Turner Syndrome

Current Concepts

CURRENT CONCEPTS

Volume 335 Number 23

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T

URNER

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S

YNDROME

P

AUL

S

AENGER

, M.D.

From the Division of Pediatric Endocrinology, Albert Einstein Collegeof Medicine–Montefiore Medical Center, 111 E. 210th St., Bronx, NY10467, where reprint requests should be addressed to Dr. Saenger.

©1996, Massachusetts Medical Society.

URRENTLY, there are 50,000 to 75,000girls and women with Turner’s syndrome inthe United States alone. Turner’s syndrome,

first described in 1938,

1

is the most common sex-chromosome abnormality in females, affecting an es-timated 3 percent of all females conceived. However,the frequency among live-born female infants is only1 in 1500 to 1 in 2500, and as many as 15 percentof spontaneous miscarriages have a 45,X karyotype.It is estimated that only 1 in 100 embryos with a45,X karyotype survive to term.

2

Molecular studieshave shown that the maternal X is retained in twothirds of patients with Turner’s syndrome and thepaternal X in the remaining patients.

3,4

More thanhalf of all patients with Turner’s syndrome have a mo-saic chromosomal complement (e.g., 45,X/46,XX).

5-7

The identification of mosaicism depends directly onthe method of ascertainment. The use of fluores-cence in situ hybridization increases the detectedprevalence from 34 percent with conventional cyto-genetic techniques to 60 percent, and the use of re-verse transcription–polymerase-chain-reaction assaysas well further increases the detected prevalence to74 percent.

8

Mosaicism with a normal cell line in thefetal membranes may be necessary for adequate pla-cental function and fetal survival.

9,10

PRENATAL MANAGEMENT

Most prenatally detected cases of Turner’s syn-drome are discovered incidentally during chorionic-villus sampling or amniocentesis performed for un-related reasons, such as advanced maternal age, orbecause of prior congenital anomalies. Advanced ma-ternal age in itself is not associated with an increasedincidence of Turner’s syndrome. One of the mostuseful tools in early prenatal diagnosis is ultrasonog-raphy.

11

Typical findings include thickening of thenuchal fold, cystic hygroma, and renal (horseshoekidney) and left-sided cardiac abnormalities. Suchfindings, although not diagnostic, necessitate chori-

C

onic-villus sampling or amniocentesis. Many fetuseswith a prenatal diagnosis of Turner’s syndrome areelectively terminated. Prenatal counseling should in-clude a detailed discussion of the variability of so-matic abnormalities and the very high likelihood ofshort stature and ovarian failure. If no fetal nuchalhygroma is present, the physical stigmata may beminimal.

12

It should also be stressed that patientswith Turner’s syndrome can be healthy, happy, andproductive members of society.

13

CARE OF INFANTS AND CHILDREN

In the neonatal period Turner’s syndrome is diag-nosed when congenital lymphedema and swellingbecome evident and lead to a webbed neck, a lowhairline, and swelling of the hands and feet

5,7,13-16

(Fig. 1). Poor development of the lymphatic chan-nels in fetal life causes these phenotypic changes andmay also result in deformities of the ears, a “shield”chest, and coarctation of the aorta. As soon as Tur-ner’s syndrome is diagnosed cytogenetically, the car-diac anatomy should be evaluated by ultrasonogra-phy or magnetic resonance imaging. The latter hasbeen more useful for the diagnosis of aortic ab-normalities. Echocardiography requires considerableexpertise because the shield chest makes imaging,particularly in children, difficult. The incidence ofbicuspid aortic valves is as high as 50 percent, andthat of coarctation of the aorta is less than 20 per-cent. If coarctation of the aorta is detected, it shouldbe surgically corrected. Patients with a bicuspid aor-tic valve are at greater risk for progressive dilatationof the aortic root in later life.

17,18

Cardiovascular dis-orders are the single source of increased mortality inpatients with Turner’s syndrome.

19

Prophylactic an-tibiotics are strongly recommended for the preven-tion of subacute bacterial endocarditis in patientswith cardiac abnormalities who are undergoing den-tal procedures or any other surgical procedure thatmight cause bacteremia. Cardiac evaluation includingechocardiography is warranted every five years tomonitor the diameter of the cardiac root, particular-ly in patients with bicuspid aortic valves.

