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There is an annual incidence of 1/50,000 male births.

The 48,XXXY syndrome differs from Klinefelter syndrome by the presence of moderate intellectual deficit (average IQ of 50), more marked genital hypoplasia (microorchidism, micropenis, hypoplasia of the scrotum) and by more frequently observed facial dysmorphism (flat nose, epicanthus, prognathism, short neck, hypertelorism, facial asymmetry). Other dysmorphic characteristics (clinodactyly of the fifth finger, coxa valga, etc.) are often associated with this syndrome. Congenital skeletal malformations (kyphoscoliosis, radioulnar synostosis, epiphyseal dysplasia) canalso be present in addition to genital anomalies (cryptorchidism) and gynecomastia. With age, other manifestations can also appear such as arthropathies, obesity, behavioral problems (hyperactivity, irritability, anxiety, immaturity, passivity, anger, communication and socialization problems) and language retardation.

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

The metaphase karyotype allows for the confirmation of a clinical diagnosis. Mosaicism with other polygonosomies is not uncommon (48,XXXY/ 48,XXYY/ 49,XXXXY).

Differential diagnoses include other aneuploidies, such as Klinefelter syndrome (47,XXY), 48,XXYY syndrome and 49,XXXXY syndrome (see these terms).

Antenatal diagnosis is possible by amniocentesis.

The risk of recurrence is very low as cases of 48,XXXY are sporadic.

Management needs to be handled by a multidisciplinary team and includes the treatment of cardiac and skeletal malformations, management of sensory, neurological, hormonal (testosterone-based hormone therapy), metabolic (supervising obesity), psychological and psychiatric care and dental follow-up.

Patients have an essentially normal life expectancy but will need to attend regular medical visits, in particular for their endocrine and infectious problems, and to undergo regular psychiatric monitoring.