Bourneville's tuberous sclerosis

Among the group of hereditary histodysplasia, Bourneville's tuberous sclerosis demonstrate original and important place. Its clinical and histopathological polymorphism make more difficult the diagnosis because many symptoms are non specific and/or appeared at different age of life. The variability of the expression and of the penetrance are a very serious unpeachement for the genetic counselling. A recent reevaluation of several series of case reports seems to demonstrate that the frequency of new mutations has been probably surestimated. The gene location in 9q3-4 is quite certain and will induce soon the possibility of a more efficient prenatal diagnosis. The gene action mechanism at the embryonic development is probably correlated with the "oncogene character" of the specific mutation.     

Molecular genetic advances in tuberous sclerosis

Over the past decade, there has been considerable progress in understanding the molecular genetics of tuberous sclerosis, a disorder characterised by hamartomatous growths in numerous organs. We review this progress, from cloning and characterising TSC1 and TSC2, the genes responsible for the disorder, through to gaining insights into the functions of their protein products hamartin and tuberin, and the identification and engineering of animal models. We also present the first comprehensive compilation and analysis of all reported TSC1 and TSC2 mutations, consider their diagnostic implications and review genotype/phenotype relationships.     

Electron microscopy as a means for carrier detection and genetic counselling in families at risk of tuberous sclerosis

Summary In otherwise asymptomatic parents of two unrelated children severely affected with tuberous sclerosis (TS), the ultrastructure of hypomelanotic skin lesions was investigated. In the hypomelanotic macules of both mothers of the two families, the population density of melanocytes was normal, melanization, however, was markedly suppressed. Therefore, these macules represent typical white leaf-shaped macules characteristic of tuberous sclerosis. Especially by applying the dihydroxyphenylalanine (DOPA) reaction to the ultrastructural level, it was possible to separate the TS-macules from the vitiliginous lesions of one father with a decrease of functional melanocytes as well as from other congenital circumscribed hypomelanoses. Thus electron microscopy in combination with the DOPA reaction may be helpful in recognizing a forme fruste of the dominantly inherited tuberous sclerosis (i.e. identification of white leaf-shaped macules) to enable genetic counselling and family planning by marking carriers of the mutant TS gene amongst the relatives of a patient and to exclude a sporadic mutation.     

High rate of mosaicism in tuberous sclerosis complex.

Six families with mosaicism are identified in a series of 62 unrelated families with a mutation in one of the two tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. In five families, somatic mosaicism was present in a mildly affected parent of an index patient. In one family with clinically unaffected parents, gonadal mosaicism was detected after TSC was found in three children. The detection of mosaicism has consequences for genetic counseling of the families involved, as changed risks apply to individuals with mosaicism, both siblings and parents. Clinical investigation of parents of patients with seemingly sporadic mutations is essential to determine their residual chance of gonadal and/or somatic mosaicism, unless a mosaic pattern is detected in the index patient, proving a de novo event. In our data set, the exclusion of signs of TSC in the parents of a patient with TSC reduced the chance of one of the parents to be a (mosaic) mutation carrier from 10% to 2%. In the five families with somatic mosaicism, the parent was given the diagnosis after the diagnosis was made in the child.     

An autopsy case of tuberous sclerosis. Histological and immunohistochemical study.

We report an autopsy case of tuberous sclerosis. A 19-year-old Japanese man had shown facial adenoma sebaceum, intractable convulsive seizures and severe mental retardation. Gross inspection of the brain showed a cortical tuber from the orbital frontal lobe to the rhinencephalon of the left side and a few subependymal nodules. Histological examination revealed many cortical tubers in the cerebral hemispheres, a few subependymal nodules with calcification and multifocal clusters of heterotopic cells in the white matter (white matter nodules). In these lesions, massive giant cells with abundant eosinophilic cytoplasm and without Nissl substances were found. Although the size and shape of the giant cells were variable, the majority of them were gemistcytic, ovoid or polygonal. Immunohistochemistry was employed in these lesions using antibodies against neurofilament protein (NFP), glial fibrillary acidic protein (GFAP), vimentin (VM) and myelin basic protein (MBP). In the cortical tuber, the majority of the giant cells were positive for both NFP and VM, but a few were positive for GFAP. All of them were negative for MBP. In the subependymal nodule and white matter nodule, the majority of the giant cells were positive for NFP, but a few were positive for VM, and none were positive for either GFAP and MBP. These findings suggest that the majority of the giant cells may be immature cells toward neuronal series and a few may be those toward astroglial series. These findings also indicate that the giant cells in the subependymal nodule and white matter nodule may be more differentiated than those in the cortical tuber. The nature of the giant cells in tuberous sclerosis is discussed.     

Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis

Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein. Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.     

Serum and tissure proteins in tuberous sclerosis. II. Immunoglobulin levels.

Serum levels of the four main immunoglobulins, IgA, IgM, IgG and IgD were estimated in a sample of 54 subjects with tuberous sclerosis and the data compared with similar findings in a sample of 100 mentally retarded subjects chosen at random. Normal levels of IgA and IgD were found in the T.S. group, but elevated levels of IgM significant at P equals 0.001 was found in 49 of the 54 cases. A reduction in IgG levels (significant at P equals 0.001) was a much less constant feature being found in 29 of the 54 subjects. The significance of these results in the light of the observation that one of the principal causes of death in T.S. is from recurrent infection is discussed.     

Evidence for genetic heterogeneity in tuberous sclerosis: one locus on chromosome 9 and at least one locus elsewhere.

Linkage of tuberous sclerosis complex (TSC), an autosomal dominant disorder, to markers on chromosome 9 was reported first in 1987. This assignment was confirmed by an international collaborative study that suggested more than one locus may be responsible for the phenotype. We studied 14 multigenerational TSC families (13 previously unreported) with markers for nine loci in the linked region of chromosome 9q32-q34. Our results confirm the previous reports that the genetic locus in one-third to one-half of families maps to chromosome 9. Comparison of clinical findings in the chromosome 9-linked families with those in the chromosome 9-unlinked families reveals only a higher incidence of ungual fibromata in the chromosome 9-linked families.     

The check-up of reproductive health and genetic counseling.

The Hungarian Family Planning Program was a feasibility study on combining methods of periconceptional care. The first step was the check-up of reproductive health, including family history of the couples, case history of females, pre-pregnancy examination (vaginal and cervical smears), and the measurement of basal body temperature, sperm examination, psycho-sexual exploration and exclusion of some risk factors. This preconception screening program was carried out by graduate trainee nurses to identify those participants secondary health services. The data of 4,240 couples attending in the Budapest Center indicated a useful relationship between the check-up of reproductive health and genetic counseling clinics, by selecting couples requiring genetic counseling and preventing other couples making unnecessary visits.