Down Syndrome, Turner Syndrome, And Klinefelter Syndrome 6n1p2a

Prim Care Clin Office Pract 31 (2004) 627–648

Down syndrome, Turner syndrome, and Klinefelter syndrome: primary care throughout the life span Carl Tyler, MD, MS*, Jennifer C. Edman, MD Cleveland Clinic Foundation Family Practice/Fairview Hospital, 18200 Lorraine Avenue, Cleveland, OH 44111, USA

Down syndrome, Turner syndrome, and Klinefelter syndrome constitute the three most common chromosomal abnormalities encountered by primary care physicians. Down syndrome typically is recognized at birth, Turner syndrome often is not recognized until adolescence, and many men with Klinefelter syndrome are never diagnosed. Although each syndrome is caused by an abnormal number of chromosomes, or aneuploidy, they are distinct syndromes with learning disabilities and a predisposition toward autoimmune diseases, endocrinologic disorders, and cancers. Optimal health care requires a thorough knowledge of the unique health risks, psychoeducational needs, functional capabilities, and phenotypic variation associated with each chromosomal condition. Unless otherwise specified, syndrome-specific health care should complement standard preventive health care recommendations.

Down syndrome Etiology and diagnosis Down syndrome is the most common chromosomal cause of mental retardation [1], with an incidence of 1 in 800 to 1000 live births [2]. In March 1999, the British Medical Journal published a survey conducted by the UK Down’s Syndrome Association, which asserted that 28% of 1509 member parents surveyed expressed a high level of dissatisfaction with the medical care received by their child. In response, the UK Down’s Syndrome

* Corresponding author. E-mail address: [email protected] (C. Tyler). 0095-4543/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.04.006

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Association recommended wider implementation of screening for specific morbidities in all affected individuals with Down syndrome and created a special 14-page insert to supplement standard child health records [3]. There is a critical need for primary care physicians to provide state-of-theart, syndrome-specific health care in addition to routine, age-appropriate health care screening and immunizations across the life span. Medical and surgical advances ensure an increasingly longer life span for individuals with Down syndrome. Primary care physicians must be prepared to assist the patient and family with life transitions and offer interventions designed to improve the functional capacity of the individual with Down syndrome. According to the American Academy of Pediatrics Committee on Genetics, key areas of emphasis throughout childhood include comprehensive medical management, family , application for Supplemental Social Security Income benefits and other medical and financial programs, developmentally appropriate prevention of injury and abuse, education and vocational training, and development of healthy eating habits and active lifestyle to promote and maintain healthy weight [4]. The cause of Down syndrome is trisomy, or presence of three copies of some or all of chromosome 21. Down syndrome is caused 95% of the time by nondisjunction of chromosome 21 during the meiotic formation of the spermatocyte or oocyte. Around 4% of individuals with Down syndrome have the ‘‘extra’’ copy of chromosome 21 attached, or translocated, to another chromosome; in one third of these cases, this translocation also is present in one of the parents. The remainder of individuals with Down syndrome have mosaicism caused by nondisjunction occurring in the embryo after conception [4,5]. Karyotyping is indicated for confirmation when the diagnosis of Down syndrome is suspected. The family should be referred for genetic counseling to learn about the disorder and to determine the family-specific risk of having another child with Down syndrome. This risk depends on the combination of karyotype and maternal age. In general, the risk of recurrence of Down syndrome in a future pregnancy is 1% greater than the baseline risk established by maternal age [2,4,6]. In the 4% to 5% of cases caused by a translocation, however, the recurrence risk could be 100%. Prenatal risk assessment and diagnosis is offered as an optional portion of standard prenatal care and offers the parents the opportunity to continue or terminate an affected pregnancy. The risk of having a child with Down syndrome increases with age of the mother, from 1 in 1351 at age 25, to 1 in 384 at age 35, and to 1 in 28 by age 45 [7]. Of infants with Down syndrome, however, 70% are born to women younger than age 35. The maternal serum triple screen, which is performed during the second trimester at 15 to 18 weeks of gestation, can detect 60% of trisomy 21 pregnancies with a 5% false-positive rate. This detection rate is improved with ultrasound assessment of gestational age. Low levels of maternal serum a-fetoprotein and unconjugated estradiol in combination with a twofold elevation in

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maternal serum human chorionic gonadotropin suggest Down syndrome and are an indication for amniocentesis and karyotyping. The triple test fails to detect 10% to 15% of pregnancies affected by trisomy 21 in women older than age 35; amniocentesis or chorionic villus sampling should be offered. In the future, first-trimester maternal serum screening with different assays may become clinically available. Increased nuchal fold thickness (translucency) secondary to subcutaneous edema at the base of the occiput is the most common finding suggesting Down syndrome on prenatal ultrasound examination. Ultrasound assessment may assist in predicting the likelihood of Down syndrome in women considered to be at increased risk secondary to either advanced maternal age or abnormal triple screen result [5]. In a systematic literature review, Mansfield et al [8] cited termination rates of 92% for fetuses diagnosed prenatally with Down syndrome. These high rates suggest disinclination toward giving birth to children with generally mild-to-moderate cognitive impairments, but they also may suggest lack of information given to parents regarding the full lives led by individuals with Down syndrome. Prenatal counseling by a trained professional is needed after confirmation of a prenatal diagnosis [4,5]. If not established antenatally, the diagnosis of Down syndrome is made easily shortly after birth. Features of Down syndrome that are commonly present in the neonatal period and facilitate diagnosis include hypotonia, poor Moro reflex, hyperflexibility of ts, excess skin at the back of the neck, flattened facies, upslanted palpebral fissures, anomalous auricles, dysplasia of the pelvis, dysplasia of the midphalanx fifth finger, and a single palmar crease [6]. Other presenting physical characteristics include brachycephaly, gap between first and second toes, low-set ears, protruding tongue, epicanthal folds, Brushfield spots (ring of iris speckles), short broad hands, high arched narrow palate, congenital cardiac defects (most commonly complete atrioventricular canal defects), transient myelodysplasia of the newborn, and duodenal atresia [2,9]. Not all infants with Down syndrome present with every feature; the phenotype is variable. Down syndrome also should be suspected in a phenotypically normal infant with a leukemoid reaction [4]. Individuals with Down syndrome usually have mild-to-moderate mental retardation. Other common associated medical complications include growth retardation; congenital heart defects; hearing loss due to chronic otitis media and/or sensorineural defects; ophthalmic disorders, including congenital cataracts, glaucoma, and strabismus; epilepsy; gastrointestinal malformations, including duodenal atresia and Hirschsprung’s disease; hypothyroidism; leukemia; atlantoaxial subluxation with spinal cord compression; early-onset Alzheimer’s disease; increased susceptibility to infections, including pneumonia, otitis media, sinusitis, periodontal disease, and pharyngitis; and infertility with anovulation present in 30% of women and sterility in greater than 99% of men [2,4,6].

