Kathleen Evans

GENETIC CLINIC: A FOLLOW-UP

Abstract The first genetic clinic in the British Isles was established at the Hospital for Sick Children in 1946. Patients are referred to this clinic by family doctors, consultants, and local-authority medical officers. The paper reports a follow-up from 3 to 10 years later of 455 couples seen at this clinic from 1952 to 1964. The sample was restricted to couples who wished for advice on the risks of recurrence of serious disorders in their children. The interval between the consultation and the visit was from 3 to 10 years. The object of the follow-up was to discover: how far couples understood the information they were given on risks; the decisions the couples took about planning further pregnancies; the outcome of any further pregnancies. First, it was found that on the whole the parents had understood the information they were given. Secondly, it was found that on the whole they took responsible decisions on the basis of the information. Where the recurrence risk was high—that is, equal to or greater than 1 in 10 —two-thirds (109 of 170) were deterred from planning further children. Where the risks were low—that is, less than 1 in 10—only a quarter (60 of 251) were deterred. No high-risk couple in the series had a planned further child with a serious long-term handicap. Thirdly, it was found that the risks given were on the whole accurate. Of 94 subsequent children born to high-risk couples, including those where the wife was already pregnant at the initial consultation, 17 were affected—a proportion of about 1 in 6. Of 229 children born to low-risk couples, 5 were affected— a proportion of about 1 in 50. With hindsight two errors, due to difficulties of diagnosis, were apparent in the information given.

CHILDREN OF ADULT SURVIVORS WITH SPINA BIFIDA CYSTICA

Abstract A consecutive series of patients with spina bifida cystica, identified from the records of The Hospital for Sick Children and St. Bartholomews Hospital before 1954, have been studied to estimate the risk of neural-tube malformation in the children of such patients who survive to adult life. The 215 survivors who were traced have had between them 104 children, 2 of whom have a neural-tube malformation. Of 100 male survivors, 14 have between them had 35 children, 1 of whom had spina bifida cystica. Of 115 female patients, 38 have between them had 69 children, of whom 1 had anencephaly. The results of this study combined with two other studies give an estimate for risk to offspring of parents of either sex of about 3%. It appears that the risk to children of male patients is at least as high as that of female patients.

CREATINE KINASE LEVELS IN WOMEN WHO CARRY GENES FOR THREE TYPES OF MUSCULAR DYSTROPHY.

Beagle. He certainly was bitten by the vector of Chagass disease, but there is no certainty that they were infected. The infection can cause myocardial damage and heart failure, megacolon and megaoesophagus, but it is often asymptomatic. Evidence from Darwins writings and those of some of his relatives indicates that his symptoms were of palpitations, lassitude, headaches, tremulousness, sleeplessness, and flatulence brought on by meeting people and by emotionally charged situations. His exercise tolerance remained good until shortly before his death at the age of 73.

A three generation family study of cleft lip with or without cleft palate.

A family study of cleft lip, with or without cleft palate, was based on those treated by operation at The Hospital for Sick Children, London, between 1920 and 1939 in order to give information on the proportion affected of children and grandchildren. The probands were those who had survived, were successfully traced, and found to have had at least one child. Care was taken to exclude patients who were traced through a child, whether normal or affected, and not through the usual tracing procedure. Patients with recognised syndromes were also excluded. Because the series was based on patients who had survived and reproduced it was biased in favour of those with milder degrees of the malformation, and against those with any severe associated malformation. The proportion affected of children of probands was 3.15% (+/- 0.56), of sibs 2.79% (+/- 0.52), and of parents 1.18% (+/- 0.37), respectively. The lower proportion of parents affected is attributed to reduced reproductive fitness of patients born two generations ago. The proportion affected of nephews and nieces, aunts and uncles, and grandchildren was 0.47% (+/- 0.18), 0.59% (+/- 0.13), and 0.8% (+/- 0.6) respectively. The proportion affected of first cousins was 0.27% (+/- 0.08). The birth frequency of cleft lip (+/- cleft palate) is estimated to be about 0.1% in England. There were two first cousin and one second cousin marriages among the marriages of the parents. There was no increase of cleft palate among the relatives of the probands. The proportion of sibs affected increased with increasing severity of the malformation in the proband, where the proband was female, and where the proband had an affected parent or already had one affected sib. It was not, however, increased where a more remote relative was affected. The proportion of children affected was not increased when the proband had an affected parent or sib, but few families provided information. The most economical hypothesis to explain the findings is the multifactorial threshold model. The birth frequency of the malformation and the family patterns found make it improbable that one single mutant gene makes a major contribution to the liability to develop the condition.

Spinal dysraphism: genetic relation to neural tube malformations.

