Turner's syndrome

The new england journal of medicine medical progress
Virginia P. Sybert, M.D., and Elizabeth McCauley, Ph.D.
urner’s syndrome, a disorder in females characterized by the From the Division of Medical Genetics, De-partments of Medicine (V.P.S.) and Psychi- absence of all or part of a normal second sex chromosome, leads to a constel- atry and Behavioral Sciences (E.M.), Univer- lation of physical findings that often includes congenital lymphedema, short sity of Washington School of Medicine; and stature, and gonadal dysgenesis.1-3 Turner’s syndrome occurs in 1 in 2500 to 1 in 3000 Group Health Permanente Seattle (V.P.S.); and Children’s Hospital and Regional Med- live-born girls. Approximately half have monosomy X (45,X), and 5 to 10 percent have ical Center (E.M.) — all in Seattle. a duplication (isochromosome) of the long arm of one X (46,X,i(Xq)). Most of the resthave mosaicism for 45,X, with one or more additional cell lineages (Table 1).
N Engl J Med 2004;351:1227-38.
Copyright 2004 Massachusetts Medical Society. In the past decade, more has been learned about the natural history of Turner’s syn- drome, and recent molecular studies have identified some genes that may be involvedin the clinical expression of the condition. This review summarizes current knowledgeand makes recommendations for care on the basis of the medical literature and on ourown experience with 532 live-born children and adults with karyotypically confirmedTurner’s syndrome (Table 1).4 When Turner’s syndrome is diagnosed prenatally, the diagnosis is usually based on thefinding of fetal edema on ultrasonography; abnormal levels of human chorionic go-nadotropin, unconjugated estriol, and alpha-fetoprotein on screening of maternal se-rum (triple screening); or abnormal results of fetal karyotyping performed because ofadvanced maternal age. Affected fetuses often abort spontaneously. A 45,X fetus iden-tified prenatally and surviving to birth has a prognosis similar to that of a child inwhom Turner’s syndrome is diagnosed postnatally. In contrast, approximately 90 per-cent of fetuses in whom 45,X/46,XX or 45,X/46,XY mosaicism is diagnosed incidentallyduring the course of screening for advanced maternal age or maternal triple screen-ing will likely have a normal phenotype, female or male, respectively, at birth. The risk ofeventual gonadal failure in these children with mosaicism is unknown.5,6 In contrast,a child in whom 45,X/46,XX or 45,X/46,XY mosaicism is diagnosed after birth is usuallyidentified because of phenotypic features suggestive of Turner’s syndrome; such chil-dren have a prognosis similar to that for 45,X children.5 One fifth to one third of affected girls receive a diagnosis as newborns because of puffy hands and feet or redundant nuchal skin (Fig. 1), the residual effect of cystic hy-gromas in utero. Turner’s syndrome should be suspected in any newborn girl with ede-ma or hypoplastic left heart or coarctation of the aorta, since the frequency of both con-ditions is increased among children with Turner’s syndrome. Approximately one thirdof girls with Turner’s syndrome receive the diagnosis in midchildhood on investiga-tion of short stature. With the exception of familial short stature or constitutional de-lay, Turner’s syndrome is the most common cause of short stature in otherwise healthygirls. In most other patients with Turner’s syndrome, the condition is diagnosed eitherin adolescence when they fail to enter puberty or in adulthood because of recurrentpregnancy loss. The diagnosis should be excluded in any teenage girl with primary orsecondary amenorrhea, especially if she is short.
Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 1. Major Clinical Features of Turner’s Syndrome.*
Karyotype
Patients
Retardation
Disease†
Malformation‡
Height§
* Data were obtained from patients in our Seattle clinic. Denominators reflect the number of patients for whom we have complete information for each feature. Plus–minus values are means ±SD. ND denotes no data.
† The category includes both structural malformations and hypertension. Patients with normal physical examinations who did not undergo ‡ The analysis includes patients with either renal-ultrasound or intravenous-pyelographic information.
§ The analysis does not include patients who received a diagnosis in adult life on the basis of recurrent pregnancy loss (four women; mean height, 167 cm). The analysis excludes patients who had received growth-promoting agents (oxandrolone, human growth hormone, or both).
