Chromosomal origins

Refinements in cytogenetic methodology over the last half of the 20th century promoted the elucidation of the chromosomal basis for Turner syndrome and other aneuploidies. The standard cytogenetic karyotype describes the number and morphologic features of condensed metaphase chromosomes under light microscopy (Figure 16-2A). Karyotype studies of the products of conception and newborns have shown that X monosomy is the only chromosomal monosomy compatible with life, as monosomy for the Y chromosome or autosomes have never been reported.⁸ This distinction among chromosomes is explained by the fact that the Y chromosome has relatively few essential genes aside from those involved in male sex determination and spermatogenesis, and the second X chromosome in females is largely inactivated, or silenced early in development. There are, however, a number of genes that escape X inactivation and that have homologs represented on the Y chromosome.⁹ Haploinsufficiency for these genes results in short stature and other aspects of the Turner phenotype (discussed later).

The loss or fragmentation of a sex chromosome is most commonly traced to error(s) of recombination and segregation occurring during meiotic divisions.⁸ The molecular triggers for such errors are poorly understood but appear to differ for autosomes and sex chromosomes.¹⁰ Thus, in contrast to trisomy 21, Turner syndrome is not preferentially linked to maternal meiotic errors or age and may be more commonly associated with paternal meiotic errors.¹¹ A less common cause of Turner syndrome is the loss of a sex chromosome due nondisjunction in early embryonic mitotic cell divisions, resulting in a 45,X cell line together with cell lines with normal or supernumerary sex chromosome complement (e.g., 45,X/47,XXX; 45,X/46,XX; 45,X/46,XY).

Epidemiology

Cytogenetic studies found that X chromosome monosomy (45,X) was present in approximately 1/300 spontaneous abortions versus 1/5000 live births,2–13 indicating that most 45,X gestations do not survive to birth. The ratio of 46,X,i(X)q and 46,X,r(X) to 45,X cases increases from early gestation to birth, leading to the view that X monosomy is incompatible with survival and that surviving 45,X girls started out as 46,X, fragmentary X or Y gestations.¹³ It was hypothesized that fragmentary sex chromosomes are lost due to mitotic instability during the course of fetal development, so the girls appear to be 45,X after birth.^13,14 Early in the study of aneuploidy it was thought that monosomy per se would interfere with normal cell proliferation and differentiation.¹⁵ However, it has since been learned that mice with pure X monosomy have normal survival, development, and fertility¹⁶ and that human 45,X cells are able to proliferate and differentiate into various cell types in vitro.^17,18 Thus, it seems that X monosomy need not always be lethal, and the survival and relatively healthy development of some 45,X girls may be related to variations in autosomal genes that compensate for the X chromosome haploinsufficiency. Newborn cytogenetic screening during the 1970s and 1980s found that approximately 1:2500 live-born females had complete or partial X monosomy consistent with Turner syndrome.^12,13,19 Danish health registry data indicate, however, that only about half the number of cases predicted by the birth incidence receive a clinical diagnosis.²⁰ This discrepancy may be due to a relatively mild phenotype in some cases. The birth rate for Turner syndrome is going down in some countries,²¹ associated with the increasing use of fetal ultrasound screening.²²

Turner syndrome is reported in all races and countries with similar prevalence. X monosomy does not run in families and is not associated with any known environmental or behavioral factors.²³ There is one known case of an apparently pure 45,X woman with spontaneous puberty and pregnancy giving birth to a 45,X daughter.²⁴ Epidemiologic observations including more than 1000 girls with Turner and their families suggest that increased parental age modestly increases the risk of having a child with Turner syndrome.^23,25 The single normal X chromosome is identified as maternal in approximately 70% and paternal in origin in ∼30% of cases with cytogenetically confirmed Turner syndrome.^26–29 The expected ratio, if each parent has an equal probability of contributing a normal X to offspring, is 2:1. The consistent finding of a slightly greater than expected prevalence of X-maternal cases suggests that there may a greater propensity for meiotic errors involving the sex chromosomes during spermatogenesis. Women with Turner syndrome due to partial Xp deletion or translocation who are fertile may pass on the abnormal X chromosome to offspring.^30–32 The possibility of passing on a fragmented sex chromosome underscores the importance of obtaining a full karyotype in the diagnosis of Turner syndrome, because if such a chromosome is found in the child, the parents need genetic testing and counseling about potential recurrence, or transmission if the daughter is fertile. There does not seem to be an increase in monosomy X or any aneuploidy in assisted pregnancies compared to natural conceptions.³³ Historical case reports have described an association of trisomy 21 and mosaic X monosomy,³⁴ but this association has not been observed in a large population-based investigation.²³

