Genetic mosaicism in normal tissues of Wilms' tumour patients.

We describe the partial loss of heterozygosity (LOH) at chromosome 11p loci in normal tissues (normal kidney and/or blood) from four of 67 Wilms' tumour patients. Autologous tumour DNA showed complete loss of the same, maternally derived, alleles. These observations indicate that the normal tissues were mosaic for cells heterozygous and homozygous for 11p markers and that tumours subsequently developed from the homozygous cells that had undergone an 11p somatic recombination event. We suggest that LOH for 11p alleles is compatible with normal growth and differentiation and is significant pathologically only when accompanied by other genetic alterations.

Angiogenic and invasive properties of neurofibroma Schwann cells.

Neurofibromas are benign tumors from patients with von Recklinghausen Neurofibromatosis (NF1) that are comprised primarily of Schwann cells. These Schwann cells are found both in association with axons and in the extracellular matrix that is prevalent in neurofibromas, and in which fibroblasts are also abundant. An unresolved question has been whether cells in neurofibromas are normal cells or are intrinsically abnormal. We have tested the hypothesis that cells in neurofibromas are abnormal and have shown that neurofibroma Schwann cells, unlike normal Schwann cells, promote angiogenesis in the chick chorioallantoic membrane model system, and invade basement membranes in this system. In contrast, neurofibroma fibroblasts neither promote angiogenic reactions nor invade basement membranes. When injected into nude mice, neurofibroma Schwann cells do not form progressive tumors. These results suggest that NF1 Schwann cells differ from normal Schwann cells, that they are preneoplastic, and that genetic and/or epigenetic changes in Schwann cells may be required for development of peripheral nerve tumors in NF1.

Familial retinoblastoma and chromosome 13 deletion transmitted via an insertional translocation.

Surviving persons from a kindred in which retinoblastoma occurred over four generations, transmitted by eight unaffected individuals, underwent chromosomal analysis. The results revealed that the development of retinoblastoma was associated with a constitutional chromosome deletion del(13)(q13.1q14.5) and that the unaffected transmitting state was associated with a balanced insertional translocation. These findings indicate that predisposition to retinoblastoma may be attributed to the loss of specific genetic material and that a chromosomal mechanism may explain apparent lack of gene penetrance in certain families. The development of unilateral, and not bilateral, retinoblastoma suggests either that the chromosome deletion is different from the mutation of heritable retinoblastoma in general, or that the chromosome deletion lessens the probability of subsequent somatic carcinogenic events.

Hereditary pancreatitis. Nonspecificity of aminoaciduria and diagnosis of occult disease.

Hereditary pancreatitis appears in many different ways and in a variety of age groups, spanning both pediatric and adult medicine. The variable expression of hereditary pancreatitis is emphasized by the difficulty in diagnosing it in a patient obviously at risk because of a severely affected father and son. The morphine prostigmine test and hypotonic duodenogram were most helpful. Aminoaciduria previously associated with this disorder is coincidental or nonspecifically related to acute pancreatic inflammation. The increased risk for pancreatic carcinoma (about 20%) is emphasized by the concern for that complication in the proband's grandfather.

De novo astrocytoma following immunosuppression in neurofibromatosis.

A 45-year-old man with a 20-year history of neurofibromatosis (NF-1) developed a massive astrocytoma 15 months following heart transplantation. CT before immunosuppressive therapy was normal. This is the 1st report of a de novo astrocytoma following immunosuppression in NF-1 and may indicate a causal relationship.

Familial spinal neurofibromatosis: clinical and DNA linkage analysis.

We studied two families with an unusual variant of neurofibromatosis (NF). The first family had spinal neurofibromas and café au lait spots (CLS), the second spinal neurofibromas without CLS. Other signs of NF1 or NF2, such as cutaneous tumors, Lisch nodules, or acoustic tumors, were absent. The inheritance pattern in both pedigrees was consistent with autosomal dominant inheritance. Using genetic linkage analysis with DNA markers tightly linked to the NF1 and NF2 loci, we determined that the likely location for the mutation in the first family was in the NF1 gene with odds of 97:1, whereas the mutation in the second family was excluded from the NF1 locus with odds greater than 100,000:1. Families such as these, in which a defined subset of the NF phenotype is passed on, are important for understanding the functional consequences of particular mutations in the NF genes.

Absence of association of HTLV-I infection with type 1 neurofibromatosis in the United States or Japan.

An HTLV-I tax transgenic mouse model develops a syndrome with similarities to type 1 neurofibromatosis (NF-1). To investigate possible associations between this human retrovirus and NF-1, we have analyzed 67 neurofibromas from Japan (where HTLV-I infection is endemic) and compared them with 21 cases from the United States. We were not able to identify virus in tumor tissue in either group. This suggests that HTLV-I infection is not commonly associated with NF-1.

