CHAPTER 6: Developmental Genetics
1 The combination of macrocephaly, odontogenic keratocysts, and basal cell carcinomas occurs in Gorlin (basal cell nevoid carcinoma) syndrome. This condition should be in the differential diagnosis of a child with macrocephaly, with appropriate exploration of the family history. It is understandable that hydrocephalus would be the main concern, but true hydrocephalus is unusual in Gorlin syndrome.
2 The child’s father is an obligate carrier for the PTCH gene mutation causing Gorlin syndrome in the family. He should be screened regularly (at least annually) by radiography for odontogenic keratocysts, and be under regular surveillance by a dermatologist for basal cell carcinomas. PTCH gene mutation analysis is possible for any affected family member.
1 The two most likely causes of sex reversal in a young ‘girl’ are androgen insensitivity syndrome (AIS), which is X-linked and results from mutations in the androgen receptor gene, and mutations in the SRY gene on the Y chromosome.
2 Mutation analysis in both the androgen receptor and SRY genes can be performed to determine the genetic basis of the sex reversal. It is very important to investigate and locate, if present, remnants of gonadal tissue because this will have to be removed to avoid the risk of malignant change. Because of this, the parents should be given a full explanation, but the phenotypic sex of the child should be affirmed as female.
CHAPTER 7: Patterns of Inheritance
1 It is possible that the problems described in family members are unrelated, but this is unlikely. If the condition has passed from the grandfather, mitochondrial inheritance is very unlikely. The condition is either autosomal dominant with variability, or X-linked.
2 The spinocerebellar ataxias are a genetically heterogeneous group of conditions that usually follow autosomal dominant inheritance and could present in this way. A form of hereditary spastic paraparesis is possible, also genetically heterogeneous and usually after autosomal dominant inheritance, although recessive and X-linked forms are described. Apart from these, X-linked adrenoleukodystrophy must be considered, especially because the man has signs of cognitive and behavioral problems. This is very important, not only because it can present early in life but also because of the potential for adrenal insufficiency.
1 The information may be correct but is probably not and other possibilities must be explained to them.
2 Most forms of osteogenesis imperfecta (brittle bone disease) follow autosomal dominant inheritance. Sibling recurrence, when neither parent has signs or symptoms, can be explained by somatic and/or germline mosaicism in one of the parents. The risk to the offspring of those affected would then be 50% (i.e., high). In this case history, the possibility of a non-genetic diagnosis must be considered, namely non-accidental injury. It is therefore important to try to confirm the diagnosis.
CHAPTER 8: Mathematical and Population Genetics
1 Clearly, it is essential to know whether the condition in question has ever knowingly occurred in the families of either of the two consultands. If this had occurred, it would potentially modify the carrier risk for one of the consultands regardless of the frequency of the disease in the population.
.1 From the figures given, four cases in the town appear to be new mutations, i.e., four new mutations per 100,000 genes inherited. The mutation rate is therefore 1 per 25,000 gametes.
2 The population sample is small and may not therefore be representative of the larger, wider population. For example, if there is a bias toward an older, retired population, the reproducing subpopulation may be smaller and the figures distorted by the migration of younger people away from the town. In addition, the four ‘new mutation’ cases should be verified by proper examination of the parents.
CHAPTER 9: Polygenic and Multifactorial Inheritance
1 Testing for factor V Leiden and the prothrombin G20210A variant is appropriate. A positive result would provide a more accurate risk of her developing thromboembolism and would inform her choice of contraception. Heterozygosity for factor V Leiden or the prothrombin G20210A variant would increase her risk by four- to fivefold. Homozygosity or compound heterozygosity would increase her risk by up to 80-fold.
1 The proband might have type 1 diabetes (T1DM), type 2 diabetes (T2DM), or maturity-onset diabetes of the young (MODY). Because both have normal hearing, a diagnosis of maternally inherited diabetes and deafness (MIDD) is unlikely. T1DM and T2DM show multifactorial inheritance with environmental factors playing a role in addition to predisposing genetic susceptibility factors. MODY shows autosomal dominant inheritance.
2 The brother’s risk of developing diabetes is 6%, 35%, or 50%, respectively. If his sister is found to have a mutation in one of the genes causing MODY, then he could have predictive genetic testing. A negative test would reduce his risk to that of the population. A positive test would allow regular monitoring in order to make an early diagnosis of diabetes and avoid diabetic complications from long-standing undiagnosed diabetes.
CHAPTER 10: Hemoglobin and the Hemoglobinopathies
1 The ethnic origin of the couple and the limited information should suggest the possibility of a hematological disorder. α-Thalassemia is the likely cause of stillbirth, hydrops being secondary to heart failure, which in turn is secondary to anemia. Rhesus isoimmunization and glucose-6-phosphate dehydrogenase deficiency are other possibilities. Severe forms of congenital heart disease are frequently associated with hydrops, but the chance of a sibling recurrence (which occurred in the case history) is low. However, there are many other causes of hydrops and these would need to be considered. Among those that are genetic with a chance of recurrence are lethal forms of rare skeletal dysplasias and a wide range of metabolic disease.
2 A full blood count, blood groups, Hb electrophoresis, and maternal autoantibody and glucose-6-phosphate dehydrogenase deficiency screens should be performed for the couple. DNA analysis may detect the common mutation seen in Southeast Asia, which would then make it possible to offer genetic prenatal diagnosis by chorionic villus sampling. If no disorder is identified by these investigations it is unlikely that further diagnostic progress will be made unless the couple has another affected pregnancy that can be fully investigated by examination of the fetus.
1 This presentation is consistent with acute intermittent porphyria and hemolytic uremic syndrome. However, the ethnic origin should suggest the possibility of sickle cell disease. The contents of the dark urine, and specific tests for porphyria, will help to differentiate these, and a sickle cell test should be performed.
2 If the diagnosis is sickle cell disease there are various agents that can be tried to reduce the frequency of sickling crises—hydroxyurea in particular. Prophylactic penicillin is important for reducing the risk of serious pneumococcal infections, and the family should be offered genetic counseling and cascade screening of relatives.
CHAPTER 11: Biochemical Genetics
1 Hypoglycemia can be part of severe illness in young children, but in this case the intercurrent problem appears relatively minor, suggesting that the child’s metabolic capacity to cope with stress is compromised. This history should prompt investigations for a possible inborn error of metabolism and, if a diagnosis is made, the younger sibling should be tested.
