Biomedical subjects
Publications and source records attributed to D W Webb.
We describe two patients less than 13 years of age with thrombotic thrombocytopenic purpura, a rare disorder in childhood. Both children were treated with plasma exchange therapy, which resulted in a rapid resolution of symptoms. This disorder is a cause of childhood encephalopathy, which can be treated effectively with plasma exchange.
We have investigated a family in which three siblings with the autosomal dominant disorder tuberous sclerosis had unaffected parents. The family were typed for polymorphic markers spanning the two genes known to cause tuberous sclerosis located at 9q34 (TSC1) and 16p13.3 (TSC2). TSC1 markers showed different maternal and paternal haplotypes in affected children, excluding a mutation in TSC1 as the cause of the disease. For the TSC2 markers all the affected children had the same maternal and paternal haplotypes, as did three of their unaffected siblings. Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp insertion TACT following nucleotide 2077 in exon 18 which was present in the three affected children but not in five unaffected siblings or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by our finding of identical chromosome 16 haplotypes in affected and unaffected siblings, providing unequivocal evidence of two different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in the affected subjects showed that the mutation had been inherited from the mother. This is the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism.
A 6 year old boy presented with meningoencephalitis and was found to have serological evidence of acute human herpes virus-6 (HHV-6) infection. He did not develop symptomatic seizures or the rash of exanthum subitum (roseola). His course was marked by severe spastic quadriparesis associated with radiological evidence of basal ganglia infarction. HHV-6 infection should be considered in any child with acute meningoencephalitis.
Neurological complications and other causes of morbidity were studied in 122 of 131 individuals (64 males, 67 females) with tuberous sclerosis, in a popululation in which its prevalence was 1/26,500. Seizures occurred in 78 per cent, beginning at less that one year of age in 69 per cent (in more males than females in both cases) and after age 16 in 4 per cent. More males than females also had infantile spasms and persistent seizures. Learning disorder occured in 53 per cent (also in more males), all with a history of seizures, and was strongly correlated with age at onset of seizures, type of seizure and outcome for seizure control. Of subjects with learning disorder, 85 per cent required supervision for daily living and 65 per cent had little or no language; 97 per cent were fully mobile. Hemiparesis had occurred in eight of the 131, giant cell astrocytomas in nine bilateral polycystic kidney disease in two, and haemorrhagic complication relating to renal angiomyolipomas in six.
We report the cross-sectional age-related prevalence of cutaneous features of the tuberous sclerosis complex in a defined population. Of 131 affected individuals, 126 (96%) exhibited skin signs. Although there is considerable variation in the age of expression of all the skin lesions, there is a trend towards the earlier expression of hypomelanic macules and forehead fibrous plaques compared with facial angiofibromas and ungual fibromas. Shagreen patches are usually present by puberty. Ungual fibromas appeared for the first time as late as the fifth decade and were the only clinical feature in three individuals. Gum fibromas were present in 36%. Ten individuals (8%) presented because of the skin manifestations and 21% received treatment for symptomatic skin lesions. Two individuals had large hamartomas at unusual sites (occiput and forearm).
Follicular atrophoderma has always been associated with other congenital malformations including, Conradi-Hünermann syndrome, Bazex's syndrome and keratosis palmaris et plantaris dissipata. Congenital pseudarthrosis of the tibia has usually been associated with neurofibromatosis. We report a case of follicular atrophoderma in association with congenital pseudarthrosis of the tibia: a previously unreported association with, in our case, a good outcome for the pseudarthrosis.
OBJECTIVE: To establish the prevalence of renal disease, asymptomatic renal lesions and possible renal symptoms in a geographically defined population of individuals with tuberous sclerosis. PATIENTS AND METHODS: The study involved 131 patients (64 men, 67 women) with tuberous sclerosis who were resident in nine of the districts within the Wessex Region and three Bristol Health Districts and who had been identified by a prevalence study [1]. The patients' mean age was 22 years (range 6 months-74 years). Established renal disease was identified by history. Where possible individuals were seen and were examined. Specific enquiry was made for flank pain and macroscopic haematuria. Renal ultrasound, blood pressure measurement and urine analysis was offered to all individuals with tuberous sclerosis who were resident in the Bath Health District. RESULTS: Eight patients (6%) had a history of either renal polycystic kidney disease (two patients) or haemorrhage from renal angiomyolipomas (five female patients, one male patient). A further 21% of female and 3% of male patients had a history of severe flank pain or haematuria. Renal ultrasound screening revealed abnormalities in 10 of 21 individuals; angiomyolipomas > 1 cm were found in seven and were twice as common in female patients. CONCLUSIONS: Regular clinical review of individuals with tuberous sclerosis should include enquiry for renal symptoms and abdominal examination. Lesions > 4 cm are most likely to be symptomatic but longitudinal studies are needed before renal ultrasound screening of adolescents or adults can be recommended.