Presymptomatic diagnosis of neurofibromatosis 2 using linked genetic markers, neuroimaging, and ocular examinations.

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that causes nervous system tumors and ocular abnormalities such as early-onset lenticular opacities. We assessed the clinical spectrum of NF2 at the time of presymptomatic DNA diagnosis in at-risk first-degree relatives. We studied five multigeneration NF2 families with short tandem repeat markers near the NF2 gene (NF2); gadolinium-enhanced high-resolution magnetic resonance imaging (GE-MRI); and ocular, dermatologic, and neurologic examinations. Eleven of 31 asymptomatic at-risk first-degree relatives were predicted by segregation analysis to be NF2 mutation carriers. Nine of the 11 NF2 mutation carriers were clinically evaluated. Four mutation carriers, including a 7-year-old, had vestibular schwannomas, early-onset cataracts, or both. However, five mutation carriers did not have clinical abnormalities, including a 38-year-old with normal cranial and spinal GE-MRIs and a normal ocular examination. These results indicate that clinical abnormalities can be present in young, but absent in middle-aged, presymptomatic NF2 mutation carriers. By identifying presymptomatic NF2 mutation carriers, DNA diagnosis of NF2 can improve genetic counseling and clinical management, and possibly reduce psychosocial difficulties in at-risk individuals.

Discounting an adverse maternal effect on severity of neurofibromatosis.

Neurofibromatosis, a common, progressive, autosomal dominant disorder, is markedly variable in its expressivity. Some authors have suggested that some contribution to neurofibromatosis's variability may be an adverse effect of a mother's neurofibromatosis on the overall severity seen in her offspring with neurofibromatosis. In the present study of 188 maternal affected, paternal affected, and sporadic von Recklinghausen neurofibromatosis cases, the maternal influence question was systematically examined. Overall severity, selected features most likely to reflect in utero maternal influence, and other common neurofibromatosis-I features were analyzed statistically. Age, racial composition, and gender of the three groups were similar. No significant differences were found (P less than or equal to .01) between maternal affected, paternal affected, and sporadic cases in terms of overall severity, probability of reaching advanced severity as a function of age, indications of possible prenatal influence (eg, congenital neurofibromas, tibial pseudarthrosis), or other neurofibromatosis features. These results demonstrate that the nature and severity of neurofibromatosis for maternal affected cases are essentially the same as for paternal affected and sporadic cases.

Chromosomal imbalance in the Aniridia-Wilms' tumor association: 11p interstitial deletion.

The triad of aniridia, ambiguous genitalia, and mental retardation (AGR triad) is the characteristic clinical feature of three unrelated patients with previously unreported chromosome 11 short arm interstitial deletions. A Wilms' tumor in one patient establishes one cause for the aniridia-Wilms' tumor association. The genetic heterogeneity of aniridia, the AGR triad, and Wilms' tumor are demonstrated, and Wilms' tumor is indicated to be a neoplastic birth defect which can result from a variety of embryologic insults, some of which may be chromosomal or heritable.

Acute leukemia associated with trisomy 8 mosaicism and a familial translocation 46,XY,t(7;20)(p13;p12).

A patient is shown to have acute granulocytic leukemia, bone marrow mosaicism, and cutaneous fibroblast mosaicism for trisomy 8, an inherited reciprocal translocation involving the short arms of chromosomes 7 and 20, and a family history of cancer. A normal sister who had the same balanced chromosome translocation was evaluated for a preleukemic state; the results were unremarkable. The inherited translocation and postzygotically derived trisomy 8 are thought to represent additive factors contributing to the development of leukemia in the patient.

Triplication of chromosome arm 20p due to inherited translocation and secondary nondisjunction.

A patient with triplication of all of chromosome arm 20p is presented to illustrate the relatively modest degree of developmental delay that can result from autosomal triplication and the role of nondisjunction as a mechanism for deriving a partial triplication status.

Brief clinical report: aqueductal stenosis leading to hydrocephalus--an unusual manifestation of neurofibromatosis.

Two brothers and an unrelated male with neurofibromatosis (NF) developed hydrocephalus in childhood. Aqueductal stenosis (AS) was demonstrated by ventriculography and required shunt operation. Genetic counselors had to decide whether to invoke an X-linked gene for AS or whether AS could be caused by the NF mutation. Reports of 13 patients of both sexes with AS and NF suggest that AS with resulting hydrocephalus may be a rare manifestation of the NF gene. AS should be looked for in young NF patients with signs of hydrocephalus or with neurologic abnormalities.