Turner karyotypes

Cytogenetic nomenclature reports the total number of chromosomes followed by the sex chromosomes listed individually, thus the normal female karyotype is “46,XX” and Turner syndrome patients with a single X chromosome are “45,X.” The most common karyotype found in Turner syndrome is 45,X.^11,35,36 Mosaicism is defined as the presence of two or more cell lines showing different chromosome constitutions. If more than one cell line is detected, the karyotypes are separated by a slash, with the relative cell counts in brackets. For example, 45,X [10]/46,XX[10] describes an individual with 50:50 mosaicism for X monosomic and normal 46,XX cells based on scoring 20 metaphases. This type of cell line mosaicism occurs due to sex chromosome nondisjunction during postzygotic cell divisions. Depending on the developmental timing and cell populations affected, the clinical phenotype may be attenuated by mosaicism for a normal cell line.

The isoXq chromosome is the most common structural abnormality causing Turner syndrome.^11,35,37 It is a mirror image chromosome composed of two copies of the long arm fused head to head with a variable amount of centromeric and proximal Xp sequences in between, most commonly reported as 46,X,i(X)q. Variants that have subtotal Xp deletion are termed isodicentric and pseudo-isodicentric X chromosomes.^38,39 Individuals with isoXq chromosome are monosomic for the X short arm and trisomic for the X long arm. The presence of an isoXq chromosome is commonly associated with a 45,X cell line, as the abnormal isoXq chromosome is frequently lost during postzygotic cell divisions. This mosaic chromosomal constitution is reported as 45,X/46,X,i(X)q. Because all cells are monosomic for Xp, there is no tendency for moderation of the monosomic phenotype in this type of cell line mosaicism. The isoXq chromosome is not associated with mosaicism for a normal 46,XX cell line.

A ring X chromosome (rX) is fairly common in the etiology of Turner syndrome; the ring results from fusion of broken ends of short and long arms. Most often the ring has lost a major portion of Xp but retains the large part of Xq, and it is functionally equivalent to Xp deletion. The ring X is commonly lost during cell divisions in the course of development, resulting in mosaicism denoted as 45,X/46X,r(X). A ring X missing the X inactivation site (XIST) at Xq13.2 has been associated with severe mental retardation and somatic features atypical of Turner syndrome.^40,41 The XIST locus is required for inactivation of the second X chromosome, and deletion or deficient transcription of XIST may result in failure of X inactivation. The severe phenotype in girls with a small rX or with unbalanced Xp translocation is thought to be due to functional disomy of certain Xp loci that are normally inactivated.⁴²

About 5% of clinically diagnosed Turner syndrome patients have a significant Xp deletion, denoted 46,X,del(X)p, with or without mosaicism for a 45,X cell line. Xq deletions are associated with clinical features of Turner syndrome mainly in patients with 45,X/46,X, del(X)q mosaicism; women with terminal Xq deletion without 45,X cells do not usually have short stature or other features aside from premature ovarian failure.⁴³

Conventional karyotyping reveals mosaicism for 45,X/46,XY or 46,X,fragmentaryY cell lines in about 10% of clinically diagnosed girls with Turner syndrome.¹¹ In cases where the Y chromosome is intact, it is likely that the proportion of normal 46,XY cells was too low in the developing gonad to induce normal testis development and male differentiation. Phenotypic males with 45,X/46,XY chromosomal constitutions may have short stature and congenital cardiovascular malformations similar to those with Turner syndrome^44,45 but are considered under the diagnostic category of Disorders of Sexual Differentiation. In girls with Y chromosome structural abnormalities, the sex determining gene SRY may be deleted or inactivated, resulting in absent male differentiation.⁴⁶ The presence of Y chromosome material is clinically relevant because of the risk for development of a gonadoblastoma in females with Y chromosome material.⁴⁷ The diagnostic issues related to Y chromosome detection and clinical implications with regard to gonadoblastoma are discussed later in sections on “Diagnostic Tests” and “Gonadoblastoma.”

