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Summary Table

Category	Details
Risk Factors	Sporadic chromosomal nondisjunction; not associated with advanced maternal age (unlike trisomies). Increased fetal loss rate, so live births are rare.
Etiology	Complete or partial monosomy X. Classic karyotype is 45,X (~50% of cases). Remainder are mosaics (45,X/46,XX) or have structural X abnormalities (isochromosome Xq, ring X, deletions of Xp).
Patient Presentation	Three classic age-based presentations: (1) prenatal cystic hygroma or hydrops on ultrasound, (2) newborn with lymphedema of hands and feet plus redundant nuchal skin, (3) older girl with short stature, delayed puberty, or primary amenorrhea.
Classic Physical Exam	Short stature (most consistent feature), webbed neck (pterygium colli), low posterior hairline, shield chest with widely spaced nipples, cubitus valgus, short fourth metacarpal, multiple pigmented nevi, high-arched palate, low-set ears.
Key Diagnostic Results	Karyotype showing 45,X or variant. Elevated FSH and LH (hypergonadotropic hypogonadism) with low estradiol. Streak ovaries on pelvic imaging. Bicuspid aortic valve or coarctation on echocardiogram. Horseshoe kidney on renal ultrasound.
Management	Recombinant growth hormone starting in early childhood, estrogen replacement starting around age 11 to 12 to induce puberty, then cyclic estrogen and progestin for menstruation and bone health. Lifelong cardiac, thyroid, audiologic, and metabolic surveillance.
Keywords	"Short girl with primary amenorrhea," "webbed neck and shield chest," "newborn with puffy hands and feet," "streak ovaries," "delayed puberty with elevated FSH," "coarctation in a phenotypic female," "horseshoe kidney," "45,X karyotype."

1. Pathophysiology

Turner syndrome results from the complete or partial loss of one X chromosome in a phenotypic female. The single functioning X cannot fully compensate because certain genes on the X chromosome escape X-inactivation and require two copies for normal dosage. The most clinically relevant of these is the SHOX gene (Short stature HOmeoboX-containing) on the pseudoautosomal region of Xp. SHOX haploinsufficiency drives the short stature, cubitus valgus, short fourth metacarpal, and Madelung deformity that characterize the skeletal phenotype.

The gonadal dysgenesis is mechanistically distinct. Oogenesis requires two intact X chromosomes; with only one, primordial follicles undergo accelerated atresia in utero. By the time the patient reaches the age of puberty, the ovaries have already been replaced by fibrous tissue, the so-called streak ovaries. Because the gonads cannot produce estrogen, the hypothalamic-pituitary axis loses negative feedback, producing hypergonadotropic hypogonadism with markedly elevated FSH and LH. This is the mechanistic explanation for primary amenorrhea, lack of secondary sexual characteristics, and infertility.

The lymphatic abnormalities explain the most visually distinctive features. Defective lymphatic development in the fetus causes jugular lymphatic obstruction, producing cystic hygroma on prenatal ultrasound. When these dilated sacs eventually decompress, the redundant skin remains, manifesting postnatally as the webbed neck and low posterior hairline. Persistent lymphatic dysfunction in the periphery causes the puffy hands and feet that often prompt diagnosis in the newborn nursery.

The cardiovascular abnormalities are the most testable because they drive mortality. Aortic arch malformations are thought to result from in-utero distention of lymphatic channels compressing the aortic arch during development. The two highest-yield lesions are bicuspid aortic valve (most common, present in 30 percent) and coarctation of the aorta (present in 10 percent). Adults with Turner syndrome remain at lifelong risk for aortic root dilation and dissection, which is a leading cause of premature death.

2. Classification and Clinical Manifestations

System	Manifestations
Growth and Skeleton	Short stature (final adult height around 143 cm without treatment), cubitus valgus, short fourth metacarpal, Madelung deformity of the wrist, scoliosis, genu valgum, micrognathia, high-arched palate.
Reproductive	Streak ovaries, primary amenorrhea, absent or incomplete pubertal development, infertility. A minority of mosaic patients have spontaneous puberty and rare spontaneous pregnancies.
Cardiovascular	Bicuspid aortic valve, coarctation of the aorta, partial anomalous pulmonary venous return, elongated transverse aortic arch, aortic root dilation, hypertension.
Renal	Horseshoe kidney (most common), duplicated collecting system, malrotation, ectopic kidney.
Lymphatic	Cystic hygroma in utero, hydrops fetalis, congenital lymphedema of dorsum of hands and feet, redundant nuchal skin progressing to webbed neck.
Endocrine and Metabolic	Autoimmune (Hashimoto) thyroiditis, type 2 diabetes and insulin resistance, dyslipidemia, metabolic syndrome, osteoporosis from estrogen deficiency.
Gastrointestinal and Hepatic	Celiac disease, inflammatory bowel disease, elevated transaminases, increased risk of hepatic steatosis.
Sensory	Sensorineural hearing loss progressing in adulthood, recurrent otitis media, strabismus, amblyopia, red-green color blindness.
Dermatologic	Numerous pigmented nevi, keloid formation, lymphedema.
Karyotype Variants	45,X classic (~50%); 45,X/46,XX mosaic (milder phenotype, occasional spontaneous menses); 46,X,i(Xq) isochromosome (more autoimmune disease); 45,X/46,XY mosaic (risk of gonadoblastoma in dysgenetic gonads).

