pediatric endocrinology || turner syndrome

109S. Radovick and M.H. MacGillivray (eds.), Pediatric Endocrinology: A Practical Clinical Guide, Second Edition, Contemporary Endocrinology, DOI 10.1007/978-1-60761-395-4_7, © Springer Science+Business Media New York 2013

M. L. Davenport , M.D. (*) Division of Pediatric Endocrinology , University of North Carolina , 3341 MBRB, CB #7039, 111 Mason Farm Road , Chapel Hill , NC 27599-7039 , USA e-mail: [email protected]

J. Ross , M.D. Division of Pediatric Endocrinology, Department of Pediatrics , Thomas Jefferson University , Philadelphia , PA , USA

P. F. Backeljauw , M.D. Department of Endocrinology , Cincinnati Children’s Hospital , Cincinnati , OH , USA

7

Abstract

Turner syndrome (TS) is one of the most common human chromosome anomalies. It occurs in approximately 1:2,000 female live births regardless of ethnic background. Girls with TS have an abnormal or missing X chro-mosome that causes short stature and may cause lymphedema, cardiac abnormalities, gonadal dysgenesis, dysmorphic features, nonverbal learn-ing disabilities, and other problems.

Keywords

Gonadal dysgenesis • Growth failure • Sex chromosome abnormalities • X chromosome • Growth hormone • Ovarian failure

Turner Syndrome

Marsha L. Davenport, Judith Ross, and Phillippe F. Backeljauw

110 M.L. Davenport et al.

Introduction

Turner syndrome (TS) is one of the most com-mon human chromosome anomalies. It occurs in approximately 1:2,000 female live births [ 1 ] regardless of ethnic background. Girls with TS have an abnormal or missing X chromosome that causes short stature and may cause lymphedema, cardiac abnormalities, gonadal dysgenesis, dys-morphic features, nonverbal learning disabilities, and other problems [ 2, 3 ] .

Pathogenesis

Approximately 50–60% of girls with TS are reported to have a 45,X karyotype. The loss of one X chromosome usually occurs as a result of a nondisjunction error during paternal meiosis since the single X chromosome in 60–80% of girls with TS is maternal in origin. Advanced maternal age may increase these errors [ 4 ] . These girls tend to have the most severe pheno-type and are frequently diagnosed as newborns [ 5, 6 ] . 20–30% have structural abnormalities of the X chromosome such as rings, isochromo-somes of the long arm, and partial deletions of the short arm. Thirty to 40% have mosaic pat-terns (karyotypes having two or more distinct cell types) involving the X chromosome such as 45,X/46,XX, 45,X/46,X,i(X), and 45,X/46,XY. This is thought to result from chromosome loss after fertilization [ 7 ]

In normal 46,XX females, either the maternal or paternal X chromosome is randomly inacti-vated in somatic cells during the late blastocyst stage and all descendants of that cell have the same inactive X. However, many genes escape inactivation [ 8 ] . In fact, about 15% of genes are expressed from both X chromosomes regularly and another 10% of the genes do so variably [ 9 ] . Many of the genes that remain active are located at the tip of the X chromosome and have homolo-gous genes on the Y chromosome. These “pseudo-autosomal” regions (PAR) are the only ones in

which the male X and Y chromosomes recom-bine during meiosis.

Loss of all or part of an X chromosome may lead to clinical abnormalities through the follow-ing mechanisms: (1) haploinsuf fi ciency of gene expression, (2) failure to express imprinted genes (genes expressed from a chromosome derived from one parent and not the other), and (3) unmasking of X-linked mutations.

Haploinsuf fi ciency of Gene Expression

Most of the TS phenotype appears to be caused by haploinsuf fi ciency of expression from genes that are normally expressed on both X chromosomes. To date, only one such gene has been identi fi ed with assurance—short-stature homeobox-con-taining (SHOX) gene [ 10 ] . SHOX belongs to a family of homeobox genes, transcriptional regu-lators that are key controllers of developmental processes [ 11 ] . Short stature, the most common physical fi nding in TS, is caused in large part by haploinsuf fi ciency of the short-stature homeobox-containing (SHOX) gene on the X chromosome expression in chondrocytes. Localization of SHOX expression during embryogenesis also correlates with many of the phenotypic abnormal-ities found in TS. For example, SHOX expression in the developing limbs (particularly at the elbow, knee, and wrist) correlates with common skeletal abnormalities such as cubitus valgus, genu val-gum, and Madelung wrist deformity [ 12 ] . Bone alterations including mesomelia (evidenced by reduced arm span) and tibial bowing suggest that SHOX haploin suf fi ciency particularly affects growth of the forearm and the lower leg. SHOX localization in the fi rst and second pharyngeal arches which form the maxillary shelves, mandi-ble, auricular ossicles, and the external auditory meatus [ 10 ] correlates with a narrow palate, ret-rognathism, prominent ears, recurrent otitis media, obstructive sleep apnea, and problems with suck-ing and articulation.

Brain natriuretic peptide (BNP) is the fi rst tran-scriptional target of SHOX to be discovered [ 13 ] .

1117 Turner Syndrome

BNP is primarily expressed by cardiac tissue and is best known for its natriuretic and vasodilatory properties. However, it is also expressed in other tissues, including the cartilage where it is neces-sary for normal chondrogenesis. Therefore, decreased expression of BNP secondary to SHOX haploinsuf fi ciency may contribute to the short stature of TS [ 14, 15 ] .

Haploinsuf fi ciency of pseudoautosomal gene(s) has been postulated to cause maldevelop-ment of the lymphatics. Absence or hypoplasia of peripheral lymphatics causes generalized lym-phedema, and a cystic hygroma, a collection of lymph in the mesenchyme of the posterior cervi-cal region, may result. It is estimated that >99% of 45,X conceptuses do not survive beyond 28 weeks gestation [ 16 ] and that most die in the fi rst trimester. It has been postulated that the prior cause of death is severe lymphatic obstruction that causes thoracic, pericardial and peritoneal effusions, and cardiac failure [ 16 ] . Others have hypothesized that myocardial hypoplasia is the primary defect causing lymphedema in utero [ 17 ] . In one study, a heart weight less than the third percentile was present in more than 90% of 117 mid-gestation fetuses with hydrops and pheno-typic TS, but uncommon in fetuses with hydrops of other etiologies. Most recently, it has been postulated that early death may be due to defects in placental differentiation [ 18 ] . A webbed neck, low upward sweeping hairline, and low-set prom-inent ears often result during fetal development from a resolving cystic hygroma. Lymphedema and nail dysplasia may result from the more peripheral process. Structural abnormalities of the heart and vascular system such as coarctation of the aorta and bicuspid aortic valve are much more common in girls with coexistent cystic hygroma or lymphedema [ 19 ] , suggesting that dilated lymphatics encroaching on cardiac out fl ow or disordered intramyocardial lymphatic development may be responsible for their devel-opment. Another possibility is that there is haploinsuf fi ciency of a gene common to both the lymphatic system and the vascular system, from which it arises.

Zinn et al. have hypothesized the existence of a pseudoautosomal gene that causes the neu-rocognitive problems in TS. They identi fi ed a small 8.3 Mb interval of the distal Xp (Xp22.33) which is suf fi cient for expression of the TS neu-rocognitive phenotype [ 20 ] . Haploinsuf fi ciency of two candidate genes, STS and NLGN4X, within the 8.3 Mb critical region are current can-didates for this TS-associated neurocognitive phenotype. Nonetheless, the neurocognitive de fi cits observed in TS are certainly multifacto-rial and related to interactions between genetic abnormalities, gonadal dysgenesis and resulting estrogen and androgen de fi ciencies, and other unknown determinants.

Both X chromosomes normally remain active in oocytes. Haploinsuf fi ciency of multiple genes on the X chromosome have been postulated to cause gonadal dysgenesis. Gonadal dysgenesis occurs in the vast majority of individuals with TS and is marked by massive apoptosis of germ cells in mid-gestation rather than a de fi ciency of germ cell formation [ 21 ] . Genes on both the X short arm (such as BMP15) and long arms (such as FMR1 and FMR2) are important for maintenance of ovarian function [ 22 ] and are likely to be involved. Although it was initially postulated that oocyte loss was caused by failure of normal mei-otic pairing, loss of germ cells occurs at the very early stages of meiotic prophase even before chromosome pairing is established [ 23 ] .

The genes involved in other problems associ-ated with TS such as metabolic disturbances, renal abnormalities, and autoimmune diseases have not been identi fi ed.

Imprinted Genes

The phenomenon of imprinting is related to dif-ferential effects of the parent of origin of the single X chromosome in 45,X TS on the pheno-type. The physical phenotype and response to growth hormone (GH) do not appear to be imprinted [ 24, 25 ] . However, Skuse and colleagues have suggested that an imprinted gene is involved in


social cognition [ 26 ] ; although these human studies have not been con fi rmed [ 27 ] , an imprinted gene, Xlr3b [ 28 ] , has been demonstrated to in fl uence cognition in an animal model of “Turner” 39,X mice [ 29 ] .