X chromosome genes and turner syndrome

In a classic article published in 1965, Ferguson-Smith analyzed the karyotypes of 307 patients with various forms of gonadal dysgenesis in relation to their clinical findings.⁴⁸ He proposed that monosomy for the short arm of the X chromosome was responsible the short stature and congenital malformations found in Turner syndrome, and he noted that Yp deletion was associated with a similar phenotype. Based on this analysis, Ferguson-Smith hypothesized that some Xp genes escape from X-inactivation in 46,XX females and that homologous genes were located on the Y chromosome short arm.⁴⁸ In addition, he reported that patients with mosaicism for a normal 46,XX line (i.e., 45,X/46,XX) tended to have fewer phenotypic abnormalities.⁴⁸ These observations were confirmed in subsequent chromosomal banding³⁵ and molecular studies.⁴⁹

As predicted, genes currently implicated in the Turner phenotype are located on the X chromosome short arm, escape the process of X inactivation, and have functional homologs on the Y chromosome.⁵⁰ The human sex chromosomes share homologous gene encoding regions located at the termini of the short and long arms. They are termed pseudoautosomal because genes in these regions behave like autosomal genes and do not undergo X inactivation. These regions ensure that X-Y meiotic pairing and recombination takes place, which is essential for male meiosis. The major pseudoautosomal region (PAR1) is located at the Xp and Yp terminal regions and includes at least 25genes.⁵¹ Two groups independently identified a PAR1 gene, which when deleted was associated with skeletal deformities and short stature.^52,53 This gene is termed SHOX, for “short stature homeobox” and is located ∼500 kb from the telomere of the sex chromosomes at Xp22.3 and at Yp11.3 (Figure 16-3). SHOX encodes a transcription factor that is highly expressed in human bone morphogenetic tissue.⁵⁴ SHOX haploinsufficiency due to mutation or microdeletion causes Leri-Weill dyschondrosteosis, characterized by mesomelic short stature and shortening and bowing of the radius with a dorsal subluxation of the distal ulna (Madelung deformity).⁵⁵ Homozygous SHOX deficiency causes Langer mesomelic dysplasia, producing extreme short stature, profound mesomelia, and limb deformity. SHOX mutations or deletions are found in 2% to 15% of children with idiopathic short stature, without obvious skeletal dysmorphology.^55,56 These observations have established the view that SHOX haploinsufficiency due to deletion of Xp or Yp terminal regions causes the skeletal anomalies and short stature occurring in Turner syndrome.

Isolated SHOX haploinsufficiency in Leri-Weil or Langer syndromes has not been linked to nonskeletal features of Turner syndrome such as lymphatic obstruction, congenital heart defects, renal anomalies, or hearing loss. It seems likely that haploinsufficiency for other, as yet unknown PAR1 gene(s) contributes to these important defects. This is inferred from the fact that rats and mice that lack PAR1 genes on the sex chromosomes are normal in size, fertile, and without apparent somatic or visceral defects.¹⁶ In contrast, canine, feline, and equine species that share a conserved PAR1 region with humans exhibit dwarfism, infertility, and aortic coarctation in X monosomy.⁵⁰ Several Xp genes outside of PAR1 escape X-inactivation and have Y-homologues, and thus may play a role in Turner syndrome, as recently reviewed.⁵⁰ Xp deletion mapping data suggested that distinctive neurocognitive characteristics of Turner syndrome are linked to haploinsufficiency for PAR1 or nearby loci.⁵⁷ Ogata and colleagues ascertained a “lymphedema critical” region at Xp11.4,⁵⁸ although this localization was not confirmed in a more recent study.⁵⁹ Bondy and associates have demonstrated that the locus for bicuspid aortic valve and aortic coarctation is telomeric to Xp11.4.⁶⁰ Hearing loss also maps to Xp deletion.^61,62 Genes located on the X chromosome long arm (Xq) are not likely candidates given that girls with normal Xq constitution (e.g., 46,X,del(X)p) and girls that actually have an extra copy of Xq (46,X,i(X)q) have the consistent Turner phenotype.⁶³

X chromosome genomic imprinting

Although haploinsufficiency for Xp genes is clearly implicated in major features of Turner syndrome,⁶⁴ it is also possible that the exclusive expression of maternally or paternally derived X chromosome may differentiate 45,X girls from the 46,XX population that express an equal ratio of X maternal to X paternal genes secondary to random X inactivation. Important male-female differences such as adult height, brain size, risk for autistic spectrum disorders, abdominal adiposity, and atherosclerosis are independent of gonadal effects and could be influenced by X chromosome genomic imprinting.⁶⁵ Skuse and colleagues reported impaired social and verbal skills among girls with Turner syndrome who were monosomic for a maternal X chromosome compared to a group monosomic for a paternal X, and they suggested that imprinting of X-linked genes contributes to sex-based differences in risk for autism spectrum disorders.⁶⁶ Subsequent studies have not supported this view⁶⁷; however, one MRI study found that brain volumes are greatest in prepubertal girls monosomic for X-maternal, intermediate in 46,XX girls, and smallest in girls monosomic for X-paternal, consistent with a maternal X chromosome dose effect on brain volume.⁶⁸

Adult height is a sexually dimorphic trait; however, there is no apparent height difference between Turner groups monosomic for either parental chromosome.69–73 Interestingly, adult height in women with Turner syndrome, regardless of X parental origin, tracks maternal but not paternal height.^{29,70,72–74} One study suggested that response to growth hormone treatment was influenced by the parental origin of the single X chromosome,⁷⁴ but this has not been confirmed in larger, more recent studies.^37,75 Male-pattern abdominal adiposity is observed in females with monosomy for the maternal X chromosome and is associated with an atherogenic lipid profile,⁷⁶ which may contribute to greater risk for atherosclerosis among women with Turner syndrome and among the general male population, as males are constitutionally monosomic for a maternally derived X chromosome.

