TURNER SYNDROME
 
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TURNER SYNDROME

 

DEFINITION:

A chromosomal disorder resulting in a syndrome characterized by specific dysmorphic features (short stature) and organ malforations (gonadal dysgenesis).

EPIDEMIOLOGY:

  • incidence: 1:2000-5000 live-born girls
  • age of onset:
    • infant - lymphedema
    • childhood - short stature
    • adolescence - primary or secondary ammenorrhea
  • risk factors:
    • females only
    • advanced paternal age (ioschromosome X cases)
    • mother with mosaic or deletional Turner's

PATHOGENESIS:

1. History

  • 1938 - first described by H. H. Turner
    • sexual infantilism, webbed neck, cubitus valgus, short
  • 1959 - chromosomal basis of syndrome recognized by Ford et al.

2. Chromosomal Anomalies

1. 45, XO karyotype

  • 55% of cases

2. 46, XX karyotype

  • 25% of cases, (12-20% of all cases have isochromosome X)
  • with alteration in the structure of one of the x chromosomes i.e., deletion, duplication, isochromosome

3. Mosaics

  • 15% of cases
  • may involve 2-3 separate cell lines
  • 45X, 46XX, 46XY, 47XXX
  • 46XY karyotype:
    • 2-5% of total Turner's patients
    • essential to perform a bilateral gonadectomy because of increased risk of gonadoblastoma (a tumor of abdominally located gonads that have Y-containing cells)
    • variable clinical presentation from typical Turners to normal male phenotype
  • a trend towards fewer clinical features with more normal cells
  • severity of clinical features does not correlate with karyotype
  • principle: different anomalies result in a single functional X chromosome -> Turner's phenotype

3. Pathogenesis

  • lymphangiectasia during prenatal development first proposed by Ullrich:
    • absence of the gene responsible for the early opening of lymphatic channels -> intolerance of edema in fetal state -> lymph-edema at critical points in development -> imbalance or failure of normal growth and/or failure of regression of particular tissues -> congenital Turner phenotypes

CLINICAL FEATURES:

1. Classic

  • short stature
  • gonadal dysgenesis (primary and secondary amenorrhea)
  • lymphedema

2. Newborn

  • small for dates
  • lymphedema of hands and feet
  • excessive skin at nape of neck

3. Childhood/Adolescence

  • short stature (98%)
  • gonadal dysgenesis (95%)
  • high palate (82%)
  • short neck, low hairline (80%)
  • hypoplastic, widely-spaced nipples (78%)
  • broad chest, cubitus valgus, nail hypoplasia (75%)
  • lymphedema, prominent anomalous ears, excessive nevi (70%)

4. Dysmorphic Features

1. Eyes

  • downslanting, epicanthal folds
  • ptosis and strabismus are the most common lesions
  • complications: bluphthalmus, cataracts, nystagmus, colour blind, amblyopia, myopia

2. Ears

  • prominent upturned lobules
  • comp.: chronic otitis media (80%), middle ear disease, sensorineuronal hearing impairment (50-70%),

3. Mouth

  • palate - high, cleft, 'Gothic'; small mandible
  • complications: crowding of teeth, malocclusion (crossbite, distal molar occlusion, maxillary overset)

4. Others

  • Head - triangular face, midfacial hypoplasia, mandibular retrognathy
  • Neck - short, webbed, low hairline
  • Chest - broad (scutiform thorax), pectus excavatum, inverted, hypoplastic, widely-spaced nipples
  • Joints - cubitus valgus (>15%), congenital hip dislocation (5-10%)
  • Hands
    • short 4th metacarpal & metatarsal, short distal phalanges with tufting and broadening
    • distal triradii, carpal bone fusion
    • nail hypoplasia - small convex or concave upturned nails,
  • Skin
    • lymphedema - hands, feet, neck (pterygium coli)
    • pigmented nevi, vitiligo, keloid, seborrheic dermatitis; increased body hair with alopecia

5. Organ Malformations

1. Cardiovascular

1. Congenital Heart Malformations (20-30%)

  • 1. Coarctation of the Aorta (15-30%)
    • correlated with webbed neck
    • associated with hypertension
  • 2. Bicuspid Aortic Valve (33%)
    • predisposes to atherosclerotic disease
    • may stenose or calcify
    • should receive antibiotic prophylaxis
  • 3. Aortic Aneurysms
    • coarctation, hypertension, and aortic valve anomalies predispose to aneurysms
  • 4. Others
    • mitral valve prolapse (25%), ectopia cordis, hypoplastic left heart, pulmonary stenosis