Renal ultrasonography should be performed atthe time of diagnosis. Any structural abnormalities(such as abnormal location of the kidney, abnormalvascular supply, or a double collecting system) shouldprompt a full evaluation and treatment of any infec-tion. Anomalies associated with obstruction of theureteropelvic junction can produce clinically signifi-cant hydronephrosis or pylonephritis. Idiopathic hy-pertension is common in Turner’s syndrome, even inthe absence of recognizable cardiac or renal malfor-mations. Blood pressure should therefore be moni-tored carefully, and hypertension vigorously treated(Table 1).

Primary hypothyroidism develops in 10 to 30 per-cent of those with Turner’s syndrome and is gener-

Downloaded from www.nejm.org on March 31, 2004. This article is being provided free of charge for use in Indonesia:NEJM Sponsored.Copyright © 1996 Massachusetts Medical Society. All rights reserved.

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The New England Journal of Medicine

ally associated with antithyroid antibodies (Hashi-moto’s thyroiditis). In adulthood the prevalence mayreach 50 percent. Repeated screening with thyrotro-pin measurements should be part of the long-termcare of girls and women with Turner’s syndrome.

20

Otitis media is frequent because of the congenitalanatomical distortion of the eustachian tube. Aggres-sive treatment for ear infections is recommended. Inaddition to conductive middle-ear disease, there isalso a high incidence of progressive sensorineuralhearing loss. Adenoidectomy is not routinely recom-mended because the high arched palate and the smalllower face cause a change in voice resonance that theadenoids buffer.

12

Micrognathia is common, as arestrabismus, amblyopia, and ptosis, which need to betreated appropriately.

13

Scoliosis develops in approximately 10 percent ofgirls with Turner’s syndrome, most commonly dur-ing adolescence. Scoliosis must be monitored care-fully because it may lead to an additional reductionin adult height. The carrying angle of the elbow (cu-bitus valgus) is frequently increased because thetrochlear head of the ulna is distorted. The medialtibial and femoral condyles may be prominent, caus-ing knee pain.

12,21

Abnormal mesenteric vascular development shouldbe considered if there is gastrointestinal bleeding ofunknown cause. An increased incidence of Crohn’sdisease and ulcerative colitis has also been reported.

5

Congenital edema due to lymphatic obstruction canusually be controlled with support stockings. Vascu-

lar surgery aimed at the correction of the lymphede-ma is rarely indicated. Because of increased keloidformation, all surgical procedures should be carefullyconsidered. Hypoplastic, hyperconvex, and upturnednails are often present, and they, too, are a conse-quence of the fetal lymphedema.

Glucose intolerance is common, with mild insulinresistance.

22,23

Routine glucose-tolerance tests areunnecessary, since no therapy for insulin resistance isindicated. The incidence of neither insulin-depend-ent diabetes mellitus nor non-insulin-dependent di-abetes mellitus is increased in Turner’s syndrome. In-sulin resistance increases with growth hormone oranabolic-steroid therapy and diminishes again afterthe drugs are discontinued.

23

Insulin resistance mayworsen with obesity, and the body-mass index (theweight in kilograms divided by the square of theheight in meters) of patients with Turner’s syn-drome is greater than that of controls (mean [

�

SE],25.6

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1.3 vs. 21.4

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0.6).

24

Cholesterol levels are fre-quently increased, independently of weight, age, orkaryotype, and these changes precede treatment withgrowth hormone or estrogens.

25

Every attempt shouldbe made to achieve weight control through appro-priate counseling.

Short stature combined with a square appearanceis the most common clinical feature of Turner’s syn-drome. It is characterized by a tendency for mild in-trauterine growth retardation (1 SD below the nor-mal length at birth) as well as decreased growth ratesduring infancy and childhood and a pronounced

Figure 1.

Frequency of Physical Abnormalities in Turner’s Syndrome.The light shading indicates the maximal frequency, and the dark shading the minimal frequency. Mod-ified from Ranke

16

with the permission of the publisher.