3. Diagnostic Workup

Test	Role	Key Finding
Prenatal ultrasound	Suggestive	Cystic hygroma, increased nuchal translucency, hydrops, cardiac or renal anomaly
Cell-free fetal DNA (NIPT)	Screening	Suggests monosomy X; not confirmatory
Peripheral blood karyotype (30-cell count)	Confirmatory (Gold Standard)	45,X or variant
FISH or chromosomal microarray	Adjunct	Detects mosaicism missed on standard karyotype, identifies cryptic Y material
FSH, LH, estradiol	Functional assessment	Elevated FSH and LH, low estradiol (hypergonadotropic hypogonadism)
Echocardiogram and cardiac MRI	Mandatory at diagnosis	Bicuspid aortic valve, coarctation, aortic root dilation
Renal ultrasound	Mandatory at diagnosis	Horseshoe kidney, collecting-system anomalies
TSH, anti-TPO, anti-tTG IgA	Surveillance	Autoimmune thyroiditis, celiac disease
Bone age and DXA	Growth and skeletal monitoring	Delayed bone age, low bone density

The diagnostic pathway depends on the age at presentation. In the prenatal setting, suggestive ultrasound findings (cystic hygroma, increased nuchal translucency, coarctation, horseshoe kidney) prompt diagnostic chromosomal testing through chorionic villus sampling or amniocentesis. NIPT can suggest the diagnosis but is not confirmatory because of placental mosaicism and confined placental abnormalities. In the newborn, lymphedema of the hands and feet plus redundant nuchal skin is the classic trigger to send a karyotype.

In older children, the two most common entry points are unexplained short stature in a girl (height crossing percentiles downward, height below the 5th percentile, or height substantially below the midparental target) and delayed puberty or primary amenorrhea with elevated gonadotropins. A useful teaching rule: any girl with otherwise unexplained short stature deserves a karyotype, because the phenotype can be subtle in mosaic cases and 30 percent of patients are diagnosed only in adolescence or adulthood.

The best initial test for screening is therefore a directed clinical examination plus measurement of FSH (which will be elevated even before puberty in classic 45,X). The most accurate confirmatory test is the peripheral blood karyotype, counting at least 30 cells to detect low-level mosaicism. If clinical suspicion remains high despite a normal blood karyotype, additional tissue (skin fibroblasts) can be analyzed because mosaicism may be confined to gonadal tissue. FISH or chromosomal microarray is added to look for hidden Y-chromosome material, because patients with any Y material have a 15 to 30 percent risk of gonadoblastoma and require prophylactic gonadectomy.

Once the diagnosis is confirmed, every patient needs a baseline echocardiogram with cardiac MRI (because echo can miss aortic arch elongation and root dilation), renal ultrasound, thyroid panel, celiac screening, audiometry, and fasting glucose and lipid panel. These investigations are not optional; they form the diagnostic standard of care.

4. Management and Treatment

Issue	Treatment	Timing and Notes
Short stature	Recombinant human growth hormone	Start when height drops below the 5th percentile (often as early as age 4 to 6); typical dose 0.375 mg/kg/week divided into daily subcutaneous injections; continue until bone age is around 14 years or growth velocity is below 2 cm/year.
Pubertal induction	Low-dose transdermal 17-beta-estradiol	Start around age 11 to 12 to mimic physiologic puberty. Begin low and titrate up over 2 to 3 years.
Menstrual cycling and bone health	Add cyclic progestin once breakthrough bleeding occurs or after about 2 years of estrogen	Continue combined estrogen and progestin until at least the average age of natural menopause (around 50).
Fertility	Donor oocyte in vitro fertilization	Cardiac clearance (including aortic root assessment) is mandatory before pregnancy because of dissection risk.
Cardiovascular surveillance	Serial echocardiogram and cardiac MRI every 5 years (more often if abnormalities present)	Strict blood pressure control. Surgical or catheter intervention for coarctation or progressive aortic root dilation.
Thyroid disease	Levothyroxine	Annual TSH screening starting at diagnosis.
Celiac disease	Gluten-free diet	Screen with anti-tTG IgA every 2 to 5 years.
Otologic and audiologic	Aggressive otitis media management; serial audiometry	Hearing loss progresses through adulthood.
Gonadectomy	Prophylactic bilateral gonadectomy if any Y-chromosome material detected	Performed at diagnosis to prevent gonadoblastoma.
Bone health	Calcium, vitamin D, weight-bearing exercise, adequate estrogen	DXA scan at the transition to adult care.
Psychosocial	Neurocognitive evaluation (visuospatial deficits common despite normal verbal IQ)	Educational support, social skills counseling.

The acute management priorities at diagnosis are: confirm the karyotype, evaluate the cardiovascular system, and screen for renal, thyroid, and celiac disease. The long-term management rests on three pillars: growth hormone for height, sequential estrogen then estrogen-progestin for puberty and bone health, and lifelong multisystem surveillance.

