Current Issues in Pediatric and Adolescent Endocrinology

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Turner Syndrome and Its Variants

Judith G. Hall, MD, MS, FAAP, FRCPC, FCCMG, FABMG,* and Dawna M. Gilchrist, MD, FRCPCt

In 1938, Henry Turner described the combination of sexual infantilism, webbed neck, and cubitus valgus as a distinct entity.140 In subsequent years, gonadal dysgenesis was also recognized as part of the syndrome. Not until 1959, however, was the chromosomal basis of Turner syndrome defined, when Ford et al recognized that one of the X chromosomes was missing. 37 Subsequently, chromosomal studies have shown that Turner syndrome is characterized by the presence of only one normal functioning X chromosome; the other sex chromosome can be missing or abnormal, or mosaicism may be present. 126 Typically, Turner syndrome is suspected because of the combination of short stature, gonadal dysgenesis, and lymphedema. There are, however, no pathognomonic clinical features of Turner syndrome. Almost any combination of physical features can be seen with any X chromosomal abnormality, and severity of clinical features does not necessarily correlate with karyotypic findings. The diagnosis of Turner syndrome should be considered in any infant with lymphedema or any young woman with short statute or primary or secondary amenorrhea. The minimal diagnostic criterion for Turner syndrome is an abnormal karyotype present at birth in at least one tissue in which a portion or all of the X chromosome is missing.

INCIDENCE Turner syndrome occurs in 1 of 4,000 to 10,000 live births, giving an approximate incidence of 1 of 2500 live female births. 51 This incidence may From the Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

*Professor tClinical Fellow

Pediatric Clinics of North America-Vol. 37, No.6, December 1990

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vary geographically, seasonally, and over time. llo Environmental factors that might affect conception and birth rate have not been defined.

CHROMOSOME ABNORMALITIES

Approximately half the patients with Turner syndrome have "straight" (only) 45,X cells in peripheral blood lymphocytes. 31, 51.110,123,141 From 12% to 20% of Turner syndrome patients have an isochromosome X (duplication of one arm of the X chromosome with loss of the other arm). Mosaicism (the presence of two or more chromosomally different cell lines with regard to sex chromosome constitution in the same person) is found in 30% to 40% of Turner syndrome patients, approximately 10% to 15% of the total group being 45,Xl46,XX and 2% to 5% being 45,Xl46,XY mosaics. 25 Rarely, Turner syndrome occurs associated with Xlautosome translocations. 26 There is a trend of fewer clinical features as there are more cells with two normal XS.27

The presence of a Y chromosome is significant because it predisposes affected individuals with Turner syndrome to have gonadoblastomas in the gonadal streaks. 45,Xl46,XY individuals have a very broad spectrum of clinical presentation, from typical Turner syndrome stigmata to normal male phenotype. 20, 53 Although on the average these patients are more likely to have mild masculinization of genitalia, any patient with a diagnosis of Turner syndrome who has not been karyotyped or who was diagnosed on the basis of a negative buccal smear in the past should have karyotype analysis to rule out the presence of a Y chromosome.

HERITABILITY In general, Turner syndrome is not familial, and there is no increased risk for those women who have already had a Turner syndrome baby to have some other chromosomally abnormal child, miscarried or liveborn. Turner syndrome mothers who are themselves chromosomally mosaic, however, have been reported to give birth to Turner syndrome daughters who are also chromosomally mosaic. 82 Also, fertile Turner syndrome women with X chromosome deletions have given birth to girls with the same deletions. 38, 62 There are rare cases of fertility in 45,X women 59, 61 and more commonly in mosaic or X deletion Turner syndrome women. 127, 136 There appears to be an increased incidence of nondisjunction for both sex chromosomes and autosomes in the pregnancies of all types of Turner syndrome. 107, 136 Thus, it seems appropriate to offer prenatal diagnosis, looking for chromosomal anomalies, to any woman with Turner syndrome who becomes pregnant. The risk of bearing a liveborn child with Turner syndrome does not seem to be correlated with either advanced maternal age or young maternal age. 110 In general, an increased incidence of Turner syndrome is not seen in families that seem to have a predisposition to aneuploidy for other reasons. On the other hand, age is lower among women who have aborted

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Turner syndrome embryos and fetuses. 56. 143 In cases studied, the paternally derived X ~eems more likely the one to be lost, and in iso-X cases, there is a suggestion of advanced paternal age. 18. 48. 146

PRENATAL LOSS AND PRENATAL DIAGNOSIS

As at least 15% of all conceptions abort, at least half of all early spontaneous abortions have a chromosomal anomaly, and 1 in 15 spontaneous abortuses with a chromosomal anomaly has a 45,X karyotype, Turner syndrome has been estimated to be in the range of 1% of all conceptions. 51. 110 It is also estimated that 98% to 99% of pregnancies with a missing sex chromosome abort spontaneously. 51, 56 Some investigators suggest that all individuals with Turner syndrome who survive embryonic and fetal life and are liveborn must have some normal 46,XX cells in their tissues 17, 47 or, possibly, in the placenta. 57 Interestingly, the incidence of mosaicism among spontaneously aborted 45,X conceptions is much lower than it is among liveborns with 45,X karyotypes. 51, 110 Others have proposed that those conceptions with Turner syndrome that survive to birth have a better overall genetic makeup.47 It has also been postulated that a single rare gene is responsible for early opening of lymphatic channels, which then leads to tolerance of edema in the embryonic or fetal state. 9, 65 Between 60% and 75% of liveborn Turner syndrome individuals have lost the paternally derived X.48, 49, 119 There is also some suggestion that 46,X isochromosome X conceptions have less early mortality than 45,X conceptions. 51 Embryos and fetuses affected with Turner syndrome are frequently recognized in utero, particularly if the pregnancy is complicated or ultrasound has been performed. 54 The presence of fetal edema or hydrops suggests the diagnosis of Turner syndrome. If a nuchal mass with septations can be identified by ultrasound, the possibility of Turner syndrome is further reinforced. Whenever fetal hydrops is found, amniocentesis or chorionic villus sampling99 should be performed to confirm or exclude the diagnosis of Turner syndrome or some other chromosomal anomaly. Serum and amniotic alpha-fetoprotein can be elevated. 132 Ideally, all female abortus material with hydropic changes should be karyotyped, as Turner syndrome does not carry a recurrence risk, although many of the other causes of fetal hydrops do carry such a risk.

