Chromosomal abnormalities and patterns of inheritance

Overview

Genetic disorders are a major cause of childhood death and handicap. Akbar estimates that about 1% of newborns have a single-gene disorder, about 0.5% a chromosomal disorder, and 1-3% a multifactorial disease. There are three broad groups:

Chromosomal abnormalities

• Chromosome errors are found in about 8% of fertilised eggs but only about 0.6% of live births; most affected conceptions miscarry (Nelson).
• About half of spontaneous miscarriages have a chromosome abnormality, most often 45,X.
• Clues in a child: small for gestational age, failure to thrive, developmental delay, and three or more malformations.

Karyotyping

• Usually done on blood lymphocytes, stimulated to divide in culture, arrested in metaphase and stained (Giemsa banding).
• Other sources: bone marrow, skin fibroblasts, and before birth amniotic fluid or chorionic villi.

Abnormalities of number (aneuploidy)

• Nondisjunction: a chromosome pair fails to separate during cell division, giving gametes with an extra or a missing chromosome, so the child has trisomy (three copies) or monosomy (one copy).
• Trisomy is the commonest numerical abnormality.
• The older the mother, the more likely nondisjunction becomes.
• Mosaicism: an error after fertilisation gives two cell lines in one person (some cells 47, some 46 chromosomes).

Abnormalities of structure

A balanced translocation carrier is healthy but can have children with unbalanced chromosomes.

The main chromosomal syndromes

Down syndrome and Turner syndrome have their own chapters.

Klinefelter syndrome (47,XXY)

• About 1 in 500 (Nelson) to 1 in 1000 (Akbar) male births; the commonest genetic cause of male hypogonadism and infertility.
• An extra X from nondisjunction in egg or sperm; some boys are mosaic (46,XY/47,XXY).
• Normal-looking before puberty; usually diagnosed in adolescence: tall, long limbs (arm span greater than height), small testes that stay small while pubic hair develops, gynaecomastia, sparse body hair, learning and behaviour problems.
• High FSH, low testosterone, infertility (very few sperm); osteoporosis later.
• Treatment: testosterone replacement; assisted reproduction can sometimes allow fatherhood.

Single-gene (mendelian) inheritance

• Dominant: one copy of the faulty gene causes disease (seen in heterozygotes).
• Recessive: disease only when both copies are faulty (homozygotes); one copy makes a healthy carrier.

Autosomal dominant (AD)

• Males and females equally affected.
• Risk to each child of one affected parent: 50%.
• Vertical pattern: seen in every generation; unaffected relatives do not pass it on.
• Male-to-male transmission occurs (rules out X-linked).
• Usually affects structural or regulatory proteins, not enzymes.
• Reduced penetrance: some gene carriers show no signs. Variable expressivity: severity differs between carriers (for example NF1).
• New mutations explain cases with healthy parents (about 80% of achondroplasia), linked with older fathers.
• Anticipation: worse or earlier disease in each generation in repeat disorders such as myotonic dystrophy.

Examples: achondroplasia, Marfan syndrome, neurofibromatosis, tuberous sclerosis, Huntington disease, myotonic dystrophy, hereditary spherocytosis, von Willebrand disease, osteogenesis imperfecta, adult polycystic kidney disease, familial hypercholesterolaemia, Noonan syndrome. Akbar notes that conditions called "hereditary" or "familial" are usually dominant.

Autosomal recessive (AR)

• Parents are usually healthy carriers; the disease appears in siblings but not in parents or offspring (horizontal pattern).
• Each child of two carriers: 25% affected, 50% carriers, 25% normal.
• Consanguinity (cousin marriage) increases the risk; highly relevant in Pakistan.
• Usually enzyme defects: most inborn errors of metabolism are AR (porphyrias are an exception, being dominant).
• An affected person who marries a non-carrier has children who are all carriers.

Examples: cystic fibrosis, beta thalassaemia, sickle cell disease, phenylketonuria, galactosaemia, glycogen storage disease, congenital adrenal hyperplasia, Wilson disease, spinal muscular atrophy, Friedreich ataxia, albinism, Gaucher disease, mucopolysaccharidoses (except Hunter).

