XXXX syndrome

Tetrasomy X, also known as 48,XXXX, is a chromosomal disorder in which a female has four, rather than two, copies of the X chromosome. It is associated with intellectual disability of varying severity, characteristic "coarse" facial features, heart defects, and skeletal anomalies such as increased height, clinodactyly (incurved pinky fingers), and radioulnar synostosis (fusion of the long bones in the forearm). Tetrasomy X is a rare condition, with few medically recognized cases; it is estimated to occur in approximately 1 in 50,000 females.

The disorder has a wide range of symptoms, with phenotypes (presentations) ranging from slight to severe. It is suspected to be underdiagnosed, as are other sex chromosome disorders. Life outcomes vary; some women have had education, employment, and children, while others have remained dependent into adulthood. Life expectancy does not appear to be substantially reduced. Tetrasomy X has phenotypic overlap with a number of more common disorders, such as trisomy X and Down syndrome, and diagnosis is usually unclear prior to chromosomal testing.

Tetrasomy X is generally not inherited, but rather occurs via a random event called nondisjunction during gamete or zygote development. The formal term for the karyotype observed in tetrasomy X is 48,XXXX, as the condition is typified by a 48-chromosome complement rather than the 46 chromosomes observed in normal human development.

Presentation

Tetrasomy X has a variable presentation with a spectrum of severity, and lacks obvious defining clinical abnormalities that can lead to a diagnosis in the absence of testing. Recognizable characteristics include increased height and mild intellectual disability; the average adult height in tetrasomy X is compared with a reference height of around for women in the Anglosphere, while a review of the first 27 women to be diagnosed with tetrasomy X found IQs ranging from 30 to 101 with a mean of 62. Although some degree of intellectual disability is traditionally characteristic, two medically reported cases were of normal intelligence, and patient organizations report members who are only afflicted by specific learning disabilities such as dyslexia. Speech and language delays may be associated with tetrasomy X, although the matter is unclear; some reports describe speech and language abilities in line with overall intelligence, while others describe problems independent of intelligence, in particular with subjects who have normal intelligence but significant language delays.

A number of facial and musculoskeletal anomalies are common to all aneuploidies of the sex chromosomes, including X chromosome polysomy such as tetrasomy X. Epicanthic folds (additional skin folds in the corners of the eyes) and hypertelorism (wide-spaced eyes) are frequent facial features. Multiple reports have described the characteristic facial features as "coarse". These dysmorphic features are relatively mild and do not necessarily "stand out from the crowd"; in general, X chromosome polysomy is not associated with severe physical dysmorphism, although tetrasomy and pentasomy X tend to be somewhat more noticeable in this respect than the milder and more frequent trisomy X. Hypotonia (low muscle tone), often severe and early-onset, is a commonly observed musculoskeletal abnormality. Clinodactyly, the bending inwards of the pinky finger, and radioulnar synostosis, the fusion of the long bones in the forearm, are frequent. Dental abnormalities are associated with the syndrome, in particular taurodontism, where the pulp of the teeth is enlarged and extends into the roots. These findings are not unique to tetrasomy X; epicanthic folds and hypertelorism are seen in trisomy X, while clinodactyly and radioulnar synostosis are findings common to all sex chromosome aneuploidies and taurodontism is prevalent in X-chromosome polysomy specifically.

Heart defects of various types have been associated with the syndrome, albeit at unclear prevalence. A patient organization reports approximately one-third of cases in its membership had congenital heart defects, a larger proportion than reported in the medical literature. Frequently reported heart defects include patent ductus arteriosus and ventricular septal defects. Kidney and bladder issues have been loosely associated with the syndrome, as has epilepsy. Epilepsy in sex chromosome aneuploidies generally is mild, amenable to treatment, and often attenuates or disappears with time. There is also a potential association between tetrasomy X and autoimmune disorders, particularly lupus, which has been recorded in two women with tetrasomy X and appears to become more common as the number of X chromosomes increase.

The psychological and behavioural phenotype of tetrasomy X is understudied. Some reports describe girls and women with tetrasomy X as generally placid and pleasant, while others report emotional lability and inappropriate behaviour. Family background and environment has a significant impact on behaviour, and cases with severe behavioural dysfunction frequently have similarly dysfunctional unaffected relatives. Expressive language delays and executive dysfunction are common heralds of behavioural issues, due to the difficulties they cause for educational, vocational, and social functioning. In both men and women X-chromosome polysomy is known to be associated with psychosis, and a case is known of a girl with tetrasomy X and childhood-onset schizophrenia. Parent reports describe children and young adults who are generally pleasant and affectionate yet shy, and have issues relating to temper tantrums, mood swings, and frustration at an inability to communicate.

Tetrasomy X can interfere with pubertal development. Of the adult women recorded with tetrasomy X, half have had normal pubertal development with menarche at an appropriate age, while the other half have had some form of pubertal dysfunction such as primary amenorrhea, irregular menstrual cycles, or incomplete development of secondary sex characteristics. Premature ovarian failure, or early menopause, has been recorded. In trisomy X, premature menopause has occurred between the ages of 19 and 40, while in tetrasomy X, it has been recorded as young as 15. In tetrasomy X as for other causes of premature menopause or incomplete puberty, some writers have recommended hormone replacement therapy. Fertility in tetrasomy X is possible. In the first discussion of the phenomenon, three cases have been reported of women bearing children. One woman had two children, one with a normal chromosome complement and the other with Down syndrome. Two women had one child each; one had a daughter with normal chromosomes, while the other had a stillbirth with an omphalocele. An additional woman was reported as having three children, all with normal chromosomes.

Causes

Tetrasomy X, like other aneuploidy disorders, is caused by a process called nondisjunction. Nondisjunction occurs when homologous chromosomes or sister chromatids fail to separate properly during meiosis, the process that produces gametes (eggs or sperm), and result in gametes with too many or too few chromosomes. In the specific case of sex chromosome tetrasomy and pentasomy, nondisjunction occurs multiple times with the same parent; for tetrasomy X specifically, all known cases have inherited either three maternal X chromosomes and one paternal, or four maternal X chromosomes with no paternal contribution. The cause of this specific pattern of inheritance is unclear. An early research group proposed that due to the gap in prevalence between the related conditions 49,XXXXY, which has a similar prevalence to tetrasomy X, and pentasomy X, which is far rarer, the paternal X chromosomes may frequently be lost in high-level aneuploidy. More recently, speculation has been based in genomic imprinting, with the suggestion that a similarly high number of paternal X-chromosomes would be incompatible with life. Nondisjunction can also occur after conception, which frequently results in a mosaic karyotype.

Nondisjunction is related to advanced maternal age

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