20 10040 60 80

Frequency (%)

Growth failure

Gonadal dysgenesisInverted, widely spaced nipplesWebbed neck

Nail dysplasiaDefective dental developmentRenal dysgenesis

Cardiac malformation

Skeletal dysgenesis

Otitis mediaEdema of hands and feetEye deformities


CURRENT CONCEPTS


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*Data were modified from Saenger

5

and Hall.

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HARACTERISTICS

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YNDROME

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HARACTERISTIC

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EONATAL

P

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HILDHOOD

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DOLESCENCE

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DULTHOOD

Gonadal dysgenesis Look for mosaicism. Lookfor Y-chromosome mate-rial if marker chromo-some or virilization is present.

Discuss reproductive options when appro-priate.

Check follicle-stimulating hormone and luteinizing hormone levels before initiating hormone-replacement therapy at14 years (estrogen should not be given before this time). Begin therapy with conjugated estrogens at a dose of 0.3 mg/day.

Continue hormone replace-ment (e.g., conjugated estrogens, 1.25 mg/day; medroxyprogesterone acetate, 5–10 mg/day; or cyclical therapy with con-jugated estrogens–med-roxyprogesterone acetate).

Growth failure Plot growth on growthcurve specific for those with Turner’s syndrome.

Continue to monitor growth. Check thyroxine and thyrotropin levels. Check for obesity. Insti-tute dietary counseling.Start growth hormone therapy with or without anabolic steroid when growth velocity declines.

Stop growth hormone when bone age exceeds 15 yr or growth velocity drops below 2 cm/yr.

Check thyroxine and thy-rotropin levels. Continue dietary counseling.

Skeletal dysgenesis Check for dislocated hips. Watch for scoliosis. Watch knee for tibial problems.

Watch for scoliosis. Ensure adequate calcium intake (1.2 g/day). Encourage weight-bear-ing exercise.

Craniofacial malformation Otitis and high arched palate are common.

Otitis is common and should be treated aggres-sively. Orthodontic work may be necessary.

Continue to monitor hearing.

Continue to monitor hearing.

Abnormal carbohydrate metabolism

— Glucose-tolerance test may be abnormal. Insulin resistance is common.

Glucose-tolerance test may be abnormal. Insulin resistance is common. Insulin levels increase with growth hormone therapy.

Glucose-tolerance test may be abnormal. Insulin resistance is common. Insulin levels decline after growth hormone therapy is stopped.

Cardiovascular abnormalities

Check for congenitallymphedema and treat symptomatically. Rule out coarctation and bicuspid aortic valve. Use prophylactic antibiotics if lesion is present.

Rule out hypertension. Check yearly for hyper-tension; treat as neces-sary. Try weight reduc-tion for treatment.

Watch for fluid retention and recurrence of edema when hormone-replace-ment therapy begins; treat symptomatically. Check for hypertension and measure aortic-root diameter. Growth hor-mone therapy appears to have no effect on aortic-root diameter and left ventricular mass.

Observe for lymphedemaand treat symptomatical-ly. Check yearly for hypertension, and moni-tor aortic root diameter every 3–5 yr.

Genitourinary abnormalities

Perform renal ultra-sonography to rule out structural anomalies. If present, screen yearly for urinary tract infection.

Continue to monitor for urinary tract infection, if necessary.

Continue to monitor for urinary tract infection,if necessary.

Continue to monitor for urinary tract infection, if necessary.

Skin problems — Remove multiple nevi only if in area where rubbed by clothing. Warn patients to avoid unnecessary sur-gery because of keloid formation.

Remove multiple nevi only if in area where rubbed by clothing. Warn patients to avoid unnecessary surgery because of keloid formation.

Remove multiple nevi only if in area where rubbed by clothing. Warn patients to avoid unnecessary sur-gery because of keloid formation.

Central nervous system abnormalities

— Screen for intellectual func-tioning, visuospatial organization. Attention deficit disorder may be more frequent. IQ is generally normal.

Establish contact with Turner’s syndrome support groups. Counsel about learning disabil-ities.

