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Distal Xq duplications refer to chromosomal disorders resulting from involvement of the long arm of the X chromosome (Xq). Clinical manifestations vary widely depending on the gender of the patient and on the gene content of the duplicated segment. The prevalence of Xq duplications remains unknown.
ORPHA:1762Classification level: Disorder
About 40 cases of Xq28 functional disomy due to cytogenetically visible rearrangements, and about 50 cases of cryptic duplications encompassing the MECP2 gene have been reported (intellectual deficit-progressive spasticity, X-linked; see this term).
The most frequently reported distal duplications involve the Xq28 segment and yield a recognizable phenotype including distinctive facial features (premature closure of the fontanels or a ridged metopic suture, a broad face with full cheeks, epicanthal folds, large ears, a small and open mouth, ear anomalies, a pointed nose, an abnormal palate and facial hypotonia), major axial hypotonia, severe developmental delay, severe feeding difficulties, abnormal genitalia and susceptibility to infections.
Xq duplications may be caused either by an intrachromosomal duplication or by an unbalanced X/Y or X/autosome translocation. In XY males, structural X disomy always results in functional disomy. In females, failure of X chromosome dosage compensation could result from a variety of mechanisms, including an unfavorable pattern of inactivation, a breakpoint separating an X segment from the X-inactivation centre in cis, or a small ring chromosome. The MECP2 gene in Xq28 is the most important dosage-sensitive gene responsible for the abnormal phenotype in duplications of distal Xq.
Diagnosis is based on clinical features and is confirmed by CGH array techniques.
Differential diagnoses include Prader-Willi syndrome and Alpha thalassaemia-mental retardation, X linked (ATR-X) syndrome (see these terms).
Prenatal diagnosis is performed by cytogenetic testing including FISH and/or DNA quantification methods.
The recurrence risk is significant if a structural rearrangement is present in one of the parents, the most frequent situationbeing that of an intrachromosomal duplication inherited from the mother.
Management and treatment
Management is multidisciplinary and symptomatic only, with special attention to prevention of malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients.
Malformations do not contribute significantly to the morbidity associated with this syndrome, but early death (before 25 years of age) has been reported in 55% of patients with a MECP2 duplication and a few cases of death during infancy due to infection have also been described.
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