Diagnostic tests

A chromosomal karyotype has been required for the definitive diagnosis of Turner syndrome.^77,78 This test usually entails obtaining a fresh blood sample from which mononuclear cells are extracted and placed into culture medium. A mitogen such as phytohemagglutinin is used to stimulate lymphocyte proliferation, and after several days, colchicine is used to arrest the cells in metaphase. After fixation, cells are spread on glass slides and treated with Giemsa stain to produce the G-banding pattern, which allows chromosome identification and characterization of major structural anomalies under the light microscope (see Figure 16-2A). Fluorescent-labeled molecular probes corresponding to specific DNA sequences are used to further identify chromosomal deletions or translocations in a process termed fluorescent in situ hybridization or FISH (Figure 16-2B).

For the diagnosis of Turner syndrome, the American College of Medical Genetics recommends scoring a minimum of 20 metaphases from peripheral blood cells.³⁷ If there is a high degree of clinical suspicion but the initial karyotype is normal, another 10 metaphase spreads should be analyzed. In addition, a standard metaphase karyotype may be performed on cultured fibroblasts or interphase FISH may be used on available cells or tissue, although such tests are not well established. In fact, all the clinical and prognostic information guiding standard practice is based on diagnosis using the standard 20-cell karyotype from peripheral blood mononuclear cells. In some cases the standard karyotype reveals small fragments of chromosomal material known as marker or ring chromosomes that cannot be identified as derived from X or Y chromosomes based on morphology. These fragments require identification using FISH with X and Y chromosome specific probes. Some authors suggest further screening for potential Y chromosome sequences using FISH or polymerase chain reaction (PCR) in girls that have a nonmosaic 45,X karyotype.³⁷ This approach has not been widely adopted because of uncertainty about the diagnostic reliability and the unclear clinical significance of “cryptic” Y chromosome sequences.

One study showed that measuring the allelic expression of X chromosome single nucleotide polymorphisms (SNPs) by high throughput sequencing of DNA samples from buccal swabs was able to confirm cytogenetic diagnoses of girls with Turner syndrome.⁷⁹ The conceptual basis for this approach is that individuals with a single X chromosome will demonstrate lack of heterozygosity for polymorphic X sequences. This method could be used for noninvasive screening of newborns, although the diagnosis would have to be confirmed by standard karyotyping.

A new diagnostic technology relevant to Turner syndrome and other chromosomal disorders uses array-based hybridization to assess both chromosomal sequence copy number and SNP diversity across the entire genome. This new technology provides high resolution virtual, or in silico karyotype analysis (Figure 2C) and is performed on stored blood or tissue samples without need for cell culture. These arrays are able to demonstrate X monosomy, X chromosome deletions, and detect Y chromosome presence equivalent to conventional metaphase karyotypes.⁸⁰ Their accuracy in detecting low level mosaicism needs further evaluation, however, and additional studies are needed to confirm a correlation between clinical features of Turner syndrome and array-based hybridization diagnoses in a prospective manner.

Indications for karyotype testing

There is a distinct biphasic pattern in the diagnosis of Turner syndrome with a substantial proportion being diagnosed around the time of birth and another large group diagnosed around 12 years of age (Figure 16-4). During infancy, the most common indication for karyotype screening is lymphedema. Residual signs of fetal lymphedema include neck webbing, low hairline, malrotated, low-set ears, and drooping eyelids. Swelling or puffiness of the hands and feet accompanies peripheral lymphedema, which is common in infants with Turner syndrome. Skeletal features and growth delay may be present but difficult to appreciate during the first few years. Another important indication for karyotype analysis is the presence of congenital cardiovascular malformation, especially aortic coarctation and aortic valve disease in a female infant or young girl.

A karyotype should be considered in the evaluation of girls with short stature, especially if associated with typical skeletal features such as micrognathia, high-arched palate, short metacarpals, or cubitus valgus as described later (skeletal anomalies and growth failure). Girls and young women presenting with delayed or absent puberty associated with elevation of gonadotropins should have a karyotype analysis. Finally, Turner syndrome is not infrequently discovered by karyotype analysis in women with infertility or premature menopause, as illustrated by the late age of diagnosis for 7% of the National Institutes of Health (NIH) cohort (see Figure 16-4).