Establish contact with Turner’s syndrome sup-port groups. Counsel about learning disabil-ities.

Other problems Perform stool guaiac test to check for gastrointestinal bleeding.

Perform stool guaiac test to check for gastrointestinal bleeding.

Watch for anorexia nervosa and inflammatory bowel disease.

Watch for anorexia nervosa and inflammatory bowel disease.


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lack of pubertal growth, resulting in a markedly re-duced height of approximately 143 cm (56 in.).

26

The final height of untreated patients correlates sig-nificantly with mid-parental height (the average ofthe heights of the mother and the father) (r

�

0.7).

27

The timely management of growth failure will affectmany other aspects of Turner’s syndrome, includingthe age at which estrogen-replacement therapy shouldbegin, socialization, and academic achievement.Height should be plotted on growth curves specificfor Turner’s syndrome. Since there is no growth hor-mone deficiency, provocative growth hormone test-ing need not be performed unless growth velocity isabnormal relative to that expected for Turner’s syn-drome. Growth-promoting therapy with growth hor-mone alone or in combination with anabolic agentssuch as oxandrolone has now become standard ther-apy in many countries. Growth hormone therapyshould be initiated as soon as the height of a girlwith Turner’s syndrome drops below the 5th percen-tile of the normal female growth curve, which usu-ally occurs between two and five years of age. Initial-ly, growth hormone should be given at a dose of0.05 mg per kilogram of body weight per day. Ingirls 9 to 12 years of age, combination therapy withgrowth hormone and an anabolic steroid (e.g., ox-androlone at a dose of 0.0625 mg per kilogram perday) is recommended. Higher doses of oxandrolonemay result in virilization and may hasten skeletalmaturation. Therapy should be continued until thebone age exceeds 15 years and growth slows to lessthan 2 cm per year. Final heights well above 153 cm— a gain in predicted height of 10 cm — have beenachieved in many treated patients.

28,29

There is no ra-tionale for estrogen therapy as a growth-promotingagent. In fact, in patients in whom estrogen therapywas initiated at or before 12 years of age, the degreeof improvement in final height was significantly less(approximately 4 to 5 cm) than in those in whomtherapy was started after 14 years of age.

29

Poor out-comes are generally due to late initiation of growthhormone therapy and early estrogen therapy.

30,31

Growth hormone therapy does not change the di-ameter of the aortic root.

32

Other alternatives for growth promotion are or-thopedic leg-lengthening procedures. These proce-dures are still possible even after epiphyseal fusionhas occurred. Experience with this approach in Tur-ner’s syndrome is still limited.

Discussion with the patient and her family shouldhelp the physician decide when to initiate estrogentherapy to promote the development of secondarysex characteristics. I generally begin therapy whenthe girls are 14 to 15 years of age, with excellent ac-ceptance. Treatment should be with a natural estro-gen, always beginning with a low daily dose — forexample, 0.3 mg of conjugated estrogens (Prema-rin), 0.5 mg of micronized estradiol (Estrace), or

0.3 mg of esterified estrogens (Menest or Estratab).The dose should gradually be increased to 1.25 mgin the case of conjugated estrogens so that femini-zation progresses gradually. This seems to producebetter breast development than do maintenance dos-es of hormone-replacement therapy. Patients maythink that breast development is suboptimal even af-ter entirely appropriate estrogen-replacement thera-py. This may be due in part to poor breast anlage,widely spaced nipples, and the shield chest. Ade-quate estrogen is essential to complete adolescentbone maturation, and estrogen requirements in thesepatients are therefore greater than those for olderwomen treated with hormone-replacement therapy.Maintenance therapy should consist of 1.25 mg ofconjugated estrogens, 2 mg of micronized estradiol,or 1.25 mg of esterified estrogens per day. Progestintherapy, ideally medroxyprogesterone acetate (Pro-vera or Cycrin), is added for 12 days each month ei-ther when the first vaginal breakthrough bleeding oc-curs or in the second year of therapy.