PATHOPHYSIOLOGY

The pathophysiology in Turner syndrome is not understood. However, the phenotype must be produced by a gene dosage inequality that occurs with the absence of part or all of the second normal sex chromosome. Many attempts have been made to correlate the type of X chromosome anomaly (such as totally missing, partial deletions of short and long arms, isochromosomes, and various mosaicisms) in specific individuals and in groups of Turner syndrome individuals with their phenotypic finding and

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Figure 1. Classical phenotype of 45X female.

natural history. * There seem to be genes involved in gonadal maintenance on both the proximal part of the X chromosome short arm and the middle and distal parts of the X chromosome long arm. The other somatic features of Turner syndrome are reminiscent of autosomal aneuploidies. There must be relevant factors on the short arm (perhaps including the pseudoautosomal region) of the X and Y chromosomes as well as on the middle section of the long arm of the X. 62, 126 There is a rough correlation between the absence or deletion of the short arm of the X chromosome and the clinical features that are thought of as typical for Turner syndrome (Fig. 1).18, 25, 31, 65, 89, 92, 120, 126, 146 These clinical features include short stature, broad chest, widespread nipples, webbing of the neck, peripheral edema at birth, short fourth metacarpal, hypoplastic nails, multiple pigmented nevi, and coarctation of the aorta (Table 1). Absence or deletion of the long arm of the X chromosome has been thought to be associated with infertility and gonadal dysgenesis. More recently, it has been postulated that the genes involved in maintaining gonadal function are located on the proximal part of the short arm of X (particularly band pll.2) and on two segments of the long arm of X (band q13 and q26 to qter); the other somatic stigmata of Turner syndrome are *18, 31, 44, 51, 89, 92, 120, 126, 137, 138, 146

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Table 1. Percentage of Frequency of Certain Physical Features in Various Karyotypic Types of Turner Syndrome

Short stature Gonadal dysgenesis Lymphedema Broad chest Hypoplastic, wide-spaced nipples Prominent, anomalous ears High palate Neck Appears short Posterior webbing Low hairline Cubitus valgus Short fourth metacarpal Nail hypoplasia Excessive nevi Renal structural anomalies Cardiac malformations Hearing impairment

45X

XlXX

98 95 70 75 78 70 82

90 75 12 65 50 40 55

80 65 80 75 65 75 70 45-60 20--30 50--70

65 45 45 65 50 50 60 25 10 45

p-

q-

95 80 42 65 80 33 50

90 80 4 32

80 90 0 20

12

0

80 20 60 30 50 50 65 20 5 100

44 8 24 36 32 12 28 8 8

20 4 16 16 20 4 24 0 0

ISOCHROMOSOMES

P - indicates deletion of the short arm on the second X chromosome.

q - indicates deletion of the long arm on the second X chromosome. Data from references 44, 45, 47, 65, 94, 126, and 137.

present, with deletions all along Xp and in the middle segment of Xq (bands q1.3 to 2.1).44,62,92,137,138,146 There is also a rough correlation between the degree of mosaicism and the presence of clinical features of Turner syndrome. 12o Isochromosome Turner syndrome patients (thought to be almost entirely isochromosomes of Xq) seem to have fewer physical stigmata that are thought to result from intrauterine edema. 89 It is still unclear how X inactivation or dosage effects lead to the expression of the phenotype, what genes or factors are left activated after inactivation, when development of various features are determined, and what allows for survival. The hypothesis that the authors favor is that most of the congenital anomalies can be explained on the basis of the presence of lymphedema at critical points in development, leading to imbalances in growth forces and failure of normal development or regression of particular tissues. It has been thought that the lymphedema in Turner syndrome is present on the basis of the failure to open embryonic lymph channels. DIAGNOSIS

The diagnosis of Turner syndrome is often suggested in the newborn by small size, lymphedema of hands and feet, and excessive skin at the nape of the neck (see Table 1). In the young child, unexplained shortness of stature with any of the known physical features of Turner syndrome suggests the diagnosis. Primary amenorrhea in an adolescent raises the possibility of Turner syndrome. Turner syndrome must be considered in any girl with short stature in whom no other diagnosis has been made. The diagnosis is established only by chromosome analysis. Usually

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peripheral blood leukocyte culture is used, but occasionally fibroblast culture will be indicated because of normal leukocyte studies and striking clinical features. The diagnosis should never be based on a buccal smear. The diagnosis is made when a portion or all of one of the X chromosomes is missing in all or some cells in the tissue being tested. Another important reason to confirm the clinical impression by cytogenetic studies is to identify 45,x/46,XY mosaics, as the presence of a Y chromosome predisposes the individual with Turner syndrome to the development of gonadoblastomas in gonadal streaks. 25, 42, 74, 75, 83, 96, 131 A combination of cytogenetic and molecular techniques using in situ hybridization to Y-chromosomal material may be useful for such identification. 42 , 131 The differential diagnosis of Turner syndrome is broad and is primarily related to short stature and amenorrhea, although other clinical features, such as webbed neck, short metacarpals, and peripheral edema, may raise diagnostic possibilities (Table 2).