Differential diagnosis

The standard karyotype analysis plays an essential role in differential diagnosis of Turner syndrome. Noonan described male and female children with neck webbing, short stature, and congenital heart disease,⁸¹ and in the past boys with this disorder were classified as “male Turner syndrome.” Noonan syndrome is a genetically heterogeneous autosomal dominant disorder with no sex predominance and is associated with a normal karyotype. The Noonan congenital heart defects include pulmonic valve stenosis and hypertrophic cardiomyopathy⁸¹—in contrast to the Turner cardiovascular phenotype that includes mainly left ventricular outflow tract defects. Puberty may be delayed, but girls are usually fertile whereas boys may have cryptorchidism. The nomenclature, evaluation, genetic counseling, and endocrine management that are appropriate to the girl with Turner syndrome do not apply to patients with Noonan syndrome. Another consideration in the differential diagnosis of a girl undergoing evaluation for short stature with some skeletal features associated with Turner syndrome and similarly affected siblings is SHOX mutation/deletion or Leri-Weill syndrome. Girls with delayed or absent puberty, normal height, and 46,XX or 46,XY karyotypes are thought to have isolated mutations/deletions of genes involved in gonadal differentiation. These patients were historically grouped with girls with Turner syndrome under the category “gonadal dysgenesis,” but they clearly have very different genetic, medical, and psychosocial issues.

Prenatal diagnosis

The prognosis for prenatally detected Turner syndrome depends in large measure on the indications for the testing. When an abnormal fetal ultrasound showing cystic hygroma or fetal hydrops leads to genetic testing and demonstration of nonmosaic 45,X fetal karyotype, there is virtual certainty of a clinically significant diagnosis of Turner syndrome and a high risk of fetal demise.⁸² A characteristic ultrasound of a 14-week-old Turner fetus with a cystic hygroma is shown in Figure 16-5. In contrast, an incidental prenatal diagnosis of Turner syndrome with a normal fetal ultrasound is often associated with a mild postnatal phenotype.⁸³ The postnatal outcomes for fetuses mosaic for 45,X and normal 46,XX or 46,XY cell lines are quite variable and correlate poorly with phenotypes of children ascertained on clinical grounds with Turner syndrome or mixed gonadal dysgenesis.⁸⁴ Over 90% of 45,X/46,XY cases ascertained by amniocentesis or villous chorionic sampling appear to be normally developed males at birth.⁸⁵ The outcome for fetuses with 45,X/46,XX karyotypes appears to be similarly mild.^83,86 Given these observations, it is important that prenatal counseling inform families that 45,X/46,XY and 45,X/46,XX gestations with normal fetal ultrasound may present a milder phenotype than that of patients diagnosed clinically. Moreover, even the 45,X fetus with cystic hygroma may be viable and enjoy a good quality of life. Importantly, prenatal diagnoses of sex chromosome anomaly should be reevaluated postnatally with a standard peripheral blood karyotype in all cases.

As genomic technology advances, we are seeing new approaches to prenatal screening for genetic abnormalities. Massively parallel genomic sequencing is able to characterize small amounts of cell free fetal DNA in the maternal blood stream by 10 weeks’ gestation, and this approach may eventually supplant the use of the maternal “analyte” screen. However, suspicions of aneuploidy based on cell free fetal DNA, maternal analytes or fetal ultrasound still require direct confirmation of the chromosomal complement from in situ fetal tissue obtained from amniocentesis or chorionic sampling. More advances on the genomic technology front may replace the traditional karyotype of fetal tissue. Comparative genomic hybridization (CGH) arrays are equal to traditional karyotype in identification of trisomy 21 and sex chromosome anomalies, including 45X from fetal samples obtained by amniocentesis or chorion samples.⁸⁷ CGH is more sensitive to microdeletions or duplications compared to traditional karyotype analysis, but it may not detect balanced translocations or cell line mosaicism associated with Turner syndrome, for example, 45,X/47,XXX. The clinical outcomes of pregnancies identified by the new genomic technologies have not yet been studied.