¶ Secondary amenorrhea developed in all five patients with spontaneous menarche.
Karyotyping of a blood sample is definitive in nads.7 Although the use of flow cytometry or DNA most cases. Detection of mosaicism depends on the hybridization to search for Y-chromosome mate-proportion of cells present from the additional cell rial has been suggested for all girls with a 45,Xlineages. In routine karyotyping, 20 cells are count- karyotype,8 clinical evidence indicates that such aned, since this number is sufficient to detect mosa- approach is merited only in those with masculin-icism at a level of about 5 percent.
ization or mosaicism for an unidentified marker.
Mosaicism for a second, normal 46,XX cell pop- The use of polymerase-chain-reaction testing for ulation occurs in approximately 15 percent of girls Y-chromosome sequences has a high false posi-with Turner’s syndrome. Extensive searching for tive rate.946,XX cells in a girl with a 45,X karyotype is not nec- Which chromosomal regions and genes account essary, since the detection of a normal cell lineage for the physical characteristics of Turner’s syndromein fewer than 5 percent of cells does not change the remains uncertain (Fig 2).10-12 It has been hypoth-prognosis or the management. Conversely, if the esized that the physical manifestations of Turner’sdiagnosis of Turner’s syndrome is suspected clini- syndrome are due either to the absence of two nor-cally but the result of routine testing is normal, in- mal sex chromosomes before X-chromosome in-creasing the number of cells counted to 100 and activation or to haploinsufficiency of genes in theperforming a skin biopsy for karyotyping of fibro- pseudoautosomal regions of the X or Y chromo-blasts are indicated to rule out mosaicism for an some, as well as to aneuploidy itself.13,14 Both theabnormal cell lineage.
short arm and the long arm of the X chromosome Girls with mosaicism for a cell population with contain genes important for ovarian function, and a Y chromosome are at increased risk for gonado- aneuploidy alone may lead to a reduction in theblastoma (risk, 7 to 30 percent) in their streak go- number and survival of oocytes. Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. an function.11,12 Loss of this region usually con-fers short stature and the typical skeletal chang- es, in part as a result of haploinsufficiency of theshort stature–homeobox (SHOX) gene, located inthe pseudoautosomal region of Y and Xp.16 TheSHOX gene is probably not the only gene responsi-ble for the skeletal features. Aneuploidy itself maycontribute to growth failure.14 Loss of a region atXp22.3 appears to be associated with the neurocog-nitive problems in Turner’s syndrome.17 Loss of thetestis-determining factor (SRY) gene locus on theshort arm of the Y chromosome (e.g., 46,X,del(Yp))also leads to the phenotype of Turner’s syndrome,even without a 45,X cell population. A region onXp11.4 has been proposed as critical for the devel-opment of lymphedema.18 There are some correlations between karyotype and phenotype (Table 1). Infants with a 45,X kary-otype are the most likely to have congenital lymph-edema. Patients with a karyotype of 45,X/46,XX or45,X/47,XXX are the most likely to have spontane-ous menarche and fertility.4,19 As a group, womenwith mosaicism for 45,X/46,XX are marginally tall-er than other women with Turner’s syndrome. Thepresence of an isochromosome Xq suggests an in-creased risk for hypothyroidism and inflammatorybowel disease.3,4,20 The presence of a ring or mark- er chromosome confers an increased risk of men-tal retardation and atypical phenotypic features.
Nonetheless, phenotypic predictions for a givenpatient that are based on karyotype are unreliablein patients with Turner’s syndrome. Women witha 45,X karyotype have conceived; women with a45,X/46,XX karyotype and a preponderance of 46,XXcells may have all the findings of the disorder.