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Care in childhood Children with Down syndrome should have height, weight, and head circumference plotted on the standard and Down syndrome–specific growth charts to ensure appropriate evaluation for growth delay [4,10]. (Growth charts are available at http://www.growthcharts.com or in the article by Myrelid et al [10].) Children with Down syndrome manifesting growth delay on Down syndrome–specific charts must be evaluated for undiagnosed medical problems, such as congenital heart defect, leukemia, or gastrointestinal problems such as gastroesophageal reflux disease or celiac disease [10]. Evaluation for onset of hypothyroidism is essential in children showing decreased growth velocity or unexplained weight gain [2]. Evaluation of thyroid function should continue throughout the life span. Of infants with Down syndrome, 40% to 60% have congenital heart defects, the most prevalent being atrioventricular canal defects, ventricular septal defect, tetralogy of Fallot, ostium secundum, atrial septal defect, and isolated mitral cleft. It is recommended that all individuals with Down syndrome, even individuals without a murmur, undergo evaluation by a pediatric cardiologist, including electrocardiogram and echocardiogram by age 3 months to minimize the risk of development of severe pulmonary hypertension as a compensatory mechanism for undiagnosed congenital heart defects [4,11]. Celiac disease is found in 4% to 17% of children with Down syndrome and may present as growth failure without accompanying symptoms. Institution of a gluten-free diet in individuals with celiac disease normalizes the small intestine and prevents anemia. Children with Down syndrome presenting with chronic diarrhea or another gastrointestinal complaint should be evaluated for possible celiac disease. In addition, Csizmadia et al [12] recommended determining HLA-DQ status on all children with Down syndrome, then measuring IgA endomesial antibodies in children positive for HLA-DQ alleles associated with celiac disease. Biopsy of the small bowel is indicated if the child tests positive for IgA endomesial antibodies. Treatment with a gluten-free diet should be instituted in individuals with villus atrophy. Csizmadia et al [12] recommended periodic serum screening for IgA endomesial antibodies in individuals with HLA DQ alleles associated with celiac disease. Some authorities recommend screening for selective IgA deficiency to assure IgA endomesial antibody results are not falsely negative. In addition to cognitive impairment (average IQ reported to be 50, but ranging from 30 to 70), individuals with Down syndrome have been described as having specific impairments in expressive language and auditory processing. Despite weaknesses in communication, individuals with Down syndrome are described as socially adept and generalized to have a ‘‘happy, good-tempered, affectionate, placid’’ personality [1]. They tend to have lower rates of psychiatric and behavioral health problems than other individuals with mental retardation but commonly do have difficulties with

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attention, impulsivity, and hyperactivity. Incidence of anxiety, depression, and withdrawal tends to increase with increasing age [13]. Prompt referral to early intervention programs at birth is indicated due to the high rate of developmental delay. Children with Down syndrome require comprehensive developmental assessments throughout childhood to evaluate fine and gross motor skills, speech and language comprehension, cognitive ability, and social and adaptive skills. Comprehensive preschool programs designed for children with special needs may minimize developmental delay and facilitate later mainstreaming into schools, the workforce, and the community [2,4,13]. The prevalence of abuse is higher in individuals with disabilities, and screening for and counseling about prevention of abuse is important beginning in early childhood [14]. Health care guidelines for children with Down syndrome are available from the American Academy of Pediatrics [4], Down Syndrome Medical Interest Group (US) [15], and Down Syndrome Medical Interest Group (UK) at http://dsmig.org.uk/pdf/downs6.pdf. Each guideline promotes routine audiologic, ophthalmologic, and dental evaluation; routine annual thyroid function screening; and close monitoring of developmental and educational progress. In addition to the screening guidelines outlined earlier, the Down Syndrome Medical Interest Group (US) recommends universal screening for celiac disease beginning at age 2 years. Primary care clinicians caring for individuals with Down syndrome are strongly encouraged to include copies of one of the guidelines and accompanying flow sheet in the patient’s medical record. Care in adulthood Regular physician is particularly important in the early adult years, when changes in educational/vocational, social, and residential domains frequently occur simultaneously. Stress and anxiety over transitions may result in physical or psychological symptoms. Obtaining employment that the young adult with Down syndrome finds meaningful and challenging but not overtaxing may be difficult. Inquiry about social and sexual relationships is important, along with counseling regarding the prevention of violence, sexually transmitted diseases, and pregnancy. No one should assume that individuals with Down syndrome are infertile. Although there are rare reports of males with documented offspring, there are far more documented reports of women with Down syndrome bearing children. As with the general population, individuals who were followed by a pediatrician during childhood should transfer their care to a family physician or general internist when they reach adulthood. There is a risk for social networks to constrict as formal educational programs are completed; peers and siblings leave the community for advanced education, jobs, and marriage; and older family become ill, relocate, or die. Prolonged grief reactions may result, requiring formal mental health referrals.

