Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon?
Although recent studies have often revealed the presence of multilocus imprinting disturbance (MLID) at differentially methylated regions (DMRs) in patients with imprinting disorders (IDs), most patients exhibit clinical features of the original ID only. Here we report a Japanese female patient with Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib. Molecular studies revealed marked methylation defects (MDs) at the Kv-DMR and the GNAS-DMRs and variable MDs at four additional DMRs, in the absence of a mutation in ZFP57, NLRP2, NLRP7, KHDC3L and NLRP5. It is likely that the MDs at the Kv-DMR and the GNAS-DMRs were sufficient to cause clinically recognizable IDs, whereas the remaining MDs were insufficient to result in clinical consequences or took place at DMRs with no disease-causing imprinted gene(s). The development of MLID and the two IDs of this patient may be due to a mutation in a hitherto unknown gene for MLID, or to a reduced amount of DNA methyltransferase-1 (DNMT1) available for the methylation maintenance of DMRs because of the consumption of DNMT1 by the maintenance of X-inactivation. In support of the latter possibility, such co-existence of two IDs has primarily been identified in female patients, and MLID has predominantly been identified as loss of methylations.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Shinichiro
S
Sano
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Keiko
K
Matsubara
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Keisuke
K
Nagasaki
Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
Toru
T
Kikuchi
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kazuhiko
K
Nakabayashi
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kenichiro
K
Hata
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Maki
M
Fukami
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Masayo
M
Kagami
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Tsutomu
T
Ogata
D001506:Beckwith-Wiedemann Syndrome / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D055028:Comparative Genomic Hybridization; D018899:CpG Islands; D019175:DNA Methylation; D019066:Facies; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011547:Pseudohypoparathyroidism / Q000175:diagnosis* / Q000235:genetics*; D040641:Quantitative Trait Loci; D012737:Sex Factors