5

Any patient who presents with virilization or gon-adoblastoma (a germ-cell tumor) should also bestudied for low-level Y-chromosome mosaicism. Thepresence of the

SRY

(sex-determining region on theY chromosome) gene product itself does not in-crease the risk of virilization or gonadoblastoma.Only if an entire Y chromosome, identifiable peri-centromeric fragments, or markers are found is therean increased risk of gonadoblastoma. In these casesprophylactic removal of the gonad is usually indicat-ed, even though it may look grossly like a streak.

8,33

Routine molecular searches for Y-derived DNA arenot useful, since the gene that increases the riskof gonadoblastoma has not yet been identified.

33

Hysterectomy is not recommended, since donor-ovum transplantation has resulted in pregnancy inwomen with Turner’s syndrome.

34

In patients withthe 45,X karyotype, the streak gonad need not beexplored, examined by biopsy, or removed.

If surgery becomes necessary in patients with Tur-ner’s syndrome, narrow endotracheal tubes are oftenrequired for the induction of anesthesia.

CARE OF ADULTS

Women with Turner’s syndrome should be fol-lowed by physicians knowledgeable about the natu-ral history of and the unique problems associatedwith the syndrome.

10,13,35

Key components of man-agement are estrogen-replacement therapy, preven-tion of bone deterioration by providing an adequatecalcium intake (1.2 g per day), and regular weight-bearing exercise.

Women with Turner’s syndrome require long-term estrogen and progestin replacement, with suf-ficient estrogen to prevent symptoms, signs, and long-term sequelae of hypoestrogenism. Only naturalestrogens are recommended, since synthetic estro-


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gens, such as ethinyl estradiol and diethylstilbestrol,are incompletely metabolized. The dose of estrogenin oral contraceptives is much too high and may leadto cardiopulmonary complications. Most women re-quire the daily equivalent of 0.625 to 1.25 mgof conjugated estrogens. Alternatives include 1 to2 mg of micronized estradiol, 0.625 to 1.25 mg ofesterified estrogens, or 0.625 to 1.25 mg of estropi-pate (Ortho-Est). Sometimes breakthrough bleed-ing is a problem at the lower dose, whereas at thehigher dose breast tenderness becomes troublesome.The transdermal estradiol patch (Estraderm; 50 to100

m

g), which is applied twice a week, is conven-ient and preferred by many adult patients. Adher-ence and skin irritation may occur with reservoirpatches; however, these problems seem to be lesscommon with the new transdermal estradiol matrixpatch (Climara), which is applied once a week.

Progestogen can be prescribed either cyclically orcontinuously in a combination regimen. For cyclicalprogestogen therapy, either 5 to 10 mg of medroxy-progesterone acetate or 1 to 2 mg of norethindrone(Aygestin) should be prescribed daily for 12 dayseach month. Norethindrone may be slightly moreandrogenic and lead to higher lipid levels. A varietyof cyclical combination packs are now available —for example, conjugated estrogens with medroxy-progesterone acetate (Prempro). Continuous com-bined therapy with estrogen and progestogen is anoption for women who do not wish to menstruate.Typical daily regimens consist of 0.625 to 1.25 mg ofconjugated estrogens with 2.5 to 5 mg of medroxy-progesterone acetate. Patients should be reassuredthat the spotting that commonly occurs in the firstfew months of continuous combined therapy is tran-sient. The regimen eventually leads to amenorrhea.Spotting can be minimized by initiating therapywith low-dose estrogen (e.g., 0.3 mg of conjugatedestrogens and 5 mg of medroxyprogesterone acetatedaily) and by gradually increasing the dose of con-jugated estrogens during the first eight weeks. Rec-ommendations for breast self-examination and mam-mography are the same as those for the generalpopulation.

With growth hormone therapy, bone acquisitionis adequate through mid-adolescence in Turner’ssyndrome.

36

The bone mineral density of the lumbarspine and hips correlates with the number of yearsof hormone-replacement therapy in adult patientsand should be measured every three to five years.

In many women with Turner’s syndrome the abil-ity to detect sounds at frequencies of 1.5 to 2 kHzdecreases with age. About 15 percent have substan-tial conductive or sensorineural hearing loss (orboth) that is due to premature aging.