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Optimizing health and function of an adult with Down syndrome requires knowledge of how aging progresses differently than in the general population and differently compared with individuals with mental retardation of other etiologies. Adults require continued screening for auditory impairments and ophthalmologic diseases. In addition to conductive loss, sensorineural hearing loss can emerge in early adulthood. Glaucoma, keratoconus, and early-onset cataracts occur more commonly in individuals with Down syndrome. Without routine ophthalmologic examinations, visual impairments may progress without detection until they become severe and irreversible. Obstructive sleep apnea, manifested by morning irritability and headache, memory difficulty, daytime somnolence, fatigue, depression, or decline in work performance, is common in Down syndrome. Individuals reluctant to undergo a full sleep laboratory polysomnography study may accept a screening overnight continuous nocturnal pulse oximetry study as an initial test. This two-step screening approach has not yet been studied rigorously in adults with Down syndrome, however. Because physicians have difficulty predicting who would accept treatment of sleep apnea, confirmatory testing should be conducted in all individuals suspected to have it. Acquired motor impairments deserve careful evaluation. Ligamentous laxity in the neck (sometimes accompanied by congenital craniocervical malformations) may lead to spinal cord compression, cervical nerve root compression, or vertebrobasilar insufficiency. Signs of cervical cord compression include muscle weakness, increased muscle tone, and increased deep tendon reflexes in the lower extremities; ankle clonus; new-onset urinary incontinence; change in hand preference; or positive Babinski’s sign. Hypotonia may persist, however, and interfere with clinical recognition of cord compression. Individuals with dementia may have long tract neuropathic signs without cord compression. Symptoms of cervical root compression include pain in the upper neck and occiput that radiates to the eyes, ears, or throat. Vertebrobasilar insufficiency may cause dizziness, vertigo, diplopia, or syncope. Although torticollis should be considered to be due to atlantoaxial instability until proven otherwise, it also can be caused by cervical osteoarthritis. Routine screening for ‘‘asymptomatic’’ atlantoaxial instability using cutoff measurements of the atlanto-dens distance (required for sports participation in Special Olympics in the United States) does not reliably identify individuals at risk for cervical myelopathy. A narrow neural canal width may be a better predictor of cord compression [16]. Individuals with symptoms suggesting cervical myelopathy should undergo MRI of the cervical spine. Other orthopedic issues include patellar instability and hip disease. Down syndrome is associated with an increased incidence of hip dislocation, hip dysplasia, slipped femoral capital epiphysis, Perthes’disease, and avascular necrosis. Hip disease may progress rapidly in midlife requiring total hip arthroplasty [17]. Decline in ambulatory capacity should be evaluated

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aggressively with attention to the entire spine and lower extremity ts and not simply attributed to ‘‘old age’’ or dementia. Individuals with Down syndrome seem to achieve a lower peak bone mineral density and are at risk for developing osteoporosis by midlife [18]. Screening for thyroid disorders and for gluten-sensitive enteropathy should continue in adulthood. It is reasonable to measure thyroid-stimulating hormone annually. There is no clear-cut recommended frequency of screening antiendomysial antibody or tissue transglutaminase level determinations. Classic malabsorption symptoms of diarrhea and weight loss may not occur even in individuals with biopsy-proven, gluten-sensitive enteropathy. Vitamin B12 deficiency due to autoimmune gastritis may emerge independent of enteropathy. Obesity is not an inevitable consequence of Down syndrome [19]. Attention to caloric intake, adequate physical activity, and early detection of hypothyroidism can prevent obesity from emerging in adulthood. Although individuals with Down syndrome may be at less risk for coronary heart disease, other health consequences of obesity include exacerbation of gastroesophageal reflux, asthma, arthritis, and sleep apnea; difficulty with personal hygiene; and limitations in opportunities for recreation and socialization. Although psychiatric conditions are difficult to diagnose in individuals with mental retardation, several studies have reported that psychiatric disorders affect about one quarter of adults with Down syndrome. Of these, the most common condition is depression [20]. Conduct disorder, obsessivecompulsive disorder, attention-deficit disorder, autism, and dementia also are reported. Schizophrenia is rare, but unfamiliar clinicians may misinterpret the ‘‘self-talk’’ and elaborate storytelling of some individuals with Down syndrome as psychotic in nature. In the United States, the median age of death of persons with Down syndrome increased from 25 years in 1983 to 49 years in 1997 [21]. More than one quarter of individuals with Down syndrome are alive at age 65 [22]. Causes of mortality are different than in the general population. Individuals with Down syndrome have greater risk for leukemia and perhaps testicular cancer, but lower risk for all other solid tumors, including breast and colon cancer. This information should be shared with patients and their families when discussing cancer screening recommendations [23]. Increased mortality also is attributed to dementia, epilepsy, congenital heart disease, infectious disease, ischemic and other heart disease, and cerebrovascular disease. Excess mortality from infectious disease is primarily due to influenza and pneumonia. Annual influenza vaccination is important. Many clinicians provide pneumococcal vaccination in early adulthood. Pneumonia prevention also requires attention to subtle signs of dysphagia followed by appropriate evaluation and management. Nearly all adults with Down syndrome manifest Alzheimer’s-type neuropathology by age 40 [24]. Prospective studies of cognitive change in

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adults suggest, however, that only a subset of individuals actually develop clinically evident dementia. Additional factors thought to be associated with earlier onset of dementia include the apoE 4 allele, estrogen deficiency, and high levels of Ab 1–42 peptides [25]. In higher functioning individuals, initial manifestations of dementia include memory impairment, temporal disorientation, and reduced verbal output; apathy, inattention, and decreased social interaction are observed initially in individuals who are lower functioning at baseline. As in the general population, the diagnosis of Alzheimer’s disease requires careful evaluation to rule out other causes of functional decline, including visual and hearing impairment, depression and other mental health disorders, adverse drug effects, nutritional deficiencies, and sleep disorders. Most individuals with Down syndrome who develop Alzheimer’s disease eventually manifest seizures. The use of cognitive-enhancing agents in adults with Down syndrome and Alzheimer’s disease is being investigated. Reported adverse drug effects of donepezil include agitation, aggression, and urinary incontinence [26]. Serotonin-specific reuptake inhibitors may ameliorate the depression that often precedes or coexists with dementia. Many adults with Down syndrome outlive their parents. Later life considerations include long-term residential and financial planning; retirement; bereavement over the death of friends and family; advance directives, guardianship, and durable power of attorney for health care; and accommodations to declines in health and function. Siblings may need education and counseling as they assume responsibilities previously handled by parents. Family and service coordinators should investigate local resources for the aged, including adult day care, meals on wheels, and other social service programs.

Turner syndrome Etiology and overview Turner syndrome is caused by complete or partial X monosomy. The incidence of Turner syndrome is approximately 1 in 2000 among live female infants. In contrast to Down syndrome, there is no association between Turner syndrome and advanced maternal age [27]. Different karyotypes are associated with varying phenotypic expression. The most prevalent karyotype in patients with Turner syndrome is 45,X monosomy. The Xq isochromosome is associated with autoimmune disorders but not congenital abnormalities. Women with the ring X chromosome are less likely to display congenital abnormalities but are more likely to have spontaneous menses and cognitive disability [28]. Women with Turner syndrome also can have a mosaic pattern with additional Y chromosome material (45,X/46,XY). Although this mosaic pattern is uncommon, these women have an increased risk for the development of gonadoblastoma, dysgerminoma, and masculinization, and prophylactic gonadectomy is warranted [29].

