Sayaka Kawashima1,2, Akie Nakamura1, Takanobu Inoue1, Keiko Matsubara1, Reiko Horikawa3, Keiko Wakui4, Kyoko Takano4, Yoshimitsu Fukushima4, Toshi Tatematsu5, Seiji Mizuno5, Junko Tsubaki6, Shigeo Kure2, Yoichi Matsubara7, Tsutomu Ogata8, Maki Fukami1, Masayo Kagami1. 1. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. 2. Department of Pediatrics, Tohoku University School of Medicine, Sendai, Miyagi, Japan. 3. Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan. 4. Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan. 5. Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, Japan. 6. Department of Pediatrics, Japan Community Health Care Organization Hokkaido Hospital, Sapporo, Hokkaido, Japan. 7. National Research Institute for Child Health and Development, Tokyo, Japan. 8. Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Abstract
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. These patients manifested a phenotype similar to 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 α-subunit of the stimulatory G protein expression. Participants: Patients 1 to 5 showed nonmosaic heterodisomy and/or isodisomy for the entire chromosome 20. Patients 1 to 3 and 4 were identified through UPD(20)mat screening for 55 patients with etiology-unknown SRS and 96 patients with SGA-SS, respectively. Patient 5 was identified through molecular analysis for patients with developmental defects. Patients 1 to 5 manifested postnatal growth failure and feeding problems, with or without developmental delay, and other clinical features. Patients 1 to 4 were born SGA. Patients 4 and 5 exhibited hypercalcemia and low or low-normal parathyroid hormone levels. Patient 1 showed constantly decreased thyroid-stimulating hormone (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 >5% of etiology-unknown SRS and small percentages of SGA-SS. Most important, this study provides an indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age.
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. These patients manifested a phenotype similar to 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 α-subunit of the stimulatory G protein expression. Participants: Patients 1 to 5 showed nonmosaic heterodisomy and/or isodisomy for the entire chromosome 20. Patients 1 to 3 and 4 were identified through UPD(20)mat screening for 55 patients with etiology-unknown SRS and 96 patients with SGA-SS, respectively. Patient 5 was identified through molecular analysis for patients with developmental defects. Patients 1 to 5 manifested postnatal growth failure and feeding problems, with or without developmental delay, and other clinical features. Patients 1 to 4 were born SGA. Patients 4 and 5 exhibited hypercalcemia and low or low-normal parathyroid hormone levels. Patient 1 showed constantly decreased thyroid-stimulating hormone (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 >5% of etiology-unknown SRS and small percentages of SGA-SS. Most important, this study provides an indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age.
Authors: Quixia Cui; Cagri Aksu; Birol Ay; Claire E Remillard; Antonius Plagge; Mina Gardezi; Margaret Dunlap; Louis C Gerstenfeld; Qing He; Murat Bastepe Journal: Front Genet Date: 2021-06-17 Impact factor: 4.599