X-Linked Recessive Disorders

Girls with TS are at increased risk for many of the disorders that are more prevalent in males than females such as mental retardation and autism. The mechanism is thought to be related to expression of X-linked mutations on the single X chromosome in 45,X TS. For example, girls with TS have a risk of red-green color blindness (an X-linked disorder) similar to that of boys. Case reports of other X-linked recessive disor-ders in TS include hemophilia B and Duchenne muscular dystrophy.

Functional Disomy

The mechanism for this genetic alteration relates to overexpression of X chromosome genes. For exam-ple, individuals with small ring X chromosomes often have a severe phenotype that is not typical of TS and includes mental retardation [ 30, 31 ] . In these cases, the loss of the XIST gene, which is involved in X-inactivation, may allow for normally inactivated genes to be expressed, thereby causing functional disomy.

Clinical Presentation

Introduction

Clinical presentations vary widely and are respon-sible in part for the broad range of ages at which the diagnosis of TS is made [ 32, 33 ] . For the majority of those diagnosed in prenatal life, the diagnosis is based upon an abnormal karyotype obtained for advanced maternal age, an abnormal serum screen, and/or ultrasound evidence of a cystic hygroma, hydrops fetalis, or cardiac defects. Girls diagnosed during infancy almost

invariably have lymphedema with or without a webbed neck and other dysmorphic features [ 34 ] . In contrast, girls lacking these classic features are often not diagnosed until late childhood or ado-lescence when they are investigated for short stat-ure and/or delayed puberty or as adults when they develop premature ovarian failure.

Lymphedema

Lymphedema is common in TS and begins in utero. Fetuses with 45X TS may present with increased nuchal thickness alone on ultrasound or more generalized lymphedema [ 35 ] . Mortality is high in this population. Virtually all girls diag-nosed during infancy have lymphedema second-ary to maldevelopment of the lymphatic system. Lymphedema differs from that seen in congestive heart failure, in that it is most prominent over the metatarsals and metacarpals, with a crease across the wrist and ankle joints. Lymphedema usually improves over the fi rst few months of life but may progress with puberty or hormonal therapy. Older children and adults initially without clini-cally apparent lymphedema have been demon-strated to have hypoplastic super fi cial lymphatic vessels, explaining the fi rst appearance of lym-phedema in some individuals after infancy [ 36 ] .

Dysmorphic Features

Most girls with TS have one or more dysmorphic features caused by lymphedema and/or skeletal abnormalities. However, the phenotype varies greatly and some girls with TS will have no or very subtle dysmorphic features. Of those diag-nosed, more than half have a high-arched palate and/or retrognathia [ 34 ] . Ears are often low-set and posteriorly rotated with poor helix formation. The hairline tends to be low and upward sweep-ing, and in the minority, a webbed neck repre-sents redundant skin that once stretched over a cystic hygroma. Ptosis, epicanthal folds, and downward-slanting palpebral fi ssures are com-mon eye fi ndings. Some degree of nail dysplasia is found in three-quarters. Nails tend to be small,


narrow, and inserted at an acute angle. Cubitus valgus and short 4th metacarpals are also com-mon. About one-quarter of patients have pectus excavatum and a smaller number have hypoplas-tic breast tissue and inverted nipples [ 32 ] .

Cardiovascular Abnormalities

Cardiovascular abnormalities are recognized as the most clinically signi fi cant anomalies of TS. Some individuals with TS are diagnosed in the neonatal period or infancy secondary to cardiac lesions such as coarctation of the aorta or hyp-oplastic left heart. Aortic obstruction from a coarctation, which is usually periductal, may be minimal until the ductus arteriosus closes. Congestive heart failure can then develop rapidly. In older children, signs of coarctation generally include decreased pulse and blood pressure in the legs compared with the arms, and a systolic mur-mur radiating to the back.

It has long been recognized that individuals with TS are at increased risk for left-sided car-diac abnormalities, especially bicuspid aortic valve and coarctation of the aorta [ 37 ] . A study of 99 Danish women with TS (mean age = 37 ± 10 years) using both MRI and echocardiography revealed that common cardiovascular fi ndings are an elongated transverse aortic arch (47%), bicuspid aortic valve (27%), dilation of the ascending aorta (20%), aortic coarctation (13%), aortic arch hypoplasia (2%), and aortic aneu-rysm (2%) [ 38 ] . The bicuspid aortic valve was functionally abnormal in many patients, causing aortic stenosis in 16% and regurgitation in 18%. This study and others have demonstrated that the arterial pathology is not limited to the aorta, but also affects other intrathoracic arteries [ 39 ] . For example, the right subclavian artery was aberrant in 8% and dilations of the innominate, left carotid, and left subclavian arteries were found in 22, 25, and 58% of the subjects, respec-tively. Another common structural cardiac abnormality is partial anomalous pulmonary venous return (PAPVR). In 1998, Mazzanti et al. detected PAPVR in 2.9% of TS patients, giving it the highest relative risk compared to heart

defects in the general population [ 40 ] . Using current MRI techniques, that percentage appears to be much higher. Kim et al. studied 51 patients with TS (median age, 18.4 years; range, 6–36 years) and detected PAPVR in 15.7% of that population [ 39 ] . Patients with PAPVR had increased right heart mass ( p < 0.05), increased ratio of main pulmonary artery to aortic valve blood fl ow ( p = 0.0014), and increased right ven-tricular volume ( p < 0.05). In one patient, sur-gery was required.

Aortic dissection is estimated to occur in 1.4% of the TS population [ 41 ] . This devastating com-plication of TS usually occurs in adulthood, but has occurred as young as 7 years. Although most cases have been associated with coarctation of the aorta, bicuspid aortic valve, hypertension, and/or aortic root dilatation, 10% did not have any of these risk factors [ 42– 44 ] . Nonstructural abnormalities such as hypertension, conduction defects, or mitral valve prolapse are also more common than in the general population, occur-ring in approximately 16% [ 37 ] . In a study of 62 TS patients, age 5.4–22.4 years, more than 30% were found to be mildly hypertensive and over 50% had an abnormal diurnal blood pressure pro fi le. The investigators were unable to correlate the presence of renal or cardiac abnormalities with hypertension. This may indicate the pres-ence of an underlying vasculopathy inherent to the diagnosis of TS [ 45 ] .

Short Stature and Skeletal Abnormalities

Short stature is the single most common physical abnormality and affects virtually all individuals with TS. Untreated individuals achieve an aver-age adult stature 20 cm shorter than that of their peers, which results in a height about 3 standard deviations (SDs) below the mean [ 46, 47 ] . This growth de fi cit is similar from country to country, and the individual scatter around the mean height is not signi fi cantly different from that of the normal population [ 48 ] .

Growth failure is due to (a) mild to moderate growth retardation in utero, (b) slow growth


during infancy, (c) delayed onset of the childhood component of growth, (d) slow growth during childhood, and (e) failure to experience a puber-tal growth spurt [ 49– 51 ] . Girls with TS average −0.5 to −1.2 SDs below the mean for birth weight. In one longitudinal study, mean height SDS fell from −0.5 at birth to −1.5 at age 1 year and −1.8 at age 1.5 years [ 50 ] . Poor growth in the fi rst year of life may be exacerbated in some by poor feed-ing due to oro-motor dysfunction and inadequate weight gain [ 52 ] . Problems that may contribute to poor feeding in TS are low orofacial tone, poor jaw strength, a low tongue position, an abnor-mally narrow palate, and broad lateral palatal ridges (the latter two being common in disorders in which there is a lack of tongue thrust into the palatal vault) [ 53 ] . Velopharyngeal and lower gastroesophageal tract dysfunction may also con-tribute to poor breast and bottle-feeding. This can be followed by re fl ux, gagging, and regurgitation of solids when they are introduced.

Growth during childhood is slow, there is a diminished pubertal growth spurt, and growth is often prolonged into the early twenties. Individuals with TS tend to appear stocky since they have a greater relative reduction in body height than in body width, and are often over-weight. The increased relative width to height of the thorax accounts for the illusion of widely spaced nipples. Hands and feet are also rela-tively large [ 54 ] . Developmental abnormalities of individual bones are responsible for many common fi ndings such as short neck, cubitus valgus, genu valgum, and short 4th metacar-pals. The short neck is due in many cases to hypoplasia of one or more cervical vertebrae. Cubitus valgus occurs in almost 50% of patients and is caused by developmental abnormalities of the radial head. About 35–40% of patients have a short or borderline short 4th metacarpal and many have abnormally acute angulation of their proximal row of carpals. A short 4th meta-carpal causes a depression instead of a knuckle when the fi st is clenched.

Scoliosis and kyphosis are common. In a 2002 study of 25 patients between the ages of 5 years and 18 years, 20% were found to have scoliosis (lateral curvature >10°), and 40% were found to

have excessive kyphosis (anterior-posterior cur-vature >40°) [ 55 ] . The youngest children with kyphosis and scoliosis were ages 5.9 and 9.8 years, respectively. The incidences of both skel-etal abnormalities increased with age.

A delayed bone age is found in more than 85% of patients with TS, but the degree of delay is not uniform among bones. This fi nding likely re fl ects the estrogen de fi ciency that is present in many patients early in childhood. The delay is greatest in the phalangeal bones, intermediate in the car-pals, and least in the metacarpals, radius, and ulna [ 56 ] .