The mean birth length of infants with Turner’s syn- Figure 1. Redundant Nuchal Skin (Panel A) and Puffi-
drome falls within the low end of the normal range.
ness of the Hands (Panel B) and Feet (Panel C) in Turner’s
A decrease in growth velocity occurs as early as 18 Syndrome.
months of age.21 Many patients will not be the short-est child in kindergarten but will have had a sig-nificant decrease in linear growth rate by third or Loss of interstitial or terminal long-arm materi- fourth grade. Some present only when the normal al of the X chromosome (Xq) can result in short pubertal growth spurt fails to occur. It is easy to mis-stature and primary or secondary ovarian failure.15 interpret the absence of puberty and small size ofDeletions distal to Xq21 appear to have no effect on these patients as due to constitutional delay; 104stature. In general, loss of the short arm (Xp) results of 150 patients who came to our attention as teen-in the full phenotype. Very distal Xp deletions are agers had had evidence of growth failure earlier incompatible with, but do not ensure, normal ovari- childhood that had been overlooked.4 Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine A study of the efficacy of recombinant human growth hormone in patients with Turner’s syn- PAR1 (contains SHOX)
Visuospatial or perceptual abilities?
drome was initiated in 1983 in the United States22 and led to approval of this agent by the Food and Drug Administration in 1997. Treatment with re- combinant human growth hormone is now stan- dard in many centers, though physiologically sig- nificant alterations in growth hormone secretion have not been identified in patients with Turner’s syndrome. Studies that followed treated patients to Lympedema gene?
their final height23-36 have based therapeutic suc- cess on one of three measures: the mean final height of the treated group, as compared with a historical mean height of 143.2 cm37; the height achieved by each subject, as compared with her projected height on the basis of her centile on the Lyon curve (a growth chart specific to patients with Turner’s syndrome)37 at the onset of treatment with recombinant human growth hormone; and the sub- ject’s predicted height, which was derived from midparental height.38 Only one published, non- randomized study has included a concurrent con- trol group.30 Two studies that include randomized control groups have been initiated — one in Cana- POF2
da and one at the National Institutes of Health.
Only interim results in abstract form are available for the former39; the latter is ongoing.
Comparisons of the final heights of girls treated with recombinant human growth hormone with projected or predicted heights range from no gain to an increase of as much as 11.9 cm.22-36 Differ-ences in ages at the commencement of treatment POF1
and differences in the doses and duration of ther- apy complicate analysis. The use of historical con- trols whose measurements led to the Lyon growth curves may not be valid for contemporary popula-tions. For example, the mean adult height in 149 PAR2
of our untreated patients is currently 148 cm, 4.8 cmtaller than the mean adult height of the Lyon curve.
Figure 2. The Banding Pattern on the X Chromosome,
Although one study suggested that all treated girls the Location of Pseudoautosomal Regions (PAR1
reached or exceeded their predicted adult height,22 and PAR2), and the Putative Locations of Regions
other studies have not.33,38-41 The ideal dosing and Genes Responsible, in Part, for the Phenotypic
regimens and duration of treatment have not been Features of Turner’s Syndrome.
established.36,42 It has been estimated that the cost POF2 denotes the premature ovarian failure gene, an of recombinant human growth hormone per cen- unidentified gene hypothesized to be responsible for ovarian failure on the basis of the study of translocations. timeter of final gain in height is approximately The POF1 gene is homologous to the diaphanous gene (DIAPH2) in the fruit fly. SHOX is located within PAR1.
The short-term safety of treatment with recom- binant human growth hormone in patients with Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. Turner’s syndrome appears to be acceptable. In- trols, particularly in the right posterior regions ofcreased insulin resistance and increased blood pres- the brain.52,53 How these differences may relate tosure have occurred during therapy and resolve on neurocognitive findings is unknown.
its cessation.43 The long-term effects of recombi- A meta-analysis of 13 studies involving 226 pa- nant human growth hormone treatment on car- tients with Turner’s syndrome and 142 controlsdiovascular status,44 especially on aortic-root di- identified deficits in visuospatial organization, so-ameter, and the lifetime risk of type 2 diabetes cial cognition, nonverbal problem-solving, and psy-are unknown. No systematic studies have exam- chomotor functioning in the patients.49 Deficitsined whether treatment with recombinant human in nonverbal memory,54 executive function,55,56 andgrowth hormone improves the psychosocial out- attentional abilities47 are common. As with nonver-comes and the quality of life of patients with Tur- bal learning disabilities,57 these deficits translatener’s syndrome.
