Mental retardation and Ullrich‐Turner syndrome in cases with 45,X/46,X,+ mar: Additional support for the loss of the X‐inactivation center hypothesis

Abstract

Four cases having mosaicism for a small marker or ring [45,X/46,X,+mar or 45,X/46,X,+r] chromosome were ascertained following cytogenetic studies requested because of minor anomalies (cases 1, 3, and 4) and/or short stature (cases 2 and 4). While all 4 cases had traits typical of Ullrich-Turner syndrome (UTS), cases 1, 3, and 4 had manifestations not usually present in UTS, including unusual facial appearance, mental retardation/developmental delay (MR/DD) (cases 3 and 4), and syndactylies (case 1). The facial appearances of cases 1 and 3 were similar yet distinct from that of case 4. Using fluorescence in situ hybridization (FISH), each of the markers in these 4 cases was identified as having been derived from an X chromosome. The level of mosaicism for the mar/r(X) cell line in these cases varied from 70% (case 1) to 16% (case 4) but was not apparently correlated with the presence of MR/DD. Replication studies demonstrated a probable early replication pattern for the mar/r(X) in cases 1, 3, and 4, while the marker in case 2 was apparently late replicating. To date, 41 individuals having mosaicism for a small mar/r(X) chromosome have been described. Interestingly, most of the 14 individuals having a presumedly active mar/r(X) demonstrated clinical findings atypical of UTS, including abnormal facial changes (11) and MR/DD (13). MR was noted most frequently in those cases having at least 50% mosaicism for the marker or ring. In contrast, atypical UTS facial appearance or MR/DD was not noted in 14 of the 16 cases with UTS who carried a probable late replicating marker or ring. In conclusion, although the phenotype of 45,X/46,X,mar/r(X) individuals appears to be influenced by the genetic content and degree of mosaicism for the mar/r(X), the most significant factor associated with MR/DD appears to be the activity status of the mar/r(X) chromosome. Thus, our 4 cases provide further support for the hypothesis that a lack of inactivation of a small mar/r(X) chromosome may be a factor leading to the MR and other phenotypic abnormalities seen in this subset of individuals having atypical UTS.

A unique mosaic Turner syndrome patient with androgen receptor gene derived marker chromosome

“…Unusual facial appearance, MR/DD, and syndactylies were observed. They noted that among their patients, mental retardation was noted most frequently in the cases having at least 50% mosaicism for the marker [Cole et al 1994]. Similar features were found in our patient, namely a Turner syndrome picture with abnormal facial appearance, MR, short stature, and DD.…”

“…This concurs with the observations of the patient presented here with the absence of ovaries detected by the USG examination. Cole et al [1994] and Liehr et al [2007] reported MR for these Turner syndrome variant patients. Badeschi and colleagues [2008] described a male with severe MR with duplication on the X chromosome Xq12 to Xq12.1, which contains the OPHN1 gene.…”

Multiple congenital anomalies in a fetus with 45,X/46,X,r(X)(p11.22q12) mosaicism

“…Anomalous X inactivation has been postulated to be associated with NTDs [James, 1988], especially in cases of monozygotic twins. Faulty X inactivation, as shown in cases of small marker chromosomes that do not express XIST, may result in mental retardation and malformation [Cohen et al, 1967;Van Dyke et al, 1992;Cole et al, 1994;Kushnick et al, 1987;Migeon et al, 1993Migeon et al, , 1994Wolff et al, 1994]. Our observation of a small r(X) occurring in a female fetus with a NTD commonly showing female excess suggests that faulty X inactivation may result in abnormalities of neurulation.…”

“…In addition to mental retardation [Kushnick et al, 1987;Van Dyke et al, 1992;Cole et al, 1994;Callen et al, 1995;Cantú et al, 1995], some of these patients have limb defects [Kushnick et al, 1987;Wolff et al, 1994;Collins et al, 1994;Cantú et al, 1995], agenesis of corpus callosum [El Abd et al, 1997], Kabuki makeup facial changes [Dennis et al, 1993;McGinniss et al, 1997;El Abd et al, 1997], and prune belly sequence [Guillén et al, 1997]. More severe phenotypes, especially mental retardation, have been shown to be associated with a lack of inactivation of the small ring X chromosome due to deletion of the X inactivation center (XIC) or lack of expression of the XIST gene (X inactivation specific transcript) [Van Dyke et al, 1992;Zenger-Hain et al, 1993;Migeon et al, 1994;Callen et al, 1995].…”

Usefulness of Fluorescence in situ Hybridization for the Diagnosis of Turner Mosaic Fetuses with Small Ring X Chromosomes

“…Although the large r(X) occurrences have already been described in Turner mosaic, in females with moderate clinical manifestations and, even more, able to undergo spontaneous pregnancies [3][4][5], the tiny ones are frequently associated with a more severe phenotype and/or with mental retardation [6][7][8][9]. This phenomenon has been attributed to the inability of these small abnormal X chromosomes to inactivate, resulting in two active copies of genes in the pericentromeric region [10][11][12][13][14].…”