Osteoporosis and fractures are more frequent among women with TS [ 57 ] . Many girls have radiographic osteopenia and a coarse trabecular bone pattern, even in the prepubertal years. Although interpretation of most studies of bone mineral density (BMD) in TS is dif fi cult due to reporting of areal rather than volumetric BMD, some conclusions can be made. Prepubertal girls with TS have decreased levels of markers of bone formation, consistent with a low bone turnover state and decreased bone deposition. There is a de fi cit in radial BMD, a largely cortical site [ 58 ] . Osteopenia at predominantly trabecular sites develops during adolescence, progresses in adult-hood, and is associated with increased bone turn-over. The pathogenesis of the demineralization is unclear, but is most likely an intrinsic bone defect that is exacerbated by suboptimal replace-ment of gonadal estrogen de fi ciency [ 59 ] Rubin, 1998 1427.

Orthodontic Problems

Individuals with TS have a posterior cranial base that is short and positioned at a shallow angle [ 60 ] . Because the mandible is pushed posteriorly and is relatively more hypoplastic than the rest of the face, retrognathia is common. There is an increased incidence of anterior open bite and lateral crossbite due to a narrow maxillary arch [ 61 ] . The palate is high-arched with unusual palatal bulges on the medial aspect of the poste-rior alveolar ridges. Girls with TS tend to have advanced dental age rather than the delayed


dental age expected for bone age-delayed indi-viduals [ 62 ] . Tooth morphology is often abnor-mal: tooth crown size is reduced [ 63, 64 ] and roots tend to be short, placing these girls at an increased risk for root resorption [ 65 ] . Often, there is a need for orthodontic correction of these dental problems.

Hearing Loss

Ear and hearing disorders are very common prob-lems among girls and women with TS. The majority of patients suffer from conductive hear-ing losses secondary to recurrent otitis media during infancy and childhood. The high incidence of otitis media in this population (60–80%) [ 66, 67 ] seems to result from an abnormal ana-tomical relationship between the middle ear and the Eustachian tube. A short, more horizontally oriented Eustachian tube in TS girls results in poor drainage and ventilation of the middle ear space and predisposes more nasopharyngeal microorganisms to reach the middle ear. Many girls require tympanostomy tube placement and a signi fi cant number develop complications such as mastoiditis and cholesteatoma. In a study in which 56 girls with TS between the ages of 4 and 15 years were examined, 57% had eardrum pathology, such as effusion, myringosclerosis, atrophic scars, retraction pockets, and perfora-tions. A conductive hearing loss (air-bone gap >10 dB HL) was found in 43%. In addition, a mid-frequency sensorineural hearing loss (SNHL) between 500 and 2,000 Hz was present in 58% of the girls, four of whom required hearing aids [ 67 ] . The presence of such a mid-frequency dip appears to be a strong predictor for future rapid hearing decline with resulting social conse-quences [ 68 ] . SNHL has been reported as early as age 5 and appears to be progressive [ 69 ] . By their mid-forties, more than 90% of women with TS have a hearing loss >20 dB, with greater than 25% requiring hearing aids. Audiometry has revealed high-frequency (above that used for speech) SNHL in almost all individuals with TS studied (ages 6–38 years), suggesting “premature aging” of the cochlea [ 70 ] .

Strabismus and Other Eye Problems

Ocular morbidity in TS is common. Strabismus is present in about one-third of the patients with TS, a frequency about ten times greater than that in the general population, and usually develops between 6 months and 7 years [ 71 ] . In a large report, 19% were reported to have amblyopia (loss of vision), most likely as a result of uncor-rected strabismus. Esotropia (20%) was more common than exotropia (9%), and nearsighted-ness (40%) more common than farsightedness (13%) [ 72 ] . Anterior chamber abnormalities have also been reported to be more common in girls with TS and may present as congenital glaucoma [ 73 ] . Eight to 10% of the patients are also red-green color blind, an X-linked recessive trait, related to an X-linked mutation on the single X chromosome in 45,X TS [ 72 ] .

Renal Abnormalities

Renal malformations occur in approximately 35–40% of individuals with TS [ 74, 75 ] . Of those with malformations, about half have abnormali-ties of the collecting system and half have posi-tional abnormalities, the most common being horseshoe kidney. Horseshoe kidney is more com-monly associated with a 45,X karyotype, while collecting system malformations are more fre-quently associated with mosaic/structural X chro-mosome abnormalities [ 74 ] . Developmental abnormalities of the kidneys and collecting sys-tem predispose to urinary tract infections and pos-sibly hypertension [ 75 ] . Vascular supply anomalies are observed with higher frequency [ 75 ] .

Gastrointestinal Disorders

Elevated liver enzymes are often observed in patients with TS, who are usually asymptomatic. In a study of 218 adults with TS (mean age = 33 years), 36% had one or more liver enzyme levels higher than the reference level, the most preva-lent being gamma-glutamate transferase (GGT) [ 76 ] . After 5 years of follow-up, that percentage


had risen to 59%. In a study of 27 individuals with TS who were biopsied for persistently elevated liver enzymes, 10 had marked architectural changes, including cirrhosis, nodular regenerative hyperplasia, and focal nodular hyperplasia, postu-lated to be caused by congenital abnormalities of the blood vessels. The remaining 17 individuals had nonalcoholic liver disease with steatosis, ste-atohepatitis, and steato fi brosis, most likely related to increased adiposity [ 77 ] . An autoimmune patho-genesis may be also be operative in some cases since many have elevated antinuclear and/or anti-smooth muscle antibodies [ 78 ] .

Celiac disease, an immune-mediated disease of the small intestines triggered by the ingestion of gluten-containing grains, occurs in about 6% of those with TS, a prevalence nearly ten times that in the general population. Although it can cause bloating, abdominal pain, and malabsorption, it may also present with growth failure alone [ 79 ] . In fl ammatory bowel disease occurs in about 3% of those with TS [ 80 ] , with Crohn’s disease being at least as common as ulcerative colitis. Gastric and intestinal hemangiomas, telangiectasias, and phlebectasias are rare, but can produce massive gastrointestinal bleeding when present [ 81, 82 ] .

Dermatological Problems

Individuals with TS often have nail dysplasia. Fingernails and toenails are small, hyperconcave, and deeply implanted secondary to the presence of lymphedema in utero. Hemangiomas are more common than in the general population and may be related to lymphatic abnormalities. They usu-ally enlarge during the fi rst year of life and then undergo slow regression. TS patients have an increased number of benign appearing melano-cytic nevi (50%) that increase in size and number throughout childhood and particularly during adolescence [ 83 ] . Although there has been a theo-retical concern for the effect of GH therapy on the growth of nevi, studies have failed to demonstrate a pathologic impact of GH therapy on the number or density of melanocytic nevi [ 84, 85 ] . Despite the increased numbers of nevi, the risk of melanoma

in this population appears to be markedly reduced [ 86 ] .

Pilomatrixomas, generally benign cutaneous tumors of the hair matrix cells, appear to be more common [ 87 ] . Other common skin problems include atopic dermatitis, seborrheic dermatitis, and keratosis pilaris [ 88 ] . Patients with TS have been thought to be at increased risk of keloid for-mation (hypertrophic scarring); however, this may simply re fl ect an increased frequency of sur-geries involving the neck or upper chest, areas that are predisposed to hypertrophic scar and keloid formation. In one report, 5 of 92 patients with TS undergoing surgery developed keloids or hypertrophic scars [ 89 ] .

Hypothyroidism and Other Autoimmune Disorders

Autoantibodies and autoimmune diseases are more common in individuals with TS than in the general population [ 90 ] . The most common auto-immune disorders in TS are Hashimoto’s thy-roiditis, celiac disease, and in fl ammatory bowel disease (IBD) [ 91 ] . In a study that evaluated 71 children with TS under 20 years of age (mean age of 11.4 years), 15.5% were hypothyroid, 17% were positive for thyroid peroxidase and/or thyroglobulin antibodies, and 33.8% had thyro-megaly [ 92 ] . The frequency of thyroid abnor-malities increased with age, with no abnormalities observed before 4 years of age. In one study, 18% of TS patients had celiac autoantibodies, and 26% of the antibody-positive patients had celiac disease (a prevalence of 4.5%) [ 93 ] . A survey of 15,000 JRA patients from pediatric rheumatology centers in the USA, Europe, and Canada revealed 18 girls with a diagnosis of TS. This represents a prevalence at least six times greater than would be expected if the two condi-tions were only randomly associated. Patients had either polyarticular disease with early-onset and progressive disabilities or oligoarticular arthritis with a benign course [ 94 ] . TS patients may also be at increased risk for type I diabetes mellitus [ 57 ] .


