First identified in the early 1960s, 48,XXXX is such a rare sex chromosomal disorder that only about 100 cases have been reported, with fewer than 50 described in scientific literature. Due to the scarcity of this XY variation, it is difficult to define a common phenotypic presentation. Furthermore, 48,XXXX is characterized by a lack of congenital malformations, mild dysmorphology, and varied developmental trajectory–which suggests that 48,XXXX is likely underdiagnosed.
Girls with 48,XXXX may have fifth-finger clinodactyly, a depressed nasal bridge, ocular hypertelorism, and decreased muscle tonus in their core, as well as in their upper and lower extremities. Reports of eye anomalies, such as myopia and iridoschisis, dental anomalies, and radioulnar syostosis have also been reported.
The cognitive profile for 48,XXXX girls ranges from severely impaired to within normal limits, with developmental delays, Childhood Apraxia of Speech (CAS), developmental dyspraxia, and neuromotor deficits described. The latter deficits involve gross motor, graphomotor, and oral-motor planning realms. Receptive language and verbal comprehension may be higher than expressive language. Deficits in visual motor integration and visual perception skills may also be present.
Behaviorally, these girls have been variously described as timid and fearful, friendly, as well as defiant and aggressive. Problem behaviors in social and school settings have commonly been observed. These externalizing behaviors may be associated with expressive language delays and frontal lobe dysfunction.
Girls that exhibit developmental delays, and neuromotor, language and intellectual deficits should be considered for genetic testing, given that neurodevelopmental intervention could help with these issues.
Reference List: Carr et al., 1961; Linden et al., 1995; Berkeley and Faed, 1970; DiCagno and Franceschini, 1968; Pena et al., 1974; Samango-Sprouse et al., 2015; Duncan et al., 1970; Nielsen et al., 1977