The families of 207 index patients treated for spinal dysraphism at The Hospital for Sick Children were studied to discover whether the condition was aetiologically related to the classical neural tube malformation--spina bifida cystica and anencephaly. The index patients had all had a tethered conus medullaris and one or more of a variety of anomalies of the spinal cord, vertebrae, or skin overlying the vertebral column. Of 364 sibs of index patients, 9 had an encephaly and 6 spina bifida cystica, a pro-proportion of 4.12%. This approximates to the proportion of sibs affected by neural tube malformations in the London region when the index patients themselves have spina bifida or anencephaly. It is, therefore, appropriate that the mothers of children with spinal dysraphism should be offered prenatal screening for neural tube malformations.

Offspring of patients with tracheo-oesophageal fistula

One previous study has shown that the proportion affected of sibs of index patients with tracheo-oesophageal fistula is low. The survivors of the first successful operations for tracheo-oesophageal fistula are now reaching adult life, thus making possible a preliminary estimate of the proportion affected of children of index patients. From the records of two London hospitals a list of 99 consecutive patients was compiled; they were alive after operation and not known to have died since. Of these, 7 were living abroad, 4 were not willing to co-operate, and 9 (alive when last seen at hospital and probably still living) were not traced. The families of the remaining 79 were visited. Of the 79, 15 were found to have had children; 13 of these had the common type 3b oesophageal atresia (with a fistula between the trachea or main bronchus and lower segment of the oesophagus) and the other two probably had the same lesion. These 15 patients have so far had 28 children and only one had tracheo-oesophageal fistula (again type 3b). The 79 patients had had 130 sibs, of whom one had oesophageal atresia (without fistula), 3 had neural tube defects, and 2 had pyloric stenosis. The series, though small, already indicates that the proportion affected of children of patients is too small for the disorder in the parents to have been caused by a dominant mutation. For genetic counselling it is, perhaps, reasonable for the present to assume that the risk to children is similar to the risk for sibs and may not be more than 1%.

A family study of the late infantile and juvenile forms of metachromatic leucodystrophy.

Classification within the disorder formerly known as diffuse sclerosis has been much improved in the past decade. Lumsden pointed out in I95I that Schilder (I9I2, I913, I924) had described three distinct conditions, the one in his 1913 paper corresponding to what is now known as familial metachromatic leucodystrophy. In I957 Hirsch and Peiffer introduced a new stain for metachromasia (cresyl violet in I% acetic acid giving a golden brown colour), re-examined (Peiffer, I962) the necropsy material from several earlier cases, and reclassified them in the group of metachromatic leucodystrophy. The age of onset of metachromatic leucodystrophy extends from infancy to adult life. The most homogeneous group of these is the late infantile, in which the age of onset is between 7 and 36 months, with a mode at II-24 months. The child develops a progressive weakness, incoordination of limb and eye movements, dysphagia, and then increasing spasticity and dementia. The latest age at death recorded in this group is 7 years, apart from one survivor at 8 years. Without exception, the affected sibs of patients with this form of the disease have had a similar form of the disease. There has been little discussion of the genetics of the condition, with the exception of Jervis (I960) who suggested that the condition was autosomal recessive, and no family study of a consecutive series of index patients has yet been reported. The group of leucodystrophies with a later onset is heterogeneous. In a few families there is clear evidence of a dominant mode of inheritance with a wide range of age of onset, and the duration of the illness may be more than 20 years (Poser, Dewulf, and van Bogaert, I957). Other families (Scholz, I925; Walthard, I933; Pfister, 1936; Curtius, 1930; Hoefnagel, van den Noort, and Ingbar, I962) show a probable recessive X-linked inheritance with occasional manifestation in females: in this group there may be clinical evidence of skin pigmentation and, at necropsy, adrenal atrophy. Other adult cases are isolated. When these three subgroups are excluded, the remainder appears to form a homogeneous group, with age of onset between 4 and I0 years, the duration of the illness from i to ii years, and the earliest recorded age at death 7 years; there is, however, a male preponderance.

A family study of isolated cleft palate.

A family study was based on 245 boy and 329 girl patients treated surgically for non-syndromic cleft palate between 1920 and 1929; 86 and 81 respectively were traced and had had children. These 167 were the probands for the family study and were interviewed in their homes. None was born to a consanguineous marriage. Altogether they had had 384 children of whom 11 had cleft palate (2.9 +/- 0.9%). They had 398 sibs of whom five had cleft palate, 117 grandchildren of whom one was affected, and 517 nephews and nieces of whom one was affected. This is the largest series yet available on which to base an estimate of the risks to children of patients with non-syndromic cleft palate. The risk is probably increased where a parent or sib of the proband is affected and increased to a lesser degree where a second or third degree relative is affected. The family patterns in these and other studies suggest that the aetiology of cleft palate is heterogeneous, with some families showing modified dominant inheritance. This is in contrast to cleft lip (+/- cleft palate) where the data are consistent with a multifactorial threshold model.