Obesity, Lipids, and Glucose Homeostasis

Individuals with TS have a modestly decreased life span. In a study of the Danish TS population, approximately 50% of all deaths were caused by cardiovascular disease, and these occurred 6–13 years earlier than expected [ 57 ] . They were at increased risk for abnormalities constituting “the metabolic syndrome” including hypertension, dyslipidemia, type 2 diabetes, obesity, hyperinsu-linemia, and hyperuricemia [ 57 ] . Body mass index (BMI) SDS begins to increase around the age of 9 years [ 95 ] and may exacerbate a ten-dency toward type 2 diabetes [ 96 ] . In one study of adult women (mean age = 42.5 years), visceral fat mass was increased, while trunk lean body mass (LBM), appendicular LBM, and skeletal muscle mass were decreased when compared to age-matched controls. VO2 max and physical activity were also signi fi cantly lower in TS. Interestingly, however, studies in adults have pointed toward b (beta)-cell failure rather than insulin resistance as the primary defect in glucose homeostasis [ 97, 98 ] .

Gonadal Failure

Although the majority of girls with TS have gonadal failure and pubertal delay, some girls with TS enter puberty at a typical age. In an Italian retrospective multicenter study of 522 patients older than 12 years with TS, 32% of the girls with cell lines containing more than one X and 14% of nonmosaic, 45,X patients had spon-taneous breast development [ 99 ] . Sixteen per-cent had spontaneous menarche that occurred at a mean age of 13.2 ± 1.5 years and a similar bone age. Although some developed secondary amenorrhea, others had regular menses for many years. Therefore, the diagnosis of TS should still be considered in girls with short stature, even if they are menstruating and should be con-sidered in the differential diagnosis for women experiencing premature ovarian failure [ 100 ] . Spontaneous, unassisted pregnancy occurred in

three patients (3.6%), of whom two had chro-mosomal abnormalities and malformations. Other studies have demonstrated a high risk of spontaneous abortion (25–40%), chromosomal abnormalities in the offspring (20%), and peri-natal death (7%) [ 101 ] . When unassisted preg-nancies occur, they are generally in patients with structural anomalies of the X chromosomes in which the Xq13-q26 region is spared or in patients with a mosaic karyotype containing a 46,XX cell line.

There is a broad range of gonadal dysfunction in TS, making it dif fi cult to accurately predict who will enter puberty spontaneously and who will not. Traditionally, follicle-stimulating hor-mone (FSH) levels have been used. FSH follows a biphasic pattern in normal girls, with increased levels in infancy, decreased levels in childhood, and increased levels early in puberty. This pattern is exaggerated in girls with ovarian dysfunction. They have increased levels during the fi rst 2 years of life which decline gradually to reach low lev-els (often indistinguishable from those in normal girls) between 5 and 10 years of age and rise again to castrate levels around the usual age for puberty [ 102, 103 ] . In healthy girls, serum inhibin B and estradiol levels follow a similar biphasic age pattern with high levels at 3 months of age and low levels during the prepubertal period [ 104, 105 ] with levels rising at puberty [ 106, 107 ] . In a longitudinal study of 70 TS girls with or without spontaneous puberty, Hagen et al. predicted ovarian failure in 20/20 patients with undetectable inhibin B on repeated measures, while 9/10 with detectable inhibin B entered puberty spontaneously [ 108 ] .

Fertility is an area of great concern for women with TS [ 109 ] . Traditionally, assisted pregnan-cies using donor eggs have been the principal means by which women with TS achieved preg-nancy. Recently, cryopreservation of ovarian tis-sue or oocytes from the TS individual has been offered in experimental protocols [ 110 ] .

Girls with karyotypes containing Y material, such as 45,X/46,XY, are at increased risk for developing gonadoblastomas [ 111 ] . A gonado-blastoma is a gonadal tumor in which normal


components of the ovary, such as oogonia, granu-losa-Sertoli-type cells, and thecal-Leydig-type cells, are present in varying amounts within circumscribed nests. The latter may produce sex steroids, which may cause virilization or occa-sionally feminization, depending on the predomi-nant sex steroid produced. Although the pure gonadoblastoma is not a malignant tumor, the germ cell component may invade the ovarian stroma, producing a germinoma which is potentially malig-nant [ 112 ] . Occasionally a more malignant tumor, such as embryonal carcinoma or choriocarcinoma, may develop in a gonadoblastoma.

Using standard cytogenetic techniques, approximately 5% of patients with TS have Y chromosomal materials, and of those, gonado-blastoma has been thought to develop in 15–25%. Fluorescence in situ hybridization (FISH) studies using Y-speci fi c DNA probes have demonstrated that the percentage of girls with TS having Y chromosome material is higher; however, the occurrence of gonadoblastoma in this population seems to be low [ 113 ] . Therefore, cytogenetic screening for Y chromosome material on periph-eral karyotype is the current screen for increased risk for gonadoblastoma.

Learning Disabilities

Individuals with TS are at increased risk for speci fi c neurocognitive de fi cits and problems in psychosocial functioning. These problems include de fi cits in visual-spatial/perceptual abili-ties, nonverbal memory function, motor function, executive function, attention, and social skills [ 114, 115 ] . Abnormalities in cognitive function in TS are accompanied by structural differences in older children and adult brains. For example, parietal lobes, parietal-occipital areas, and pre-frontal areas, areas known to be associated with visuospatial processing, are small when com-pared with controls [ 116 ] .

Although their distribution of verbal IQs is relatively normal, lower performance, and full-scale IQs are more prevalent in this population due to lower scores on performance than verbal

tasks. For example, results of Wechsler IQ tests in 226 women with TS revealed a 12-point dis-crepancy between mean verbal and performance IQs (101 versus 89). This verbal-performance IQ discrepancy, consistent with a nonverbal subtype of learning disability, has not been well corre-lated to age or karyotype [ 117 ] .

The neurocognitive de fi cits put them at a higher risk for educational problems. Rovet found that 48.2% of girls with TS versus only 20% of control subjects were recognized by their parents as having problems at school [ 118 ] . Mathematics is particu-larly problematic, and girls with TS score signi fi cantly lower than control subjects in overall arithmetic achievement. In Rovet’s study, girls with TS obtained a mean global mathematics score 2.1 grades below their current placement level [ 118 ] . In a more recent study, a higher percentage of girls with TS made operation and alignment errors on a mathematics calculations test than did controls or another group with mathematic dif fi culties (fragile X syndrome) [ 119 ] . Although math is a consistent problem for girls with TS, hyperactivity, inatten-tion, distractibility, and slowness may impair achievement in all educational disciplines. Many girls with TS repeat grades because of lagging cog-nitive and psychosocial skills.

Although individuals with TS do not appear to be at an overall higher risk for psychiatric prob-lems, there is some evidence to suggest that obsessive-compulsive tendencies [ 120 ] and autism are more prevalent [ 121 ] .

Tumors and Miscellaneous

Besides gonadoblastoma, the risks for most can-cers do not appear to be elevated in TS. Exceptions may include colon cancer [ 57 ] , neuroblastoma [ 122 ] , and pilomatrixomas [ 87 ] .

Diagnostic Guidelines

The diagnosis of TS requires that the individual have both phenotypic features and genetic fea-tures of TS. That is, they must have one or more


clinical features such as short stature as well as deletion of the distal end of Xp (Xp11.2-p22) where the majority of genes associated with TS features appear to reside. Recent guidelines established by the American College of Medical Genetics (ACMG) [ 123 ] suggest criteria for diag-noses in the prenatal versus postnatal periods and investigation of Y chromosome mosaicism as outlined below.

Most prenatal diagnoses of TS are made when karyotypes on amniotic fl uid (less commonly by chorionic villous biopsy) are obtained for advanced maternal age, an abnormal maternal serum screen or abnormal fetal ultrasound. Although serum screens in pregnancy have been designed to pick up diagnoses of trisomies 13, 18, and 21, elevated levels of human chorionic gonadotropin (hCG) and inhibin and slightly low levels of alpha fetoprotein (AFP) and unconju-gated estriol are associated with an increased risk of TS. Other fetuses with TS have karyotypes obtained for abnormalities such as increased nuchal thickness, cystic hygroma, or hypoplastic left heart. For fetuses diagnosed “incidentally,” most have a mosaic karyotype. Although those with 45,X/46,XX mosaicism can have a severe phenotype, most will be phenotypically normal at birth. All girls diagnosed prenatally should have a repeat karyotype performed after birth.

For those children diagnosed postnatally with a 45,X karyotype, at least 30 cells should be counted to explore for the possibility of mosa-icism. This will allow for identi fi cation of at least 10% mosaicism with 95% con fi dence. If the 30-cell analysis fails to reveal mosaicism, fl uorescent in situ hybridization (FISH) with X and Y centromere probes on at least 200 cells should be used to look further. FISH studies using speci fi c DNA probes to the Y chromosome should also be performed when a small marker chromosome (a piece of chromosome material not otherwise identi fi ed) is identi fi ed to deter-mine if Y-chromosome material is present. Polymerase chain reaction (PCR) has been used to detect Y-chromosome material, but the false positive rate is high. Therefore, if PCR is used, the fi nding should be con fi rmed with FISH.

Genomic copy number microarray studies can be used to characterize genetic abnormalities but should not be used as a frontline screen for TS since low levels of mosaicism may be missed. In most cases, cytogenetic testing on blood lympho-cytes is suf fi cient, but if TS cannot be con fi rmed on such peripheral blood karyotype testing and the TS is still being considered based on the clini-cal features, then cytogenetic testing of skin fi broblasts should be considered.