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Characteristic features, common findings, and conditions associated with Turner syndrome are summarized in Box 1 [6,29]. The most consistently associated features include short stature and gonadal dysgenesis [6]. Average life span of an individual with Turner syndrome is 69 years according to Scandinavian studies [27]. Recognition through the lifespan Antenatal diagnosis may occur incidentally with chorionic villus sampling or amniocentesis performed for other indications, such as advanced maternal age [30]. Ultrasound findings suggesting Turner syndrome include increased nuchal translucency, cystic hygroma, coarctation of the aorta or other left-sided cardiac defect, brachycephaly, renal anomalies, polyhydramnios, oligohydramnios, and growth retardation [30]. An abnormal maternal serum screen (elevated a-fetoprotein, dimeric inhibin A, and free b human chorionic gonadotropin) also may suggest Turner syndrome. Ultrasound findings and abnormal maternal serum screen are not sufficient to diagnose Turner syndrome; a karyotype is required for definitive diagnosis. Chromosomes always should be re-evaluated postnatally because abnormal prenatal karyotypes may reflect cytogenetic abnormalities found only in the placenta, but not in the fetus [31]. During the newborn period, physical features characteristic of Turner syndrome include lymphedema of the hands and feet, nuchal folds, leftsided cardiac anomalies (coarctation or hypoplastic left heart), webbed neck, and low hairline. During childhood, declining growth velocity with short stature and elevated levels of follicle-stimulating hormone (FSH) should prompt evaluation for Turner syndrome. In adolescence, absence of breast development by age 13, pubertal arrest, amenorrhea with elevated FSH, or unexplained short stature warrants a karyotype and evaluation for Turner syndrome [32]. Throughout the life span, the physical signs of Turner syndrome may be subtle and remain unrecognized by the clinician. Turner syndrome should be considered in any woman with short stature or with premature ovarian failure. Additionally the phenotypic expression of any X-linked recessive disorder in a female (eg, hemophilia A, red-green color blindness, or Duchenne muscular dystrophy) might suggest X monosomy [29]. In one retrospective chart review, two thirds of girls with Turner syndrome not diagnosed in infancy would have been diagnosed by age 4 had their physicians obtained a karyotype when their height fell below the 5th percentile [33,34]. Box 2 lists indications for obtaining a karyotype to screen for Turner syndrome [30,32,33,54]. Screening and management of co-morbidities At the time of diagnosis, all individuals with Turner syndrome, regardless of age, should have an echocardiogram interpreted by a cardiologist with

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Box 1. Common physical features and associated conditions in Turner syndrome Common physical features Short stature (reduced final height averaging 143 cm [56 inches]) Gonadal failure Cubitus valgus (>10( carrying angle between the extended supinated forearm to the upper arm) Low posterior hairline High-arched palate Multiple pigmented nevi Webbed neck Lymphedema of hands and feet Nail dysplasia Deep-set hyperconvex nails Short fourth metacarpal Unusual shape and rotation of ears Narrow maxilla with dental crowding Micrognathia Broad shieldlike chest with inverted or hypoplastic nipples Tibial exostosis Associated conditions Tendency toward obesity Recurrent otitis media Hearing loss Renal abnormalities Left-sided cardiac anomalies; aortic coarctation Strabismus Hypertension Hypothyroidism Glucose intolerance Hyperlipidemia Kyphoscoliosis Lordosis Osteoporosis Gonadoblastoma Inflammatory bowel disease Colon cancer Neuroblastoma Juvenile rheumatoid arthritis Liver disease

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Box 2. Recognition of Turner syndrome: when to obtain a screening karyotype Antenatal Abnormal maternal serum screen (triple check) Abnormal ultrasound findings: increased nuchal translucency, cystic hygroma, coarctation, brachycephaly, renal anomalies, polyhydramnios, oligohydramnios, growth retardation Newborn Lymphedema of hands and feet Nuchal folds Left-sided cardiac anomalies (coarctation, hypoplastic left heart) Webbed neck Low hairline Childhood Declining growth velocity with short stature (height \ 5th percentile) Elevated levels of FSH Girls with two or more of the following: nail dysplasia, high arched palate, shortened fourth metacarpal, strabismus [33] Adolescence Lack of breast development by age 13 Pubertal delay or arrest Amenorrhea with elevated FSH levels Unexplained short stature (height \ 5th percentile) Adulthood Short stature Premature ovarian failure

experience in congenital heart disease, a renal ultrasound, initial blood pressure screening, and referral to an endocrinologist for optimization of hormone replacement therapies across the life span [30]. Beginning at age 2 years, growth should be plotted on a Turner syndrome–specific growth curve [35]. Growth hormone treatment istered by a pediatric endocrinologist should begin when the patient falls below the 5th percentile for normal female growth; treatment may be initiated at 2 years of age. Initial recommended doses of growth hormone are 0.05 mg/kg/d (0.1 IU/kg/d). Early initiation of growth hormone therapy allows for maximal duration of therapy before estrogen is introduced with resultant growth plate closure [30,34,36,37]. In girls age 9 to 12, combination therapy with the anabolic steroid oxandrolone (0.0625 mg/kg/d) may optimize growth and skeletal maturity [30].

