Chromosomal disorders and syndromes

Nondisjunction is failure of chromosomes to separate during meiosis, so an egg or sperm ends up with 24 or 22 chromosomes instead of 23. Fertilized by a normal gamete, it gives a trisomic (47) or monosomic (45) conceptus. Most autosomal monosomies and many trisomies are lost as miscarriages; the survivors are trisomy 21, 18 and 13, and the sex-chromosome aneuploidies (45,X; 47,XXY; 47,XXX; 47,XYY).

The error can happen in either division. In meiosis I the two homologs fail to part: the disomic gamete receives one of each homolog (one originally from the parent's father, one from the parent's mother). In meiosis II the sister chromatids fail to part: the disomic gamete receives two copies of the same homolog. Polymorphic DNA markers next to the centromere tell them apart: two different alleles from one parent mean meiosis I (heterodisomy), two identical alleles mean meiosis II (isodisomy). Most maternal trisomy 21 arises in maternal meiosis I, the step that has been paused in the oocyte since before the mother was born, which is why risk climbs with maternal age.

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Mosaicism is the presence of two or more cell lines with different karyotypes in one person, derived from a single zygote. It arises from a mitotic error (nondisjunction or anaphase lag) in the early embryo. Because only some cells are abnormal, mosaics are usually milder; mosaicism is most common with sex chromosomes (milder Turner syndrome, 45,X/46,XX) and causes about 1% of Down syndrome.

Structural changes move or remove pieces. What matters clinically is whether the change is balanced (every gene still present in two doses) or unbalanced (a net gain or loss). A balanced carrier is usually healthy but can produce unbalanced gametes, which show up as recurrent miscarriage or an affected child.

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Acrocentric short arms carry only repeated ribosomal RNA genes that also exist on the other acrocentrics, so losing two of them costs nothing. The carrier's problem appears at meiosis: the der chromosome and the two free chromosomes can segregate in several ways, and some gametes carry an extra or a missing long arm.

The 22q11.2 deletion (DiGeorge/velocardiofacial syndrome) is a microdeletion of about 3 Mb, too small for a routine karyotype; FISH or microarray finds it. Loss of TBX1 and neighboring genes disturbs the third and fourth pharyngeal pouches and the outflow tract of the heart, giving the CATCH-22 picture: conotruncal heart defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch), abnormal face, thymic hypoplasia (T-cell deficiency), cleft palate and hypocalcemia from parathyroid hypoplasia. Most cases are de novo; an affected parent passes it on as an autosomal dominant trait.

Females have two X chromosomes but the same X-gene output as males because, early in embryonic life (around the late blastocyst), one X in each cell is silenced at random (Lyon hypothesis). The XIST RNA coats the chosen X; its promoters are silenced by methylation of cytosines in CpG islands, and its histones are deacetylated and methylated into tight heterochromatin. The condensed X is visible at the edge of the interphase nucleus as the Barr body (in neutrophils, a “drumstick”). The choice is permanent and passed to every daughter cell, so every woman is a mosaic of two cell populations.

If inactivation silenced the whole chromosome, a 45,X woman or a 47,XXY man would have exactly normal X dosage and no syndrome. They do not, because about 15% of X genes escape inactivation, including the pseudoautosomal genes shared with Y such as SHOX. Two active copies of these genes are needed: one copy gives Turner short stature; a third copy contributes to Klinefelter tall stature.

Maternal age is the main risk factor for free trisomy: about 1 in 1,500 live births at age 20, rising to about 1 in 25 after 45. Because younger women have most babies, most children with Down syndrome are still born to mothers under 35. Every gene on chromosome 21 is normal; the disease is the 1.5-fold dose. The extra APP gene, for example, explains Alzheimer pathology by 35–40 years.

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Both are usually free trisomies from maternal nondisjunction, both cause severe intellectual disability and congenital heart disease, and most affected infants die in the first year. The separating clues are where the malformations cluster: Edwards syndrome in the hands, feet and jaw; Patau syndrome in the midline (brain, face) and with extra digits.

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Turner syndrome is complete or partial loss of the second sex chromosome in a phenotypic female: 45,X (about half), mosaics such as 45,X/46,XX, and structural X abnormalities (isochromosome Xq, ring X, Xp deletions). Most 45,X conceptuses miscarry; survivors are often mosaics. Each feature has a mechanism: one copy of SHOX (an escape gene) gives short stature with normal growth hormone; fetal lymphatics fail to drain, giving cystic hygroma that leaves a webbed neck and hand and foot lymphedema at birth; oocytes are lost at an accelerated rate, so the ovaries become streak gonads.

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Klinefelter syndrome (47,XXY, about 1 in 600 males) is the commonest cause of male hypogonadism. The extra X comes from paternal meiosis I in about half of cases and from maternal meiosis I or II in the rest; about 15% are 46,XY/47,XXY mosaics. The seminiferous tubules hyalinize: few Sertoli and germ cells (low inhibin B, so FSH rises; azoospermia) and dysfunctional Leydig cells (low testosterone, so LH rises). More testosterone is aromatized and sex hormone–binding globulin rises, so the estrogen-to-androgen balance tips toward estrogen: gynecomastia and a female pattern of hair and fat. Late epiphyseal closure plus an extra SHOX copy make them tall with long legs (eunuchoid).

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47,XYY (about 1 in 1,000 males) arises from paternal meiosis II nondisjunction (the YY sperm). Boys are taller than average with normal testes, hormones and fertility; IQ is on average about 10 points lower, with more speech, learning and attention problems.