49,XXXXY - The Focus Foundation


The first case of 49,XXXXY syndrome was reported in the 1970s, and it remains one of the rarest sex chromosome disorders, with an estimated prevalence of 1 in 85,000 to 1 in 100,000 live male births. 49,XXXXY results from nondisjunction (an error in chromosomal separation) of the X chromosome during both Meiosis I and Meiosis II.

Boys with 49,XXXXY are typically more affected than boys with other sex chromosome variations, such as 48,XXYY and 48,XXXY. This syndrome is associated with severe speech and motor delays, hypotonia (low muscle tone), as well as learning disabilities and physical manifestations affecting the skeletal, cardiac, and genital systems. Mean height is typically below average, and growth deficiency is associated both prenatally and postnatally, which could be due to the extreme over-
dosage of sex chromosome genes in multiple organ sites and growth pathways. Common features presenting in 49,XXXXY boys include arched eyebrows, ocular hypertelorism, flat nasal bridge with upslanting palpebral fissures, and radioulnar synostosis.

Verbal and oral motor dyspraxia is evident, and it has been reported that more nonverbal skills are more intact than verbal skills. Moderate-to-severe language-based learning disorders can affect these boys’ social interactions and result in behavioral manifestations of difficulties in tolerating even low frustration, and oppositional behavior.

Boys with 49,XXXXY may have an increased incidence of atopy (a heightened immune response to common allergens) and antibody deficiency, recurrent otitis media, and asthma than the general population. Brain imaging studies have shown reduced total brain volumes, as well as white matter lesions, minor skull deformities, and thinning of the corpus callosum.

Boys with 49,XXXXY typically have phallus length below the 10th centile, suggestive of lifelong androgen deficiency. Microorchidism occurs in almost all cases in adolescence and adulthood. Early androgen therapy has been suggested to have a positive effect in speech and language, gestural communication, and vocabulary development.

Reference List: Hayek et al., 1971; Kleczkowska et al., 1988; Linden et al., 1995; Peet et al., 1981; Gropman et al., 2010; Ottesen et al., 2010; Keller et al., 2013; Blumenthal et al., 2013; Hoffman et al., 2008; Samango-Sprouse et al., 2011

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,XXXX (also known as Tetrasomy X or Tetra X) is a rare sex chromosome disorder that was first identified in the early 1960s. Since that time, approximately 100 cases have been reported, although less than 50 are described in scientific literature. Due to the scarcity of this female chromosomal variation, it is difficult to define a common phenotypic presentation. A lack of congenital malformations, mild dysmorphology, and varied developmental trajectory suggests that 48,XXXX is largely underdiagnosed…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

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