48,XXXX - The Focus Foundation


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

Klinefelter Syndrome & Other Names You May hear

X & Y Variations is a neurogenetic disorder known by many names, among them: Sex Chromosome Disorders, X & Y Chromosomal Variations, Sex Chromosome Anomaly and Sex Chromosome Aneuploidy Variations. Within the disorder are many sub-categories, which are identified by names including 47 XXY (Klinefelter Syndrome), 49 XXXXY, Tetrasomy X, 49 XXXXXX, Pentasomy X, 48 XXY.

Related X & Y Disorder Research

X&Y Variation Disorders encompass individuals who are born with 45, 47, 48, or 49 chromosomes, rather than the standard 46. The Focus Foundation’s efforts are centered on disorders resulting from having 47, 48, and 49 chromosomes. 45, X (also known as Turner’s Syndrome) occurs in one out of 2,000 live female births and is actively and effectively served by The Turner Syndrome Society. Below are more details about X&Y Variations involving 47, 48, and 49 chromosomes:

Only 25% of males with 47,XXY are ever diagnosed during their lifetimes; fewer than 10% of 47,XXY individuals are identified prior to adolescence. This means that millions of affected children remain undiagnosed–often because they are commonly misdiagnosed as simply having speech or motor delays. More than 500,000 people are believed to have 47,XXY disorders in the United States alone, with an equal distribution across all racial and socio-economic groups.

Based on scientific studies, it is important to consider early hormonal replacement therapy (EHRT) for 47,XXY boys (who experience decreased testosterone production during three critical developmental periods) before they are 18 months old. Testosterone treatment given then has been shown to have a positive impact on brain function through 9 years of age…READ MORE

At least 85% of those with 47,XYY are never diagnosed. 47,XYY boys consistently present with language-based Learning Disabilities and difficulties with Motor Planning–both issues that are related to the high rate of dyspraxia and dyslexia associated with the disorder. However, 47,XYY boys are commonly misdiagnosed as simply having speech or motor delays.

Boys with 47,XYY typically reach an average height of between 6’3” and 6’5”…READ MORE

As many as 1 in 900 girls have 47,XXX. Unfortunately, millions of affected girls are undiagnosed. Girls who are prenatally diagnosed and receive early intervention services typically exhibit fewer and less severe cognitive disabilities.

There is an equal distribution of 47,XXX across all racial and socio-economic groups…READ MORE

Boys with 48,XXYY consistently exhibit Language-Based Learning Disabilities (LLD) and difficulties with Motor Planning, issues that are related to the high rate of dyslexia associated with the disorder. However, they seem to be stronger in math and such visual-spatial activities as assembling puzzles or remembering directions.

Intellectual disabilities are common in 48,XXYY, with average full-scale IQs in the range of 70-80. Verbal IQs are seen to be significantly lower than performance IQs, due to language-based learning difficulties…READ MORE

48,XXXY can result from meiotic or mitotic nondisjunction (errors in chromosomal separation) and is often considered a variant of Klinefelter syndrome (47,XXY). However, boys with 48,XXXY often exhibit a more complicated neurodevelopmental profile than boys with 47,XXY…READ MORE

The first case of 49,XXXXY syndrome was reported in the 1970s, and this chromosomal variation remains one of the rarest sex chromosome disorders. 49,XXXXY results from nondisjunction (errors in chromosomal separation) of the X chromosome occurring during both Meiosis I and Meiosis II…READ MORE

Penta X Syndrome is an extremely rare chromosomal disorder that only affects females. While girls normally only have two X chromosomes, girls with Penta X have five X chromosomes. As of 2011, less than 40 cases have been reported.…READ MORE

What You Can Do Now

If you have received a prenatal diagnosis indicating that your child has an X & Y chromosomal variation, or feel that your son or daughter is experiencing developmental delays or developmental dysfunction, the following options are designed to help you take the next step in securing appropriate treatment or an early diagnosis.


Take The Child Questionnaire



Learn About Chromosomal Microarray

Chromosomal Testing


Begin Syndrome-specific Therapy