What happens if you have 45 chromosomes?

Hypergonadotropic Hypogonadism

Abnormalities of Sexual Differentiation

Abnormalities of Sexual Differentiation

Monosomy X (Turner's Syndrome)

Turner's syndrome results from monosomy of chromosome X [45 (XO)] with a prevalence of 1 in 2000–2500 liveborn females (see Table 8-1).5 Cardiac lesions are noted in 25–35% of affected patients and most commonly involve the left side of the heart.6 Some hypothesize that the abnormal lymphatic flow seen in Turner's syndrome alters blood flow in the developing aortic arches and causes the associated left-sided cardiac defects. The most common malformations include coarctation of the aorta or bicuspid aortic valve, or both, whereas hypoplastic left heart syndrome is rare. Other important cardiovascular features that are rare but are often overlooked include the late occurrence of hypertension and aortic dilation resulting in death secondary to aortic dissection. These late risks suggest that even patients without overt CHD should be followed regularly by examination and echocardiography. Turner's syndrome is also characterized by lymphedema of the hands and feet as a neonate, webbed neck, widely spaced nipples, short stature, and primary amenorrhea, as well as renal, skeletal, and thyroid anomalies.

32.7.1 X Chromosome Abnormalities

Females completely lacking an X chromosome include those with pure 45,X karyotypes as well as those with another cell line (46,XY, 46,XX, 47,XXX, or 46,X iXq). About 90% of females with a 45,X cell line with or without mosaicism present with primary amenorrhea, the complete lack of sexual development, and irreversible ovarian failure (6,114). About 5–10% of 45,X females have normal puberty and menarche, but these menses are usually short-lived and often cease before age 40. Women with a 45,X cell line who menstruate may be fertile, but reproductive loss may occur in the form of spontaneous abortions, stillbirths, and chromosomal abnormalities (including 45,X and Down syndrome) and is common (114). Patients with a 45,X cell line (Turner syndrome) manifest phenotypic features such as short stature, widely spaced nipples, webbed neck, shield chest, multiple skin nevi, and a short fourth metacarpal. However, the most consistent feature is short stature with heights under 5 ft. The most serious associated somatic anomalies include cardiac (in about 50%) and renal abnormalities (114). A dilated aorta has a several percentage estimated chance of rupturing during pregnancy, suggesting that donor egg in vitro fertilization should be discouraged (115). If there is a coexistent Y chromosome with a 45,X cell line, gonadoblastomas may occur within the streak gonads, which may give rise to more serious germ cell tumors. Therefore, the gonads should be removed in these patients with a Y cell line.

Individuals with a 45,X/46,XY karyotype may manifest any of several different phenotypes. If bilateral abdominal streak gonads are present, the phenotype resembles other 45,X females who do not have a Y cell line with short stature, absent breast development, but with an intact vagina and Müllerian system. If an intra-abdominal streak and a contralateral testis either in the abdomen or in the labioscrotum are present, sexual ambiguity will result. Much less commonly, 45,X/46,XY patients have bilateral scrotal testes, which renders them a male phenotype (116).

Turner syndrome is thought to result from haploinsufficiency of multiple genes on the X chromosome that affect embryologic development, stature, and ovarian function. The short stature likely results from the deletion of one allele of SHOX (short stature homeobox gene), a transcription factor on Xp22 that is primarily expressed in osteogenic cells (117). Similarly, patients with idiopathic short stature (without Turner syndrome) may harbor mutations in SHOX. The phenotype of patients possessing SHOX mutations varies depending upon the mutation type—either Langer mesomelic dysplasia resulting from deletions or Leri–Weill dyschondrosteosis, a skeletal dysplasia with disproportionate short stature, mesomelic limbs, and the Madelung deformity (a radial bone anomaly also sometimes seen in Turner syndrome) caused by nonsense mutations (117,118).

Partial deletions of the X chromosome may also impair ovarian function. In general, deletions affecting Xp11 result in ovarian failure in about half of the patients, while the other half have menstrual function (119). Even if menstrual function is normal, fertility is typically impaired. With more distal deletions, such as at Xp21, the phenotype is usually less severe. Most women with Xp deletions are short, regardless of ovarian function, further supporting that other statural determinant genes could reside within these regions. Several families with Xp deletions have also been reported (119).