37

Pigmented nevi have primarily cosmetic impor-

tance. They should be removed if they become irri-tated or are rubbed by clothing.

Scandinavian studies show that women with Tur-ner’s syndrome have a higher mortality rate than un-affected women. The mean age at death was 69years. About 50 percent died of cardiovascular dis-ease, and 20 percent of malignant disease.

19

FERTILITY AND FAMILY PLANNING

Currently, centers specializing in in vitro fertiliza-tion with sibling and anonymous egg donors reportpregnancy rates of 50 to 60 percent among womenwith Turner’s syndrome. The endometrial responseof such patients to adequate estrogen treatment isnot substantially different from that of women withsecondary ovarian failure. Before attempting to be-come pregnant, women with Turner’s syndromeshould undergo a complete medical evaluation, withparticular attention paid to cardiovascular and renalfunction, as recommended by the American FertilitySociety.

38

To avoid multiple pregnancies, no morethan two donated oocytes (in the case of gamete in-trafallopian-tube transfer) or embryos (in the case ofin vitro fertilization) should be transferred in eachattempt. The pregnancy should be monitored bya team of endocrinologists and perinatologists at atertiary care facility.

34

Twenty to 25 percent of girls with Turner’s syn-drome have spontaneous pubertal development(breast budding), and 2 to 5 percent have spontane-ous menses, due to residual ovarian function.Adrenarche (the development of pubic and axillaryhair) progresses normally. Those who enter pubertyspontaneously should receive advice about birth con-trol and genetic counseling. Rising follicle-stimulat-ing hormone levels indicate that the ovary is failing.Approximately 30 pregnancies among spontaneouslymenstruating patients with Turner’s syndrome havebeen reported.

39

Genetic counseling should stressthat any offspring have a 30 percent chance of con-genital anomalies, such as Down’s syndrome, spinabifida, and congenital heart disease.

PSYCHOLOGICAL AND EDUCATIONAL

ISSUES

Psychological assessment should be part of thetreatment plan for each child with Turner’s syndrome.Assessment of intellectual skills, learning skills, motorskills, and social maturity is recommended before en-rollment in preschool programs.

40,41

Intelligence isgenerally normal except in the rare patient with a tinyX-ring chromosome, who may present with severemental retardation.

42,43

If cognitive strengths andweaknesses are identified, preventive and interventivestrategies can be helpful. Patients with Turner’s syn-drome may have problems with visuospatial organiza-tion (e.g., difficulty driving; deficits in social cogni-tion; difficulty with nonverbal problem-solving taskssuch as mathematics problems; and psychomotor def-icits, such as clumsiness) and attention-deficit disor-


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der. The neurodevelopmental abnormality may resultfrom the X-chromosome monosomy or from hormo-nal deficiencies due to gonadal dysgenesis. It is com-patible with right cerebral dysfunction, and the defi-cits generally involve nonverbal skills. The adjuvantrole of pubertal estrogen replacement on cognitivefunction remains unclear.

44

As these young womenmake the transition to independent living, counselorsshould stress that their learning difficulties do not dis-appear with age.

12,13

Our best chances to improve not only the healthbut also the quality of life for all those with Turner’ssyndrome lie in the joint efforts of informed physicianscaring for these patients and the increasing number ofefficient and compassionate support groups.

I am indebted to Drs. Barbara Lippe, Ron Rosenfeld, TheodoreNagel, and Alan Shanske for helpful discussions.

REFERENCES

1.

Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology 1938;28:566-74.

2.

Cockwell A, MacKenzie M, Youings S, Jacobs P. A cytogenetic and mo-lecular study of a series of 45,X fetuses and their parents. J Med Genet 1991;28:152-5.

3.

Lippe B. Turner syndrome. Endocrinol Metab Clin North Am 1991;20:121-52.

4.

Mathur A, Stekol L, Schatz D, MacLaren NK, Scott ML, Lippe B. The parental origin of the single X chromosome in Turner syndrome: lack of correlation with parental age or clinical phenotype. Am J Hum Genet 1991;48:682-6.

5.

Saenger P. The current status of diagnosis and therapeutic intervention in Turner’s syndrome. J Clin Endocrinol Metab 1993;77:297-301.

