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Sex Chromosome Anomalies

by Nina N. Powell-Hamilton, MD, FAAP, FACMG

Sex chromosome anomalies may involve aneuploidy, partial deletions or duplications of sex chromosomes, or mosaicism.

Sex chromosome anomalies are common and cause syndromes that are associated with a range of congenital and developmental anomalies. The majority are not suspected prenatally but may be incidentally discovered if karyotyping is done for other reasons, such as advanced maternal age. The anomalies are often hard to recognize at birth and may not be diagnosed until puberty.

The effects of X chromosome anomalies are not as severe as those from analogous autosomal anomalies. Females with 3 X chromosomes often appear normal physically and mentally and are fertile. In contrast, all known autosomal trisomies have devastating effects. Similarly, whereas the absence of 1 X chromosome leads to a specific syndrome (Turner syndrome), the absence of an autosome is invariably lethal.

Lyon hypothesis (X-inactivation)

By virtue of having 2 X chromosomes, females have 2 loci for every X-linked gene, as compared with a single locus in males. This imbalance would seem to cause a genetic “dosage” problem. However, according to the Lyon hypothesis, 1 of the 2 X chromosomes in each female somatic cell is inactivated genetically 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, molecular genetic studies have shown that some genes on the inactivated X chromosome (or chromosomes) remain functional, and these few are essential to normal female development. XIST is the gene responsible for inactivating the genes of the X chromosome, producing RNA that triggers inactivation.

Whether the maternal or paternal X is inactivated usually 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 having 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 chromosomes (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 postinactivation selection.

Turner Syndrome

(Monosomy X; Gonadal Dysgenesis)

In Turner syndrome (monosomy X, gonadal dysgenesis), girls are born with 1 of their 2 X chromosomes partly or completely missing. Diagnosis is based on clinical findings and is 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 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 girls, phenotype may vary from that of typical Turner syndrome to normal. Occasionally, affected girls have 1 normal X and 1 X that has formed a ring chromosome. 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 syndrome; thus, deletion of the X chromosome’s short arm seems to play an important role in producing the phenotype.

Pathophysiology

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. Hearing loss occurs; strabismus and hyperopia (farsightedness) are common and increase the risk of amblyopia. Thyroiditis, diabetes mellitus, and celiac disease are more common than among the general population.

Infants are at a higher risk of developmental dysplasia of the hip. Of adolescents, 10% have scoliosis. Osteoporosis and fractures are fairly common among women with Turner syndrome. Gonadal dysgenesis (ovaries replaced by bilateral streaks of fibrous stroma and devoid of developing ova) occurs in 90% of females.

Intellectual disability is rare, but many girls have nonverbal learning disability, attention-deficit/hyperactivity disorder, or both and thus score poorly on performance tests and in mathematics, even though they score average or above in the verbal components of intelligence tests.


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.

Symptoms of cardiac anomalies depend on severity. Coarctation of the aorta can cause high BP in the upper extremities, diminished femoral pulses, and low or absent BP in the lower extremities. Gonadal dysgenesis results in the inability to undergo puberty, develop breast tissue, or begin menses. Other medical problems that are associated with Turner syndrome develop with aging and may not be evident without screening.


Diagnosis

  • Clinical appearance

  • Karyotype analysis

  • Testing for associated conditions

In neonates, diagnosis may be suspected based on the 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 done 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 syndrome. They are at high risk of gonadal cancer, especially gonadoblastoma, and it is often recommended that the gonads be removed prophylactically.


Concomitant medical conditions

Certain routine evaluations help identify problems that may be associated with Turner syndrome:

  • Cardiovascular evaluation by a specialist; MRI and echocardiography at time of diagnosis to rule out coarctation and bicuspid aortic valve and every 3 to 5 yr thereafter to evaluate aortic root diameter

  • Renal ultrasonography at time of diagnosis, annual urinalysis, BUN, and creatinine for patients with renal system anomalies

  • Hearing evaluation by an audiologist and audiogram every 3 to 5 yr

  • Evaluation for scoliosis/kyphosis annually during childhood and adolescence

  • Evaluation for hip dislocation

  • Eye examination by pediatric ophthalmologist

  • Thyroid function tests at diagnosis and every 1 to 2 yr thereafter

  • Celiac screen (eg, endomysial antibody levels)

  • Glucose tolerance test may be abnormal; fasting blood sugar and lipid profile annually during adulthood (started earlier if indicated)


Treatment

There is no specific treatment for the underlying genetic condition and management is based on an individual's findings. 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 and other techniques such as massage.

Treatment with growth hormone can stimulate growth. Estrogen replacement is usually needed to initiate puberty and is typically given at age 12 to 13. 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 stopped. Continuation of estrogen replacement helps establish optimal bone density and skeletal development.


Key Points

  • Girls are missing all or part of one of their two X chromosomes.

  • Manifestations vary, but short stature, webbed neck, broad chest, gonadal dysgenesis, and cardiac anomalies (commonly coarctation of the aorta and bicuspid aortic valve) are common; intellectual disability is rare.

  • Risk of gonadal cancer is high; it is often recommended to remove the gonads prophylactically.

  • Do routine age-specific screening to detect associated medical conditions (eg, cardiac and renal anomalies).

  • Give estrogen to initiate puberty, followed by use of birth control pills with progestin to maintain secondary sexual characteristics.

  • Treat specific manifestations, and provide social and educational support and genetic counseling.


Klinefelter Syndrome (47,XXY)

Klinefelter syndrome is 2 X chromosomes plus 1 Y, resulting in a phenotypic male.

Klinefelter syndrome is the most common sex chromosome disorder, occurring in about 1/700 live male births. The extra X chromosome is maternally derived in 60% of cases. Germ cells do not survive in the testes, leading to decreased sperm and androgens.

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 verbal learning disorders. Clinical variation is great, and many 47,XXY males have normal appearance and intellect. Many are diagnosed during an infertility evaluation (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 about 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 intellectual disability and of malformations also increases. Each extra X is associated with a 15- to 16-point reduction in IQ, with language most affected, particularly expressive language skills. Males with Klinefelter syndrome should have lifelong testosterone supplementation beginning at puberty to ensure the development of male sexual characteristics, muscle bulk, bone structure, and better psychosocial functioning.

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 a 47,XXX (trisomy X) 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 intellectual disability and congenital anomalies increases markedly when there are > 3 X chromosomes. The genetic imbalance in early embryonic life may cause anomalous development.

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