A delay in diagnosis of TS is often the greatest obstacle to health care for girls with TS. In one study, the delay in diagnosis for those diagnosed in childhood or adolescence averaged more than 7 years (based on the presence of dysmorphic features and/or short stature). At the time of diag-nosis, patients averaged 2.9 SD below the mean in height and had fallen below the 5th percentile for height an average of 5.3 years earlier [ 34 ] .

In many girls with TS who have a delayed diagnosis, the TS phenotype is either absent or mild. This was the case when a systematic search for TS in 375 female children referred to a center with growth retardation (less than −2 SD) and/or decreased height velocity identi fi ed 18 cases of TS, an incidence of 4.8% [ 124 ] . To facilitate timely diagnoses, Savendahl and Davenport have

Table 7.1 Guidelines: Screening girls for Turner syndrome

Karyotype any girl with one or more of the following a Unexplained growth failure Webbed neck Peripheral lymphedema Coarctation of the aorta Delayed puberty

or Any girl with at least two or more of the following

Nail dysplasia High arched palate Short 4th metacarpal Strabismus

Adapted from Savendahl L, Davenport ML. Delayed diagnoses of Turner’s syndrome: proposed guidelines for change. J Pediatr. 2000;137(4):458, with permission from Elsevier a Other suggestive features include a nonverbal learning disability, epicanthal folds, ptosis, cubitus valgus, multi-ple nevi, renal malformations, bicuspid aortic valve, recurrent otitis media, and need for glasses


suggested guidelines for screening girls for TS [ 34 ] . Modi fi ed guidelines are presented in Table 7.1 .

Therapy

Introduction

The patient should be referred to a physician expert in the care of individuals with TS if at all possible. Primary care physicians and involved subspecialists should be aware of published con-sensus guidelines for their health supervision, most recently outlined by Carolyn A. Bondy for the Turner Syndrome Consensus Study Group in 2007 [ 2 ] . Health-care checklists can serve as reminders for routine evaluations. An example of one such checklist recently published by one of the authors [ 125 ] is presented in Table 7.2 .

Lymphedema

Lymphedema usually improves over the fi rst few months of life. However, it may be severe or recur with puberty or hormone replacement therapy [ 126 ] . Combined decongestive therapy (CDT) which uses manual lymphatic drainage, bandag-ing, exercises, skin care, and low stretch support garments is an effective and noninvasive treat-ment [ 127, 128 ] .

Dysmorphic Features

Plastic surgery may be recommended for some individuals with severe webbed neck and/or ear anomalies. With all surgeries, the risk of keloid formation must be considered [ 129 ] .

Cardiovascular Abnormalities

At diagnosis, all patients should have an imaging study done: echocardiography for young children and echocardiography plus cardiac MRI for ado-

lescents and adults. Girls who had imaging stud-ies performed when in utero should be reimaged after birth. Patients who underwent echocardiog-raphy only during childhood should be reimaged with a cardiac MRI when they can do so without sedation. An electrocardiogram should be done along with the imaging studies to evaluate for conduction/repolarization defects/arrhythmia. A pediatric cardiologist should direct the care of any patient in whom a cardiovascular malfor-mation is detected. If appropriate, prophylactic antibiotics should be prescribed to prevent sub-acute bacterial endocarditis. Even in those with a normal baseline cardiovascular structure, a cardi-ology evaluation and imaging procedure should be repeated during adolescence and every 3–5 years thereafter to rule out dilation of the aortic root, a process that can be advanced even in the absence of clinical fi ndings or other cardiovascu-lar pathology. Patients should be encouraged to carry a medical alert card and demand evaluation for aortic dissection if they experience the sudden onset of chest pain. Blood pressure should be closely monitored. Hypertension is common, often worsens with age and obesity, and is the most easily modi fi able risk for circulatory dis-ease in this high-risk population. The risk for aor-tic dissection or rupture during pregnancy may be 2% or higher [ 130 ] . Therefore, TS is a relative—and sometimes absolute—contraindication for pregnancy. For example, some have recom-mended that coarctation of the aorta and/or BAV be absolute contraindications for pregnancy. Any woman considering pregnancy should consult with a cardiologist and be monitored carefully throughout the pregnancy.

Short Stature and Skeletal Abnormalities

Introduction Once the diagnosis of TS is made, growth should be assessed regularly using a TS-speci fi c growth chart. Use of a TS-speci fi c growth chart will facilitate detection of concurrent problems that affect growth, such as hypothyroidism, and aid in


Tab

le 7

.2

Hea

lth-c

are

chec

klis

t for

indi

vidu

als

with

Tur

ner

synd

rom

e a

Tim

ing

of te

sts

Prob

lem

s Sc

reen

ing

test

/ref

erra

l A

t Dx

Q v

isit

Q y

ear

Oth

er

Hip

dis

loca

tion

Feed

ing

prob

lem

s St

rabi

smus

O

titis

med

ia

Gro

wth

fai

lure

Pu

bert

al d

elay

Sc

olio

sis/

kyph

osis

D

yspl

astic

nev

i Ly

mph

edem

a H

yper

tens

ion

Phys

ical

exa

m (

incl

udin

g he

ight

, w

eigh

t, B

P, a

nd c

alcu

latio

n of

BM

I)

X

X

X

X

X

X

X

X

X

X

In in

fanc

y In

infa

ncy

4 m

o–5

yrs

All

child

hood

A

ll ch

ildho

od

Ado

lesc

ence

W

hile

gro

win

g Sc

hool

-age

on

Lif

elon

g L

ifel

ong

Nee

ds in

form

atio

n/su

ppor

t R

efer

to T

SS, o

ther

sup

port

gro

ups

X

Stru

ctur

al r

enal

abn

orm

aliti

es

Ren

al u

ltras

ound

X

C

ardi

ac a

bnor

mal

ity b

Exa

m b

y ca

rdio

logi

st; E

KG

; MR

I/ec

ho

X

Q 5

–10

yrs

Con

duct

ive

and

SNH

L

Form

al a

udio

logy

exa

m

X

Q 1

–3 y

rs

Gon

adal

dys

func

tion

FSH

, LH

X

A

t age

s 0.

5–3

and

10–1

2 St

rabi

smus

and

hyp

erop

ia

Form

al e

ye e

xam

X

A

t 1–1

.5 y

ears

C

elia

c di

seas

e Se

rum

IgA

, TT

G I

gA A

b X

Q

2–5

yrs

[be

gin

~age

4]

Aut

oim

mun

e th

yroi

d di

seas

e T

4, T

SH

X

Beg

in ~

age

4 D

evel

opm

enta

l, ed

ucat

iona

l, an

d so

cial

pro

blem

s D

evel

opm

enta

l, ed

ucat

iona

l, an

d/or

psy

chos

ocia

l exa

m

X

Bef

ore

scho

ol e

ntry

Pa

lata

l/occ

lusi

ve a

bnor

mal

ities

O

rtho

dont

ic e

valu

atio

n A

t age

7

Sexu

ality

; sch

ool a

nd/o

r w

ork

plan

s C

ouns

elin

g B

egin

~ag

e 10

R

enal

and

live

r dy

sfun

ctio

n C

r, B

UN

, LFT

s, C

BC

X

B

egin

~ag

e 15

M

etab

olic

dys

func

tion

Fast

ing

BG

and

lipi

ds

Beg

in ~

age

15

Low

BM

D

DE

XA

sca

n A

t ~ag

e 18

G

H a

ctio

n IG

F-I/

IGFB

P-3

Dur

ing

GH

tx

Rep

rodu

ced

with

per

mis

sion

, Dav

enpo

rt M

L. A

ppro

ach

to th

e pa

tient

with

Tur

ner

synd

rom

e. J

Clin

End

ocri

nol M

etab

. 201

0;95

:148

7–14

95, C

opyr

ight

201

0, T

he E

ndoc

rine

Soc

iety

A

bbre

viat

ions

: BM

D b

one

min

eral

den

sity

, BU

N b

lood

ure

a ni

trog

en, C

BC

com

plet

e bl

ood

coun

t, cr

cre

atin

ine,

Dx

diag

nosi

s, B

P b

lood

pre

ssur

e, E

cho

echo

card

iogr

am, E

KG

ele

c-tr

ocar

diog

ram

, exa

m e

xam

inat

ion,

IgA

im

mun

oglo

bulin

A, I

GF

BP

-3 I

GF

bind

ing

prot

ein-

3, L

FT

s liv

er f

unct

ion

test

s, m

o m

onth

s, M

RI

mag

netic

res

onan

ce i

mag

ing,

PE

phy

sica

l ex

amin

atio

n, S

NH

L s

enso

rine

ural

hea

ring

loss

, TT

G I

gA A

b tis

sue

tran

sglu

tam

inas

e Ig

A a

ntib

odie

s, Q

eve

ry, T

SS T

urne

r Sy

ndro

me

Soci

ety,

tx tr

eatm

ent,

yrs

year

s a T

hese

gui

delin

es w

ere

adap

ted

from

Dav

enpo

rt a

nd C

alik

oglu

[ 18

8 ] a

nd B

ondy

(A

Gui

delin

e of

the

Tur

ner

Synd

rom

e St

udy

Gro

up)

[ 2, 3

] an

d re

fl ect

the

auth

or’s

clin

ical

pra

ctic

e.