6.

Ferguson-Smith MA. Karyotype-phenotype correlations in gonadal dys-genesis and their bearing on the pathogenesis of malformations. J Med Genet 1965;2:142-55.

7.

Simpson JL. Gonadal dysgenesis and abnormalities of the human sex chromosomes: current status of phenotypic-karyotypic correlations. Birth Defect Orig Artic Ser 1975;11(4):23-59.

8.

Binder G, Koch A, Wajs E, Ranke MB. Nested polymerase chain reac-tion study of 53 cases with Turner’s syndrome: is cytogenetically undetect-ed Y mosaicism common? J Clin Endocrinol Metab 1995;80:3532-6.

9.

Held KR, Kerber S, Kaminsky E, et al. Mosaicism in 45,X Turner syn-drome: does survival in early pregnancy depend on the presence of two sex chromosomes? Hum Genet 1992;88:288-94.

10.

Hall JG. The management of the adult with Turner syndrome: the nat-ural history of Turner syndrome. In: Rosenfeld RG, Grumbach MM, eds. Turner syndrome, New York: Marcel Dekker, 1990:495-506.

11.

Boyd PA, Anthony MY, Manning N, Rodriguez CL, Wellesley DG, Chamberlain P. Antenatal diagnosis of cystic hygroma or nuchal pad — report of 92 cases with follow up of survivors. Arch Dis Child Fetal Neo-natal Ed 1996;74:F38-F42.

12.

Lippe BM. Turner syndrome. In: Sperling M, ed. Pediatric endocri-nology. 3rd ed. Philadelphia: W.B. Saunders, 1996:387-421.

13.

Rosenfeld RG, Tesch LG, Rodriguez-Rigau LJ, et al. Recommenda-tions for diagnosis, treatment, and management of individuals with Turner syndrome. Endocrinologist 1994;4:351-8.

14.

Page DC. Mapping and targeting Turner genes. In: Albertsson-Wik-land K, Ranke MB, eds. Turner syndrome in a life span perspective: re-search and clinical aspects. Amsterdam: Elsevier, 1995:11. abstract.

15.

Schellhas HF. Malignant potential of the dysgenetic gonad. Obstet Gynecol 1974;44:298-309, 455-62.

16.

Ranke MB. An introduction to Turner’s syndrome. Oxford, England: Oxford Clinical Communications, 1989.

17.

Lin AE, Lippe BM, Geffner ME, et al. Aortic dilation, dissection and rupture in patients with Turner syndrome. J Pediatr 1986;109:820-6.

18.

Allen DB, Hendricks SA, Levy JM. Aortic dilation in Turner syn-drome. J Pediatr 1986;109:302-5.

19.

Naeraa RW, Gravholt CH, Hansen J, Nielsen J, Juul S. Mortality in Turner syndrome. In: Albertsson-Wikland K, Ranke MB, eds. Turner syn-drome in a life span perspective: research and clinical aspects. Amsterdam: Elsevier, 1995:323. abstract.

20.

Pai GS, Leach DC, Weiss L, Wolf C, Van Dyke DL. Thyroid abnor-malities in 20 children with Turner syndrome. J Pediatr 1977;91:267-9.

21.

Stratakis CA, Rennert OM. Turner syndrome: molecular and cytoge-netic dysmorphology, endocrine and other clinical manifestations and their management. Endocrinologist 1994;4:442-53.

22.

Caprio S, Tamborlane WV. In vivo study on insulin action in children with Turner syndrome. In: Albertsson-Wikland K, Ranke MB, eds. Turner syndrome in a life span perspective: research and clinical aspects. Amster-dam: Elsevier, 1995:275-83.

23.

Saenger P, Wesoly S, Wasserman EJ, Glickstein J, Issenberg H. Safety aspects of GH therapy in Turner syndrome (TS): no evidence for ventric-ular hypertrophy (VH) and normalization of insulin levels after discontin-uation of GH. Pediatr Res 1996;39:98A. abstract.

24.