The FG syndrome: further characterization, report of a third family, and of a sporadic case.

We report 5 new cases of the FG syndrome, 1 sporadic, 3 brothers from a European family, and another affected male born in the first FG syndrome family reported by Opitz and Kaveggia in 1974. The pedigree data confirm the hypothesis of X-linked inheritance of this multiple congenital anomaly/mental retardation (MCA/MR) syndrome. Its manifestations include shortness of stature with a disproportionately large head, mental retardation, hypotonia with or without congenital joint contractures, seizures and a strikingly characteristic personality of facial appearance, imperforate anus and/or orthe gastrointestinal defects, congenital heart defects, and many minor manifestations. Chronic pulmonary disease in some affected males may be a complication of hypotonia.

A genetic linkage study in 15 families of individuals with von Recklinghausen neurofibromatosis.

A linkage analysis between the gene for von Recklinghausen neurofibromatosis (NF) and 21 genetic markers was carried out using the computer program LIPED. The study group included 15 families composed of 84 individuals, 51 of whom were affected with NF; there were six three-generation families and nine two-generation families. Lod scores excluded tight linkage (Z less than -2.0) between eight genetic markers and NF and were inconclusive for nine markers. Four markers were not informative. The analysis failed to confirm either the previously suggested linkage between NF and the plasma vitamin D-binding protein Gc or the possibility of linkage of NF to the secretor locus suggested by reports of two families segregating for NF and myotonic dystrophy.

The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations.

Von Recklinghausen neurofibromatosis is characterized by a relatively large proportion of apparently nonfamilial cases, presumed spontaneous mutations. This paper analyzes the distribution of paternal and maternal ages for 187 patients with von Recklinghausen disease representing the first definite case in their respective families. Mean paternal age was 32.8 years and mean maternal age was 27.4 years, both being significantly greater than for control populations (P equal to or less than .001). The advanced paternal age was not accounted for by the increase in maternal age. The methodology of controlling the general population paternal ages for each patient's birth year is described.

Prenatal diagnosis of congenital adrenal hyperplasia.

The accurate prenatal diagnosis of 21-beta-hydroxylase deficiency, based on amniotic fluid levels of 17-hydroxyprogesterone, is documented for a fetus 14 1/2 weeks old. In addition, family HLA genotyping data are consistent with the purported linkage between the HLA locus and the locus for 21-beta-hydroxylase.

Duplication 11p11.3 leads to 14.1 to meiotic crossing--over.

An infant with macular dysfunction, cleft lip and palate, and developmental delay was shown to have an inverted duplication of 11p11.3 leads to p14.1 on the basis of meiotic recombination subsequent to an intrachromosomal "shift" in his mother. A half-sister had previously been shown [3] to have the reciprocal recombinant with resultant deletion of 11p11.3 leads to 11p14.1.

Phenotypic variability in monozygotic twins with neurofibromatosis 2.

Mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene on chromosome 22q12 cause a clinically variable autosomal dominant syndrome characterized by bilateral vestibular schwannomas (VSs), other nervous system tumors, and early onset lenticular cataracts. We studied three pairs of monozygotic (MZ) twins with NF2, all with bilateral VSs, to separate genetic from nongenetic causes of clinical variability. The evaluation included gadolinium-enhanced high-resolution magnetic resonance imaging of the head and spine, neuro-ophthalmic examination with slit lamp, physical examination, and zygosity testing with microsatellite markers. Each MZ pair was concordant for general phenotypic subtype (mild or severe) and often for the affected organ systems. However, the MZ pairs were discordant for some features of disease presentation or progression. For example, all three pairs were discordant for presence or type of associated cranial tumors. We hypothesize that phenotypic differences between NF2 MZ twins are at least partly due to stochastic processes, such as the loss of the second NF2 allele or alleles of other genes.

Phenotype associated with ring 10 chromosome: report of patient and review of literature.

A 15-month-old infant's peripheral blood chromosome analysis showed the following defects: 46,XY,r(10)(p15.3q26.1) in 84 cells, 45,XY,-r(10) in 13 cells, and 47,XY,r(10),+r(10) in one cell. Clinical abnormalities included growth retardation, microcephaly, prominent nasal bridge, macular hypoplasia, persistent pulmonary hypertension, and posterior urethral valves with hydronephrosis. Comparison of the phenotype of five other patients with a ring chromosome 10 with the present case showed the following common manifestations: growth retardation, microcephaly, undescended testes, hydronephrosis, and, in males, posterior urethral valves. To date, this last anomaly has not been seen in patients with either a del(10p) or a del(10q) abnormality.