The

y su

gges

t min

imal

rou

tine

scre

enin

g ev

alua

tions

. If

the

patie

nt h

as a

pro

blem

in o

ne o

r m

ore

area

s, s

he w

ill g

ener

ally

be

follo

wed

up

by a

spe

cial

ist i

n th

ose

area

s an

d ev

alua

ted

mor

e fr

eque

ntly

b I

f di

agno

sed

in in

fanc

y or

ear

ly c

hild

hood

, an

echo

card

iogr

am m

ay b

e pe

rfor

med

. An

MR

I sh

ould

be

obta

ined

onc

e th

e ch

ild is

abl

e to

und

ergo

an

MR

I ev

alua

tion

with

out s

edat

ion


the evaluation of growth-promoting therapies. Growth charts for American girls [ 131 ] and Northern European girls [ 132 ] ages 0–3 years are available as well as growth charts for girls ages 2–18 years [ 133 ] . These growth data are appli-cable to girls with TS from the United States. Untreated patients are expected to follow a percentile on the TS curve throughout childhood and adolescence. As for the normal population, there is a strong genetic component to each indi-vidual’s growth pattern. In fact, the height of any individual with TS is expected to be about 20 cm less than that of their midparental height (MPH).

The goals of hormonal therapies for growth are to (a) attain a normal height for age early in childhood, (b) progress through puberty at a nor-mal age, (c) attain a normal adult height at a nor-mal age, and (d) avoid the adverse effects of therapy [ 134 ] . Clinical observation has suggested, but not proven, that women treated with GH dur-ing childhood and achieving a height near or within the normal range face fewer obstacles, have higher self-esteem, and are more successful in social life and careers [ 135 ] .

The timing and administration of hormonal therapies for girls with TS are still evolving as experience is gained in their use. GH is the agent of choice. Clinical trials of GH have demon-strated that GH improves fi nal height in girls with TS [ 136, 137 ] . When given in conjunction with GH therapy, anabolic steroids appear to have a bene fi cial effect [ 138– 142 ] . However, anabolic steroids, including oxandrolone, when used alone, increase short-term height velocity, but do not appear to improve fi nal height. Recent studies also suggest synergistic effects on growth with the combination of very low doses of estrogen and GH [ 137 ] .

Effects of GH on Linear Growth GH therapy is considered standard of care for girls with TS who have linear growth failure [ 2 ] . Girls with TS are not GH de fi cient, but supra-physiological doses of GH drive growth. Demonstration that GH is effective in increasing adult stature was fi rmly established in 2005 with publication of the fi rst randomized, controlled study of GH therapy in girls with TS to fi nal

height [ 136 ] . Girls who were in the treatment arm received GH supplementation (0.30 milli-gram per kilogram per week (mg/kg/week) divided into 6 doses/week). After a mean of 5.7 years, the girls in the GH arm averaged 7.2 cm taller than those in the control arm. This increase in adult height is roughly average for the many studies in which height gains achieved by GH therapy were compared with the growth of his-torical controls and varied from no signi fi cant change to as high as 17 cm [ 115 ] . Factors that determine the effect of GH on height include age at initiation of therapy (the earlier the better), GH dose (the higher the better), use of anabolic steroids (an additive effect), and age at initia-tion of feminizing doses of estrogen (the later the better) [ 143 ] .

Of the factors determining GH ef fi cacy, young age at GH initiation is the most important [ 136, 144 ] . A randomized, controlled 2-year “Toddler Turner” study of GH therapy in 89 girls with TS whose treatment was initiated between the ages of 9 months and 4 years (mean age, 2.0 ± 1.0 year) indicated that GH therapy is effective beginning in infancy [ 145 ] . After 2 years, the height of the GH-treated group was very close to average for the general population (±0.3 SD), and there was a between-group difference in height gain of 1.6 SDS (6.8 cm). These girls are being followed to fi nal height in an observational study.

Early normalization of height has a number of potential bene fi ts for girls with TS: negating the physical limitations of short stature, prevention of stature-related juvenilization, improvement in peer group integration, and the opportunity to ini-tiate estrogen replacement at a physiologically appropriate age [ 145– 147 ] . It is now recom-mended that treatment with GH begin as soon as growth failure (decreasing height percentiles on the normal curve) is demonstrated [ 2 ] .

GH therapy should be optimized for each indi-vidual, given its high costs and potential risks. In one study, untreated patients with TS were treated initially with a GH dose of 0.23 mg/kg/week that was doubled or tripled when growth velocity declined to less than twice that of its pretreatment level. The estimated fi nal height bene fi t was 10.6 ± 3.8 cm compared to 5.2 ± 3.7 cm in a group


who received a fi xed dose of 0.3 mg/kg/week. In the group receiving incremental increases in GH dose, 83% attained heights in the normal range compared to 29% in the fi xed dose group [ 148 ] .

Early work by Rosenfeld et al. demonstrated an additive effect of oxandrolone, an anabolic steroid that cannot be aromatized to estrogen, on fi nal adult stature when compared with historic controls [ 149 ] . In a multicenter, prospective, ran-domized trial in which patients began therapy at a mean age of 7–8 years and received treatment for a mean of 6 years, therapy with GH alone ( n = 17) resulted in a height that was 8.4 ± 4.5 cm taller than the mean projected adult height at enrollment. Subjects receiving GH plus oxan-drolone at a dose of 0.0625 mg/kg/day ( n = 43) attained a mean height of 152.1 ± 5.9 cm, 10.3 ± 4.7 cm taller than their mean projected adult height [ 149 ] . Recently, Menke et al. exam-ined the effect of oxandrolone in a randomized, placebo-controlled, double-blind, dose–response study in the Netherlands [ 138 ] . One hundred and thirty-three girls with TS were treated with GH combined with placebo, GH combined with oxandrolone in a low dose (0.03 mg/kg/day), or GH combined with oxandrolone at a conventional dose (0.06 mg/kg/day) from the age of 8 years. GH plus low-dose oxandrolone resulted in a greater height gain than those in the GH plus pla-cebo group (9.5 ± 4.7 versus 7.2 ± 4.0 cm ( p = 0.02)). However, height gain in the GH plus conventional-dose oxandrolone group was not signi fi cantly different from the placebo group.

It has long been thought that adult stature is improved by delaying estrogen therapy as long as possible [ 150 ] . Chernausek et al. conducted a multicenter study in which 60 girls starting GH therapy were randomized to initiate estrogen therapy (conjugated estrogens begun at a dose of 0.3 mg po q day) at either 12 or 15 years of age. The patients were all less than 11 years of age at entry (mean, 9.5 years) and received 0.375 mg/kg/week of GH for approximately 6 years. Patients in whom estrogen treatment was delayed until age 15 years gained an average of 8.4 ± 4.3 cm over their projected height, whereas those start-ing estrogen at 12 years gained only 5.1 ± 3.6 cm. Growth was stimulated for approximately 2 years

after the initiation of estrogen, but then declined as bone age advanced.

However, more recent studies indicate that good, if not better, height results can be obtained by starting estrogen therapy (speci fi cally estra-diol) at 12 years of age than at ages 14 years and above [ 151, 152 ] . Most reassuring is a recently published randomized, placebo-controlled study to adult height of girls with TS ages 5–12.5 years of age who were randomized to four groups: dou-ble placebo, estrogen alone, GH alone, or GH and estrogen. Very low-dose ethinyl estradiol (or placebo) was given prior to age 12 years, after which all treatment groups received escalating feminizing doses. GH treatment (0.3 mg/kg/day divided into 3 dosed per week) alone increased adult height by approximately 5.0 cm over an average period of 7.2 years. Adult height was greater in the GH-estrogen group than the GH group by 0.32 + 0.17 SDS (2.1 cm). The modest growth bene fi t observed with the combination of ultralow-dose childhood estrogen replacement and GH suggests that the practice of delaying estrogen therapy should be reconsidered.

Effects of GH on Body Proportions As expected, there are differences in the response of speci fi c bones to GH treatment. On average, untreated girls with TS have relatively large trunks, hands, and feet, and broad shoulders and pelvis compared to height. GH treatment appears to exacerbate the disproportionate growth of feet and to modestly improve the disproportion between height and sitting height. There is no signi fi cant effect on relative width of the shoul-ders and pelvis [ 153 ] .

Effects of GH on Bone Mineral Density For girls with TS, GH therapy is likely to help maintain prepubertal bone mineral density (BMD) [ 154 ] . Preliminary BMD data on patients after long-term GH therapy show an absence of osteopenia [ 155 ] .

Effects of GH on Craniofacial Development GH therapy in girls with TS has not been demon-strated to have a signi fi cant effect on craniofacial


growth [ 156 ] , with the exception, perhaps, of an increase in the length of the mandible [ 157 ] . However, in these relatively short-term studies, the mean ages at initiation of GH therapy were 9 and 14 years. The growth of the cranial base is largely complete by age 6, whereas the synchon-drosis of the mandible does not close until late adolescence and can be reactivated in adulthood. The effect of early-onset, prolonged, and/or high-dose GH therapy on craniofacial development is unknown. GH therapy also does not appear to affect the rate of dental development.