GONADAL FAILURE AND HORMONAL REPLACEMENT Prior to 12 weeks of in utero development, the ovaries in a 45,X female appear normal histologically and apparently have the normal complement of ova,19 but thereafter there is a decrease in the number of follicle cells per oocyte. In the absence of a functional second X chromosome, the oocytes degenerate more rapidly than normal, so that by birth there are Table 2. Differential Diagnosis of Turner Syndrome Short Stature Noonan syndrome Familial short stature Dyschondrosteosis (Uiri-Weill syndrome) Brachydactyly E Growth hormone defiCiency Hypothyroidism Glucocorticoid excess Klippel-Feil anomaly Short stature due to chronic disease Amenorrhea or failure to begin puberty Pure gonadal dysgenesis Stein-Levintbal syndrome Primary/secondary amenorrhea Lymphedema Hereditary congenital lymphedema Milroy type Lymphedema with recurrent cholestasis Lymphedema with intestinal lymphangiectasia Other syndromes Multiple pterygium syndrome Pseudopseudohypoparathyroidism

Abbreviations: AD

=

autosomal dominant; AR

AD AD AD AR and AD forms

AR forms ? AD

AD AR AD AR XD

=

autosomal recessive; XD

=

X-linked

dominant.

Data from Hall JG, Sybert VP, Williamson RA, et al: Turner's syndrome, West J Med 137:32-44, 1982.

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usually few, if any, left, and the affected individual has fibrotic streaks where ovarian tissue should be. Because of failure to maintain ovarian tissue, normal pituitary feedback is missing; gonadotropin levels become elevated and may already be markedly elevated at birth. Thus, even in the first year of life, often it can be determined whether or not there is functional ovarian tissue in a child with Turner syndrome by finding elevated serum gonadotropins. Because of normal hypothalamic damping between the approximate ages of 3 and 8 years, gonadotropins will not necessarily be elevated even with gonadal dysgenesis, so it is not until teenage years that one can again depend on elevated gonadotropins as an indicator of ovarian dysgenesis. Between 5% and 15% of girls with Turner syndrome undergo spontaneous puberty94; the remainder will need hormonal replacement. Spontaneous puberty is less likely with 45,X karyotype but does occur sometimes. Replacement of hormones should be not undertaken unless they are in fact deficient. The female sex hormones can be replaced relatively simply by appropriate cycling of estrogen and progesterone. Hormonally dependent tissues such as uterus and breast tissues may not develop normally because of intrauterine and childhood hormone deficiency; thus, there will be less than normal response when estrogen replacement is given at puberty. About one third of women with Turner syndrome have poor response in terms of breast development with estrogenization. Replacement estrogen therapy does, however, almost always bring about prompt development of endometrial tissue and the beginning of menstrual periods. Once the first menstrual period has occurred, monthly cycling of estrogen-progesterone combinations should be instituted. About 10% of nonmosaic women and about 20% of mosaics have spontaneous menses and do not require medication to initiate puberty. 94 Nevertheless, many of these women with spontaneous puberty have irregular periods and premature menopause. Hormone replacement therapy in Turner syndrome used to be delayed into late teen years in the hope of allowing maximum linear growth. However, it has been shown that the predicted height gain in Turner syndrome can be achieved by initiating hormonal therapy at the time appropriate for their teenage peers. 68• 114. 133 Usually small dosages of estrogen are used for 1 or 2 years unopposed; then larger dosages are cycled with progesterone. It is important not to use any higher dosage of estrogen than necessary, as linear growth may be inhibited by high dosages during the induction of puberty. Once the menses and secondary sexual characteristics have been established for a couple of years, therapy can be shifted to a convenient birth control pill for maintenance. It is important that the estrogen dosage be cycled with progesterone, as unopposed estrogen use is known to lead to endometrial hyperplasia. 95 For a general sense of well-being and for the possible prevention of osteoporosis and arteriosclerosis, it is desirable to maintain cycled estrogenprogesterone therapy in women with Turner syndrome in the dosage the ovaries would normally have made until their late forties, thus duplicating the physiological state. 9

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FERTIliTY Fertility, though rare, has been reported in women with Turner syndrome. 59• 61, 98,107,127,145 In particular, it occurs primarily in those women who have undergone puberty spontaneously. More than 10 conceptions have occurred in 45,X women in whom no chromosomal mosaicism had been found61 , 145; over 100 pregnancies have been reported in women with X chromosome mosaicism. 59, 127 Women with Turner syndrome who have undergone spontaneous puberty are likely to experience early menopause59 and also to have a greater number of abnormal pregnancies, including both miscarriages (about 50%)59, 127 and chromosomally abnormal liveborn children. l36 Among reported cases, nearly a third of the live births to women having Turner syndrome have had some type of congenital abnormality.l45 It is not clear whether there is an increased risk for nonchromosomally related congenital anomalies in the children of affected women. Women with Turner syndrome who become pregnant should be offered prenatal diagnosis using second trimester amniocentesis or first trimester chorionic villus sampling if available. It is extremely important to discuss fertility with patients and their families, starting at an early age. Women with Turner syndrome will be most likely to have their children by adoption. However, oocyte donation and gamete or embryo transplantation have been shown to be feasible alternatives.23,50, 122 It is important to stress to affected individuals and their families that women with Turner syndrome can have satisfactory sexual relationships and rewarding, meaningful personal relationships and family lives.