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Children with Turner syndrome must be monitored for signs of virilization. Testing for the presence of Y chromosome mosaicism is warranted if virilization is present. Prophylactic gonadectomy is advised if Y chromosome mosaicism is present because of the increased risk for gonadoblastoma or dysgerminoma [29]. Few individuals with Turner syndrome undergo spontaneous puberty (2% to 16%). Pediatric endocrinologists should supervise introduction and titration of estrogen therapy. Induction of puberty must be balanced with achievement of optimal adult height; introduction of estrogen replacement therapy should begin after age 12 with a gradual increase in dose to mimic natural puberty and to facilitate bone maturation [30,32]. Cyclic menstruation is accomplished with either monthly estrogen withdrawal or progesterone use to prevent endometrial hyperplasia [32]. Women with Turner syndrome require long-term estrogen and progesterone replacement to help prevent the sequelae of hypoestrogenism, especially low bone mineral density [28]. Except for women with the ring X chromosome karyotype, mental retardation is not more prevalent in women with Turner syndrome than in the population at large. They do have lower nonverbal IQ, however, with impairment in nonverbal visual-spatial organization and nonverbal problem solving. Other disabilities include impairments in mathematics, memory, ability to formulate goals, and attention span. Attention-deficit disorder is more common. School-based intervention to facilitate acquisition of lifelong coping skills should be initiated early because learning disabilities have an impact on vocational success. Girls with Turner syndrome also may show impaired motor skills and coordination. This impairment may be improved with occupational therapy and motor skills training [32,38]. Infants should be referred to early intervention programs when delayed neuromuscular development is detected [29]. It is suggested that some of the aforementioned deficits may be related to estrogen deficiency and may be reversed partially with estrogen supplementation [30,38]. As a group, women with Turner syndrome are not believed to be at increased risk for mental health problems. Girls with Turner syndrome consistently and clearly identify with the female gender. They are described as having ‘‘high stress tolerance, limited emotional arousal, high degree of dependence, unassertiveness and overcompliance’’ [32], although these traits are common in all women with short stature and delayed sexual development. Compared with girls with other causes of short stature, girls with Turner syndrome often exhibit delayed social maturation, impaired social relationships, and lack of self-esteem. Girls must be encouraged to develop and maintain friendships through involvement in formal and informal recreational activities. Parents and teachers must intervene aggressively at the onset of teasing or bullying. Meeting with other children and adults with Turner syndrome and their families provides invaluable for affected girls and their parents [38]. Health care of individuals with Turner syndrome involves far more than recognition of the disorder and endocrinologic management. Additional

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comorbidities requiring recognition and surveillance, organized by organ system, are as follows. All infants with Turner syndrome should be checked carefully for hip dysplasia. Monitor Children and adolescents should be monitored for tibial problems and for the development of scoliosis. Beginning in childhood, the importance of optimizing bone density with dietary/supplemental calcium, vitamin D, and weight-bearing exercise should be discussed [29]. There is an increased incidence of fractures in Turner syndrome patients older than age 45. It is essential to measure bone mineral density at the initial adult visit and to repeat 2 to 5 years later. Rate of change detected should guide the periodicity of future testing. Osteoporosis treatment should be instituted when decreasing bone mass is detected. Oral calcium intake of at least 1200 mg/d is recommended for all women with Turner syndrome [28]. Congenital heart defects, most commonly left-sided defects, including bicuspid aortic valve and coarctation of the aorta, are present in 30% of patients with Turner syndrome. Women with Turner syndrome also are more susceptible to aortic root dilation and rupture. At time of diagnosis, regardless of age, all women with Turner syndrome should be referred to a cardiologist, and a thorough cardiovascular evaluation including echocardiogram should be performed [27,30]. Throughout childhood, blood pressure and peripheral pulses must be monitored closely. Arm and leg systolic blood pressure should be compared with evaluation for possible coarctation. Elevated blood pressure must be treated aggressively throughout the life span and a cardiac or renal cause excluded [29]. If cardiac malformations are present, the patient needs lifelong subacute bacterial endocarditis prophylaxis. Even if initial cardiac evaluation does not reveal congenital defects, an echocardiogram is warranted during adolescence (age 12–15) [29], again at time of transition to an adult provider, then periodically throughout adulthood (every 3–5 years) [28,30]. Less than 2% of women with Turner syndrome are able to conceive a child spontaneously [32]. Given the increased cardiac demands of pregnancy, women with Turner syndrome may have an unacceptable risk for aortic dissection or rupture. Aortic root dimension must be monitored by serial echocardiography throughout the pregnancy [30]. Currently, no national guidelines exist regarding the advisability of pregnancy for women with Turner syndrome despite the increasing availability of assisted reproductive technologies. Counseling regarding high rates of maternal mortality must begin early in adolescence and accompany discussion of assisted reproductive technology [32]. Women with spontaneous menses must be educated regarding contraception and prevention of unwanted pregnancy. All women with Turner syndrome need education regarding sexuality and the prevention of sexually transmitted disease. Congenital renal anomalies, including horseshoe kidney and duplicate collection system, are present in 30% to 60% of women with Turner syndrome. At minimum, individuals with urinary tract abnormalities

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require a yearly screening urine culture, serum blood urea nitrogen and creatinine, and periodic ultrasound evaluation to assess for progression of the anomaly [28–30]. Women with Turner syndrome have increased rates of autoimmune disease, including Hashimoto’s thyroiditis, Graves’ disease, inflammatory bowel disease (ulcerative colitis and Crohn’s disease), myasthenia, IgA deficiency, celiac disease, juvenile rheumatoid arthritis, and membranoproliferative glomerulonephritis. Any unexplained diarrhea or bleeding must be evaluated promptly [28,32]. Fifty percent of adults are affected by hypothyroidism, and if undetected, hypothyroidism increases the individual’s risk for dyslipidemia and obesity [32]. Routine screening thyroid-stimulating hormone and free thyroxine levels should be obtained annually beginning at age 4, unless clinical signs warrant evaluation sooner. Thyroid autoantibodies also may be evaluated [29]. In addition to the previously described increased risk for malignant germ cell tumors (dysgerminomas), women with Turner syndrome are at a five to six times increased risk for colon cancers independent of the increased relative risk of 2.25 for inflammatory bowel disease [32]. Women with Turner syndrome manifest micrognathia and mild ear malformations. Screening at birth must be done to assess for adequacy of the suck and swallow reflex owing to impaired oral motor function. Orthodontic evaluation is recommended between 8 and 10 years of age [29]. Progressive midfrequency sensorineural hearing loss is common in Turner syndrome, affecting children and approximately 40% of women by their mid-40s. Hearing should be evaluated at birth, 6 and 12 months of age, and periodically throughout the remainder of childhood and adulthood with prompt referral for hearing aid evaluation if sensorineural hearing loss is detected [30,39]. Beginning in infancy, children should be evaluated for serous otitis and otitis media at every heath care visit because of eustachian tube distortion. When these conditions are present, aggressive treatment including tympanostomy tube placement should be instituted. Strabismus, amblyopia, and ptosis also are common, warranting ophthalmology referral [29]. Beginning with the family in early childhood, a comprehensive program of lifestyle education emphasizing diet and physical activity aimed at the prevention of obesity is desirable for the long-term health of individuals with Turner syndrome. Problems experienced by women with Turner syndrome, such as glucose intolerance, hypertension, and osteoporosis, are compounded by obesity [28–30]. Although individuals with Turner syndrome are at increased risk for glucose intolerance, whether or not they are at increased risk for overt diabetes is controversial [40]. Although multiple pigmented nevi are associated with Turner syndrome, there is not believed to be an increased risk for melanoma. Additionally, keloid formation is common with any dermal procedure in individuals with Turner syndrome and must be discussed before surgery. Experts suggest that nevi be removed only if necessary, using plastic surgery techniques to minimize scarring [27].