Effects of GH on Psychosocial Function There is abundant anecdotal evidence that GH therapy improves psychosocial function, one of the principal goals of this therapy. Unfortunately, few studies have formally addressed this very important question, and controlled studies are unlikely in the future. However, there are some data con fi rming the observations of physicians, families, and girls with TS that certain aspects of social interactions and behavior, but not cogni-tion [ 158 ] , are improved with GH therapy. In a study of 38 girls with TS treated for 2 years with GH, improvements were demonstrated in social and emotional functioning. The investigators reported that a quarter of the patients became more independent, happier, and socially involved [ 159 ] . In a study in which girls with TS were evaluated after 3 years of GH therapy, attention, social problems, and withdrawal were reported as improved [ 160 ] . In a Canadian study in which girls were randomized to either a GH or control group, analysis after 2 years revealed that there was a correlation with higher growth rate and the girls’ perceptions of themselves as more intelligent, more attractive, having more friends, greater popularity, and experiencing less teasing than the untreated group [ 161 ] . However, the effect of GH therapy on adult quality of life (QoL) has been more dif fi cult to demonstrate. A recent study of QoL compared 58 women with TS who had been treated with GH with 53 women with TS who had not been treated with GH. Except for less pain, no signi fi cant impact on QoL attributable to GH treatment could be

found, despite the mean 5.1-cm increase in fi nal height [ 162 ] .

Safety of GH Therapy Extensive postmarketing surveillance programs have documented that side effects of GH therapy in children are relatively rare. However, families should be fully apprised of the risks associated with GH therapy, many of which are more common in girls with TS than other patients receiving GH. In the most extensive report to date, a study of 5,220 girls with TS who received GH revealed higher incidences for disorders for whom they are known or expected to be at higher baseline risk: scoliosis (0.39%), slipped capital femoral epiphysis (0.24%), diabetes mellitus (0.19%), and serious cardiovascular events (0.32%) than for non-TS patients receiving GH [ 163 ] . However, incidences were also increased for intracranial hypertension (0.23%), pancreati-tis (0.06%), and new malignancies (0.11%). Other problems potentially caused or exacerbated by GH therapy but not captured in this report, include lymphedema, carpal tunnel syndrome, and an increase in the number, size and degree of pigmentation of nevi. No adverse effects of GH on cardiac size, aortic diameter, or cardiovascular function have been found [ 164, 165 ] .

Increased insulin resistance has been of con-siderable concern in this population at high risk for diabetes. Insulin resistance increases, but there is generally no effect on glucose levels [ 166, 167 ] . In a study in which girls with TS treated with GH for 7 years, the prevalence of impaired glucose tolerance was low; all hemo-globin A1c levels were normal, and none of the girls developed diabetes mellitus. Insulin levels decreased to values close to or equal to pretreat-ment values after discontinuation of GH treat-ment [ 168 ] . Although insulin resistance is increased during GH therapy, it may actually be improved after discontinuation due to the bene fi cial effects of GH therapy on body compo-sition [ 169 ] .

Safety of Anabolic Steroids Side effects of anabolic steroids may include (a) virilization with development of acne, deepening


of the voice, and growth of facial hair; (b) tran-sient elevation of liver function tests; (c) insulin resistance; and (d) premature skeletal maturation. It has been known for more than two decades that mild virilization can occur when oxandrolone is used at a dose of 0.125 mg/kg/day [ 170 ] . Recently, virilizing effects were documented at a dose of 0.0625 mg/kg/day, a dose commonly used in clinical practice, and slower breast development was reported at that dose as well as a lower dose of 0.03 mg/kg/day po [ 138 ] .

General Recommendations for Growth-Promoting Therapies

It is now clear that with early diagnosis and ini-tiation of treatment, a normal adult height is a reasonable goal for most girls with TS. GH should be offered as a therapy for all girls with TS who are predicted to have a subnormal height. The predicted response to GH should be carefully reviewed with patients and their families to help limit unrealistic expectations of future height. Routine evaluation of GH secretory status in girls with TS is not warranted, since GH secretion in this group is similar to that of the normal popula-tion and GH secretory responses do not correlate with responses to exogenous GH [ 171 ] . Because GH therapy for this population is a pharmaco-logical one, it requires somewhat higher doses than those used for GH-de fi cient patients. Standard GH therapy in the USA for TS is 0.375 mg/kg/week divided into 6 or 7 doses. Division of GH dosing into two shots per day does not appear to be advantageous over one shot per day [ 172 ] . Although GH has been initiated at a mean age of 9–11 years in most studies, it is becoming clear that girls who begin GH therapy at an earlier age and receive GH for a longer period of time will experience a greater incre-ment in height. Therefore, it is suggested that GH therapy be initiated once growth failure (decreas-ing height percentiles on the normal growth curve) is documented. Therapy should be contin-ued until the individual reaches a satisfactory adult height or it is no longer bene fi cial (growth rate below 2–2.5 cm/year).

Adjunctive therapy with oxandrolone at a dose of approximately 0.03 mg/kg/week can be con-sidered at the age of 8 years and above. Ultralow-estrogen replacement in early childhood may improve growth but remains experimental at this point. Initiation of feminizing doses of estradiol should be begun during the time of normal puberty (approximately 12 years of age).

Orthodontic Problems

Because many girls with TS have orthodontic problems (narrow maxilla with high-arched and narrow palate, micrognathic mandible), early eval-uation by an orthodontist is suggested. The timing of any orthodontic treatment to address dental malocclusion should take into consideration long-term growth-promoting therapies that may alter tooth and jaw alignment. In addition, because the dental roots are short, unnecessary tooth move-ment should be minimized to avoid root resorption and loss of teeth. Because of this, TS girls should be evaluated by a pediatric dentist around 2 years of age, and by an orthodontist around 7 years of age [ 2, 189 ] .

Hearing Loss

Screening for hearing problems should be done as soon as the diagnosis of TS is made. Children with TS should have pneumatic otoscopy done at every visit to the physician, and tympanometry should be considered if otoscopy is equivocal. Any child who has fl uid in both middle ears for a period of 3 months should undergo an evaluation by a pediat-ric otolaryngology [ 173 ] . In general, tympanos-tomy tubes are recommended when bilateral conductive hearing de fi ciency of at least 20 dB HL is associated with bilateral effusions for a period of more than 3 months. Chronic or recurrent mid-dle ear disease should be managed aggressively to minimize the likelihood of conductive middle ear damage and permanent hearing loss. In patients with TS, early tube placement may be justi fi ed since otitis media with effusion is less likely to resolve spontaneously than in the normal population.


Because infection of the tonsils and adenoids may contribute to sinus and middle ear infections, ton-sillectomy and/or adenoidectomy may have to be considered as additional therapeutic options for some patients. Patients should be warned to pro-tect their hearing by avoiding exposure to loud noises unless appropriate ear protection is in use. Audiology evaluation should be part of the hear-ing screening both at the time of diagnosis, and during monitoring of the hearing function. It should be obtained on an annual basis for patients with ongoing problems of otitis media, or who have already developed hearing loss. In those TS patients without hearing loss, audiological surveillance should still occur every 2–3 years.

Strabismus and Other Eye Problems

Children should be evaluated for strabismus at every clinic visit between the ages of 6 months and 5 years of age. Because early correction of visual alignment is critical for normal binocular vision to develop, any child with strabismus should be referred immediately to an ophthal-mologist for further evaluation. In fact, it may be prudent for every child with TS to have an oph-thalmology exam before or at 2 years of age.

Renal Abnormalities

All patients with TS should be routinely screened by ultrasound for renal abnormalities. If no uri-nary tract abnormalities are found, the kidney evaluation can stop here, as it has been shown that during an average of 6 years of follow-up these patients do not develop renal problems [ 74 ] . If renal abnormalities are found, additional testing will be directed in collaboration with a pediatric nephrologist, as these patients are at increased risk of hypertension and urinary tract infection.

Gastrointestinal Disorders

GI bleeding should be in the differential diagnosis of children with anemia. Celiac disease and IBD

should be considered for those with unexplained weight loss. Celiac disease should be screened for (by measurement of tissue transglutaminase IgA antibody titer) after the patient turns 4 years of age and repeated every 2–5 years, or as indicated by the review of systems. In older TS patients, rescreening for celiac disease also depends on the clinical presentation. Screening for liver disease has also been recommended during the school-age years and thereafter. It may be more impor-tant to do so in those patients who are obese, or are taking oral estrogen or androgen therapies. Steatosis and steatohepatitis or more serious pathologies need to be considered if an upward trend in the liver transaminases is detected.

Dermatological Problems

Because an increased tendency for keloid and hypertrophic scarring has been reported in TS, until the exact risk for the development of these lesions after surgical procedures is better under-stood, patients should be forewarned before hav-ing their ears pierced or undergoing surgical procedures that keloids may arise. The risk of keloid formation should certainly be discussed when cosmetic surgery is being considered, as the neck and chest are known to be higher-risk areas for these lesions. The patient, family, and physician should examine nevi regularly to look for dysplastic features such as asymmetry, border irregularity, color variability, and diameter greater than 5 mm. Patients should also be advised to limit sun exposure, as TS patients tend to have more of these nevi, especially on the skin of the face, neck, and upper extremities.

