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/

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 st udies 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 n ot usually present in UTS, including unusual facial appearance, mental retardation/developmental delay (MR/DD) (cases 3 and 4), and syndacty lies (case 1). The facial appearances of cases 1 and 3 were similar ye t distinct from that of case 4. Using fluorescence in situ hybridizati on (FISH), each of the markers in these 4 cases was identified as havi ng been derived from an X chromosome. The level of mosaicism for the m ar/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. Repl ication 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 appa rently late replicating. To date, 41 individuals having mosaicism for a small mar/r(X) chromosome have been described. Interestingly, most o f 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 wit h UTS who carried a probable late replicating marker or ring. In concl usion, although the phenotype of 45,X/46,X,mar/r(X) individuals appear s to be ifluenced by the genetic content and degree of mosaicism for t he 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 cas es provide further support for the hypothesis that a lack of inactivat ion of a small mar/r(X) chromosome may be a factor leading to the MR a nd other phenotypic abnormalities seen in this subset of individuals h aving atypical UTS. (C) 1994 Wiley-Liss, Inc.