into problems with diverse activities such as math- Our view is that recombinant human growth ematics,58,59 driving, multitasking, and social func- hormone should be considered for every girl with tioning.49,56 Spatial and math deficits appear early;Turner’s syndrome. Parents and children should be problems with reading comprehension emerge astold of the limitations of current knowledge about more complex academic demands are made. At-treatment and be given realistic expectations with tention-deficit–hyperactivity disorder is relativelyrespect to the resulting gain in height, so that they common.60 Early cognitive testing and appropri-can make informed decisions.28 Most adults with ate accommodations, such as tutoring; enrollmentTurner’s syndrome cope successfully with their in small, structured classes; and the use of untimedsmall stature.45 Weight management is an issue in patients with Girls with Turner’s syndrome have typical fe- Turner’s syndrome. Obesity is neither inherent nor male-sex identification. Most affected women re-unavoidable.46 Affected girls should be encouraged port being heterosexual, although they are lessto engage in physical activities such as swimming, likely than their peers to have sexual relationshipswalking, and bicycling beginning in childhood and and do so at an older age.45,61 Prevalence rates ofcontinuing throughout their lives.
coexisting psychiatric diagnoses range from 2 to10 percent,4,62 which are actually lower than the developmental and behavioral concerns
rate of 14 percent among the general population.
Most people with Turner’s syndrome have normal Younger patients may have impaired peer rela- intelligence. Approximately 10 percent of patients tionships and anxiety and may be preoccupied with(Table 1), irrespective of karyotype, will have sub- keeping things in order and inflexible regardingstantial developmental delays, need special educa- changes in their routine.64-66 They have relativelytion, and require ongoing assistance in adult life. poor self-esteem, particularly in the social arena,The risk of mental retardation is highest among pa- as compared with both girls with short stature fromtients with a marker chromosome (66 percent) or other causes and girls with normal height.60,66,67a ring (X) chromosome (30 percent).4 During adolescence, immaturity, social isola- Approximately 70 percent of patients with Tur- tion, and anxiety are common.60,64 People with Tur- ner’s syndrome have learning disabilities affect- ner’s syndrome may misread social cues, facial ex-ing nonverbal perceptual motor and visuospatial pressions, and body language,47,65,68 contributingskills.47-49 These deficits appear to be more com- to awkwardness in social interactions; special train-mon among patients with a 45,X karyotype than ing in recognizing social cues may be helpful.
among those with a 45,X/46,XX karyotype.50 Bet- Successful transition of these patients into the ter verbal and executive skills may be associated working world requires age-appropriate, not size-with inheritance of a paternally derived X chromo- appropriate, expectations. During driver’s train-some,51 although these findings have not been cor- ing, many adolescents will require attention to beroborated. Findings on magnetic resonance im- paid to their impaired navigational planning, visuo-aging and positron-emission tomography have motor integration, and spatial and directional abil-suggested the presence of nonspecific differences ities. Most adults with Turner’s syndrome reportbetween patients with Turner’s syndrome and con- satisfaction with their lifestyle45,69; they have fewer Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine social contacts than their peers but do not perceive at onset is in the third decade, though 5 to 10 per-themselves to be isolated.45 They react with appro- cent of cases occur before adolescence. Acute thy-priate depression and feelings of loss related to roiditis is uncommon. Screening of thyroid func-their physical limitations and usually cope well; tion, including measurement of thyrotropin levels,their sense of self appears to be directly related to should begin at about 10 years of age in asymptom-their health status.45 atic patients. We do not monitor antithyroid anti- Women with Turner’s syndrome are often em- body status, since the presence of these antibodies ployed at occupational levels below that predicted does not alter management.
on the basis of their education and training. They Gonadal dysgenesis is a cardinal feature of may fail at jobs requiring a rapid response and mul- Turner’s syndrome; 90 percent of patients will re-titasking, reflecting the effect of nonverbal learn- quire hormone-replacement therapy to initiate pu-ing disabilities.70 Nonetheless, many have success- berty and complete growth. In utero, the ovaries haveful professional careers.