GENITOURINARY TRACT ABNORMALITIES Between 33% and 60% of all patients with Turner syndrome have been reported to have either structural or positional abnormality of the kidneys, compared to only 10% of normal births. 29, 71, 76, 103 The kidney abnormalities rarely result in obvious renal malfunction, although recurrent urinary tract infections and obstruction may occur. 1 Horseshoe kidneys are seen in about 10%, double collecting systems or absence of a kidney in another 20%, and malrotation in about 15%.29, 76 Prune belly with genitourinary anomalies has been described in Turner syndrome,72 and 6% to 10% of adults have silent hydronephrosis. It is recommended that as soon as the diagnosis of Turner syndrome has been made, an abdominal ultrasound be done to establish whether there are normal renal structures and collecting system. If the collecting system is found to be abnormal, regular screening for urinary tract infection should be instituted. If abnormalities are not found, then a second ultrasound in the patient's 20s and a third in her 40s to screen for silent hydronephrosis may be appropriate. Vaginal agenesis has been reported in Turner syndrome, but it is rare. 97

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GROWTH PROBLEMS Average birth length is just over 48 cm, approximately 2.8 cm (1 in) shorter than normal. 15, 66, 73, 94,104 Average birth weight of 2800 g is also low, about 500 mg below the norm. There seems to be a correlation between birth weight and adult height in Turner syndrome, 15, 66, 73, 94, 104 During infancy untreated girls tend to be small (around the 3rd to 10th percentile for height) and then slowly fall below or stay at the 3rd percentile until age 9 or 10 years. 104 At that time, the average growth curve for untreated girls with Turner syndrome falls below the 3rd percentile, as they fail to go through the adolescent growth spurt. 73 At 14 years of age (bone age 12 years), the untreated Turner syndrome girl has fallen to - 4 SO. 104 Various surveys have reported the adult average height of untreated Turner syndrome women to range from 122 cm to 152 cm, with the average between 142 cm and 146 cm. 15, 65, 66, 73, 92, 94,104 It has been suggested that the height of 45,X nonmosaic girls will be shorter than those with mosaicism or with an isochromosome of the long arm of the X chromosome; however, not all investigations support this impression, 128, 133 Weight is disproportionately increased compared to normal, with an increased weight to height ratio, particularly after age 12.104 Other disproportions, such as a broad chest, lOB large waist, and short legs,65 have been reported, It appears that there may be a biphasic growth response to estrogen in Turner syndrome, with the best growth rate in response to very low levels of estrogen early in puberty, or even in childhood, During the second phase of puberty, in which somatomedin C is increased, there is less growth promotion from estrogen. 115-117 By starting on low dosages of estrogen at an early age and slowly progressing to higher dosages, girls with Turner syndrome may be able to achieve the best total height. Recent work using combinations of anabolic steroids with genetically engineered growth hormone or small dosages of estrogens is very encouraging. 13, 112, 113 Maturation of bones is usually slowed for Turner syndrome (when compared to the norms), with the result that the girls often present with a delayed bone age of at least 1V2 to 2 years. 104 Epiphyses of Turner syndrome women who have received no hormonal therapy fail to fuse until after 20 years of age. 2,104 The Bayley Pinneau charts seem to be the most accurate at predicting ultimate height. 15, 16, 73 If the rate of growth is slow for Turner syndrome, the possibility of growth hormone deficiency or hypothyroidism should be ruled out.

SKELETAL ABNORMALITIES Unusual skeletal findings (Table 3) may be helpful in suspecting a diagnosis on clinical grounds. 11, 35, 67 Such findings may include short fourth metacarpal and metatarsals; short distal phalanges with tufting; increased angulation of the carpal bones; carpal bone fusion; pes cavus; Madelung deformity; irregular tibial metaphyses with mushroom projections on the medial surface of the proximal tibial metaphyses; SchmorI's nodules; and

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Table 3. Commonly Reported Roentgenographic Changes Hand Drumstick distal phalanges Short fourth metacarpals Carpal sign: change in angulation of the carpal bones Shortening of all hand bones Madelung's deformity Feet Similar to hands Pes cavus Knees Lateral dislocation of the patellae Hypoplastic patellae Irregularity of tibial metaphysis and epiphysis "Mushroom" projections, medial surface of the proximal tibial metaphyses (medial tibial condyle) Spine Scoliosis Lack of lumbar lordosis Schmorl's nodes (abnormalities of cartilaginous end plates) Hypoplasia of the arch of the atlas Shortening of anteroposterior diameter of vertebral bodies Ribs Thin Developmental abnormalities Pelvis Android configuration (50%) Occasional widening of symphysis pubis Skull Midfacial hypoplasia Deepening of posterior cranial fossa Widening of the space between mandibular rami

Data from Bercu BB, Kramer SS, Bode HH: A useful radiolOgic sign for the diagnosis of Turner's syndrome. Pediatrics 58:737-739, 1976; Findby N, Archibald RM: Skeletal abnormalities associated with gonadal dysgenesis. American Journal of Radiology 9:354-361, 1965; and Lesczynki S, Kosowica J: Radiologic changes in the skeletal system in Turner's Syndrome-Review of 102 cases. Prog Radioll:510-517, 1965.

Scheurermann's disease of the vertebrae, a somewhat android configuration in the pelvis; and midfacial hypoplasia with an obtuse cranial base angle and short cranial base. Scoliosis and lack of lumbar lordosis are seen in 10% to 15% of girls with Turner syndrome; about 5% are severe enough to require bracing or surgery. Congenitally dislocated hips are seen in Turner syndrome in 5% to 10% of newborns. 24 Anterior dislocation of the knees has been reported. 41 Osteoporosis is said to occur with increased frequency and at an earlier age in women with Turner syndrome. 35. 67. 109. 129 Patients with Turner syndrome, however, do not seem to have an increased number of fractures or collapse of vertebrae, even without therapy. Thus, it is not entirely clear whether osteoporosis is a medical problem in older women with Turner syndrome, whether it is analogous to the postmenopausal osteoporosis seen in non-Turner syndrome women, or whether it is a justification for continued estrogen therapy past normal menopausal age.