The "next best step" logic on examinations typically falls into one of these patterns. If the vignette shows a newborn with lymphedema and webbed neck, the next step is karyotype. If a girl with confirmed Turner syndrome has not yet had cardiac evaluation, the next step is echocardiogram with cardiac MRI. If a teenager with Turner syndrome is approaching pubertal age and has not yet entered puberty, the next step is low-dose estrogen therapy. If a Turner patient is planning pregnancy, the next step is comprehensive cardiac evaluation including aortic root measurement before conception.

Contraindications and cautions worth memorizing: growth hormone is contraindicated in active malignancy, severe scoliosis progression, and uncontrolled diabetes. Pregnancy in Turner syndrome carries a 100-fold increased risk of aortic dissection, so any aortic root dilation (indexed aortic size index above 2.0 to 2.5 cm/m²) is a relative contraindication to pregnancy. Estrogen should be started transdermally at a low dose and titrated slowly to mimic physiologic puberty; starting too early or too high compromises final adult height by accelerating epiphyseal closure.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why it is similar	Key Discriminator
Noonan Syndrome	Webbed neck, short stature, low-set ears, congenital heart disease, lymphedema. Often called "male Turner" in older texts.	Affects both sexes equally, normal karyotype (autosomal dominant, PTPN11 and other RAS pathway genes), heart lesion is pulmonic valve stenosis rather than left-sided lesions, normal ovarian function, normal fertility.
Constitutional growth delay	Short stature in a girl, delayed puberty.	Bone age is delayed, FSH and LH are low or appropriate for prepubertal stage, family history of late bloomers, normal karyotype, eventual normal final height.
Familial short stature	Short stature in a girl.	Bone age matches chronological age, parents are short, normal puberty timing, normal FSH and LH, normal karyotype.
Premature ovarian insufficiency (non-Turner)	Primary or secondary amenorrhea with elevated FSH.	Often presents after puberty has progressed normally, normal karyotype, may have FMR1 premutation or autoimmune cause.
Mullerian agenesis (MRKH)	Primary amenorrhea in a phenotypic female.	Normal pubertal development with breast development because ovaries are functional, normal 46,XX karyotype, absent uterus on ultrasound, normal estrogen and FSH.
Androgen Insensitivity Syndrome	Phenotypic female with primary amenorrhea.	46,XY karyotype, normal or tall stature, breast development present (peripheral aromatization), absent or sparse pubic and axillary hair, undescended testes, elevated testosterone.
Hypothalamic amenorrhea	Primary or secondary amenorrhea.	Low FSH and LH (hypogonadotropic), often associated with low body weight, intense exercise, or stress, normal karyotype.
Down Syndrome	Congenital syndrome with short stature and cardiac disease.	Trisomy 21 karyotype, characteristic facies (epicanthal folds, flat nasal bridge, single palmar crease), intellectual disability, AV canal defects rather than coarctation.

6. Traps and High-Yield Pearls

The classic trap is mistaking Turner syndrome for Noonan syndrome when the vignette describes a webbed neck and congenital heart disease. The discriminators to lock in are sex (Turner is phenotypic female only, Noonan affects both sexes), karyotype (Turner has 45,X, Noonan is normal), and which side of the heart is involved (Turner equals left-sided lesions like bicuspid aortic valve and coarctation, Noonan equals right-sided lesions like pulmonic stenosis).

A second high-yield trap is dismissing a girl with isolated short stature as constitutional delay. The teaching point is that Turner syndrome can present with short stature as the only finding, particularly in mosaic forms, so the threshold to send a karyotype must be low. Bone age, FSH, and karyotype are the workup tools that separate these.

A third trap is the adolescent with primary amenorrhea. Test writers love to layer this presentation with subtle clues that point to one of three possible answers: Turner syndrome (short stature, elevated FSH, streak ovaries), androgen insensitivity (tall stature, breast development without pubic hair, 46,XY), or Mullerian agenesis (normal pubertal development, absent uterus, 46,XX). Reading the height, the breast and pubic hair status, and the FSH carefully tells you which one is being tested.

A fourth trap concerns pregnancy planning. Patients with Turner syndrome can conceive through donor oocyte IVF, but the question being tested is recognition of the catastrophic risk of aortic dissection. The correct answer for any Turner patient considering pregnancy is comprehensive cardiac evaluation with aortic root imaging before conception, not immediate referral for fertility treatment.

A fifth trap is the mosaic patient with hidden Y material. Any Turner patient found on FISH or microarray to have Y-chromosome material requires prophylactic gonadectomy because of the risk of gonadoblastoma. This is a common "next best step" question once the diagnosis is established.

The core competency being tested across Turner syndrome questions is pattern recognition across multiple organ systems combined with appropriate sequencing of confirmatory tests and multidisciplinary surveillance. Test writers reward the candidate who recognizes that short stature plus delayed puberty plus a left-sided cardiac lesion in a phenotypic female equals one diagnosis, that the confirmatory test is always karyotype, and that lifelong surveillance is what separates standard of care from inadequate management.

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