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groups for women with Turner syndrome and their families can clarify expectations and help them cope with disease manifestations. Local Turner syndrome groups are available, and resources on the Internet include the Turner Syndrome Society (http://www.turnersyndrome-us.org/) and the Magic Foundation (http://www.magicfoundation.org/). Klinefelter syndrome Most individuals with Klinefelter syndrome bear an extra X chromosome, resulting in a karyotype of 47,XXY. Cytogenetic surveys of neonates estimate the prevalence of 47,XXY to be 1 in 600 live-born male infants [41]. Although other chromosomal variants, including mosaic 46,XY/47,XXY and supernumerary sex chromosome patterns (eg, 48,XXYY), can result in a similar phenotype, discussion here is limited to the vastly more common 46,XXY condition. The ‘‘extra’’ X chromosome occurs by nondisjunction during meiosis and may be of maternal or paternal origin. The parental origin of the extra X does not affect phenotype. Following an index case, there seems to be no increased risk for reoccurrence of Klinefelter syndrome within a family. Etiology and diagnosis Abramsky and Chapple [42] estimated that about 10% of XXY aneuploidies are diagnosed prenatally by amniocentesis; another 26% are diagnosed in childhood or adulthood. Most men are not recognized and are never diagnosed [42]. Because of the varied clinical manifestations in men with Klinefelter syndrome, physicians need to recognize potential features of Klinefelter syndrome throughout the life span. Table 1 summarizes clinical features of Klinefelter syndrome in a developmental fashion. In a systematic literature review, primarily comprising European and American studies, prenatal diagnosis of XXY aneuploidy has been Table 1 Clinical features of Klinefelter syndrome throughout the life span Age

Features

Infancy Toddler Childhood

Usually none, occasionally hypospadias, small phallus, cryptorchidism Developmental speech delay Accelerated linear growth velocity Learning disabilities Gynecomastia Eunuchoid body habitus; arm span > height Small testicular volume Sparse axillary, facial, pubic hair Infertility Leg ulcers

Adolescence

Adult

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associated with documented pregnancy termination rates of 92% [8]. Pregnancy termination rates are lowest when post-test counseling is provided by a geneticist. There is evidence of great variation in health care professionals’ knowledge regarding sex chromosome anomalies, such that some parents receive outdated and incomplete information [43]. Infancy and childhood Klinefelter syndrome rarely can be identified in infancy, after karyotyping is performed as part of a routine evaluation for hypospadias, small phallus, or cryptorchidism. The genitals in infants with Klinefelter syndrome are usually normal at birth. Affected toddlers often manifest a delay in the first use of words and phrases compared with siblings. Although motor development generally falls within the normal range, some infants are slower to walk and lack coordination due to hypotonia of the lower extremities and sensorimotor dysfunction. After age 5, boys with Klinefelter syndrome often show accelerated linear growth velocity, owing to excessive leg length. This accelerated growth velocity is the most uncommon growth abnormality a primary care physician encounters in practice and always should prompt consideration of obtaining a chromosome analysis to exclude Klinefelter syndrome [44]. Most boys with Klinefelter syndrome manifest learning disabilities. They typically have difficulty with reading and language arts secondary to poor vocabulary skills, limited abstract reasoning skills, poor auditory memory, and problems with narrative formation. These speech and language deficits correlate with lower verbal IQ scores. Although average IQ score may be 10 to 15 points below that of siblings, most individuals with Klinefelter syndrome have average-tosuperior intelligence, with less than 20% scoring lower than 90 [45]. Suggested educational accommodations may include the use of visual aids (pictures, diagrams, and graphs), rather than verbal or written directions; computer, typewriter, or tape recorder, rather than written communication; and additional time for written assignments. Speech therapists can help advance language development and communication skills. In boys with hand tremor and impairments of fine motor coordination, occupational therapy may be beneficial. Obesity may emerge in later childhood. Obesity combined with poor coordination and poor muscle development may necessitate adapted physical education [46]. Endocrinologic and reproductive issues Klinefelter syndrome is the most common congenital abnormality responsible for testicular failure in youth. Puberty often occurs at a normal age, but secondary sex changes do not follow typical progression. The testes initially may enlarge normally, but as the seminiferous tubules fibrose, the testes involute and become firm. Ultimately the testes are typically less than 2.5 cm in greatest dimension with volume of less than 5 cm3. Facial, axillary,

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and pubic hair tends to be sparse. Before adolescence, testosterone levels are within the normal range. By early adulthood, testosterone levels decrease to low or low-normal values. Concomitantly, luteinizing hormone and FSH levels begin to increase around age 11 or 12 and remain abnormally elevated [47]. More than 50% of adolescents with Klinefelter syndrome develop gynecomastia, owing to increased estradiol-to-testosterone ratio; this often persists in adulthood. (Testosterone therapy does not improve or prevent gynecomastia.) Eunuchoid proportions become evident, with lower body segment (floor to pubis) exceeding upper body segment (pubis to crown) by more than 2 cm and with arm span typically exceeding height by 7 cm or more [8]. Males with the XXY karyotype tend to have narrower shoulders and wider hips. These physical and hormonal characteristics can present significant psychosocial difficulties for adolescents with Klinefelter syndrome. The gynecomastia, eunuchoid habitus, and lack of muscle strength, along with difficulties with academic performance, can lead to low self-esteem, insecurity, and withdrawal from peers. Although Klinefelter syndrome is not associated with homosexuality or gender identity disorders, overall sexual interest may be diminished. A young man with Klinefelter syndrome may find it difficult to individuate and separate from his family [47]. Men with Klinefelter syndrome first may come to diagnosis in the context of evaluation for infertility. Although men who are mosaic 47,XXY/46,XY may be fertile, men who are purely 47,XXY are considered infertile. There are a few cases of confirmed paternity by men not found to have a mosaic phenotype. Couples may consider assisted reproductive technologies, such as intracytoplasmic sperm injection, after sperm are extracted through testicular biopsy. Although healthy and karyotypically normal infants have been born through this technique, there may be an increased risk of autosomal aneuploidies [48]. Most couples desiring children choose adoption or artificial insemination with donor sperm. Testosterone replacement generally is recommended at around age 11 or 12, when gonadotropin levels begin to rise. The dosage should be titrated gradually to provide age-appropriate normal levels of serum testosterone, luteinizing hormone, FSH, and estradiol and to induce gradual virilization. This therapy typically requires consultation with a pediatric endocrinologist. Testosterone replacement in adulthood is less complicated and may be istered by the primary care clinician. Associated medical conditions The physician should be attentive to other medical conditions associated with Klinefelter syndrome. Osteoporosis is more common, particularly in patients who did not receive testosterone replacement during adolescence and early adulthood. In addition to optimizing calcium, vitamin D, and

