Lecture 10 Part I: Turner Syndrome

What is Turner Syndrome?

• Only affects females; ~1 in 2,000–2,500 live female births.

• Complete or partial absence of the second sex chromosome in a female (45,X).

What are the main prenatal signs of Turner Syndrome?

• Large fluid-filled swelling on the neck (cystic hygroma).

• Baby swelling from too much fluid (fetal edema / nonimmune hydrops).

• Extra fluid behind the baby’s neck on ultrasound (increased nuchal translucency).

• Heart defect: narrowing of the main artery (coarctation of the aorta).

• Kidneys joined together (horseshoe kidney).

• Slow growth in the womb.

• Too much amniotic fluid (hydramnios).

What are the postnatal phenotypic features of Turner Syndrome?

• Short stature (~5' maximum height), ovarian failure, cardiovascular disease.

• Facial features: flat bridged nose, hypertelorism, ptosis, epicanthal folds, low-set ears, retrognathia.

• Autoimmune diseases.

What are the 3 peaks of Turner Syndrome diagnosis?

• <1 year: 14.9%; adolescence (10–17 yrs): 33.2%; adulthood: 38.5%.

• Median diagnosis age: 15 years.

• Significant diagnostic delay if not caught prenatally.

What are the karyotype types and frequencies in Turner Syndrome?

• Monosomy X (45,X): 40–50% → most common.

• Mosaicism with 46,XX: 15–25%; Mosaicism with 46,XY: 10–12%.

• Isochromosome Xq: 15%; Mosaicism with 47,XXX: 3%; Ring X and others: rare.

What is Mosaic Turner Syndrome vs. Classic Turner Syndrome?

• Classic: nondisjunction during gamete development → every cell has only 1 X.

• Mosaic: random error during fetal cell development → some cells 45,X, others normal.

• Mosaicism generally produces a milder phenotype.

What is a Barr body and why is it absent in Turner Syndrome?

• A Barr body is the inactivated (silenced) second X chromosome seen in normal 46,XX females.

• In Turner Syndrome (45,X), there is only one X chromosome → nothing to inactivate → no Barr body.

• This matters because genes on the single X are fully expressed with no compensatory silencing, contributing to the TS phenotype.

How does nondisjunction in Meiosis I lead to Monosomy X (Turner Syndrome)?

• X and Y chromosomes fail to separate in Meiosis I → one secondary spermatocyte gets both sex chromosomes, the other gets none.

• The "none" cell produces a sperm with no sex chromosome.

• That sperm + normal egg (23,X) → zygote with only 45,X = Monosomy X.

How does nondisjunction in Meiosis II lead to Monosomy X (Turner Syndrome)?

• Sister chromatids fail to separate in Meiosis II → one sperm gets 2 sex chromosomes, another gets none.

• The "none" sperm + normal egg (23,X) → 45,X = Monosomy X.

• Meiosis II error also produces a euploid (46,XX) zygote alongside the monosomy, distinguishing it from a Meiosis I error.

What is the SHOX gene and why is it important in Turner Syndrome?

• Located in the pseudoautosomal region PAR1 of X and Y chromosomes (Xp22.33/Yp11.3).

• Haploinsufficiency causes: short stature, Madelung deformity, reduced leg length, micrognathia, high arched palate.

  • Madelung deformity = a wrist abnormality where one of the forearm bones (the radius) doesn’t grow normally near the wrist.

• Regulates NPPB and FGFR3; codes for extracellular matrix proteins involved in bone/growth plate development.

• SHOX deletion can occur without TS → karyotype analysis is still required for definitive diagnosis.

What is the tissue/cellular basis of Turner Syndrome?

• Multisystem disease: cardiac (smooth muscle), skeletal, lymphatic, endocrine, renal.

• Lack of second X → streak ovaries form → ovarian failure → infertility + estrogen deficiency.

• Synthetic hormones required to induce puberty and preserve fertility.

What are the treatments for Turner Syndrome?

• Estrogen + progesterone to mimic puberty; growth hormone therapy.

• Symptom/condition management as they arise.

• No cure; long-term effects of hormone replacement are not yet fully known.

What were the 3 hypotheses of the Suntharalingham (2023) study?

• H1: Does loss of an X chromosome DNA repair/proofreading gene increase genome-wide autosomal mutations, contributing to excess morbidity?

• H2: Does haploinsufficiency of PAR region X genes expose hemizygous variants that increase risk for autoimmune disorders?

• H3: Are congenital cardiac abnormalities associated with TIMP3 variants when coupled with loss of TIMP1?

• Results: H1 and H2 were NOT supported; H3 WAS supported → TIMP3 is associated with cardiac abnormalities in TS

What did the Suntharalingham (2023) study find about Turner Syndrome?

• Used SNP arrays to analyze genetic variability in TS patients vs. controls.

• Women with TS did NOT have more autosomal mutations than controls → no evidence that missing X proofreading genes increase genome-wide mutation burden.

• No true association between specific missing X genes and phenotype severity

• TIMP3 gene variants ARE associated with congenital cardiac abnormalities when coupled with loss of TIMP1.

What is a SNP array and how does it work?

• Detects single nucleotide polymorphisms using a single hybridization strategy; more sensitive than standard array CGH.

• Steps: sample prep → DNA extraction → amplification + oligonucleotide/chip design → fluorescent labeling → hybridization/wash → signal scanning.

• Can detect small deletions and point mutations, not just chromosomal-level changes.

Why is diagnosis of Turner Syndrome often delayed if not made prenatally?

• Many features (short stature, subtle facial differences) are not alarming in early childhood and may be attributed to normal variation.

• Ovarian failure and infertility only become apparent at puberty when periods don't start → a major trigger for adolescent diagnosis.

• Lack of awareness among general practitioners means TS may not be considered until specialist referral.

• Mosaic TS can present even more mildly, further delaying recognition.

What reproductive effects can occur if Turner Syndrome is not found early enough?

• Without early hormone intervention, the ovaries remain as non-functional streak ovaries → permanent infertility in most cases.

• Estrogen deficiency means puberty does not occur naturally → uterine underdevelopment, reducing even the potential for assisted reproduction (e.g., egg donation/IVF).

• Early diagnosis allows for fertility preservation counseling and timely hormone replacement to support uterine development before the window closes.

Why is Turner Syndrome treatment focused on symptom management rather than a cure?

• The condition is chromosomal, present in every cell of the body, making it impossible to "correct" with current technology

• Gene therapy capable of restoring an entire chromosome to trillions of cells does not yet exist.

• Each patient's phenotype varies (especially in mosaic TS), so treatment must be individualized to the symptoms that are actually present.

• Management goals are quality of life: normal puberty, bone health, cardiovascular monitoring, and fertility options where possible.