Mrcpch Guide Genetics

MRCPCH GUIDE Genetics Parents who have had one affected child have a 3–5% risk in future pregnancies of having another affected child. In conditions inherited in a multi-factorial fashion Alpha thalassemia, chromosome 16p and Sickle cell disease, chromosome 11p are correctly paired. The correct associations for the remaining conditions would be: Tuberose sclerosis, chromosome 9q, Polyposis coli, chromosome 5q and Phenylketonuria, chromosome 12q.

Alagille syndrome comprises biliary hypoplasia, arteriohepatic dysplasia, hyperbilirubinaemia and vertebral and cardiac anomalies. Fifteen per cent of cases are autosomally dominant inherited with variable expression. Autosomal recessive inheritance and sporadic mutations are also found. It involves the deletion of p20 (jag 1) gene. A total of 20% of cases are premature/intrauterine growth retardation or small or small for gestational age infants. The aetiological factor may be a viral teratogenic factor. Typical facial appearances include frontal bossing, a pointed chin, deepset eyes and a prominent nose. Ophthalmological findings include posterior embryotoxin (70%) and pseudo-retinitis. Butterfly vertebrae (50%) are the known bony defects. Congenital heart disease is seen in 95% of cases, 10% of whom have cyanotic conditions and 50% of whom are known to have peripheral pulmonary artery stenosis. Liver complications include chronic cholestasis (paucity of the interlobar ducts), obstructive jaundice (often diagnosed when an infant), giant-cell hepatitis, pruritis and loose pale stools after the introduction of a fat-laden diet. Other clinical manifestations include learning difficulties, delayed sexual development and endocrine, neurological and renal abnormalities. The family cardiac history includes atrioventricular septal defect, hypoplastic left heart (HLH) and right ventricular outflow tract obstruction syndrome. Diagnosis is aided by a HIDA liver isotope scan. Other useful tests include liver biopsy to exclude biliary atresia, ophthalmic assessment to review the cornea, cardiac assessment, a spinal radiograph to visualise the vertebral axis, a sweat test to exclude cystic fibrosis and finally a genetics assessment. The differential diagnoses include extrahepatic biliary atresia, hepatitis syndrome, hepatic thrombosis, cystic fibrosis, galactosaemia, tyrosinaemia and Zellweger syndrome. The prognosis is satisfactory for 20–25% of cases, but the mortality rate due to liver failure is 3%.

Fetal rubella infection is not associated with limb defects. Fetal infection following maternal infection with rubella is maximum in the first two months with a declining incidence up to the fifth month. Deafness is the most frequent clinical complication – incidence ranges from 83% of infants exposed in the first month to 49% in the fourth month. After the fourth month the risk of deafness declines. Congenital heart disease, particularly patent ductus arteriosus (PDA) and peripheral pulmonary stenosis, affects around 50% of infants. Other complications include microcephaly, mental retardation, cataract, chorioretinitis and mental retardation. Fanconi’s anaemia and Holt– Oram syndrome are associated with radial ray defects. Fetal vitamin A syndrome can present with bony defects, absent thumbs, syndactyly and camptodactyly. Amniotic bands commonly present with terminal amputations and constriction bands.

Fluorescence in situ hybridisation (FISH) is a special staining technique to visualise chromosome segments of interest. The specimen is processed and the slides are prepared in the usual manner. The chromosomes are denatured (ie, DNA which is normally a double helix is rendered singlestranded) and a single-stranded DNA probe, that matches the segment of DNA on the chromosome that is thought to be missing, is added on the slide. Annealing (attachment) takes place between the single-stranded probe and its complementary sequences on the single-stranded chromosomes. The excess probe is washed away and the slide is treated with other agents to permit visualisation of the probe using fluorescence microscopy. G-banding remains the primary method of staining for routine chromosome analysis, as it is less expensive than FISH.

In neurofibromatosis type 2, cataracts can occur. Early detection in family members may be made by finding lens opacities (both congenital polar cataracts and posterior lenticular opacities). However cataracts are not seen in NF1. The eye findings in NF1 are Lisch’s nodules, which are pigmentary lesions seen on the iris and constitute one of the major diagnostic features in this condition. Incontinentia pigmenti is an X-linked dominant disorder with pigmentary skin changes, mental retardation and eye involvement in 40% of cases. Myotonic dystrophy is a triplet-repeat disorder with neurological symptoms and cataracts. Lowes’ syndrome (oculo-cerebro-renal syndrome) is an X-linked recessive condition. Males with this X-linked recessive condition have cataracts, hypotonia, mental retardation, a generalised aminoaciduria and renal tubular acidosis with hypophosphatasia. Wilson’s disease is an inborn error of copper metabolism. The clinical features include hepatic involvement, progressive neurological features, eye involvement including Kayser– Fleischer rings and cataracts.