X-linked recessive (XLR)

• Males are affected (one X); carrier females are usually healthy or mildly affected.
• A carrier mother: each son 50% affected, each daughter 50% carrier.
• An affected father: all daughters carriers, no sons affected; there is no male-to-male transmission.
• Can skip generations through carrier females (a "diagonal" pattern through the mother's side).

Examples: haemophilia A and B, Duchenne and Becker muscular dystrophy, G6PD deficiency, colour blindness, Hunter syndrome, Lesch-Nyhan syndrome, Fabry disease, nephrogenic diabetes insipidus, Wiskott-Aldrich syndrome, androgen insensitivity (testicular feminisation), adrenoleukodystrophy; both books list fragile X in the X-linked group.

X-linked dominant (XLD)

• Affects both sexes; females are affected about twice as often but more mildly (one normal X).
• An affected father passes it to all daughters and no sons; an affected mother to half her children of either sex.
• Some are lethal in males (affected boys die before birth): incontinentia pigmenti, Rett syndrome.
• Examples: X-linked hypophosphataemic (vitamin D resistant) rickets, incontinentia pigmenti, Rett syndrome.

Multifactorial (polygenic) inheritance

• Caused by several genes plus environment; disease appears when total liability passes a threshold.
• Recurrence risk for a sibling or child is about 2-5% (Akbar).
• Risk rises with the number of affected relatives and the severity of the defect (for example bilateral cleft lip and palate carries more risk than isolated cleft lip).
• Sex bias: pyloric stenosis is commoner in boys; developmental dysplasia of the hip in girls.
• After one child with a neural tube defect, the risk of another is many times higher; periconceptional folic acid lowers the risk.

Examples: cleft lip and palate, neural tube defects, congenital heart disease, pyloric stenosis, hip dysplasia, club foot, Hirschsprung disease, asthma, diabetes, idiopathic epilepsy.

Mitochondrial inheritance

• Mitochondria have their own small circular DNA and come only from the egg.
• An affected mother passes it to all her children; an affected father passes it to none.
• Heteroplasmy: the mix of normal and mutant mitochondria varies, so severity varies within a family. High-energy organs (brain, muscle, liver) suffer most.
• Examples: MELAS (stroke-like episodes, lactic acidosis), MERRF, Leber hereditary optic neuropathy, Leigh syndrome, mitochondrial myopathy, diabetes with deafness.

Unusual mechanisms

Genomic imprinting and uniparental disomy

• Imprinting: some genes are switched on only from the father's or only from the mother's copy (by methylation).
• Uniparental disomy (UPD): both copies of one chromosome come from the same parent; the karyotype looks normal.

Trinucleotide repeat expansion

Genetic counselling and prenatal diagnosis

• Counselling tells a family the chance of recurrence and their options: family history with a three-generation pedigree, examination, accurate diagnosis, explanation of the inheritance and risk, and follow-up. Ideally it comes before the next pregnancy.
• Prenatal tests: serum screening and nuchal translucency (screening only); chorionic villus sampling or amniocentesis for fetal karyotype or DNA; ultrasound at 16-18 weeks for structural defects; cordocentesis for fetal anaemia, thrombocytopenia and thalassaemia.

Quick revision

• Nondisjunction gives trisomy or monosomy; risk rises with maternal age.
• Translocation: robertsonian, acrocentric chromosomes; balanced carriers are healthy.
• Trisomy 18: overlapping clenched fingers, rocker-bottom feet, hypertonia; trisomy 13: midline clefts, polydactyly, scalp defect.
• Klinefelter 47,XXY: tall, small testes, gynaecomastia, infertile, high FSH.
• AD: every generation, 50%, male-to-male spread, structural proteins.
• AR: carrier parents, 25%, consanguinity, enzymes; healthy sibling carrier risk 2/3.
• XLR: affected males, carrier mothers, no father-to-son spread.
• XLD: affected father passes to all daughters; hypophosphataemic rickets.
• Multifactorial: 2-5% recurrence, higher with more relatives and severe defects.
• Mitochondrial: maternal only; imprinting explains Prader-Willi and Angelman.

Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).

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