a decreased number of primordial follicles; theseappear to undergo premature apoptosis78 and are cardiovascular concerns
usually absent by adult life. The uterus may be small The prevalence of congenital heart disease among owing to a lack of estrogen; structural uterine ab-patients with Turner’s syndrome ranges from 17 normalities are rare. Dyspareunia sometimes oc-to 45 percent, with no clear phenotype–genotype curs because of a small vagina or an atrophic vag-correlations.3,71,72 Death from cardiac causes is a inal lining.
serious concern.4,73 Coarctation of the aorta and The presence of normal gonadotropin levels in bicuspid aortic valve are the most common struc- the first three to six months of life suggests thattural malformations, followed by other left-sided residual ovarian function exists but does not ensuredefects. Hypertension, mitral-valve prolapse, and that the initiation and progression of puberty willconduction defects also occur. Hypertension in the be normal. Gonadotropins are suppressed in child-absence of structural cardiac malformations is usu- hood, even in those with gonadal dysgenesis. Inally not associated with arteriosclerotic heart dis- many girls with Turner’s syndrome, pubic and ax-ease or renal disease.4 The risk of hyperlipidemia illary hair will develop spontaneously, but chang-and coronary artery disease in patients with Tur- es of adrenarche are not indicative of ovarianner’s syndrome is unclear.
function. Some girls have enough residual ovari- Echocardiography is a mandatory part of the an function for breast budding or vaginal spot- diagnostic workup for Turner’s syndrome, since ting to occur, but secondary amenorrhea will de-a physical examination may be inadequate to de- velop. A minority will maintain ovulatory cyclestect a bicuspid aortic valve.71 Use of magnetic reso- for a time. Two fifths of girls with 45,X/46,XX mo-nance imaging as a screening tool for Turner’s syn- saicism will have spontaneous menarche; howev-drome has not been standardized.
er, ovarian failure usually ensues.4 If the status of There have been more than 80 reports of aor- ovarian function in adolescence is unclear, mea- tic dissection in patients with Turner’s syn- surement of follicle-stimulating hormone, lutein-drome.71,74-76 Coarctation of the aorta (unrepaired izing hormone, and estradiol levels can help deter-or repaired), bicuspid aortic valve, hypertension, mine the need for hormone-replacement therapy.
or a combination of these findings, which are risk Hormone-replacement therapy should be ini- factors for aortic dissection, were present in 93 per- tiated at about the age of 14 years.4,79 Earlier treat-cent of these patients. The normal range of aortic- ment may result in a decrement in final height. Psy-root diameters has not been established in pa- chosocial issues and the patient’s maturity andtients with Turner’s syndrome. The need for and wishes also need to be considered. Girls who havefrequency of repeated echocardiography for the as- received recombinant human growth hormone andsessment of the aortic-root diameter in those with- who have completed most of their growth, as judgedout structural cardiac abnormalities is unknown on the basis of bone age or growth velocity, mayand should be individualized (Table 2).71,76 start hormone-replacement therapy at the age of12 years if they wish.
endocrine concerns
There is no single formula for the use of hor- Hypothyroidism occurs in 15 to 30 percent of wom- mone-replacement therapy.80 Several strategiesen with Turner’s syndrome.4,20,77 The mean age are outlined in Table 3. After the first year, the use Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. Table 2. Recommendations for Care.
Procedure
Timing of Evaluation
* Physical examination should include measurement of blood pressure, growth, weight, and vision and an evaluation † Recommendations are current (best-guess) estimates with few data to support the use of this approach in patients with- out cardiac disease. If structural cardiac malformations are present, recommendations need to be individualized.
‡ Measurement of gonadotropins may be helpful, as discussed in the text. Any discussion of gonadal dysgenesis, the need for hormone-replacement therapy, sexual function, and fertility should be age-appropriate.
§ The use of recombinant human growth hormone should be discussed.