Gonadal mosaicism Very rarely, two or more sibs with an autosomal dominant trait have normal parents. This can be explained on the basis of germ-line or gonadal mosaicism. A parent could have a mutation that is limited to the germ-line (germ cells – egg or sperm) while sparing the somatic cells. Such individuals are phenotypically normal; however, they have a greater risk of recurrence than the general population. This phenomenon has been described in osteogenesis imperfecta, achondroplasia and Duchenne’s muscular dystrophy.

Burkitt’s lymphoma 90% have a 8/14 translocation or 8/2 or 8/22. Chromosomes 2,14, 22 carry Ig genes and an oncogene is on chromosome 8.

Marfan’s syndrome 15% spontaneous mutation rate. Fibrillin gene chromosome 15q.

Noonans’ is an autosomal dominant disorder often caused by mutation in PTPN11.

Prader Willi Syndrome A microdeletion is present in about 70%.

Approximately 1/3 of individuals with Turner’s syndrome have a thyroid disorder, usually hypothyroidism.

There are a number of different causes of ambiguous genitalia.  True hermaphroditism - children have both ovarian and testicular tissues and external genitalia that are partially ambiguous (46, XX, 46, XY, or mosaic).  Gonadal dysgenesis - children have an undeveloped gonad, usually female internal sex organs and external genitals that may vary between normal female and normal male, with the majority female. Chromosomes that are 45, X, 46, XY, 46, XX, or mosaic.  Pseudohermaphroditism - children who have questionable external genitalia, but have only one gender's internal reproductive organs. Male pseudohermaphroditism may be caused by Androgen insensitivity syndrome (children have 46, XY karyotype and normal female external genitalia.) or 5-alpha-reductase deficiency (children who have genital ambiguity and 46, XY karyotype). Female pseudohermaphroditism may be due to Congenital adrenal hyperplasia or other causes of increased testosterone (eg. Maternal drug treatment ).

Fraternal twins (non-identical) usually occur when two fertilised eggs are implanted in the uterine wall at the same time. The two eggs form two zygotes, and these twins are therefore also known as dizygotic. Dizygotic twins may be a different sex or the same sex, just as with any other siblings. The risk of autosomal recessive disorders in a dizygotic twin of an affected child is ¼ (as with other siblings). Identical twins occur when a single egg is fertilised to form one zygote (monozygotic) but the zygote then divides into two separate embyros. Monozygotic twins are genetically identical unless there has been a mutation in development, and they are almost always the same gender. The two embryos develop into fetuses sharing the same womb. Depending on the stage at which the zygote divides, identical twins may share the same amnion (in which case they are known as monoamniotic) or not (diamniotic). Diamniotic identical twins may share the same placenta (known as monochorionic) or not (dichorionic). Sharing the same amnion (or the same amnion and placenta) can cause complications in pregnancy. For example, the umbilical cords of monoamniotic twins can become entangled, reducing or interrupting the blood supply to the developing fetus. Monochorionic twins, sharing one placenta, usually also share the placental blood supply. These twins may develop such that blood passes disproportionately from one twin to the other through connecting blood vessels within their shared placenta, leading to twin-to-

twin transfusion syndrome. About 50% of mono-mono twins die from umbilical cord entanglement.

Mitochondrial DNA This condition is inherited in an X-linked dominant pattern.

genetic anticipation Such dynamic mutations form the basis of an increasing list of inherited neurologic disorders that includes mental retardation (fragile X syndrome), myotonic dystrophy, oculopharyngeal muscular dystrophy, Friedreich ataxia, Huntington disease, and the dominantly inherited cerebellar ataxias.

Alpha thalassemia, chromosome 16p and Sickle cell disease, chromosome 11p are correctly paired. The correct associations for the remaining conditions would be: Tuberose sclerosis, chromosome 9q, Polyposis coli, chromosome 5q and Phenylketonuria, chromosome 12q. Marfan’s syndrome is inherited in an autosomal dominant manner, with the gene locus on chromosome 15.

Treacher Collins syndrome has autosomal dominant inheritance. It is a 1 st branchial arch defect. Deafness, coloboma (mainly of the lower eyelids), recurrent ear infections and cleft palate are all recognised features, along with ventricular septal defects and fusion of the radius and ulna.

