Sex Chromosomal Abnormalities


This syndrome, characterized by a 47XXY chromosomal karyotype, is the most common human sex chromosomal aberration and is associated with the sex chromatin-positive form of seminiferous tubular dysgenesis. The frequency of the 47XXY karyotype is reported to be 0.9 in 1000; 0.15 in 1000 have a mosaic form. About half of patients with a 47XXY disorder die in utero.

Affected children have small, firm testes, and adult patients have azoospermia. y This disorder is a common cause of primary hypogonadism and male infertility. Although a male phenotype is typical, delayed or poorly developed secondary sex characteristics are present, and about half the patients have varying degrees of gynecomastia, androgen deficiency, and eunuchoid features. These patients tend to be tall and have long legs, and adults have an increased incidence of pulmonary disease, varicose veins, diabetes mellitus, and breast cancer. y Serum levels of follicle-stimulating hormone and luteinizing hormone are increased early in the second decade, whereas testosterone concentrations are normal to low. Plasma levels of estradiol are normal or high. Affected individuals have cognitive abnormalities including impaired auditory sequential memory with delayed language development and associated learning disorders. y There is a slight lowering of the mean IQ and an increased incidence of behavioral and personality abnormalities. A higher than normal prevalence of postural tremor has been reported, but the findings have not been replicated.

If androgen deficiency is present, administration of testosterone may produce an improvement in the secondary

sexual characteristics and increase the general well-being of the patient. Testosterone therapy may also lessen the degree of gynecomastia, but in those patients with notable breast enlargement, surgical reduction of the breast tissue may be important for cosmetic reasons.


The incidence of this abnormal sex chromosomal karyotype is about 1 in 1000 live male births. These patients have a normal male phenotype, although cryptorchidism and hypogonadism have been known to occur. Tall stature and acneiform eruptions are common characteristics. Although earlier studies suggested that affected patients had inordinately aggressive, impulsive behavior, this finding has not been reliably substantiated. Most patients have normal behavior, and their intelligence tends to be low normal. Delayed acquisition of speech and language skills may also be present. Other minor neurological findings include postural tremor and motor incoordination.


Turner's syndrome, a form of gonadal dysgenesis resulting from a 45,X karyotype (X-chromosomal monosomy), is characterized by female phenotype, short stature, a shieldlike chest, a short and sometimes webbed neck, low- set ears, high-arched palate, small mandible, and sexual infantilism. y The frequency of 45,X in female live births is 0.1 to 0.6 per 1000. A variety of other malformations can be associated, including congenital lymphedema, particularly of the hands and feet, cardiac and renal defects, skeletal anomalies, and abnormalities of the nails. An increased number of pigmented nevi has also been reported. Other disorders have been associated with this disorder, including Hashimoto's thyroiditis, obesity, inflammatory bowel disease, and rheumatoid arthritis. Nerve deafness occurs in approximately half the patients, and olfactory as well as taste deficits have been described. Eighteen percent of patients studied in one series were mentally retarded, although this high prevalence may be due to selection bias. The absence of the X chromosome does not cause intellectual impairment per se, but the majority of these patients have right-left disorientation and defects in perceptual orientation. y

Psychological tests demonstrate that girls with Turner's syndrome perform poorly on visuospatial and intellectual measures and have difficulty with attention and social behaviors compared with age-matched controls. y Others have reported that Turner's syndrome patients have significantly lower scores on all the Wechsler adult intelligence scale tests except verbal comprehension and reading level. y The most significant difference is found in the visuospatial construction. Volumetric brain measures derived from MRI reveal no differences in overall cerebral or subcortical volume, yet the regional distribution of gray and white matter varies in the two groups. In general, girls with Turner's syndrome have a smaller proportion of tissue in the right and left parietal regions and a larger amount in the right inferior parietal-occipital region. Additional MRI studies have shown that measured volumes of the hippocampus; the caudate, lenticular, and thalamic nuclei; and the parieto-occipital brain matter bilaterally are smaller. y

Treatment of patients with Turner's syndrome is directed at facilitating growth by administering recombinant growth hormone, y correcting associated congenital anomalies, and carefully managing hormonal replacement therapy for sexual infantilism.


Second only to Down's syndrome, the fragile-X syndrome is the most common cause of mental retardation in males and has a frequency of about 1 in 1500 males. It is found in all ethnic groups and has been identified in patients with other chromosomal abnormalities. Ihe higher incidence of mental retardation in males and reports of families in which only males are affected suggest a nonspecific X-linked inheritance, termed the Martin-Bell or Renpenning's syndrome. y , y No cytogenetic abnormality had been found in this heterogeneous subgroup of the mentally retarded population until a fragile site in the terminal region of the long arm of the X chromosome (Xq27.3) was demonstrated when the cells were cultured without folic acid.

Ihe hereditary transmission of the fragile-X syndrome has been described by Iarleton and Saul, and the fragile- X gene has been isolated, cloned, and characterized.1^ It contains a trinucleotide sequence (CGG) that repeats in the normal genome 6 to 45 times, whereas the repeat is expanded to several hundred copies in patients with fragile- X syndrome. Carriers of the fragile-X syndrome, who are asymptomatic, have about 50 to 230 copies of this sequence. Ihe expansion of the CGG repeat sequence is associated with methylation-induced inactivation of a sequence (CpG island) that is contiguous but separate from the FMR-1 gene.y This region is thought to initiate gene transcription. Ihe degree of methylation correlates with the number of repeats, suggesting that the fragility of the site of the fragile-X (FRAXA) is related to the triplet repeats.

Ihe characteristic physical features of affected males with fragile-X syndrome include a long face, prominent mandible, large ears, and macro-orchidism with no evidence of endocrine dysfunction. All signs may not be present in prepubertal males and are not always prominent in adults. Although affected children may be unusually tall, the adult male with fragile-X tends to be shorter than average. Other associated features include joint hyperextensibility, flat feet, scoliosis, mitral valve prolapse, and dilatation of the aortic root. Although no specific abnormality of connective tissue metabolism has been identified in patients with this syndrome, abnormal elastin fibrils have been observed in skin biopsies of some patients. Some heterozygote females may also have a long face, prominent ears, and joint hyperextensibility. Ihese features are more commonly observed in mentally subnormal females than in those with normal intelligence.

Ihe majority of adult males with fragile-X have mental abilities that are moderately retarded, but about 30 percent have severe mental impairment. A small number of males have low normal or mildly retarded intelligence, albeit with a variety of specific learning disabilities. Ihere may be a

delay in acquisition of speech and language skills, and older patients often have a low-pitched, somewhat hoarse voice with features of perseveration, cluttering, and staccato speech. The degree of mental impairment in females is somewhat less than in males, with about a third of patients having mental abilities in the retarded range and about a half demonstrating specific learning disabilities. Attentional deficits, hyperactivity, and impulsive and aggressive behaviors are known to occur. Patients may additionally have macrocephaly, hypotonia, oculomotor dysfunction, and inordinate clumsiness with impairment of fine and gross motor movements. y An increased incidence of convulsive disorders may occur in nearly 25 percent of patients. These seizures are generally simple or partial complex seizures and tend to occur more frequently during the first 10 to 15 years of life. The seizures are usually well controlled by the administration of standard antiepileptic medications and appear to have no relationship to the degree of mental retardation. Tic disorders have also been reported in patients with fragile-X syndrome and their families.

There is no specific treatment for fragile-X syndrome other than providing special educational programs tailored to the specific disabilities of each patient. For patients with attentional deficit disorder and hyperactivity, these behaviors are sometimes improved by the administration of CNS stimulants.


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