Lymphatic obstruction

The appearance of the 45,X fetus illustrated in Figure 16-7 dramatically shows the fetal edema that occurs in many conceptuses with Turner syndrome. The edema appears to result from lymphatic malformations and obstruction.⁸⁸ The cystic hygromas are due to delayed formation of communications between the jugular and central lymphatics draining into the heart that normally develop between the fifth and sixth weeks of gestation. Peripheral lymphatic hypoplasia or aplasia has also been demonstrated using lymphangiography in adult patients with Turner syndrome.⁸⁹

Webbed neck, or pterygium colli, is the most obvious consequence of nuchal lymphatic obstruction and this is seen in approximately 25% of patients diagnosed currently. The tenting of developing scalp and facial structures is believed to cause low-set, rotated auricular structures, down-sloping eyes, drooping eyelids, and low posterior hairline (see Figure 16-6). It has been suggested that this mechanical distention during fetal development may be responsible for lush hair growth, including eyelashes and eyebrows. Edema of the dorsum of the hands and feet at birth signals peripheral lymphedema, which usually resolves, although some patients demonstrate chronic involvement. Others may complain of intermittent or recurrent edema, often after the institution of estrogen replacement therapy.

Skeletal anomalies and short stature

The most common physical abnormality associated with Turner syndrome is short stature. The impairment is most pronounced along the longitudinal body axis. This gives affected individuals the visual appearance of being stocky or squarely shaped and accounts for the predominantly illusory finding of widely spaced nipples.⁹⁰ The short neck is secondary to hypoplasia of one or more of the cervical vertebrae.⁹¹ Long bone growth is selectively impaired, resulting in relatively short legs and an increased upper-to-lower segment ratio.⁹² Individual bones are affected to varying degrees. For example, cubitus valgus is commonly appreciated and can be measured as the angle of intersection of the long axis of the upper arm with the long axis of the supinated forearm when the elbow is fully extended. Normally, in adult women this angle is approximately 12 degrees—whereas in adult men it is approximately 6 degrees.⁹³ The major determinant of the angle is the depth of the inner lip of the trochlea of the ulna relative to the outer lip. In many patients with Turner syndrome the angle is between 15 and 30 degrees (Figure 16-8) as a consequence of developmental abnormalities of the trochlear head.

A shortened fourth metacarpal is visible on a bone age radiograph (Figure 16-9A) and is visible on exam by depression of the knuckle when the patient makes a fist. The Madelung deformity is found in 7% to 8% of patients and is caused by bowing of the radius coupled with dorsal subluxation of the distal ulna (Figure 16-10).⁹⁴ This anomaly also occurs as part of the Leri-Weill syndrome.

Spinal scoliosis or kyphosis is reported in a significant number of patients⁹⁵ and may be secondary to vertebral anomalies or leg-length inequality. Micrognathia or receding chin and high arched palate are common and thought to be due to disturbances of the development of facial bones.

Bones of the hand and wrist on bone age radiographs often demonstrate osteopenia,⁹⁶ associated with ballooning of the tips of the terminal phalanges.⁹⁷ Both findings are illustrated in Figure 16-9B.This osteoporotic appearance is observed in childhood, suggesting that it may be more related to the developmental role of SHOX than to primary estrogen deficiency. In support of this view, cortical bone mineralization is selectively reduced in girls and women with Turner syndrome, independent of estrogen exposure.⁹⁸ Long bone fractures associated with minimal trauma appear to occur more frequently among girls with Turner syndrome.⁹⁹

Short stature is the most common phenotypic feature of Turner syndrome. The first comprehensive assessment of skeletal growth deficits was reported by Ranke and colleagues in 1983.¹⁰⁰ Patterns of growth are illustrated in Figure 16-11, which shows cross-sectional height and velocity data from a series of 150 Turner children who had not received therapy to promote growth. The observations were supplemented by Davenport and coworkers,¹⁰¹ who distinguished stages of growth deficit: mild intrauterine growth retardation with average birth length 1 standard deviation (SD) below the mean; a period of mild growth deceleration from birth to age 3.¹⁰² After age 3, there is continued deceleration, so that between ages 3 and 13 years Turner syndrome girls fall farther and farther away from the normal height curves and, if untreated, fail to experience a pubertal growth spurt but continue to grow at a slow rate for several more years.

A positive correlation is found among height at diagnosis,¹⁰³ ultimate height achieved, and midparental height.¹⁰⁴ The final height deficit, using comparative data on adult heights in patients with different ethnic backgrounds, is approximately 20 cm.¹⁰⁵ Lyon and associates¹⁰⁶ used the data from Ranke and colleagues and from three other European centers to synthesize a series of growth curves for Turner syndrome. The curves provided mean height and SD values for age and determined a mean adult height 143.1 cm. Lyon and colleagues also noted a strong correlation between the initial height on these Turner curves and the adult height essentially independent of bone age at the time of the first height. Thus, they concluded that one could project the adult height of a girl with Turner syndrome based on her height at an earlier age. The deficit in longitudinal bone growth in Turner syndrome has been attributed to the deleterious effect of SHOX haploinsufficiency, and a similar deficit is seen in isolated SHOX defects such as Leri-Weill syndrome. Growth hormone deficiency is not implicated in Turner short stature.