Noonan syndrome is a common autosomal dominant condition, caused by mutations in PTPN11 on chromosome 12q. The incidence is around 1 in 2500 individuals. Affected individuals are characteristically short (mean height around 3rd centile), and have down slanting palpebral fissures, with heavy or ‘hooded’ eyelids. A low posterior neckline and short ‘webbed’ neck are often seen. 50-80% of individuals with Noonan syndrome have a cardiac defect. The most common defect is pulmonary stenosis. Hypertrophic cardiomyopathy occurs in about 20% of individuals with Noonan syndrome, and may present throughout life. Feeding problems in infancy are very common, and this appears to correlate with mild developmental delay (seen in about 30% of cases). Feeding difficulties occur in the majority, and NG feeding is often necessary. Developmental delay may bee seen early in life, but IQ is usually in the normal range, and the majority are educated in mainstream school. In children with Noonan syndrome, problems with coagulation are common, and this should be investigated if a history of easy bruising or abnormal bleeding is seen in childhood.

One main gene for Rett syndrome has been found – MECP2, located on Xq28. More than 99% of cases are de novo occurrences.

Klinefelter syndrome results from a 47XXY karyotype. It has a prevalence of 1/600-1/800 male births. It is more common with increasing maternal age. Babies appear normal at birth, but in childhood are taller than their peers. A tendency towards passive, unassertive behaviour has been noted frequently. Although boys enter puberty normally, by mid-puberty the testes begin to involute and they develop hypergonadotrophic hypogonadism with decreased testosterone production. 47, XXY males are, with occasional exceptions, infertile. Gynaecomastia is common, and occasionally requires surgical reduction. Congenital heart disease is not a feature of Klinefelter syndrome.

A child comes to see you for investigation of hyperphagia. At birth, he was extremely floppy and he required NG feeding for the first 6 months of life due to a poor suck. Uniparental disomy Your answer Sporadic occurrence Correct answer Sporadic occurrence The condition described is Prader-Willi syndrome. It results from absence of transcription of paternally inherited genes on chromosome 15. 70% of cases are sporadic. Most of the other 30% are caused by uniparental disomy (inheritance of both maternal alleles). Congenital myotonic dystrophy Myotonic dystrophy is the most common inherited neuromuscular disorder, with a prevalence of 1/8000. It is inherited in an autosomal dominant manner, and severity depends on the size of expansion within the myotonin gene on chromosome 19. Most affected individuals have muscle weakness and myotonia, together with cataracts and diabetes mellitus. Congenital myotonic dystrophy is likely to occur when an affected mother has an affected baby. The resulting problems are severe muscle weakness and respiratory problems in the infant. Crohn’s disease does not appear to be more common in individuals with DS. Coeliac disease does have a higher prevalence. Atlanto-axial subluxation occurs in 12-20 % of individuals with DS although symptoms are rare. At least 40% of individuals with DS develop Alzheimer’s later in life. This may result from a gene dosage effect for the amyloid precursor gene on chromosome 21.

Down’s syndrome is associated with an increased incidence of leukaemia, Alzheimer’s disease and duodenal atresia and atlanto-axial dislocation. It is also associated with an increased risk of congenital heart disease (In Down’s syndrome cardiac lesions are present in 30-50% of children. The most common lesions are septal defects, 30% being atrioventricular septal defects and 30% being ventricular septal defects). They also are at risk of oesophageal atresia, Hirschprung’s disease, pulmonary hypertension and cataracts. Neonatal hypotonia is an almost universal feature of Down’s syndrome. Cardiac lesions are present in 30-50% of children. The most common lesions are septal defects, 30% being

atrioventricular septal defects and 30% being ventricular septal defects. Down’s syndrome is associated with an increased incidence of hypothyroidism, cervical spine abnormalities, leukaemia, Alzheimer’s disease, duodenal and oesophageal atresia, Hirschprung’s disease, pulmonary hypertension and cataracts. The majority of cases arise from chromosomal nondysjunction at meiosis. Although it is important to examine the karyotype for translocations (as inheritance from either parent increases the risks for future pregnancies), translocations are found in fewer than 5% of children with trisomy 21.

Klinefelter’s Syndrome has a karyotype of 47XXY. It is usually due to meiotic non-dysjunction. Increased maternal age is a risk factor. Affected men are tall and thin with bilateral gynaecomastia, delayed puberty and hypogonadism leading to infertility. Intelligence tends to be below average. Microcephaly refers to a small head, where the head circumference is less than 2 standard deviations below the mean. Microcephaly can be primary or secondary to other causes. Primary causes include genetic defects such as trisomy 13,18 and 21 and Cri du Chat syndrome (5p-). Secondary microcephaly occurs due to congenital infections, placental insufficiency, maternal alcohol consumption during pregnancy and hypoxic ischaemic encephalopathy. Soto’s syndrome is a state of cerebral gigantism and thus macrocephaly.