Deletions of Xq may also result in ovarian failure. Similar to Xp deletions, proximal Xq (such as Xq13) deletions are usually more severe, and these patients have absent breast development, primary amenorrhea, and gonadal failure. If the deletion involves more distal Xq, menarche may occur with or without ovarian failure. Familial forms of Xq deletions manifesting as ovarian failure have also been reported. The mechanism of ovarian failure in patients with X chromosome abnormalities has not been clearly elucidated, but could involve a dosage phenomenon, especially if the involved gene/genes do not escape X-inactivation. Deleted/disrupted ovarian determinant genes probably increase follicular atresia of the ovary similar to that seen in patients deleted of an entire X chromosome. It is also possible that the Xq deletion contains genes that might affect mitosis or meiosis, which could result in enhanced follicular atresia (see specific genes below). Chromosomal rearrangements involving the X chromosome have also been reported to disrupt ovarian gene function (119).

Turner's Syndrome

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.14 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.15

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.16 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.17 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.16,17 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.18

Treatment of patients with Turner's syndrome is directed at facilitating growth by administering recombinant growth hormone,19 correcting associated congenital anomalies, and carefully managing hormonal replacement therapy for sexual infantilism.

Gonadal Failure

Histologic evidence suggests that the ovary of the fetus with a 45,X karyotype (and presumably the ovary of the fetus with karyotypes with X chromosome deletions, rings, or mosaicism) undergoes an initial phase of differentiation that is the same as that in the 46,XX fetus. If the ovary is examined at 14 to 18 weeks of gestation, no abnormalities are seen. Subsequently, however, when there is a chromosomal defect in the germ cells the process of oocyte loss appears to be accelerated—with a concomitant acceleration of stromal fibrosis. Thus, what is considered the normal process of oocyte loss (beginning prenatally and continuing over 30 to 50 years of postnatal life in normal females) occurs entirely prenatally or in the first few months or years of postnatal life in most females with Turner syndrome.223,224

The triggering mechanism for this premature follicular atresia is postulated to be in part secondary to meiotic pairing anomalies in prophase,225 and may be seen in other chromosomal abnormalities (such as trisomy 13 and trisomy 18).226 The molecular mechanisms presumably involve the acceleration of an oocyte-intrinsic apoptosis defect regulated by members of the Bcl-2 gene family198 and the caspase family of proteases.227 The processes of oocyte loss and fibrosis are, however, neither absolute nor inevitable. Whereas the older literature documents both spontaneous puberty and menarche in a small number of patients with Turner syndrome,228-231 the low percentages reported may be the result of ascertainment of only the most phenotypically obvious Turner syndrome patients.

The report of Pasquino and co-workers,188 which includes more than 500 patients older than the age of 12 years, documents a high rate of spontaneous puberty—with an incidence of 14% in monosomic X patients and 32% in patients with cell lines with more than one X. In the series of Lippe et al.232 of 141 girls who were in the pubertal age range, 29 (21%) had the onset of breast development to Tanner III or more—with menses occurring at least once in 25 and menses persisting into at least young adulthood in 15 (50% of those with initial ovarian function, or 11% of the entire pubertal age group).

Seven of the 29 with some degree of ovarian function had a 45,X karyotype. Of note is that although these 7 girls had some phenotypic features of Turner syndrome they did not have the webbed neck phenotype we associate with the presence of fetal lymphedema. The remaining 22 patients had mosaicism or structural abnormalities, with the highest number of girls with menses in the 45,X/46,XX group. Again, these girls lacked the webbed neck phenotype. Thus, maintenance of some degree of ovarian function can occur in Turner syndrome patients regardless of karyotype—although it is more common in those with cell lines with more than one X, and clearly more common in those who lack the webbed neck phenotype.

