Mental retardation and Ullrich-Turner syndrome in cases with 45,X/46X,+mar: additional support for the loss of the X-inactivation center hypothesis.
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.
Cole
H
H
Department of Human Genetics, Medical College of Virginia/Virginia Commonwealth University, Richmond.
Huang
B
B
Salbert
B A
BA
Brown
J
J
Howard-Peebles
P N
PN
Black
S H
SH
Dorfmann
A
A
Febles
O R
OR
Stevens
C A
CA
Jackson-Cook
C
C
D002648:Child; D004261:DNA Replication; D004303:Dosage Compensation, Genetic; D005145:Face / Q000002:abnormalities; D005260:Female; D006314:Hearing Loss, Conductive / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D009030:Mosaicism; D010641:Phenotype; D012303:Ring Chromosomes; D013576:Syndactyly / Q000235:genetics*; D014424:Turner Syndrome / Q000235:genetics*; D014960:X Chromosome / Q000648:ultrastructure*