Neurofibromatosis type I is associated with optic gliomas (15%) and Lisch iris nodules. It is an autosomal dominant condition with the gene locus on chromosome 17. At least 50% of cases arise due to new mutations. Other features include axillary freckling, 6 or more café au lait spots and bony lesions such as kyphoscoliosis. Neurofibromatosis type II is associated with bilateral acoustic neuromas. It is an autosomal dominant condition with the gene locus on chromosome 22.

Di George syndrome is associated with chromosome 22q11.2 deletion. It arises due to a defect in embryological development of the 3rd and 4th pharyngeal arches, which consequently affects the development of the thymus, parathyroid glands and the heart tube. This can lead to abnormalities of the thymus, hypoparathyroidism (therefore low calcium) and heart- such as interrupted aortic arch, truncus arteriosus, tetralogy of fallot and familial VSD. Ear abnormalities are also recognised.

Sickle cell disease is associated with a gene defect on chromosome 11p, cystic fibrosis with a gene defect on chromosome 7p and neurofibromatosis with defects on chromosome 17 (type I) and 22 (type II). Myelomeningocele does not have a specific gene locus and Klinefleter’s syndrome occurs due to the karyotype 47XXY.

Polyhydramnios is associated with an amniotic fluid volume in excess of 2000ml. Causes include Oesophageal atresia, Anencephaly, duodenal or Jejunal atresia, maternal diabetes mellitus, fetal anaemia, hydrocephalus and spina bifida. Posterior urethral valves and renal agenesis are associated with oligohydramnios.

fragile X syndrome

Boys with the FMR1 full mutation are always affected (unless they have coincidental Klinefelter syndrome). Girls with the full mutation have around a 50% chance of showing significant learning disability or behavioural features. The sons of a woman with full mutation have a 50% chance of inheriting a normal X chromosome, in which case they would be unaffected. There is also a 50% chance they would inherit the full mutation (which rarely contracts in size) and so be affected. Pre-mutation carriers of either sex are not affected. A man passes on his Y chromosome to all his sons. He passes his X chromosome to all his daughters, but the pre-mutation does not expand when transmitted through a male, which means that all his daughters will be pre-mutation carriers. In the past, testing was cytogenetic and required culturing of lymphocytes in folate-deficient media to reveal the fragile site. However, this resulted in false-negatives. Modern testing is by molecular genetic analysis to assess the size of the repeat expansion, which is far more reliable. Imprinted genes are those for which the parental origin determines the degree to which they are expressed. Imprinting can involve exclusive expression of one parental allele, or relatively greater expression from one allele compared to another. The pattern of parental expression is consistent across all normal individuals. Imprinting of some genes is tissue specific (that is, it can only be detected in certain tissues). Beckwith–Wiedemann syndrome results from abnormal imprinting of the IGF2/H19/KVLQT1/p57kip (CDKN1C) gene cluster on chromosome 11p15, although there are several different underlying molecular mechanisms. Prader–Willi syndrome results from absence of a paternal contribution for genes on chromosome 15q11–13. In around 70% it is due to a deletion on the paternal-derived chromosome 15 while in about 30% it is due to maternal uni-parental disomy for chromosome 15 (where both copies of chromosome 15 are maternally derived with no paternal contribution). Transient neonatal diabetes results from abnormal imprinting of a gene(s) on distal chromosome 6q. Most patients have been found to have paternal uni-parental disomy for the region or paternal duplications. Around 15% of patients with Silver–Russell syndrome have maternal uni-parental disomy for chromosome 7. In the remainder, the molecular mechanism is not yet clear.

FISH testing is used to detect sub-microscopic chromosome deletions (microdeletions). Patients with Williams syndrome have deletions which encompass the elastin gene and adjacent genes, DiGeorge syndrome results from 22q11 deletions, and cri-du-chat results from deletions of chromosome 5p, which may be visible on standard microscopy but may be sub-microscopic (therefore it is best tested for by FISH). Although FISH testing will detect patients with Prader–Willi who have a deletion (around 70%) it does not detect the 30% of patients with uni-parental disomy. Molecular genetic (DNA-based) testing is now used for Prader-Willi which screens for both. In translocation Down syndrome, the translocation is best seen on routine karyotyping.