Inherited duplication Xq27-qter at Xp22.3 in severely affected males: Molecular cytogenetic evaluation and clinical description in three unrelated families

Abstract

We describe the clinical phenotype in four males from three families with duplication (X)(qter-->q27::p22.3-->qter). This is an unusual duplication of the distal long arm segment, Xq27-qter, onto the distal short arm of the X chromosome at Xp22.3, as shown by fluorescent in situ hybridization analysis with multiple X-specific probes. The patients are young male offspring of three unrelated, phenotypically normal carrier women. The affected males have similar clinical manifestations including severe growth retardation and developmental delay, severe axial hypotonia, and minor anomalies. Such clinical similarity in three unrelated families demonstrates that this chromosome abnormality results in a new and distinct clinical phenotype. Replication studies, performed on two of the mothers, provided evidence that inactivation of the abnormal X chromosome permitted the structural abnormality to persist in these families for a generation or more in females without phenotypic expression.

Subterminal deletion/duplication event in an affected male due to maternal X chromosome pericentric inversion

“…There are only a few reports of a dup/del event of the terminal regions within a single X chromosome in males [9,12,15,19]. The derivative X chromosome could be the consequence of a meiotic recombination event in a family [12,15,19] or the result of an inherited abnormal X from a phenotypically normal carrier mother [9].…”

“…The derivative X chromosome could be the consequence of a meiotic recombination event in a family [12,15,19] or the result of an inherited abnormal X from a phenotypically normal carrier mother [9]. A 5% recurrence risk is cited for the recombinant chromosome if one of the parents is an inversion carrier [10].…”

“…These both result in terminal duplication of the Xq region and terminal deletion of the Xp region. Duplications of the long arm of the X chromosome are also quite rare, with about 20 reported cases, all of whom have a severe phenotypic outcome [1,9,12,16,17,18,22]. Duplications of the terminal regions of the Xq chromosome have common phenotypic features, such as growth retardation of prenatal onset, developmental delay, hypotonia and cryptorchidism/retractile testes [1].…”

MECP2 duplications in six patients with complex sex chromosome rearrangements

“…The pregnancy was complicated by influenza associated with dehydration. Literature (n¼5) [21][22][23] Literature (n¼8) [25][26][27][28] …”

“…These cases are presumed to be the result of either a recombination event in a parent carrying a pericentric inversion [23][24][25][26][27] or inherited from a phenotypically normal mother carrying the abnormal X. 28 We report two additional cases in which an Xq duplication encompassing MECP2 was accompanied by an Xp deletion, resulting from a specific intrachromosomal rearrangement in which the duplicated segment of Xq was translocated to the Xp22.3 band. In each case, the derivative X chromosome was inherited from the mother who carried a pericentric inversion (Figure 2e).…”