49, XXXXX

Pentasomy X, also known as 49,XXXXX, is a chromosomal disorder in which a female has five, rather than two, copies of the X chromosome. Pentasomy X is associated with short stature, intellectual disability, characteristic facial features, heart defects, skeletal anomalies, and pubertal and reproductive abnormalities. The condition is exceptionally rare, with an estimated prevalence between 1 in 85,000 and 1 in 250,000.

The condition has a large variety of symptoms, and it is difficult to paint a conclusive portrait of its phenotypes. Though significant disability is characteristic, there are so few diagnosed cases that confident conclusions about the presentation and prognosis remain impossible. Pentasomy X may be mistaken for more common chromosomal disorders, such as Down syndrome or Turner syndrome, before a conclusive diagnosis is reached.

Pentasomy X is not inherited, but rather occurs via nondisjunction, a random event in gamete development. In rare cases, it may be related to a parent's chromosomal mosaicism. The karyotype observed in pentasomy X is formally known as 49,XXXXX, which represents the 49 chromosomes observed in the disorder as compared to the 46 in normal human development.

Presentation

The major clinical features of pentasomy X are intellectual disability, short stature, facial and musculoskeletal abnormalities, and congenital heart defects. Although one recorded case has been of low average intelligence, all other known cases have been intellectually disabled, with an average IQ of 50. The overall portrait is one of moderate intellectual disability, defined by an adult cognitive capacity similar to that of a six- to eight-year-old and the ability to acquire basic living and employment skills with support. Some girls with pentasomy X attend special education in mainstream schools through mainstreaming or inclusion, while some attend special schools.

Pentasomy X is associated with a number of physical anomalies, including short stature, clinodactyly (incurved pinky fingers), and distinctive facial features. Common findings include microcephaly, low-set ears, hypertelorism (wide-spaced eyes), and epicanthic folds. The characteristic facies have been described as "coarse", much like those of the related disorder tetrasomy X. Pentasomy X is unique amongst X-chromosome polysomies for its association with short stature, when most related disorders are associated with tall stature; the average height in pentasomy X is one standard deviation below the norm. Hypotonia, often severe, is a frequent finding, as are related musculoskeletal issues such as hip dysplasia. The severity of repeated joint dislocations may lead to a differential diagnosis of Larsen syndrome, as suggested in one reported case. Bone maturation may be delayed. Another skeletal finding is taurodontism, where the pulp of the teeth is enlarged into the roots; other dental abnormalities, such as missing teeth and severe tooth decay, have also been reported. These findings are not specific to pentasomy X, but rather common to sex chromosome aneuploidies in general and in particular show a strong resemblance to the male counterpart 49,XXXXY. Epicanthic folds and hypertelorism are also observed in tetrasomy and trisomy X, while clinodactyly and radioulnar synostosis are seen in all sex chromosome aneuploidies and taurodontism is specifically common to X-chromosome polysomies.

Heart defects are associated with the syndrome. Pentasomy X has one of the highest rates of congenital heart defects of any chromosomal disorder, with 56.5% of recorded patients having a heart defect of some kind. Patent ductus arteriosus is particularly frequent. The majority of such conditions resolve without surgical treatment, although a minority require it. Ventricular septal defects are also frequent. Other internal medical issues frequently recorded include kidney and urinary defects. Epilepsy has been associated with the condition, though seems to be rare. In sex chromosome aneuploidies as a whole, epilepsy is usually mild and amenable to treatment, and reports of epilepsy in pentasomy X have described it resolving with treatment and allowing antiepileptic drugs to eventually be stopped.

Puberty is altered in pentasomy X, although as few adults with the condition have been reported, the full scope of such alterations is unclear. In the sister condition of tetrasomy X, half of all women undergo puberty normally, while half have no or incomplete puberty. Some adolescents and adults with pentasomy X have been prepubertal, while some have had premature ovarian failure (early menopause) and some have had apparently non-noteworthy pubertal development. Though external genitalia is generally normal, underlying gonadal dysfunction is frequent, including ovarian dysfunction or an unusually small uterus. No cases are known of women with pentasomy X having children, but although fertility is likely reduced, some may be able to.

Little is understood about the psychological and behavioural phenotype of pentasomy X. Girls and women with the disorder are frequently described as shy and cooperative. Such traits are common to other conditions involving extra copies of the X chromosome. Developmental delays can cause difficulty communicating, resulting in frustration and tantrums. Overall, the syndrome is not associated with severe behavioural issues.

A number of disorders have been reported as comorbid with sex chromosome aneuploidies, including pentasomy X. In one case report, pentasomy X occurred alongside the similarly rare hyperimmunoglobulin E syndrome. Other possibly coincidental associations have included cerebral palsy and Dandy–Walker malformation.

Causes

Pentasomy X is caused by nondisjunction, a process through which gametes (eggs or sperm) with too many or too few chromosomes are produced. In nondisjunction, homologous chromosomes or sister chromatids fail to separate properly when producing gametes. In sex chromosome tetrasomy and pentasomy, the extra chromosomes are consistently inherited from one parent. In the specific case of pentasomy X, all known cases have inherited the additional chromosomes from the mother. This has been suggested to relate to genomic imprinting; specifically, it is hypothesized that specific loci on the sex chromosomes are affected by imprinting such that only maternal overimprinting is survivable, and cases of pentasomy X where the additional chromosomes were inherited from the father would be incompatible with life. As well as during gamete development, nondisjunction can occur after conception, resulting in a mosaic karyotype.

Nondisjunction is related to advanced maternal age

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