Severe growth retardation and limb anomalies in a boy with 47,XY,+r(7) and maternal uniparental disomy for chromosome 7

Abstract

Russell-Silver syndrome (RSS) is genetically heterogeneous with maternal uniparental disomy (mat UPD) reported in approximately 10% of cases. We report a young boy with severe growth retardation and asymmetric limb anomalies found to have maternal UPD for chromosome 7 and a small ring 7 [47, XY,upd(7)mat,+r(7)]. G.D. was the 1.85 kg SGA product of a 38 week gestation to a 17 year old P0 mother. At 31 months of age, his height was 46.7 cm (5th% for birth), weight 4.29 kg (50th % for 1 month), and head circumference 47 cm (50 % for 1 year). G.D. has asymmetrically shortened femurs and absence of the left fibula. His thumbs appear digitalized and he has decreased range of motion in his elbows. He is normocephalic with a small jaw and is moderately developmentally delayed. G-banded chromosome study showed a tiny marker (ring) containing a centromere and very little euchromatin, by spectral karyotyping the marker was identified as derived from chromosome 7. Parental karyotypes are normal. Because of his severe growth retardation and low birth weight, molecular analysis for UPD(7) was performed, revealing maternal isodisomy for most of chromosome 7 due to a maternal meiotic II error. There was a non-terminal region of heterodisomy in the q arm due to a double crossover at meiosis I. The most likely explanation of the r(7) is unsuccessful trisomy rescue in which the paternal homologue was not completely lost, but rather was retained vestigially in the form of a tiny ring chromosome. A similar mechanism has been hypothesized to explain the occurrence of cases of UPD(15) + mar(15) reported in the literature. To our knowledge, this is only the second report of mat UPD(7)+r(7) in a child. The other patient was mosaic for the ring with a less severe phenotype than our case. Studies on cases of UPD(15)+mar(15) indicate that the size of the marker directly correlates with the severity of the physical and developmental phenotype. This does not hold true for our patient as he has a severe RSS phenotype and a very small marker, leading to speculation on other possible causes including homozygosity for a deleterious gene on 7.