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CRANIOFACIES

The characteristics of the craniofacies in Turner syndrome are a triangular face, downslanting palpebral fissures, epicanthal folds, ptosis, a neck that appears short and broad with a low hairline and often with webbing, midfacial hypoplasia with relative undergrowth of the maxilla, high arched palate, deepening of the posterior cranial fossa, and a small mandible with widely spaced mandibular rami. 52 The ears may be prominent with upturned lobules. Two percent to three percent of Turner syndrome patients have cleft lip or palate. 52 One percent have choanal atresia. As many as 80% of Turner syndrome individuals have had chronic otitis. 4 The incidence of hearing impairment in adults with Turner syndrome is 15% to 20%, and chronic middle ear disease is thought to be the major cause of the hearing loss, although both conductive and neurosensory losses have been observed. Sinusitis and mastoiditis are also increased. Five percent to ten percent of adults have had cholesterolosis. There is often crowding of teeth, and orthodontic work is frequently required. Malocclusions include cross bite, maxillary overset, distal molar occlusion, and tendency to open bite. 34, 64 Ophthalmological complications include strabismus, ptosis, cataracts, nystagmus, color blindness, and amblyopia. 18, 31, 92 Fully half of all patients require ophthalmologic evaluation, with one third needing surgery for strabismus.

CARDIOVASCULAR ABNORMALITIES AND LYMPHEDEMA

Lymphedema is thought to be due to congenital hypoplasia, late maturation, and delayed canalization of the lymph channels in utero. Approximately 80% of babies diagnosed with Turner syndrome are born with lymphedema, particularly distally, involving the backs of the hands and tops of the feet. 9, 65 Persistence of embryonic sacs in utero results in severe lymphedema, particularly in the neck area, which is most often seen in a Turner syndrome abortus. By the time of birth, the cystic hygroma has usually receded, leaving folds of skin in the neck, a low nuchal hairline, and protuberant ears with upturned lobules in about half the individuals with peripheral edema. Usually during childhood, the peripheral edema decreases, often leaving mildly puffy fingers. 65 At the time of estrogen therapy, edema may again become a problem. Lymphedema is seen much more frequently in individuals with Turner syndrome who have 45,X karyotype than in other cytogenetic variants. Patients with Turner syndrome have an increased risk of congenital heart malformations of all types, coarctation of the aorta being the most common. 87 Such rare conditions as ectopia cordis 40 and hypoplastic left heart84 probably have an increased frequency in Turner syndrome. Pulmonary stenosis can be seen in Turner syndrome but is more often observed in the chromosomally normal Noonan syndrome, which has a similar phenotype. Coarctation of the aorta probably occurs in 15% to 30% of patients

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with Turner syndrome but is often not of clinical importance. 3. 6, 45, 70, 79 It may be predllctal or postductal in location. A positive correlation has been made between webbing of the neck and coarctation of the aorta. Because coarctation can lead to hypertension, all Turner syndrome patients should have blood pressure measurements taken even if they have no murmur. Ultrasonic evaluation of the heart to rule out structural cardiac and aortic anomalies is probably appropriate in all Turner syndrome patients in infancy. 79 Approximately one third of Turner syndrome patients studied are found to have bicuspid aortic valves,19 and one quarter have mitral valve prolapse. 7 The bicuspid valve seems to produce a jet of greater pressure against the ascending aorta and predisposes to atherosclerotic disease. In addition, a bicuspid aortic valve may progress to stenosis and calcincate. If a Turner syndrome patient has a bicuspid or functionally bicuspid aortic valve, she should receive prophylactic antibiotics at the time of dental work or surgery to avoid infective endocarditis. A Turner syndrome individual should have echocardiography of her heart and aorta at an age when she is old enough for a clear definition of aortic valve structure (probably after 2 years of age). If a bicuspid aortic valve is found, yearly follow-up is recommended. The combination of coarctation of the aorta, hypertension, and aortic valve abnormalities seems to predispose to development of aortic aneurysms in Turner syndrome. 3, 6, 55, 69, 70, 79 When the aorta from a patient in whom there has been a dissection is examined, there are changes of cystic medial necrosis, suggesting that there may be a more generalized vascular dysplasia in Turner syndrome, including coarctatiQn, bicuspid aortic valves, incomplete differentiation of vascular tissue, and arterial and lymphatic dysplasia. 69, 79 Any patient with coarctation, bicuspid aortic valve, or hypertension should have yearly cardiac ultrasound to screen for progressive changes. Other kinds of vascular malformations, including intestinal telangiectasia, hemangiomas, lymphangioectasia, and venous ectasias, have been reported infrequently in Turner syndrome. 106, 121 Recurrent and intermittent gastrointestinal bleeding can lead to iron deficiency. With the initiation of estrogen therapy, patients who have had chronic gastrointestinal bleeding may improve dramatically.88 Surgical resection may be required for persistent bleeding. Protein-losing enteropathy due to gastrointestinal lymphangiomas has also been reported. 47 Chylous accumulation can occur in the abdomen and chest. 139 Multiple renal arteries may be seen in 20% to 40% of normal individuals, but they are seen in approximately 90% of Turner syndrome patients. 63 No correlation has been made between the extra renal arteries and hypertension, fibromuscular hypopoplasia of renal arteries, or structural renal anomalies. Hypertension is seen with increased frequency in Turner syndrome, even when those patients with coarctation and renal anomalies are treated and excluded. Approximately 20% of Turner syndrome adults have hypertension that ranges from mild to severe, with normal serum renin. Hypertension in Turner syndrome (in both those on estrogen replacement and

