|
Sex
chromosome anomalies may involve aneuploidy, partial deletions or
duplications of sex chromosomes, or mosaicisms.
Sex chromosome anomalies are common and produce syndromes that include a range of congenital and developmental anomalies. They are rarely suspected prenatally but may be incidentally discovered at that time if karyotyping is done for other reasons. They are often hard to recognize at birth and may not be diagnosed until puberty.
X chromosome anomalies are relatively benign, compared with analogous autosomal anomalies. Females with 3 X chromosomes are often normal physically and mentally and are fertile. In contrast, all known autosomal trisomies have devastating effects. Similarly, the absence of 1 X chromosome, although it leads to a specific syndrome (Turner's syndrome), is relatively benign, whereas the absence of an autosome is invariably lethal.
Lyon
hypothesis (X-inactivation):
Females have 2 loci for every X-linked gene, as compared with males' single locus. This imbalance would seem to produce a genetic “dosage” problem. However, according to the Lyon hypothesis, 1 of the two X chromosomes in each female somatic cell is genetically inactivated early in embryonic life (on or about day 16). In fact, no matter how many X chromosomes are present, all but 1 are inactivated. However, recent molecular genetic studies have demonstrated that some genes on the inactivated X chromosome (or chromosomes) remain functional, and these few are essential to normal female development. The Barr body, or sex chromatin mass within the nuclei of female somatic cells, represents the inactivated X chromosome. XIST is the gene responsible for inactivating the genes of the X chromosome.
Whether the maternal or paternal X is inactivated is a random event within each cell at the time of inactivation; that same X then remains inactive in all descendant cells. Thus, all females are mosaics, with some cells having an active maternal X and others an active paternal X.
Sometimes, random statistical distribution of inactivation in the relatively small number of cells present at the time of inactivation results in a particular descendant tissue having a preponderance of active maternal or paternal X (skewed inactivation). Skewed inactivation may account for the occasional manifestation of minor symptoms in females who are heterozygous for X-linked disorders such as hemophilia and muscular dystrophy (all would presumably be asymptomatic if they had a 50:50 distribution of active X chromosomes). Skewed inactivation also may occur by post-inactivation selection.
Turner's
Syndrome
(Bonnevie-Ullrich Syndrome)
Turner's
syndrome results from complete or partial absence of 1 of the 2
sex chromosomes, producing a phenotypic female. Diagnosis is based
on clinical findings and confirmed by karyotype analysis. Treatment
depends on manifestations and may include surgery for cardiac anomalies,
and often growth hormone therapy for short stature and estrogen
replacement for pubertal failure.
Turner's syndrome occurs in about 1/4000 live female births and is the most common sex chromosome anomaly in females. However, 99% of 45,X conceptions abort spontaneously.
About 50% of affected girls have a 45,X karyotype; about 80% have lost the paternal X. Most of the other 50% are mosaics (eg, 45,X/46,XX or 45,X/47,XXX). Among mosaic individuals, phenotype may vary from that of typical Turner's syndrome to normal. Occasionally, affected girls have 1 normal X and 1 X that has formed a ring chromosome; for this formation to happen, a piece must be lost from both the short and long arms of the abnormal X. Some affected girls have 1 normal X and 1 long arm isochromosome formed by the loss of short arms and development of a chromosome consisting of 2 long arms of the X chromosome. These girls tend to have many of the phenotypic features of Turner's syndrome; thus, deletion of the X chromosome's short arm seems to play an important role in producing the phenotype.
Symptoms and Signs
Many neonates are very mildly affected; however, some present with marked dorsal lymphedema of the hands and feet and with lymphedema or loose folds of skin over the back of the neck. Other frequent anomalies include a webbed neck and a broad chest with widely spaced and inverted nipples. Affected girls have short stature compared with family members. Less common findings include a low hairline on the back of the neck, ptosis, multiple pigmented nevi, short 4th metacarpals and metatarsals, prominent finger pads with whorls in the dermatoglyphics on the ends of the fingers, and hypoplasia of the nails. Increased carrying angle at the elbow occurs.
Common cardiac anomalies include coarctation of the aorta and bicuspid aortic valve. Hypertension frequently occurs with aging even without coarctation. Renal anomalies and hemangiomas are frequent. Occasionally, telangiectasia occurs in the GI tract, with resultant GI bleeding or protein loss.