¶ Schooling issues and the need for job and driver’s training and other steps to independence should be discussed at ap- of a cycling regimen with a progestational agent a 47,XXX cell lineage, or very distal Xp deletions.19is mandatory to minimize the risk of endometrial These women have an increased risk of spontane-hyperplasia and uterine adenocarcinoma.
ous pregnancy loss, twins, and aneuploidy in fe- The effects of hormone-replacement-therapy tuses that are carried to term.4,19,84 Efforts to cryo- on liver function, on bone density, and on the risk preserve ovarian tissue are fairly new, and theof hypertension, cancer, and obesity in patients with applicability of such techniques to preserve fertil-Turner’s syndrome are uncertain. Although there ity in women with Turner’s syndrome may be com-have been very few reports of frank liver disease in promised by a high rate of aneuploid gametes.
women with Turner’s syndrome, elevated liver en- Physicians should discuss infertility issues and zymes have been reported,81 and the use of differ- reproductive options with their patients and reas-ent forms of estrogen replacement may ameliorate sure them about their sexual function. It is impor-or exacerbate this problem.82 There are currently in- tant to acknowledge the sense of loss associatedsufficient data to make specific recommendations. with infertility, on the part of both the patient andThere has not been an increased occurrence of her parents. Pregnancy, by means of gamete intra-breast cancer among patients with Turner’s syn- fallopian transfer with donor eggs, has been at-drome.83 tempted in women with Turner’s syndrome, with Spontaneous fertility is rare among patients a success rate equal to that in other infertile wom- with Turner’s syndrome and is most likely in wom- en. However, there have been five case reports ofen with mosaicism for a normal 46,XX cell lineage, aortic dissection in women with Turner’s syndrome Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 3. Ovarian Hormone Replacement.
Variable
Start one of the following at the age of 12 years if the child has previously been treated with recombinant human growth hormone; and at the age of 14 if she has not.
Conjugated estrogens (Premarin), 0.3 mg daily; ethinyl estradiol, 2–5 μg daily; or 17b-estra- After 6 months, if the response is poor as measured by the Tanner breast stage, increase the dose. After 1 year, begin cyclical treatment on days 1–21, 1–25, or 1–28, adding progestin.
Medroxyprogesterone acetate, 10 mg on days 1–12, 15–21, 15–25, or 15–28, or norethin- drone, 0.7–1.0 mg on days 1–12, 15–21, 15–25, or 15–28.
Use any of above cycling regimens. The dose of conjugated estrogens can be increased to 1.25 mg, or that of ethinyl estradiol to 10 to 20 μg if needed. Continuous treatment can be used with daily estrogen, low-dose progestin, or low-dose oral contraceptives to increase patient compliance. Use of the transdermal patch for induction is relatively new; it can also be used for maintenance therapy in combination with progestin in an appropriate cycling regimen.
There are no data regarding the benefits or risks of continuing or stopping hormone-replace- ment therapy in women with Turner’s syndrome at the usual age of menopause. Decisions need to be made on an individual basis.
who have undergone gamete intrafallopian trans- the same frequency as in normal males.4,86 Therefer. Two of these cases may represent duplicate re- should be a low threshold for referral to ophthal-ports; inadequate details were provided to be cer- mologists for these patients.
tain. In a collected series,85 101 of 146 women with The majority of infants and children with Tur- Turner’s syndrome in whom gamete intrafallopian ner’s syndrome have recurrent otitis media, whichtransfer was attempted became pregnant; none had is probably due to a combination of small, dysfunc-aortic dissection. One woman had an aortic dis- tional eustachian tubes and palatal dysfunction.
section before the procedure. Among 93 reports of This can be a major problem in early childhood,women with Turner’s syndrome who have become causing substantial complications and many sleep-pregnant spontaneously, there have been no occur- less nights. The frequency of ear infections decreas-rences of aortic dissection.4 es with age and growth of facial structures. Palatal The prevalence of insulin resistance and type 2 dysfunction in these patients may be exacerbated diabetes may be increased in patients with Turner’s by the removal of adenoids. Such surgery should besyndrome. Among 257 patients in several large undertaken only after a careful evaluation of the pa-series, 18 (7 percent) had diabetes requiring treat- tient’s speech and palatal configuration.