Ovarian insufficiency

The earliest studies of ovarian pathology in women with Turner syndrome described fibrous streaks devoid of oocytes and follicles, and thus initially it seemed that gonads failed to develop or were “dysgenetic.” Subsequent studies revealed that early stages of ovarian development appeared normal, with expected numbers of oocytes and primordial follicles at 14 to 16 weeks of gestation in Turner fetuses.¹⁰⁷ However, at later stages of development, Turner ovaries were relatively depleted of oocytes and had few developing follicles, suggesting an accelerated rate of oocyte demise and follicular atresia,^108,109 although follicles in various stages of development are detected in some teenage girls with Turner syndrome.¹¹⁰ The cause for the high rate of oocyte attrition in most girls with Turner syndrome is unknown. It has been suggested that aneuploidy contributes to oocyte demise due to meiotic mishaps.¹¹¹ Another possible explanation for oocyte loss is that diploid expression of unknown X chromosome gene(s) is required for normal oocyte generation or survival. The chromosomal location of putative fertility genes has remained elusive, with gonadal failure frequently observed in Xp deletions with intact Xq complement and in some cases of Xq deletion with normal Xp complement.¹¹² Terminal Xq deletions have been associated with premature ovarian failure in women who have few if any features of Turner syndrome.¹¹³

Ovarian function and potential for spontaneous puberty and even pregnancy are variable and sometimes difficult to assess among girls with Turner syndrome. An important Swedish study using ovarian biopsy has shown that a karyotype with mosaicism for 45,X and 46,XX cell lines is the most significant positive predictive factor for the presence of ovarian follicles, whereas karyotypes indicating nonmosaic 45,X or structural defects of one X chromosome were significant negative correlates for the presence of follicles.¹¹⁴ Clinical factors such as normal follicle stimulating (FSH) and anti-Mullerian hormone (AMH) levels and spontaneous start of puberty were also significant positive predictors of follicle presence, although less robust than the blood karyotype.¹¹⁴ According to a large, multicenter Italian study that included more than 500 girls with Turner syndrome, spontaneous puberty occurs in about 15% of those with pure 45,X and in 30% of girls with a second cell line with more than one X chromosome (i.e., 45X/46XX; 45X,47XXX).³⁶ Puberty may fail to progress to menarche in some girls, and menarche may be followed by oligomenorrhea or anovulatory cycles in others, so that the actual percentage of young women that maintain normal menstrual cycles by age 20 is less than 5%.

Spontaneous pregnancy occurs in 2% to 3% of women with Turner syndrome.^36,115,116 This is more common among women with mosaicism for 46,XX or 47,XXX cell lines, but there are several well-documented reports of spontaneous pregnancies in 45,X women who had no evidence of mosaicism despite intensive investigation.^24,116,117 An early case series reported a high frequency of fetal mortality or malformation for spontaneous pregnancies among women with Turner syndrome.¹¹⁸ However, this has not been observed in more recent, population-based studies^116,119 nor in women with X monosomy.^116,120 If the mother has Turner syndrome due to a sex chromosome structural abnormality, the abnormal chromosome may be passed on to her offspring. The risk of maternal complications with spontaneous or assisted pregnancies is very high for women with Turner syndrome. These concerns are discussed at the end of this chapter in the “Reproductive Options” section.

Gonadoblastoma

The gonadoblastoma is a benign tumor that consists of large germ cells surrounded by small cells with variable granulosa, lutein, or Sertoli-like morphology. This type of tumor strongly resembles the histology of a developing gonad, hence the appellation “gonadoblastoma.” This proliferative island of tissue within the dysgenetic gonad has a potential for steroid production and for malignant transformation into dysgerminoma.⁴⁷ The gonadoblastoma is found in approximately 40% of females with 46,XY mixed gonadal dysgenesis; the frequency among girls with Turner syndrome and Y chromosomal material is between 10% to 30%.⁴⁷ These frequency data are based on a histologic examination of ovaries that were “prophylactically” removed from girls with Y chromosome material in their karyotype. There are no studies showing morbidity or mortality related to gonadoblastoma in Turner syndrome. Analyses of Danish health registry data did not find increased morbidity or mortality related to any type of ovarian tumor among women with Turner syndrome.^20,121 A large British registry study ascertained gonadoblastoma diagnoses in 8% of women with Y chromosome in their peripheral blood karyotype, but it did not report any clinical data associated with the diagnosis.¹²²

