who satisfied the diagnostic criteria for SRS using the Netchine-Harbison clinical scoring system and 98 patients clinically diagnosed with SGA-SS. Patients with abnormal methylation levels at the GNAS locus were subjected to microsatellite analysis for chromosome 20 using DNA samples obtained from these patients and their parents. In addition, we performed Comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) array analysis for UPD(20)mat patients to detect the region of isodisomy or cryptic heterodisomy.

Case description: Six patients showed non-mosaic hetero- and/or iso-disomy for the entire chromosome 20. Four patients were identified through UPD(20)mat screening for 59 patients with etiology-unknown SRS and one patient was identified for 98 patients with SGA-SS, respectively. One patient was identified through molecular analysis for patients with developmental defects. They manifested postnatal growth failure and feeding problems with or without developmental delay and other clinical features. Five of four patients were born SGA. Two patients exhibited hypercalcemia and low or low-normal PTH levels. One patient showed constantly decreased TSH levels after 12 years of age, although she had a normal TSH level at 5.2 years of age.

Conclusion: The results suggest that UPD(20)mat underlies growth failure and feeding problems with additional features, and could account for more than 6% of etiology-unknown SRS and 1% of SGA-SS. One patient indicate that UPD(20)mat can also underlie SS without SGA. Most importantly, this study provides the first indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age.