49,xxxxy Syndrome

The 49,XXXXY syndrome represents a chromosomal anomaly of the aneuploidic type characterized by the presence of three extra X chromosomes in males.

Epidemiology

It has an annual incidence of 1/85,000 to 1/100,000 male births.

Clinical description

The 49,XXXXY syndrome differs from Klinefelter syndrome by its variable IQ with an often subtle intellectual deficit in childhood but a progressive (moderate to severe) deterioration with age (IQ varying between 70 and 20), by the absence of tall stature with delayed growth often already visible in utero and under the third percentile after birth, and sometimes by a small stature and a deficit in growth hormones. Hypogonadism is severe with a micropenis, microorchidism, hypoplasia of the scrotum and cryptorchidism. Gynecomastia is uncommon. Remarkable facial dysmorphism (hypertelorism, large flat nose with a depressed nasal curvature, upslanting palpebral fissures, epicanthus, prognathism, folded-over ears, short neck) and other dysmorphic characteristics (cubitus valgus, flat feet, clinodactyly of the fifth finger, joint laxity) appear frequently. Congenital heart defects (arterial canal) as well as skeletal defects (radioulnar synostosis, epiphyseal dysplasia, coxa valga, kyphoscoliosis, hip and knee dislocation), cerebral (hypoplastic corpus callosum, arhinencephaly) and renal defects (renal hypoplasia) can also be present. Axial hypotonia is often seen in children. With age, the intellectual deficit worsens and is associated with a major delay in language development. Strabismus or severe and progressive myopia can occur which can lead to declining vision. Behavioral problems such as shyness can also become apparent.

Etiology

The etiology is the non disjunction of homologous chromosomes (during the first meiotic division) or of sister chromatids (during the second meiotic division) in the maternal germ cells. There is no known factor responsible for or favoring the appearance of this syndrome.

Diagnostic methods

The metaphase karyotype allows for the confirmation of a clinical diagnosis.

Antenatal diagnosis

Antenatal diagnosis is possible by an amniocentesis screening for a wide range of conditions.

Genetic counseling

The risk of recurrence is very unlikely as cases of 49,XXXXY are sporadic.

Management and treatment

Management needs to be handled by a multidisciplinary team and includes the treatment of cardiac and skeletal defects, the monitoring of psychomotor development with physiotherapy, psychomotricity, speech therapy, orthopedic and sensory management (ophthalmological examination), neurological, hormonal (if necessary) and psychological care and regular dental follow-up.

Prognosis

Patients have an essentially normal life expectancy but will need to attend regular medical visits.