Prophylactic gonadectomy has been standard practice since the time that an excess of gonadal tumors was first appreciated in females with Y chromosomes and intra-abdominal gonads. Supporting this approach was the view that the gonads in these cases were nonfunctional, essentially contributing nothing to the patient but risk. However, we have learned that spontaneous puberty and even pregnancy may occur in individuals with Turner syndrome and Y chromosome material.^32,123,124 For example, Portnoi and colleagues reported the case of a girl diagnosed with Turner syndrome at age 8 because of short stature who was found to have translocation of Y chromosome material onto the X chromosome (see Figure 16-2B). The patient’s family declined the advice for castration and the girl went on to develop spontaneous puberty and eventually had a well-supervised successful pregnancy.³² All the clinical experience with gonadoblastoma/dysgerminoma in girls with Turner syndrome derives from cases where the karyotype included visible Y chromosome material or the patient had clinical evidence of virilization, hence the recommendation for gonadectomy was applied only to individuals with visible Y chromosome material or virilization.^125,126 With the advent of molecular amplification technology, several studies have reported detection of Y chromosome sequences in 45,X girls without evidence of Y chromosome material on their karyotype, sometimes with a histologic demonstration of gonadoblastoma after gonadectomy. Some authors suggest that all 45,X patients undergo molecular screening for cryptic Y chromosome material. On the other hand, PCR amplification may yield false positive results¹²⁷ and immature ovaries may contain nests of germinal cells resembling the benign gonadoblastoma, so the risk of overtreatment is a real concern.

Unfortunately, there is little information on the use of imaging or serum markers for surveillance of potential gonadal tumors in Turner syndrome. In any case where Y chromosomes/sequences are detected and gonadoblastoma is suspected, there needs to be education and counseling of patients or family concerning gender identity, sexual functioning, and reproductive consequences relevant to the decision for gonadectomy. Moreover, preservation of follicles or oocytes may be an option for some patients undergoing gonadectomy. Further discussion of gonadoblastoma issues is found under the “Y Chromosome” section presented later in the chapter.

Cardiovascular system

Aortic complications

Complications of congenital cardiovascular disease are the leading cause of morbidity and premature mortality in Turner syndrome.^128,142,143 The major cardiovascular complications include aortic valve disease and aortic dilation, dissection, or rupture. The aortic valve is congenitally abnormal in approximately 30% of life-born girls with Turner syndrome, but it is not detected in many individuals until the third decade of life or later due to inadequate screening.^139,144 Among 74 patients with bicuspid aortic valve studied at the NIH (median age 30 year, range 7 to 67), 55% had normal aortic valve function, 30% had mild aortic regurgitation, and 15% had moderate to severe aortic regurgitation.¹³⁹ Aortic stenosis was present in only 2/74 patients with BAV in this series. BAV prevalence was equal in pediatric and adults groups, but the likelihood of valve dysfunction was higher among adults. Interestingly, the large NIH screening study utilizing advanced imaging confirmed an early small study by Miller and coworkers indicating BAV in 34% of girls with Turner syndrome.¹⁴⁵ It is clearly important to screen for aortic valve pathology in all girls and women with Turner syndrome, because the valve may deteriorate over time, leading to heart failure. Moreover, the presence of aortic valve abnormality is linked to aortic pathology with increased risk for aortic dilation, dissection, and rupture.^146–153

The presence of an abnormal aortic valve is associated with relative dilation of the ascending aorta, using age and body surface area nomograms, in girls and women with Turner syndrome.^139,151 The degree of dilation is greatest in patients with abnormal aortic valve function^139,151 but may be present in individuals with normal valve function as well. Moreover, mild-moderate ascending aortic dilation is found in approximately 10% of Turner patients who have a normal tricuspid aortic valve and normal blood pressure.^139,151 There is some evidence for a generalized vasculopathy in adults with Turner syndrome with enlarged diameter of carotid and brachial arteries¹⁵⁴ and aneurysms of other arteries.¹⁵⁵ The term aortopathy has come into wider use to describe aortic disease of diverse etiologies including Marfan syndrome and related vascular disorders that are not associated with valvular disease, in addition to aortic disease associated with BAV. It is unknown at present whether the risk for aortic complications in Turner syndrome is more similar to the former or the latter. This is a critical issue, because indications for intervention, the most effective type of surgery, and therapeutic responses to pharmacologic treatment are likely to be different in these categories.

The risk for serious aortic complications is increased in girls and women with Turner syndrome by 100-fold or greater compared to the general female population, estimated from an epidemiologic study of Danish registry data.¹⁵⁰

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