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First lactation DHI records of 4293 Holstein and 2143 Jersey cows from 14 herds for 1984 through 1992 in Florida were studied to estimate effects on milk, fat, and protein yields of milking three times daily. Analyses were by derivative-free REML using the animal model. Advantages of milking three times daily for 305 d compared with milking twice daily were 1226 (17.3%), 29 (12.3%), and 19 kg (8.8%) for the milk, fat, and protein yields for Holsteins, respectively, and 284 (6.3%), 13 (6.2%), and 7 kg (4.3%) for Jerseys. Additional research is needed to evaluate effects on other economically important traits such as composition, health, and reproduction. Economic studies are required to determine the efficacy of milking three times daily, especially for Jerseys with their relatively low response.
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A search for children presenting with signs or symptoms of cardiac rhabdomyomas was made through members of the paediatric section of the British Cardiac Society in order to establish their birth incidence, presenting features, clinical course, and the frequency of a concurrent diagnosis of tuberous sclerosis. Fifteen children were identified and 12 had tuberous sclerosis (80%). Heart failure was the presentation in six, five of whom died; six presented because of a murmur and three because of arrhythmias. The prevalence of echocardiographic evidence of cardiac rhabdomyomas in a population of patients with tuberous sclerosis was established. Twenty individuals had echocardiography and eight had echodensities consistent with cardiac rhabdomyomas. It is concluded that the minimum birth incidence for children presenting because of the effects of cardiac rhabdomyomas is 1/326,000 and a minimum of 80% have tuberous sclerosis. In a population of patients with tuberous sclerosis a minimum of 60% under 18 years have cardiac rhabdomyomas.
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OBJECTIVE: To assess echocardiography as an investigation for the detection of occult gene carriers in tuberous sclerosis. PATIENTS: Sixty parents of children with tuberous sclerosis who had been extensively investigated for signs of the disease and 60 age and sex matched controls. PROCEDURE: Blind study by two experienced echocardiographers and blind interpretation of video recordings by an adult cardiologist. SETTING: Cardiology department of a district general hospital. RESULTS: Two parents and three controls had bright echodense areas interpreted as possible rhabdomyomas. CONCLUSIONS: In our hands echocardiography of adults is not an investigation with a high specificity for gene detection in tuberous sclerosis.
The pattern of cerebral hamartomas among a population of patients with tuberous sclerosis and normal intellect was determined. All patients with tuberous sclerosis over 5 years old with normal intellect who were resident in the Bath health district were offered cranial scanning by magnetic resonance imaging. Cerebral axial and coronal images were obtained in 10 mm contiguous sections with a Picker 0.5 tesla magnetic resonance imaging unit. The number, size, and distribution of lesions found was recorded. Eleven of 13 eligible patients underwent scanning. Two patients had normal scans. Seven patients had between one and five subependymal nodules. Nine patients had between two and nine cerebral tubers best seen on T2 weighted images. Our findings suggest that the wrong conclusions may be drawn if the number of lesions alone is used to predict neurological outcome in tuberous sclerosis.
OBJECTIVES: To establish the frequency of fits and mental retardation in an unbiased group of tuberous sclerosis patients. METHODS: Known tuberous sclerosis families with more than one affected person were ascertained for a genetic linkage study. A number of members were born after genetic counselling had been given after identification of the proband. These subjects were then carefully examined clinically and in many cases with cranial computerised tomography, renal ultrasound, and skeletal survey but not echocardiography. They provide an unbiased group of tuberous sclerosis patients and allow affected patients with normal intellect to be diagnosed. PATIENTS: Thirty-seven tuberous sclerosis families were ascertained and 26 patients born after the family proband were identified. RESULTS: Sixteen of these 26 patients suffered fits (62%) and 10 patients were mentally retarded (38%). CONCLUSIONS: A lower incidence of fits and mental retardation has been found in an unbiased sample of tuberous sclerosis patients. The lifetime risk for fits might be higher had we been able to follow the patients for longer. However, we believe these are more appropriate figures to use in genetic counselling for this disease.
Non-penetrance has not been reported in tuberous sclerosis when modern non-invasive investigations have been performed. We report a four generation family in which there was a subject with minimal expression and another with non-penetrance between a great grandfather and his great grandson. This situation highlights the need for full investigation of children of tuberous sclerosis patients before counselling a low recurrence risk for the disease.