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testosterone replacement, patients may benefit from antiresorptive therapies. Although autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus, and Sjo¨gren’s syndrome, seem to be more common in males with Klinefelter syndrome compared with karyotypically normal males, the absolute risk for these conditions is unknown. Testosterone replacement may improve the clinical course of these diseases [49]. Endocrine conditions associated with Klinefelter syndrome include type 2 diabetes mellitus and chronic autoimmune thyroiditis. Some authors recommend annual thyroid-stimulating hormone testing, beginning in childhood [50]. Physicians should consider the diagnosis of Klinefelter syndrome in young men with recurrent leg ulcers, whether or not obvious venous disease is present [51]. Pulmonary conditions associated with Klinefelter syndrome include chronic bronchitis, bronchiectasis, and emphysema. Additional injury from cigarette use should be avoided. Men with Klinefelter syndrome bear a risk of breast carcinoma that approximates that of similar-aged women. This risk may exceed 20 fold that of karyotypically normal men [52]. Men should be instructed in breast selfexamination, and clinicians should perform annual clinical breast examinations. There are no studies to routine screening mammography or prophylactic mastectomy. Additionally, young adults with Klinefelter syndrome bear an increased risk, estimated around 1%, for the development of mediastinal germ cell tumors [53]. Resources for physicians and families include Klinefelter Syndrome and Associates (http://www.genetic.org/ks) and the American Association for Klinefelter Syndrome Information and (http://www.aaksis.org) (Box 3). The National Institute for Child Health and Human Development has published a booklet entitled ‘‘Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families,’’ available online at http:// www.nichd.nih.gov/publications/pubs/klinefelter.htm. Summary Primary care physicians must educate themselves regarding diagnosis and management of common chromosomal aneuploidies. Limited understanding of the life experience of persons affected by chromosomal aneuploidies can lead to inadequate prenatal counseling, resulting in high rates of termination of affected pregnancies. Throughout the life span, syndromespecific screening requirements must be integrated into general health care guidelines. Checklists and syndrome-specific growth grids should be used routinely. Ongoing communication between specialists and primary care physicians and between pediatric and adult clinicians is essential. groups and Internet resources can benefit affected individuals and their families immensely.

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Box 3. Internet resources for patients and families General Learning Disabilities Association of America: http:// www.ldanatl.org/ Federation for Children with Special Need: http://www.fcsn.org/ National Information Center for Children and Youth with Disabilities (NICHCY): http://www.nichcy.org/ American Speech-Language-Hearing Association (ASHA): http:// www.asha.org/ The International Dyslexia Association: http://www.interdys.org/ Klinefelter syndrome Klinefelter Syndrome and Associates: http://www.genetic.org/ks American Association for Klinefelter Syndrome Information and : http://www.aaksis.org National Institute for Child Health and Human Development,‘‘Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families’’: http://www.nichd.nih. gov/publications/pubs/klinefelter.htm Turner syndrome Turner Syndrome Society: http://www.turnersyndrome-us.org/ Magic Foundation: http://www.magicfoundation.org/ Down syndrome Down Syndrome Medical Interest Group UK http:// www.dsmig.org.uk/ Down Syndrome Health Issues (comprehensive link to recommended Internet sites): http://www.ds-health.com

Acknowledgment The authors express their gratitude to Dr. Jamie Wood, Fellow, Department of Pediatric Endocrinology, Rainbow Babies and Childrens’ Hospital, University Hospitals of Cleveland, and to Dr. David Eberlein, Fairview/Cleveland Clinic Family Practice Residency, Cleveland, Ohio, for their editorial assistance. References [1] State MW, King BH, Dykens E. Mental retardation: a review of the past 10 years: Part II. J Am Acad Child Adolesc Psychiatry 1997;36:1664–71.