ment.4 Diabetes has developed in 11 of our 372 pa- Progressive sensorineural hearing loss is a ma- tients older than five years of age for whom we have jor feature of Turner’s syndrome in adults. Ninetyinformation (type 1 in 3 and type 2 in 8).4 The ma- percent of 44 adults with Turner’s syndrome hadjority of patients with Turner’s syndrome and dia- sensorineural hearing loss. The loss was clinicallybetes have adult-onset diabetes, and most are over- significant in two thirds, and 27 percent requiredweight. There is conflicting evidence regarding the hearing aids.87 Five percent of children and 17 per-effect of hormone-replacement therapy on glucose cent of adults in our clinic require hearing aids. Thehomeostasis in patients with Turner’s syndrome biologic basis is not known.
and none regarding the long-term effects of recom-binant human growth hormone.
gastrointestinal manifestations
Feeding problems, gastroesophageal reflux, and ophthalmologic and otologic concerns
failure to thrive occur in both breast-fed and bot- Clinically significant strabismus occurred in 18 per- tle-fed infants with Turner’s syndrome, possiblycent of our patients with Turner’s syndrome, and as a result of anatomical differences in the orophar-ptosis in 13 percent.4 Cataracts and nystagmus also ynx as well as oral motor immaturity.88 There haveoccur more commonly in patients with Turner’s been rare reports of a variety of symptomatic vas-syndrome. Red–green colorblindness is found with cular malformations of the gastrointestinal tract.
Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. More common are instances of inflammatory bow- sive feature of a general skeletal dysplasia or is
el disease. In a series of 135 adults with Turner’s analogous to the accelerated bone loss seen in post-
syndrome, 2 had Crohn’s disease, 2 had ulcerative menopausal women primarily as a result of estro-
colitis, and 2 had chronic diarrhea of unknown gen deficiency. Both hormone-replacement ther-
cause.89 More than half of patients with Turner’s apy and recombinant human growth hormone
syndrome and inflammatory bowel disease who treatment may improve regional bone mass.95,97
have been described in the literature have had an However, one study found no differences among
i(Xq) cell lineage. There may be an increased inci- patients treated with growth hormone, estrogen re-
dence of celiac disease among patients with Tur- placement, or both and an age-matched group of
ner’s syndrome; preliminary screening studies have untreated patients with Turner’s syndrome.97
shown elevated levels of IgA–antiendomysium and
IgA–antigliadin antibodies in 2 to 10 percent of dermatologic concerns
patients who were screened but symptomatic dis- It may take several years for the congenital puffi-
ease in only a few.3,90,91 The incidence of gallblad- ness of the hands and feet to resolve in patients
der disease may be higher than expected and is not with Turner’s syndrome. In rare cases, pedal ede-
associated with diabetes or obesity.4
ma persists or recurs in late childhood, at the timeof ovarian hormone-replacement treatment, or lat- renal manifestations
er. There is an increased number of typical melano- Structural renal malformations, including horse- cytic nevi that are not clinically or histologically un-shoe kidney and duplication of the collecting sys- usual, with no recognized increase in the risk oftem, are found in up to 40 percent of patients with malignant melanoma.83Turner’s syndrome.4,92 Whereas most structural The risk of keloid formation may be more ap- malformations do not cause renal dysfunction, si- parent than real because the neck and upper chest,lent hydronephrosis resulting from obstruction of which are the typical areas for operative proce-a duplicated collecting system may occur (present dures in these patients, are more likely to have suchin 10 percent of our patients). Screening renal ul- scarring.98 Premature fine wrinkling of facial skin,trasonography is necessary for all patients with similar to that seen in smokers, occurs commonlyTurner’s syndrome.