    • 2. Vascular Malformations

    • generalized vascular dysplasia
    • intestinal telangiectasias:
      • gastrointestinal bleeding, protein-loosing enteropathy
    • others:
      • hemangiomas, venous ectasias, lymphangioectasia with chylous accumulation in chest & abdoman

    3. Lymphedema

    • dorsum of hands and feet - decreases during childhood
    • neck - cystic hygroma -> ear, neck & hairline changes

    4. Others

    • multiple renal arteries (90%)
    • hypertension: mild -> severe

    2. Genitourinary

    1. Structural Anomalies (33-60%)

    • 20% - double collecting system or absent kidney
    • 15% - malrotation
    • 10% - horseshoe kidneys
    • 6-10% - silent hydronephrosis
    • at risk for recurrent urinary tract infections, obstruction, hypertension

    3. Endocrine

    1. Short Stature

    • birth: mean length less than 48 cm
    • infancy: 3rd to 10th %
    • infancy -> puberty: 3rd % (with normal growth velocity)
    • adolescence : <3rd % (no growth spurt)
    • adult (untreated) : mean height = 144 cm (4'10")
    • will also get disproportionate increase in weight and delayed bone age (1-2 years)

    2. Fertility

    • rare but possible if undergo spontaneous puberty
    • mosaicism and deletions > 45, XO
    • greater number of miscarriages (50%)
    • " of congenital abnormalities (33%)

    3. Gonadal Dysgenesis/Failure

    • fibrotic ovarian streaks by birth:
      • degeneration of oocytes after 12 weeks in utero
      • accelerated transformation of ovaries to connective tissue
      • spontaneous puberty in 5-15% of cases
      • may have irregular periods & premature menopause after puberty

    4. Immune (Autoimmune)

    1. Hypothyroid (20-30%)

    • 50-60% have thryroid antibodies
    • higher risk of acute Hashimoto's thyroiditis and Graves' in isochromosome X

    2. Diabetes Mellitus (5%)

    • 25-60% have impaired glucose tolerance

    3. Others

    • inflammatory bowel disease (Crohn,s, Ulcerative Colitis) - increases with isochromosome X
    • rheumatoid arthritis

    INVESTIGATIONS:

    1. Diagnosis

    1. Karyotype

    • peripheral blood leukocyte and/or fibroblast cultures
    • Y chromosome detection

    2. Imaging Studies

    1. Skeletal Survey

    • changes in hands, feet, knees, spine, ribs, pelvis, skull
    • delayed bone growth

    2. Cardiovascular Malformations

    • ECG, 2D-Echo
    • follow aortic valve changes & aneurysm formation

    3. Renal Malformations

    • screen every 10 years for silent hydronephrosis

    3. Serum

    • thyroid function tests (TSH), thyroid antibodies
    • impaired serum glucose tolerance
    • increased gonadotropins:
      • with gonadoblastoma in 45,XO/46,XY
      • in 1st year secondary to degeneration of ovaries

    MANAGEMENT:

    1. Supportive

    • follow-up with ophthalmology, ENT, dentist, orthopedics, cardiology, urology, genetic couselling

    2. Surgery

    • removal of bilateral streak gonads prior to starting school in 45,XO/46,XY

    3. Endocrine

    1. Growth

    • low dose estrogen at an early age with slow progression to a higher dosage
    • combination of low dose estrogen, growth hormone, anabolic steroid

    2. Gonadal Failure

    • replacement with estrogen and progesterone
    • begin at time appropriate for teenage peers
    • start with low dose estrogen for 1-2 years then progress to larger doses cycled with progesterone and then maintain with the birth control pill

    3. Fertility

    • oocyte donation, gamete or embryo transplant

    4. Hypothyroidism

    • replacement therapy

    INTERNET LINKS:

    Turner's Syndrome Society of the United States

     

    Pediatric Database - TURNER SYNDROME

     

    Pediatric Organization - Pedbase [at] Gmail.com

     
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