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off) has been noted to be associated with obesity and to improve with weight reduction. 134

SKIN, NAILS, AND HAIR

Abnormal dermatoglyphics are seen, with a large number of whorls on the tips of the fingers and an increased percentage of distal triradii. These changes may well be related to the presence of edema early in embryonic development. Pterygium coli and low hairlines are seen in the necks of patients with Turner syndrome, apparently as part of the resolution of the cystic hygroma that was present in fetal life. Small, hypoplastic convex or concave fingernails and upturned toenails are frequently present. Pedal hemangiomas have been described. 91 There is an increased tendency for hypertrophic scarring or keloid formation. 65, 69 Pigmented nevi are common,47 tending to appear in late childhood. There is no evidence of increased rate of malignant degeneration. A substantial number of patients have seborrheic dermatitis and dryness of the skin. Facial hirsutism can occur, although axillary and pubic hair is often scanty. AUTOIMMUNE DISEASE

There is a markedly increased incidence of thyroid antibodies in Turner syndrome patients, but acute hyperthyroidism occurs rarely.33, 43 Autoimmune hypothyroidism, however, is seen in 20% to 30% of affected adult women. 14, 43, 90. 93. 130 As many as 50% to 60% of Turner syndrome patients may have thyroid autoantibodies, compared to 20% of normal adult women. Women with Turner syndrome need to be screened regularly for thyroid disease, by determining the presence of autoantibodies, an elevated TSH, or low T4. It appears that women with isochromosome X may have a higher risk for acute Hashimoto's thyroiditis and Graves disease. 14, 30, 43, 90, 130 Antibodies to other endocrine tissues (islet cells, adrenal, parietal cells) are not measurably increased. 14 Diabetes mellitus occurs in 5% of women with Turner syndrome, 105 and 25% to 60% have an impaired serum glucose tolerance. 101 The diabetes is adult-onset but without a family history. Inflammatory bowel disease (both regional enteritis and ulcerative colitis) is increased in Turner syndrome patients. 5, 50, 102, 144 Women with isochromosome of the long arm are particularly susceptible to inflammatory bowel disease. 5, 50, 102, 144 The arthritis seen in Turner syndrome may be rheumatoid. 32 MENTAL RETARDATION

Mental retardation in patients with Turner syndrome usually occurs only in the presence of an additional chromosome abnormality. 135 It appears

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that the prevalence of moderate to severe mental retardation is either not increased or increased only slightly. LEARNING DISABILITIES

Patients with Turner syndrome seem to be at increased risk for a specific problem with conceptualization of spatial relations and with numerical abilities. 8, 39. U8, 124 On full-scale intelligence testing, the total intelligence quotient is average or above average. 124 There is often, however, a deficiency in the skills required for perceptual motor organization U8 or in fine-motor execution. 8, 39, 77 PSYCHIATRIC PROBLEMS

A number of psychiatric disturbances have been reported in Turner syndrome, including anorexia nervosa,27, 58 manic depressive illness,36 and paranoid schizophrenia. 80 Approximately 10% of Turner syndrome women have had a major depression, but that percentage may not be very different from normal. It is not clear whether a specific Turner syndrome personality exists and, if so, whether it is related to early low levels of estrogen. 10, 81, 125 Nevertheless, inertia to emotional arousal, high capacity to deal with stress, and strong traditional femininity are described. Normal female gender identification develops; however, socialization, dating, and close friendships are less well developed than in women with other kinds of short stature. 28, 78, 142 CANCER

Individuals with Turner syndrome are at a higher risk than the general population for tumors of the reproductive system. The major risk relates to individuals who are mosaic for Y chromosome. 74, 75, 83, 96 This risk appears to increase substantially when gonadotropins increase. The risk for gonadoblastoma in a 45,x/46,XY individual may be higher than 25% by age 30. 47 45,x/46,XY patients should have streak gonads removed prior to starting school to avoid both masculinization and malignant degeneration of a tumor. Both streaks should be removed, as the risk for bilateral tumors is high. The risk of adenocarcinoma of the uterus appears to be increased only in individuals who have used diethylstilbestrol (DES). Unopposed estrogen therapy for a long period of time would theoretically put individuals at an increased risk. 68 Pelvic endometriosis has been reported in Turner syndrome, but this does not seem to put affected women at risk for cancer. 12, 93' COUNSELING

Genetic counseling provides families and individuals with information so that they can be aware of their options and make informed decisions.

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Information to be provided should include diagnosis, natural history, 46 recurrence risk, treatments, and prevention of complications. III There are a number of excellent pamphlets written for the families of girls with Turner syndrome. 21 , 22, 86, 100 Turner Support Groups have been formed to provide information and the opportunity to talk with other adults who have the Turner syndrome. The addresses are as follows: in Canada: Turner Syndrome Society, York University, Administrative Studies, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3; telephone: (416) 6673773. In the United States: Human Growth Foundation, Maryland Academy of Science Building, 7 West Mulberry Street, Baltimore, Maryland, USA 21201.