Hypothyroidism and Other Autoimmune Disorders

Because autoimmune hypothyroidism may develop insidiously, thyroid function tests (thy-roxine, thyroid stimulating hormone) should be monitored yearly from 4 years of age onward. For those growing poorer than expected, antibody studies for celiac disease should be obtained.


Those with positive tissue transglutaminase anti-bodies should be referred for evaluation by a gastroenterologist.

Obesity, Lipids, and Glucose Homeostasis

Patients should be encouraged to maintain their weight within an appropriate range for height and receive early dietary counseling if necessary. Girls with risk factors for type 2 diabetes mellitus should be screened with fasting blood glucoses or a modi fi ed OGTT.

Gonadal Failure

The goals of estrogen replacement therapy in girls with TS are to normalize developmental changes in secondary sex characteristics includ-ing breast size and shape, uterine size and shape for possible reproductive function, bone growth and mineral accrual, cardiovascular function, and other estrogen-dependent processes.

Estrogen de fi ciency can exacerbate several problems associated with TS. In adult women, estradiol de fi ciency is known to cause cancellous bone loss, endothelial dysfunction, decreased insulin production, an abnormal lipid pattern, increased central adiposity, and early atheroscle-rosis. Indeed, oophorectomy is an independent predictor of myocardial infarction and coronary death. Estrogens are likely to be important in childhood as well. Estrogens are produced from birth and can be measured in the serum throughout childhood in girls when sensitive assays are used. The normal mid-childhood ovary is not entirely quiescent; plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in boys [ 174 ] .

There are many options for hormone replace-ment therapy. However, systemic administration of estradiol, usually by transdermal application in a patch or gel, is the only form of therapy to achieve natural levels of estradiol in blood [ 175 ] . Oral estradiol undergoes extensive hepatic fi rst

pass metabolism, with most of it being trans-formed to estrone sulfate. Ethinyl estradiol, a potent synthetic estrogen with little hepatic metabolism used in the Ross low-dose estrogen trial [ 137 ] , is not available commercially in the United States. Conjugated equine estrogen (CEE) contains multiple sex steroids, some of which are not found in humans. Although it was historically the estrogen of choice in the United States, there is no longer justi fi cation for its use in children.

Both oral and transdermal estrogens prevent atherosclerosis. However, oral estrogens have been demonstrated to increase resistance to acti-vated protein C, decrease antithrombin III, increase C-reactive protein, increase GH resis-tance, increase SHBG, and cause triglyceride enrichment of low-density lipoprotein and high-density lipoprotein particles. TDE has little effect on these parameters [ 176 ] . None of these studies has been carried out in large randomized trials and most have involved postmenopausal women; therefore, their applicability to adolescents and young adults with TS remains to be proven. In a recent short-term metabolic study of GH-treated girls with TS, neither oral nor transdermal estro-gen adversely affected measured metabolic parameters [ 177 ] . However, in another study in which prepubertal GH-treated girls with TS were randomized to oral conjugated estrogen or TDE for 1 year, the transdermal group had signi fi cantly greater increases in spine bone mineral density (BMD) and uterine growth [ 178 ] .

A suggested protocol for puberty induction using TDE patches is presented in Table 7.3 . Beginning estrogen replacement in early adoles-cence (11–12 years of age) allows puberty to begin and to progress at a normal age [ 179 ] .

If TDE cannot be used, oral estradiol or ethi-nyl estradiol should be considered. The following doses are considered equivalent although equiva-lency depends on which assays and clinical end points are used: 100 m g TDE, ~2 mg oral estra-diol, ~20 m g ethinyl estradiol, and ~1.25 mg CEE. Oral contraceptives should be avoided if possible because they have unnecessarily high estrogen/progestin concentrations.

Androgen replacement therapy is not standard of care; however, a recent randomized, double-


blind, placebo-controlled, crossover pilot study of androgen replacement therapy (1.5 mg methyl testosterone) in TS demonstrated signi fi cant bene fi cial effects on bone health, lipid pro fi le, body composition, and QOL, whereas cognitive functions were variably affected [ 180 ] .

Long-term treatment with estrogen and pro-gestin that is initiated during mid- to late adoles-cence and is continued throughout adulthood appears necessary for a normal peak bone mass to be achieved. Additional measures to prevent osteoporosis should be used, such as ensuring adequate calcium intake (>1,000 mg of elemental calcium daily in the preteen years, and 1,200–1,500 mg daily after 11 years of age), encourag-ing weight-bearing activities, and avoiding overtreatment with thyroid hormones [ 155 ] .

Because gonadoblastomas may occur as early as young childhood, prophylactic gonadecto-mies are recommended at the time of diagnosis for most girls with karyotypes containing

Y-chromosome material or marker chromo-somes identi fi ed as Y material by FISH [ 181 ] . Recommendations for those found by PCR tech-nique alone are less clear.

The reproductive options for women with TS continue to expand. For the rare woman who is fertile, prenatal amniocentesis is recommended because of the high rate of chromosomal abnor-malities. Those who are sterile may choose to adopt children or undergo arti fi cial fertilization. The clinical pregnancy rate achieved by embryo transfer in women with TS appears to be similar to that of other oocyte recipients with primary ovar-ian failure; however, a greater percentage (40%) end in miscarriage [ 182 ] . The greater miscarriage rate may be the result of uterine factors and an increased incidence of genetic abnormalities. Therefore, preimplantation genetic diagnosis should be performed before embryos are trans-ferred. In addition, chorionic villous sampling and amniocentesis should be offered to all TS patients

Table 7.3 Pubertal induction and maintenance estrogen therapy using transdermal estradiol (TDE): a protocol using low “growth-promoting doses” for 18–24 months a

Treatment (months) Target E2 (pg/ml) b E2 dose Notes

Consider initiation of puberty at age 11–12 years if there is no breast development

0 3–4 0.1 m g/kg Cut patch and apply piece overnight only. Replace every night. Check E2 levels in a.m. before patch is removed

6 3–4 0.1 m g/kg Apply piece of matrix patch continuously c . Check E2 levels any time. Change patch as directed (once or twice weekly)

12 6–8 0.2 m g/kg 18 ~12 12.5 m g E2 levels below this are believed to accelerate growth more

than bone maturation 24 ~25 25 m g 30 ~37 37.5 m g 36 ~50 50 m g Start progestin (earlier, if breakthrough bleeding occurs):

200–300 mg micronized oral progesterone for ~12 days/month qhs (causes drowsiness); or 5 mg oral medroxypro-gesterone for ~12 days/month

42 ~75 75 m g 48 50–150 100 m g Typical adult dose; may not be high enough to protect liver,

arteries, etc.

Reproduced with permission, Davenport ML. Approach to the patient with Turner Syndrome. J Clin Endocrinol Metab. 2010;95:1487–1495, Copyright 2010, The Endocrine Society Abbreviations : CRP C-reactive protein, E2 17 b estradiol, qhs before bedtime, SHBG sex hormone-binding globulin a This protocol is but one of many that can be used. This speci fi c protocol is utilized in the author’s clinic and individual-ized depending upon patient circumstances and desires. For example, older girls may wish to be started at 25 m g b To convert pg/ml to pmol/L, multiply by 3.671. E2 levels should be monitored using liquid chromatography/tandem mass spectroscopy (LC/MS/MS) technology c Vivelle Dot, matrix transdermal patch, is small and tends to adhere well


who become pregnant. Careful assessment before and during follow-up of pregnancy is important because of the increased risk of cardiovascular and other complications. Several women with TS have died during pregnancy from aortic dissec-tion. Many physicians have recommended that only one embryo be transferred at a time to avoid the additional complications caused by twin preg-nancy [ 130, 183 ] . No matter how pregnancy is achieved, careful screening of the cardiovascular system is requisite given the increased cardiovas-cular demands [ 184 ] . There is continuing contro-versy about which women with TS should be allowed to undergo assisted reproduction. Absolute contraindications to pregnancy are surgically repaired coarctations or uncontrolled hyperten-sion, while bicuspid aortic valve is viewed by many as a relative contraindication [ 185 ] .

Learning Disabilities

Children with TS should undergo a baseline developmental evaluation at the time of initial diagnosis or at latest, during the preschool years. Academic tutoring, occupational therapy, and training in problem-solving strategies can help girls and women with TS cope with their visual-spatial and cognitive challenges. Individual psy-chotherapy may be required to address the social and emotional dif fi culties commonly experienced by individuals with TS [ 186 ] . Timely institution of estrogen therapy may be important since there is evidence that some neurocognitive de fi cits such as memory, reaction time, and speeded motor function result from estrogen de fi ciency and are at least somewhat reversible with estrogen treatment [ 187 ] . Many patients and their families bene fi t tremendously from support group programs, such as those offered by the Turner Syndrome Society of the United States (TSSUS), which can be accessed at http://www.turnersyndrome.org .

Tumors

Tumors in the TS population should be approached the same as those in the general population.

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