in women with Turner’s syndrome in their late 30sand early 40s. It is not associated with smoking or musculoskeletal characteristics
Turner’s syndrome is characterized by skeletal dys-
plasia, with short stature, mild epiphyseal dyspla- neoplasia
sia, and typical bony alterations. Dislocation of the A review of 597 women with Turner’s syndrome
patellae and chronic knee pain are common. Mal- in the Danish Cytogenetic Register found no in-
formation of the ulnar head causes the typical in- crease in the relative risk of cancer, although there
creased carrying angle of the arm and may cause were more cases of colon cancer than expected.83
limited range of motion. Chondrodysplasia of the In another review of 400 women, neither colon can-
distal radial epiphysis (Madelung’s deformity), typ- cer nor nervous system cancer was increased.99 No
ical of the Leri–Weill syndrome — the skeletal dys- history of gonadoblastoma or dysgerminoma was
plasia associated with SHOX haploinsufficiency — reported in 29 patients with Turner’s syndrome and
is a rare complication. Congenital dislocation of the a Y chromosome, but it was not known whether
hip is common (occurring in 5 percent of patients), they had undergone prophylactic gonadectomy.
as is clinically significant scoliosis (occurring in One of these patients with a 45,X/46,XY karyotype
10 percent).4
had adenocarcinoma of a gonadal streak. Two of It is unclear whether patients with Turner’s syn- our 37 patients with Y-chromosome material have drome have an increased risk of osteoporosis or had gonadoblastoma. Until better data regardingfractures.93-96 Their bones appear osteopenic on risk are available, prophylactic gonadectomy is in-radiographic evaluation, and their regional bone dicated if a Y chromosome is present. Endometri-mass is often, but not always, below that of age- al carcinoma has occurred exclusively in patientsmatched, but not height-matched, controls.95 No who received unopposed estrogen treatment or pro-longitudinal studies have been done to establish longed treatment with diethylstilbestrol.4whether the reduced bone mass is a nonprogres- Downloaded from nejm.org on December 3, 2012. For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine life expectancy
be served by their primary care practitioners, with Patients with Turner’s syndrome appear to have a the use of informed judgment about the need fordecreased life expectancy, primarily as a result of referral to specialists. Although these women havecomplications of heart disease and diabetes.100 In substantial health concerns, their care for the mostour series of 532 live-born patients, 30 have died, 13 part falls under the standard repertoire of primaryfrom heart disease (mean age at death, 27.9±25.5 care, and continued follow-up in specialty care cen-years; range, birth to 80.2 years).4 ters may inhibit their integration into society andfoster a sense of ill-being. Support groups for pa-tients with Turner’s syndrome and their families (listed in the Appendix) can be a source of valuable Most children with Turner’s syndrome are under information.
the care of specialists. It has been proposed that We are indebted to the members of the Puget Sound Turner Syn- adults should also be followed in multidisciplina- drome Society for their faith in our work and their support; to the Welch’s Fund for initial seed money; to Dr. Judith G. Hall, who was in- ry specialty clinics.3 We believe, on the basis of our strumental in establishing the clinic; to Dr. Christine Disteche for help own experience, that most affected women can best with Figure 2; and to numerous colleagues for their contributions.
a p p e n d i x
There are several support groups for patients with Turner’s syndrome and their families: The Turner’s Syndrome Society of the United States, 14450 TC Jester, Suite 260, Houston, TX 77014; telephone 800-365-9944 or 832- 249-9988; fax 832-249-9987; e-mail tssus@turner-syndrome-us.org; or see www.turner-syndrome-us.org; The Turner Syndrome Society of Canada, 21 Blackthorn Avenue, Toronto, ON M6N 3H4, Canada; telephone 800-465-6744 or 416-781- 2086; fax 416-781-7245; or see www.TurnerSyndrome.ca; The Turner Syndrome Society of Quebec (in French), telephone 888-9TURNER or 450-655-8771; or see www.turnerquebec.qe.ca; andThe Turner Syndrome Society of UK, 12 Irving Quadrant, Hardgate, Clydebank G81 6AZ, United Kingdom; telephone +44(0)1389- 380385; fax +44(0)1389-380384; e-mail Turner.Syndrome@tss.org.uk; or see www.tss.org.uk/contact.html.
Free growth charts for patients with Turner’s syndrome are available through the Turner Syndrome Society. Publications are also avail- able at cost through the Turner Syndrome Society, including Turner syndrome: A guide for families, by P.A. Reiser and L.E. Underwood (1992),and Turner syndrome: A guide for physicians, by R.G. Rosenfeld (1992). The Turner Syndrome Society also has videotapes of their annual con-ferences available for a fee.
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