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22. Charney S, Smillie A: The X's and O's of the Turner's syndrome. Presented at the annual meeting of the Turner's Syndrome Society, Downsview, Ontario, 1983 23. Christman GM: Turner Syndrome-Adulthood: Reproductive health care options. Adolescent Pediatric Gynecology 2:181-185, 1989 24. Crawford JD: Management of children with Turner's syndrome. In Papadatos CJ, Bartsocas CS (eds): Genetic Problems in Growth, pp 97-109. New York, Liss, 1979 25. De Grouchy J, Turleau C: Clinical Atlas of Human Chromosomes, pp 23-40. New York, Wiley, 1977 26. Dorus E, Amarose AP, Tredway DR, et al: A reciprocal translocation (X;ll) in a female with gonadal dysgenesis. Clin Genet 16:253-259, 1979 27. Dougherty GG, Rockwell WJK, Sutton G, et al: Anorexia nervosa in treated gonadal dysgenesis: Case report and review. J Clin Psychiatry 44:219-221, 1983 28. Downy J, Ehrhardt AA, Morishina A, et al: Gender role development in two clinical syndromes: Turner syndrome versus constitutional short stature. J Am Acad Child Adolesc Psychiatry 26:566-573, 1987 29. Egli F, Stalder G: Malformations of kidney and urinary tract in common chromosomal aberrations. Hum Genet 18:1-15, 1973 30. Engel E, Forbes AP: Cytogenetic and clinical findings in 48 patients with congenitally defective or absent ovaries. Medicine (Baltimore) 44:135-165, 1965 31. Ferguson-Smith MA: Karyotype-phenotype correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations. J Med Genet 2:142-155, 1965 32. Ferraccioli GF, Ambanelli U, Giovannelli G: Juvenile rheumatoid arthritis in Turner's syndrome. Clin Exp Rheumatol 4:61-62, 1986 33. Fialkow PJ, Uchida IA: Autoantibodies in Down's syndrome and gonadal dysgenesis. Ann N Y Acad Sci 155:759-769, 1968 34. Filipsson R, Lindsten J, Almquist S: Time of eruption of the permanent teeth, cephalometric and tooth measurement and sulphation factor activity in 45 patients with Turner's syndrome with different types of X chromosome aberrations. Acta Endocrinol (Copenh) 48:91-113, 1965 35. Findby N, Archibald RM: Skeletal abnormalities associated with gonadal dysgenesis. American Journal of Radiology 9:354-361, 1965 36. Fishbain DA, Vilasuso A: Manic-depressive illness associated with Turner's syndrome mosaicism. J Nerv Ment Dis 169:459-461, 1981 37. Ford CE, Jones KW, Polani PE: A sex chromosomal anomaly in a case of gonadal dysgenesis (Turner's syndrome). Lancet i:711-713, 1959 38. Fryns JP, Kleczkowska P, Petit P, et al: Fertility in patients with X chromosome deletions. Clin Genet 22:76-79, 1982 39. Garron DC: Intelligence among persons with Turner's syndrome. Behav Genet 7:105127, 1977 40. Garson A, Hawkins EP, Mullins CE, et al: Thoracoabdominal ectopia cordis with mosaic Turner's syndrome: Report of a case. Pediatrics 62:218-221, 1978 41. Gatrad AR: Congenital dislocation of the knees in a child with Down-mosaic Turner syndrome. J Med Genet 148-151, 1981 42. Gemmill RM, Pearce-Birge L, Bixenman H, et al: Y chromosome-specific DNA sequences in Turner syndrome mosaicism. Am J Hum Genet 41:157-167, 1987 43. Germain EL, Plotnick LP: Age related anti-thyroid antibodies and thyroid abnormalities in Turner syndrome. Acta Pediatr Scand 75:750-755, 1986 44. Goldman B, Polani PE, Daker MG, et al: Clinical and cytogenetic aspects of Xchromosome deletions. Clin Genet 21:36-52, 1982 45. Haddad HM, Wilkins L: Congenital anomalies associated with gonadal aplasia: Review of 55 cases. Pediatrics 23:885-902, 1959 46. Hall JG: The management of the adult with Turner syndrome-the natural history of Turner syndrome. In Rosenfeld RG, Grumbach MM (eds): Turner Syndrome. New York, Marcel Decker, Inc., 1990, pp 495-506 47. Hall JG, Sybert VP, Williamson RA, et al: Turner's syndrome. West J Med 137:32-44, 1982 48. Hassold T, Benham F, Leppert M: Cytogenetic and molecular analysis of sex-chromosome monosomy. Am J Hum Genet 42:534-541, 1988 49. Hassold T, Kumin E, Takaesu N, et al: Determination of the parietal origin of sex-