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[2] Saenz RB. Primary care of infants and young children with Down syndrome. Am Fam Physician 1999;59:381–96. [3] Mayor S. Parents of people with Down’s syndrome report suboptimal care. BMJ 1999;318: 687. [4] American Academy of Pediatrics. Health supervision for children with Down syndrome. Pediatrics 2001;107:442–9. [5] Newberger DS. Down syndrome: prenatal risk assessment and diagnosis. Am Fam Physician 2000;62:825–38. [6] Jones KL. Smith’s recognizable patterns of human malformation. 5th edition. Philadelphia: WB Saunders; 1997. [7] Morris JK, Wald NJ, Mutton DE, Alberman E. Comparison of models of maternal agespecific risk for Down syndrome live births. Prenat Diagn 2003;23:252–8. [8] Mansfield C, Hopfer S, Marteau TM. Termination rates after prenatal diagnosis of Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes: a systematic literature review. European Concerted Action: DADA (Decision-making After the Diagnosis of a fetal Abnormality). Prenat Diagn 1999;19:808–12. [9] Hindley D, Medakkar S. Diagnosis of Down’s syndrome in neonates. Arch Dis Child Fetal Neonatal Educ 2002;87:F220–1. [10] Myrelid A, Gustafsson J, Ollars B, Anneren G. Growth charts for Down’s syndrome from birth to 18 years of age. Arch Dis Child 2002;87:97–103. [11] Jacobs IN, Gray RF, Todd NW. Upper airway obstruction in children with Down syndrome. Arch Otolaryngol Head Neck Surg 1996;122:945–50. [12] Csizmadia CG, Mearin ML, Oren A, et al. Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome. J Pediatr 2000;137: 756–61. [13] Chapman RS, Hesketh LJ. Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev 2000;6:84–95. [14] Smith DS. Health care management of adults with Down syndrome. Am Fam Physician 2001;64:1031–8. [15] Cohen WI. Health care guidelines for individuals with Down syndrome: 1999 revision. Down Syndrome Quarterly 1999;4:1–15. [16] White KS, Ball WS, Prenger EC, Patterson BJ, Kirks DR. Evaluation of the craniocervical junction in Down syndrome: correlation of measurements obtained with radiography and MR imaging. Radiology 1993;186:377–82. [17] Kioschos M, Shaw ED, Beals RK. Total hip arthroplasty in patients with Down’s syndrome. J Bone t Surg Br 1999;81:436–9. [18] Tyler CV, Snyder CW, Zyzanski S. Screening for osteoporosis in community-dwelling adults with mental retardation. Ment Retard 2000;38:316–21. [19] Rubin SS, Rimmer JH, Chicoine B, Braddock D, McGuire DE. Overweight prevalence in persons with Down syndrome. Ment Retard 1998;36:175–81. [20] Khan S, Osinowo T, Pary RJ. Down syndrome and major depressive disorder: a review. Mental health aspects of developmental disabilities 2002;5:46–52. [21] Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet 2002;359:1019–25. [22] Baird PA, Sadovnick AD. Life tables for Down syndrome. Hum Genet 1989;82:291–2. [23] Satge D, Sasco AJ. Breast screening guidelines should be adapted in Down’s syndrome. BMJ 2002;324:1155. [24] Mann DM. Alzheimer’s disease and Down’s syndrome. Histopathology 1988;13:125–37. [25] Schupf N, Sergievsky GH. Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry 2002;180:405–10. [26] Hemingway-Eltomey JM, Lerner AJ. Adverse effects of donepezil in treating Alzheimer’s disease associated with Down’s syndrome. Am J Psychiatry 1999;156:1470. [27] Saenger P. Turner syndrome. N Engl J Med 1996;335:1749–54.

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[28] Elsheikh M, Conway GS, Wass JA. Medical problems in adult women with Turner syndrome. Ann Med 1999;31:99–105. [29] Frias JL, Davenport ML. Health supervision for children with Turner syndrome. Pediatrics 2003;111:692–702. [30] Saenger P, Wikland KA, Conway GS, et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 2001;86:3061–9. [31] Wenstrom KD, Chu DC, Owen J, Boots L. Maternal serum alpha-fetoprotein and dimeric inhibin A detect aneuploidies other than Down syndrome. Am J Obstet Gynecol 1998;179: 966–70. [32] Karnis MF, Reindollar RH. Turner syndrome in adolescence. Obstet Gynecol Clin North Am 2003;30:303–20. [33] Savendahl L, Davenport ML. Delayed diagnoses of Turner syndrome: proposed guidelines for change. J Pediatr 2000;137:455–9. [34] Rosenfeld RG. Turner syndrome: a growing concern. J Pediatr 2000;137:443–4. [35] Rongen-Westerlaken C, Corel L, van den Broeck J, et al. Reference values for height, height velocity and weight in Turner syndrome. Swedish Study Group for GH treatment. Acta Paediatr 1997;86:937–42. [36] Saenger P. Growth-promoting strategies in Turner syndrome. J Clin Endocrinol Metab 1999;84:4345–8. [37] Reiter EO, Blethen SL, Baptista J, Price L. Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner syndrome. J Clin Endocrinol Metab 2001; 86:1936–41. [38] Ross J, Zinn A, McCauley E. Neurodevelopmental and psychosocial aspects of Turner syndrome. Ment Retard Dev Disabil Res Rev 2000;6:135–41. [39] Hultcrantz M. Ear and hearing problems in Turner syndrome. Acta Otolaryngol 2003;123: 253–7. [40] Landin-Wilhelmsen K, Bryman I, Wilhelmsen L. Cardiac malformations and hypertension, but not metabolic risk factors, are common in Turner syndrome. J Clin Endocrinol Metab 2001;86:4166–70. [41] Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003;88:622–6. [42] Abramsky L, Chapple J. 47, XXY (Klinefelter syndrome) and 47, XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn 1997;17:363–8. [43] Abramsky L, Hall S, Levitan J, Marteau TM. What parents are told after prenatal diagnosis of a sex chromosome abnormality: interview and questionnaire study. BMJ 2001; 322:463–6. [44] Legler JD, Rose LC. Assessment of abnormal growth curves. Am Fam Physician 1998;58: 153–8. [45] Smyth CM. Diagnosis and treatment of Klinefelter syndrome. Hosp Pract (Office Educ) 1999;34:111–20. [46] Plumridge D, Bennett R, Dinno N, Branson C. The student with a genetic disorder: educational implications for special education teachers and for physical therpists, occupational therapists, and speech pathologists. Springfield (IL): Charles C Thomas; 1993. [47] Manning MA, Hoyme HE. Diagnosis and management of the adolescent boy with Klinefelter syndrome. Adolesc Med 2002;13:367–74. [48] Morel F, Bernicot I, Herry A, Le Bris MJ, Amice V, De Braekeleer M. An increased incidence of autosomal aneuploidies in spermatozoa from a patient with Klinefelter syndrome. Fertil Steril 2003;79 (Suppl 3):1644–6. [49] Bizzarro A, Valentini G, Di Martino G, DaPonte A, De Bellis A, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter syndrome. J Clin Endocrinol Metab 1987;64:32–6.

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[50] Hsueh WA, Hsu TH, Federman DD. Endocrine features of Klinefelter syndrome. Medicine (Baltimore) 1978;57:447–61. [51] Tyler CV Jr, Kungl PA, Green LA. Genetic diagnosis in adulthood: a case report. J Fam Pract 1998;47:227–30. [52] Lynch HT, Watson P, Narod SA. The genetic epidemiology of male breast carcinoma. Cancer 1999;86:744–6. [53] Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer 1995;71:416–20. [54] Toth PP, Jogerst GJ. Identification of Turner syndrome in an elderly woman: case report and review. Arch Fam Med 1996;5:48–51.