The Principles of Clinical Cytogenetics - Extra Materials - Springer

226 Cynthia Powell
Xp Duplications
Duplications of Xp involving bands p21.2 to 21.3 plus a Y chromosome have been reported in
patients who were phenotypic females, suggesting a sex-determining gene locus on Xp (189,190).
These patients also had mental retardation and multiple anomalies. This area of the X has been termed
the dosage sensitive sex reversal (DSS) region (see the section 46,XY Females). Dosage-sensitive
sex reversal is the result of duplication of the DAX1 gene, which, when deleted or mutated, leads to
congenital adrenal hypoplasia (191). Males with duplications involving more distal Xp have been
reported with mental retardation and autism but without sex reversal (192).
Both normal and abnormal phenotypes, and normal fertility as well as amenorrhea, have been
reported in females with Xp duplications and one normal X chromosome (189,190,193). The abnormal
phenotype, including Turner syndrome features, short stature, seizures, amenorrhea, but normal
intelligence, was seen in a female with complete inactivation of the duplicated X, suggesting that
random inactivation was not the cause (193). An interstitial duplication at Xp11.1-p21.2 was reported
in a female with macrocephaly, cleft lip, hypertelorism, and other dysmorphic features who died at age
2 months. There was random X chromosome replication pattern in this patient (194). In a review of 52
females with partial X duplications involving Xp or Xq, Matsuo et al. (195) found that random or skewed
but not completely selective X inactivation occurred in 9 of 45 patients examined for X-inactivation pattern,
independent of the size or location of the duplicated segments. For Xp duplications, 4 of 6 patients
with random or skewed X inactivation had an apparently normal phenotype, and 3 of 12 patients with
selective inactivation of the duplicated chromosome had clinical abnormalities (195).
A dicentric inverted duplication of most of the short arm of the X [dic inv dup(X)(qter →
p22.3::p22.3 → cen)] has been reported in a mother and daughter with short stature, mental retardation,
and dysmorphic features. The mother had the duplicated X as the inactive X in all cells, but the
daughter had the duplicated X active in 11% of lymphocytes (196).
Females with duplications of Xp including the SHOX gene region have been reported with both
tall (197) and normal stature (198).
Xq Duplications
Males with duplications of the long arm of the X usually have significant mental retardation and
birth defects resulting from functional disomy of the duplicated regions. Most females with Xq duplications
have normal phenotypes and are ascertained after the birth of an abnormal male child. However,
there have been females with phenotypic abnormalities, including short stature, microcephaly,
developmental delay/mental retardation, and gonadal dysgenesis, reported. Reasons for this variability
might be the size or location of the duplicated segment (199,200), random (nonskewed) X inactivation,
duplication of dosage-sensitive genes and genes that normally escape inactivation, incomplete
inactivation of a portion of the duplicated segment, or an imprinting effect (199) (see Chapter 19).
In a review of Xq duplications, phenotypically normal females had smaller and more proximal
duplicated Xq segments compared to the Xq duplications in females with clinical abnormalities (199).
In a review of X duplications, Zhang et al. reported that the duplicated segments in individuals with
abnormal phenotypes were more frequently located in proximal Xq (200). A review by Matsuo et al.
(195) showed that normal phenotypes are more commonly associated with smaller and more proximal
duplications of Xq, and abnormal phenotypes tend to have larger and more distal duplications,
but that there is a great deal of overlap.
Goodman et al. reported three families with duplication of Xq27-qter on the short arm of Xp
(201). Affected males had mental retardation and minor anomalies. The abnormal chromosomes were
inherited from the mothers, who were phenotypically normal. Replication studies in two of the mothers
showed the abnormal X to be late-replicating. However, most phenotypically abnormal females
have been reported to preferentially inactivate the abnormal X chromosome (202). Both normal and
abnormal phenotypes can be seen even when there is preferential inactivation of the abnormal X. One