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n,

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105. Rasio E, Antaki A, Van Campenhout J: Diabetes mellitus in gonadal dysgenesis: Studies of insulin and growth hormone secretion. Eur J Clin Invest 6:59-66, 1976 106. Redondo D, Swenson 0: Gastrointestinal bleeding associated with gonadal aplasia. Surgery 61:285-287, 1967 107. Reyes FI, Koh KS, Faiman C: Fertility in women with gonadal dysgenesis. Am J Obstet Gynecol 126:668-670, 1976 108. Ribeiro J, Hughes IA: Body proportion in Turner's syndrome. Arch Dis Child 61:506507, 1986 109. Risch WD, Banzer DH, Moltz L: Bone mineral content in patients with gonadal dysgenesis. Am J RadioI126:1302-1309, 1976 110. Robinson A: Demography and prevalence of Turner syndrome. In Rosenfeld RG, Grumbach MM (eds): Turner Syndrome. New York, Marcel Decker, 1990, pp 93-100 111. Rosenfeld RG, Grumbach MM (eds): Turner Syndrome. Marcel Decker, New York, 1990 112. Rosenfeld RG, Hintz RL, Johanson AJ, et al: Results from the first two years of a clinical trial with recombinant DNA-derived human growth hormone (somaticism) in Turner's syndrome. Acta Paediatr Scand Suppl 331:59-69, 1987 113. Rosenfeld RG, Hintz RL, Johanson AJ, et al: Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome. J Pediatr 113:393-400, 1988 114. Rosenfeld RL: The ovary and female sexual maturation. In Kaplan SA (ed): Clinical Pediatric and Adolescent Endocrinology. Philadelphia, WB Saunders, 1982, pp 217268 115. Ross JL, Cassoria FG, Skerda MC, et al: A preliminary study of the effect of estrogen dose on growth in Turner's syndrome. N Engl J Med 309:1104-1106, 1983 116. Ross JL, Long LM, Loreau DL, et al: Growth hormone secretory dynamics in Turner syndrome. J Pediatr 106:202-206, 1985 117. Ross JL, Long LM, Skuda M, et al: Effect of low doses of estradiol on 6-month growth rates and predicted height in patients with Turner syndrome. J Pediatr 109:950-953, 1986 118. Rovet J, Netley C: The mental rotation task performance of Turner syndrome subjects. Behav Genet 10:437-443, 1980 119. Sanger R, Tippett P, Gavin J, et al: Xg groups and sex chromosome abnormalities in people of northern European ancestry. J Med Genet 14:210-213, 1977 120. Sarkar R, Marimuthu KM: Association between the degree of mosaicism and the severity of syndrome in Turner mosaics and Klinefelter mosaics. Clin Genet 24:420-428, 1983 121. Schultz LS, Assimacopoulos CA, Lillehel RC: Turner's syndrome with associated gastrointestinal hemorrhage: A case report. Surgery 68:485-488, 1970 122. Serhal PF, Craft IL: Oocyte donation in 61 patients. Lancet 1185-1187, 1989 123. Schmid W, Naef E, Murset G: Cytogenetic findings in 89 cases of Turner's syndrome with abnormal karyotypes. Hum Genet 24:93-104, 1974 124. Shaffer J: A specific cognitive deficit observed in gonadal dysplasia (Turner syndrome). J Clin Psychol 13:403-406, 1962 125. Shaffer J: Masculinity-femininity and other personality traits in gonadal aplasia (Turner syndrome). In Beigel HC (ed): Advances in Sex Research. New York, Hoeber, 1963, pp 219-232 126. Simpson JL: Gonadal dysgenesis and abnormalities of the human sex chromosomes: Current status of phenotypic-karyotypic correlations. Birth Defects, Original Article Series 11(4):23-59, 1975 127. Singh DN, Hara S, Foster HW: Reproductive performance in women with sex chromosome mosaicism. Obstet Gynecol 55:608-611, 1980 128. Smith A, Elliott G: Occurrence of sex chromosome mosaicism and trans locative Down syndrome in the same family. Clin Genet 17:341-348, 1980 129. Smith MA, Wilson J, Price WHo Bone demineralisation in patients with Turner's syndrome. J Med Genet 19:100-103, 1982 130. Sparkes RS, Motulsky AG: The Turner syndrome with isochromosome X and Hashimoto's thyroiditis. Ann Intern Med 67:132-144, 1967 131. Stalvey JR, Erickson RP, Dasouki M, et al: Clarification of chromosomal abnormalities associated with sexual ambiguity by studies with Y chromosomal DNA sequences. Cytogenet Cell Genet 47:140-143, 1988

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132. Sutherland GR, Holt D, Rogers JG: Amniotic fluid alpha fetoprotein in Turner syndrome. Lancet i:649-650, 1977 133. Sybert VP: Adult height in Turner syndrome with and without androgen therapy. J Pediatr 104:365-369, 1984 134. Sybert VP, Hall JG: Turner syndrome-Natural history in the older woman. Am J Hum Genet 3l:85A, 1979 135. Sybert VP, Reed SD, Hall JG: Mental retardation in the Turner syndrome. Am J Hum Genet 32:131A, 1980 136. Taysi K: Brief clinical report: Del(X)(q26) in a phenotypically normal woman and her daughter who has trisomy 21. Am J Med Genet 14:367-372, 1983 137. Therman E: Mechanisms through which abnormal X chromosome constitutions affect the phenotype. In Sandburg A (ed): Cytogenetics of the Mammalian X chromosome, Part B: X chromosome anomalies and their clinical manifestations. New York, Liss, 1983, pp 159-173 138. Therman E, Denniston C, Sarto GE, et al: X chromosome constitution and the human female phenotype. Hum Genet 54:133-143, 1980 139. Triesman J, Collins FS: Adult Turner syndrome associated with chylous ascites and vascular anomalies. Clin Genet 31:218-223, 1987 140. Turner HH: A syndrome of infantilism, congenital webbed neck and cubitus valgus. Endocrinology 23:566-578, 1938 141. Uchida lA, deSa DJ, Whelan DT: 45,X/46,XX mosaicism in discordant monozygotic twins. Pediatr 71:413-417, 1983 142. Waber DP: Neuropsychological aspects of Turner's syndrome. Dev Med Child Neurol 21:58-70, 1979 143. Warburton D, Kline J, Stein Z, et al: Monosomy X: A chromosomal anomaly associated with young maternal age. Lancet i:167-169, 1980 144. Williams ED, Engel E, Taft PD, et al: Gonadal dysgenesis and ulcerative colitis. J Med Genet 3:51-55, 1966 145. Wray HL, Freeman MVR, Ming P-ML: Pregnancy in the Turner syndrome with only 45,X chromosomal constitution. Fertil Steril 35:509-514, 1981 146. Wyss D, DeLozier CD, Daniell J, et al: Structural anomalies of the X chromosome: Personal observation and review of non-mosaic cases. Clin Genet 21:145-149, 1982

Address reprint requests to Judith G. Hall, MD Department of Medical Genetics University of British Columbia University Hospital-Shaughnessy Site 4500 Oak Street Vancouver, BC Canada V6H 3N 1