Holl RW, Kunze D, Etzrodt H, Teller W, Heinze E. Turner syndrome: final height, glucose tolerance, bone density and psychosocial status in 25 adult patients. Eur J Pediatr 1996;153:11-6.

25.

Ross JL, Feuillan P, Long LM, Kowal K, Kurshner H, Cutler GB Jr. Lipid abnormalities in Turner syndrome. J Pediatr 1995;126:242-5.

26.

Ranke MB, Pfluger H, Rosendahl W, et al. Turner syndrome: sponta-neous growth in 150 cases and review of the literature. Eur J Pediatr 1983;141:81-8.

27.

Brook CGD, Murset G, Zachmann M, Prader A. Growth in children with 45,XO Turner’s syndrome. Arch Dis Child 1974;49:789-95.

28.

Nilsson KO, Albertsson-Wikland K, Alm J, et al. Improved final height in girls with Turner’s syndrome treated with growth hormone and oxan-drolone. J Clin Endocrinol Metab 1996;81:635-40.

29.

Rosenfeld RG, Attie KM, Frane J, et al. Growth hormone therapy of Turner syndrome: beneficial effect on final height. J Pediatr (in press).

30.

Taback SP, Collu R, Deal CL, et al. Does growth-hormone supplemen-tation affect adult height in Turner’s syndrome? Lancet 1996;348:25-7.

31.

Van den Broeck J, Massa GG, Attanasio A, et al. Final height after long-term growth hormone treatment in Turner syndrome. J Pediatr 1995;127:729-35.

32.

Saenger P, Wesoly S, Glickstein J, Appel P, Issenberg H. No evidence for ventricular hypertrophy in Turner syndrome after growth hormone therapy. In: Albertsson-Wikland, K, Ranke MB, eds. Turner syndrome in a life span perspective: research and clinical aspects. Amsterdam: Elsevier, 1995:259-62.

33. Tsuchiya K, Reijo R, Page DC, Disteche CM. Gonadoblastoma: mo-lecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet 1995;57:1400-7.34. Navot D, Laufer N, Kopolovic J, et al. Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med 1986;314:806-11.35. Sybert VP. The adult patient with Turner syndrome. In: Albertsson-Wikland K, Ranke MB, eds. Turner syndrome in a life span perspective: re-search and clinical aspects. Amsterdam: Elsevier, 1995:205-18.36. Neely EK, Marcus R, Rosenfeld RG, Bachrach LK. Turner syndrome adolescents receiving growth hormone are not osteopenic. J Clin Endo-crinol Metab 1993;76:861-6.37. Hultcrantz M, Sylven L, Borg E. Ear and hearing problems in 44 mid-dle-aged women with Turner’s syndrome. Hear Res 1994;76:127-32.38. American Fertility Society. Guidelines for oocyte donation. Fertil Ster-il 1993;59:Suppl 1:5S-7S.39. Kaneko N, Kawagoe S, Hiroi M. Turner’s syndrome — review of the literature with reference to a successful pregnancy outcome. Gynecol Ob-stet Invest 1990;29:81-7.40. Bender B, Puck M, Salbenblatt J, Robinson A. Cognitive development of unselected girls with complete and partial X monosomy. Pediatrics 1984;73:175-82.41. Rovet JF. Behavioral manifestations of Turner syndrome in children: a unique phenotype? In: Albertsson-Wikland K, Ranke MB, eds. Turner syn-drome in a life span perspective: research and clinical aspects. Amsterdam: Elsevier, 1995:285-95.42. Migeon BR, Luo S, Stasiowski BA, et al. Deficient transcription of XIST from tiny ring X chromosomes in females with severe phenotypes. Proc Natl Acad Sci U S A 1993;90:12025-9.43. Becker B, Kaminsky E, Held KR. XIST-expression in patients with an apparent 45,X status. Med Genet 1995;2:233.44. Ross JL, Reiss A, Freund L, Roeltgen D, Cutler GB Jr. Estrogen ef-fects on cognition and social function in Turner syndrome. In: Hibi I, Takano K, eds. Basic and clinical approach to Turner syndrome. Amster-dam: Excerpta Medica, 1993:215-23.


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Turner Syndrome