Gonadal dysgenesis (ovaries are replaced by bilateral streaks of fibrous stroma and are devoid of developing ova) occurs in 90%, resulting in the inability to go through puberty, develop breast tissue, or begin menses. However, 5 to 10% of affected girls do go through menarche spontaneously, and, very rarely, affected women are fertile and have children.
Mental retardation is rare, but many have some diminution of certain perceptual abilities and thus score poorly on performance tests and in mathematics, even though they score average or above in the verbal components of intelligence tests.
Diagnosis
In neonates, diagnosis may be suspected based on presence of lymphedema or a webbed neck. In the absence of these findings, some children are diagnosed later, based on short stature, lack of pubertal development, and amenorrhea. Diagnosis is confirmed by karyotype analysis. Echocardiography or MRI is indicated to detect cardiac anomalies.
Cytogenetic analysis and Y-specific probe studies are obtained for all people with gonadal dysgenesis to rule out mosaicism with a Y-bearing cell line (eg, 45,X/46,XY). These people are usually phenotypic females who have variable features of Turner's syndrome. They are at high risk for gonadal malignancy, especially gonadoblastoma, and should have the gonads removed prophylactically as soon as the diagnosis is made.
Treatment
There is no specific treatment for the underlying genetic condition. Coarctation of the aorta is usually repaired surgically. Other cardiac anomalies are monitored and repaired as needed. Lymphedema can usually be controlled with support hosiery.
Recombinant human growth hormone therapy may be initiated if height is < 5th percentile, beginning with 0.05 mg/kg sc once/day. Estrogen replacement is usually needed to initiate puberty and is typically given at age 12 to 13 as conjugated estrogens 0.3 mg po or micronized estradiol 0.5 mg once/day. Thereafter, birth control pills with a progestin are given to maintain secondary sexual characteristics. Growth hormone can be given with estrogen replacement until epiphyses are fused, at which time growth hormone is discontinued. Continuation of estrogen replacement helps establish optimal bone density and skeletal development.
Klinefelter's
Syndrome (47,XXY)
Klinefelter's
syndrome is ≥ 2 X chromosomes plus
1 Y, resulting in a phenotypic male.
Klinefelter's syndrome occurs in about 1/800 live male births. The extra X chromosome is maternally derived in 60% of cases.
Affected boys tend to be tall, with disproportionately long arms and legs. They often have small, firm testes, and about 30% develop gynecomastia. Puberty usually occurs at the normal age, but often facial hair growth is light. There is a predisposition for learning disorders, and many have lower verbal IQ, auditory processing, and reading. Clinical variation is great, and many 47,XXY males have normal appearance and intellect. Many are diagnosed during an infertility workup (probably all 47,XXY males are sterile). Testicular development varies from hyalinized nonfunctional tubules to some production of spermatozoa; urinary excretion of follicle-stimulating hormone is frequently increased.
Mosaicism occurs in 15% of cases. These men may be fertile. Some affected men have 3, 4, and even 5 X chromosomes along with the Y. As the number of X chromosomes increases, the severity of mental retardation and of malformations also increases.
47,XYY
Syndrome
47,XYY
syndrome is 2 Y chromosomes and 1 X, resulting in a phenotypic male.
The 47,XYY syndrome occurs in about 1/1000 live male births. Affected boys tend to be taller than average and have a 10- to 15-point IQ reduction compared with family members. There are few physical problems. Minor behavior disorders, hyperactivity, attention deficit disorder, and learning disorders are more common.
Other X Chromosome
Anomalies
About 1/1000 apparently normal females have 47,XXX karyotype. Physical anomalies are rare. Menstrual irregularity and infertility sometimes occur. Affected girls may have mildly impaired intellect and may have more school problems than siblings. Advanced maternal age increases risk of the triple X anomaly, and the extra X chromosome is usually maternally derived.
Although rare, 48,XXXX and 49,XXXXX females exist. There is no consistent phenotype. The risk of mental retardation and congenital anomalies increases markedly when there are > 3 X chromosomes. The genetic imbalance in early embryonic life before X-inactivation may cause anomalous development.
Last full review/revision November 2005
Content last modified November 2005
| 