Pregnancy has been reported in more than 60 patients with Turner syndrome, including those with a 45,X karyotype on multiple tissues.234-238 Although these latter cases remain rare enough to continue to merit individual reports, they illustrate the spectrum of ovarian function in this condition. Counseling about the expectations and future management of the patient with Turner syndrome diagnosed before puberty needs to include the probability of gonadal failure and infertility but not its inevitable occurrence. Even in those instances in which fertility does occur, however, reproductive failure is high and the risk of an abnormal offspring (notably one with trisomy 21) appears significant.237-239

In the series of Pasquino and co-workers,188 there were three patients with spontaneous pregnancies (3.6%). One patient had two pregnancies, one with a normal male karyotype and one female with the same structurally abnormal X as the mother (i.e., Turner syndrome). One patient had twins with normal karyotype but severe cleft palate, and one patient had a normal infant. Ultimately, morethan 90% of indiduals with Turner syndrome will have gonadal failure.61 Physiologic evidence for gonadal failure in Turner syndrome is provided by the response of the hypothalamic-pituitary axis to functional agonadism.

It has long been recognized that the negative feedback loop between the gonad and the hypothalamic-pituitary axis is operative in the fetus and demonstrable at birth. In normal infants, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) rise after birth. In the male, the gonadotropin rise is accompanied by a significant surge in plasma testosterone in the first months of life. Gonadotropin and testosterone then gradually decline to prepubertal concentrations by the end of the first year. In the female, although the gonadotropin rise does not appear to be accompanied by as striking a response in estradiol secretion from the ovary the plasma FSH remains slightly elevated for a period of several years.

In Turner syndrome, a markedly exaggerated rise in both plasma gonadotropins (but especially in FSH) has been demonstrated as early as 5 days of age in one study.240 In a more recent study, however, with the blood spot obtained used for neonatal screening241 a clear-cut elevation of FSH could not be demonstrated in patients with known karyotype abnormalities consistent with Turner syndrome—suggesting that FSH cannot be used for neonatal screening for Turner syndrome. In the series by Lippe et al.,232 the investigators evaluated 14 patients with karyotypes consistent with Turner syndrome at 2 weeks of age or later in the first year of life. Of those who presented with lymphedema at birth, all had FSH determinations of more than 40 mIU/mL.

Conversely, of the patients who had the diagnosis of an X chromosome abnormality made by amniocentesis only 50% had evidence of castrate levels of FSH. Thus, although an abnormally high FSH in the neonatal or infancy period is useful to detect gonadal failure a normal level does not preclude the diagnosis of Turner syndrome. Whether the girls with normal FSH levels in infancy will go on to have gonadal failure at adolescence or will turn out to be the 10% to 30% who have some gonadal function remains to be determined. Pelvic ultrasound may have prognostic value in predicting the future sexual development of patients with normal gonadotropins. Data of Mazzanti and associates242 suggest that detection of ovaries bilaterally in patients without castrate levels of gonadotropins and mosaic karyotypes correlated best with preservation of some ovarian function at puberty.

When abnormally elevated in infancy, the gonadotropin levels decline again after the first 2 years—although to mean concentrations significantly higher than those in gonadally competent female children. Between ages 4 and 10 to 11 years, a trough is noted, which is followed by the gradual rise of gonadotropins in normal children and a more rapid and exaggerated rise in most children with Turner syndrome. This diphasic pattern of FSH, determined on a large number of patients with gonadal dysgenesis, is illustrated in Figure 15-17 A. In Figure 15-17 B, serial determinations graphically demonstrate the fall that occurs in the first years of life and the abrupt rise that occurs in early adolescence. The range of values considered normal for a female varies with the assay method and the standard used, and thus the values in the figure are illustrative but will not be normative for most current commercial assays.

The mechanisms responsible for the feedback suppression of gonadotropin secretion in the normal child and the similar pattern, although at a higher set point, in the child with gonadal dysgenesis are unclear. It has been presumed that increased sensitivity to circulating steroids of gonadal and adrenal origin results in decreased hypothalamic gonadotropin-releasing hormone (GnRH) release in the prepubertal subject. Studies in primate species suggest that one component of the feedback inhibition may be at the level of the pituitary and that another may be at the hypothalamic level. There may also be significant central neuronal inhibition that is not affected by gonadal steroids.

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