Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma

Carriers of a ring chromosome 22 are mentally retarded and show variable facial dysmorphism. They may also present with features of neurofibromatosis type II (NF2) such as vestibular schwannomas and multiple meningiomas. In these cases, tumourigenesis has been suspected to be caused by the loss of both alleles of the NF2 gene, a tumour suppressor localized in 22q12.2. Here, we describe an 18-year-old patient with constitutional ring chromosome 22 and mental retardation who developed rapid-onset spastic paraparesis at the age of 15 years. The causative spinal meningioma at the level of T3, which compressed the spinal cord, was surgically removed, and the patient regained ambulation. Array comparative genomic hybridization (array CGH) and multiplex ligation-dependent probe amplification (MLPA) analyses in blood revealed a terminal deletion in 22q13.32, not comprising the NF2 gene. In tumour tissue, loss of the whole ring chromosome 22 including one NF2 gene due to mitotic instability constituted the likely first hit, while a point mutation in the other allele of the NF2 gene (c.784C>T, p.R262X) was shown as second hit. We review all cases from the literature and suggest clinical guidelines for surveillance of patients with ring chromosome 22.     

Multiple meningiomas in a patient with constitutional ring chromosome 22

We report on a patient with multiple congenital anomalies and ring chromosome 22 who died at age 16 years of bronchopneumonia. Autopsy documented multiple psammomatous meningiomas of the spinal dura and tentorium. Tumor tissue for cytogenetic analysis was not available. Although abnormalities of chromosome 22 in tumor tissue have been reported, to our knowledge, this is only the third report of a constitutional chromosome 22 abnormality associated with the development of meningiomas. Thus, a constitutional chromosome 22 abnormality may predispose to the development of meningiomas. © 1993 Wiley-Liss, Inc.     

Phenotypic variation in two patients with a ring chromosome 22

Two severely mentally retarded patients with a ring chromosome 22 presented with disparate phenotypes: one patient manifested only minimal dysmorphic features, whereas the other had a distinctive pattern of anomalies consisting of an abnormal skull configuration with mild maxillary hypoplasia, a large nose, thick full lips, a protruding tongue, lymphedema, hypotonia and an unsteady gait. The findings in these and previously reported patients indicate that a ring chromosome 22 is usually associated with moderate to severe mental retardation, with a range of dysplastic features from mild and nonspecific to more marked and distinctive.     

Deleted ring chromosome 22 in a mentally retarded boy

A mentally retarded boy with a ring chromosome 22, where most of band q13 was deleted, is reported. The fact that the leucocyte beta-galactosidase and alpha-galactosidase B activities were normal, but the arylsulphatase A activity only half of the normal is consistent with a gene dosage effect and that the arylsulphatase A locus is located more distally, than the gene loci for the other two enzymes, in the deleted part of 22q13.     

Constitutional translocation t(4;22) (q12;q12.2) associated with neurofibromatosis type 2

We report on a female patient with bilateral acoustic neurinomas and other tumors in the central nervous system (neurofibromatosis type 2: NF2) and the constitutional translocation, t(4;22) (q12;q12.2). The precise identification of the translocation breakpoint (q12.2) on chromosome 22 implies the refined localization of a gene responsible for NF2, and would provide a clue to its molecular characterization and to the isolation of the gene. Chromosomes of a paraspinal neurinoma from the patient were also analyzed, and the same karyotype as seen in cultured peripheral lymphocytes was found. The patient's father was also a carrier of the translocation, but he had no clinical symptoms of NF2, nor did other relatives. Several explanations are offered for the different expression of the translocation between the patient and her father. © 1992 Wiley-Liss, Inc.     

Five new subjects with ring chromosome 22

Ring chromosome 22, a rare cytogenetic finding, was first described by Weleber et al. in 1968. Since then approximately 50 patients have been reported in the medical literature. We describe five previously unreported subjects with ring chromosome 22 syndrome, summarize the clinical findings of reported patients from the literature and discuss the involvement of the ring chromosome and clinical outcome. Our subjects demonstrated the prominent features of this syndrome including mental retardation, hypotonia, motor delay, lack of speech, full eyebrows, and large ears. In addition, two of our subjects had central nervous system malformations and regression. The lack of consistent physical abnormalities in our subjects further supports no consistent phenotype manifestations in this cytogenetic syndrome. The variable clinical manifestations seen in ring chromosome 22 subjects may be associated with loss of chromosome 22 sequences near the telomere or attributed to the genetic background of each subject. Similarly, recessive alleles unmasked by the deletion could also contribute to the phenotype.     

Ring chromosome 17: phenotype variation by deletion size

Ring chromosome 17 is a rare cytogenetic abnormality, with 12 previous reports in the literature. Some have a relatively mild phenotype characterized by seizures, mental retardation, skin changes and short stature. Other patients have Miller-Dieker syndrome (MDS), which includes lissencephaly, multiple dysmorphic features, severe mental retardation and shortened life expectancy. We describe two new cases of ring chromosome 17 and review the literature. Our cases and the other reports of patients without a deletion encompassing the Miller-Dieker region, delineate a fairly distinctive subgroup of individuals with ring 17, whose phenotype consists of growth and mental retardation, seizures, minor dysmorphic features, café-au-lait spots and retinal flecks. This classification of ring 17 into two distinct groups based on the size of the deletion and the phenotypic manifestations should facilitate clinical suspicion of this rare chromosomal abnormality.     

Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers

Neurofibromatosis type 1 (NF1), an autosomal dominantly-inherited disorder, is mainly characterized by the occurrence of multiple dermal neurofibromas and is caused by mutations in the NF1 gene, a tumor suppressor gene. The variable expressivity of the disease and the lack of a genotype/phenotype correlation prevents any prediction of patient outcome and points to the action of genetic factors in addition to stochastic factors modifying the severity of the disease. The analysis of somatic NF1 gene mutations in neurofibromas from NF1 patients revealed that each neurofibroma results from an individual second hit mutation, indicating that factors that influence somatic mutation rates may be regarded as potential modifiers of NF1. A mutational screen of numerous neurofibromas from two NF1 patients presented here revealed a predominance of point mutations, small deletions, and insertions as second hit mutations in both patients. Seven novel mutations are reported. Together with the results of studies that showed LOH as the predominant second hit in neurofibromas of other patients, our results suggest that in different patients different factors may influence the somatic mutation rate and thereby the severity of the disease.     

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. © 1996 Wiley-Liss, Inc.     

Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors

One of the main features of neurofibromatosis type 1 (NF1) is benign neurofibromas, 10-20% of which become transformed into malignant peripheral nerve sheath tumors (MPNSTs). The molecular basis of NF1 tumorigenesis is, however, still unclear. Ninety-one tumors from 31 NF1 patients were screened for gross changes in the NF1 gene using microsatellite/restriction fragment length polymorphism (RFLP) markers; loss of heterozygosity (LOH) was found in 17 out of 91 (19%) tumors (including two out of seven MPNSTs). Denaturing high performance liquid chromatography (DHPLC) was then used to screen 43 LOH-negative and 10 LOH-positive tumors for NF1 microlesions at both RNA and DNA levels. Thirteen germline and 12 somatic mutations were identified, of which three germline (IVS7-2A>G, 3731delT, 6117delG) and eight somatic (1888delG, 4374-4375delCC, R2129S, 2088delG, 2341del18, IVS27b-5C>T, 4083insT, Q519P) were novel. A mosaic mutation (R2429X) was also identified in a neurofibroma by DHPLC analysis and cloning/sequencing. The observed somatic and germline mutational spectra were similar in terms of mutation type, relative frequency of occurrence, and putative underlying mechanisms of mutagenesis. Tumors lacking mutations were screened for NF1 gene promoter hypermethylation but none were found. Microsatellite instability (MSI) analysis revealed MSI in five out of 11 MPNSTs as compared to none out of 70 neurofibromas (p=1.8 x 10(-5)). The screening of seven MPNSTs for subtle mutations in the CDKN2A and TP53 genes proved negative, although the screening of 11 MPNSTs detected LOH involving either the TP53 or the CDKN2A gene in a total of four tumors. These findings are consistent with the view that NF1 tumorigenesis is a complex multistep process involving a variety of different types of genetic defect at multiple loci.     

No evidence for linkage to the type 1 or type 2 neurofibromatosis loci in Noonan syndrome families

A linkage analysis has been performed on 6 two-generation families with classical Noonan syndrome to determine whether the shydrome is linked to neurofibromatosis type 1 on chromosome 17q or to neurofibromatosis type 2 on chromosome 22q. A significantly negative location score was obtained between 10cM centromeric to and 15 cM telomeric from the neurofibromatosis type 1 locus. A significantly negative lod score was obtained with a marker mapping within the region where neurofibromatosis type 2 is thought to be located. These data indicate that Noonan syndrome is not tightly linked to either neurofibromatosis type 1 or type 2. © 1993 Wiley-Liss, Inc.     

Ring chromosome 5 associated with severe growth retardation as the sole major physical abnormality

We report on a case of ring chromosome 5 in a 36-month-old girl with severe growth retardation, clinodactyly, mild psychological abnormalities, and normal facial appearance. Endocrine tests showed partial growth hormone deficiency. Cytogenetic investigation failed to demonstrate any apparent microscopic deletion of either short or long arm of chromosome 5 as consequence of ring formation. In 12% of cells examined, the ring was either absent or present in multiple copies. Only 3 previous cases of ring chromosome 5 have been reported in association with short stature of prenatal onset and minor anomalies, without mental retardation. © 1994 Wiley-Liss, Inc.     

Ring chromosome 11 and café-au-lait spots

We report on the segregation of a cytogenetically non-deleted ring chromosome 11 and café-au-lait spots in a family. This appears to be the largest inherited ring autosome yet reported.     

Ring chromosome 2 in a child with growth failure and few congenital abnormalities

A ring chromosome 2 mosaic [46,XX/46,XX,r(2)(p25q37)] was found in a newborn female with severe intrauterine growth retardation (IUGR), postnatal growth failure, and a few minor abnormalities. Psychomotor development has been normal to 19 months old. A ring chromosome 2 is present in 77.8% of the nuclei examined and is not found in the parents or a sibling. G- and R-banding reveal the break points to be p25q37. The presence of a normal cell line indicates that the chromosome abnormality arose after conception.     

Ring chromosome 17 in a mentally retarded young man—clinical,cytogenetic, and biochemical investigations

A young, mentally retarded man with seizures was discovered to have a ring chromosome 17. He had no major anomalies. The phenotype associated with r(17) probably is variable. The patient's deletion and genotype allowed us to reduce further the chromosome location of the acid α-glucosidase gene.     

Chromosome 22q alterations and expression of the NF2 gene product, merlin, in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. A characteristic genetic alteration in GISTs is constitutive activation of the c-kit proto-oncogene, but alterations in chromosomes 14 and 22 may also play a role in the molecular pathogenesis. In this study, 42 GISTs were analyzed for loss of heterozygosity (LOH) on the long arm of chromosome 22 (22q). Overall, 69% of the tumors studied showed LOH with at least 1 of the 22q markers. Allele losses were compared with tumor mitotic activity, the most commonly used prognostic marker for this tumor. Interestingly, allele deletion at 22q was significantly more frequent in tumors with high mitotic activity (>/= l2 mitoses/10 high-power fields [HPF]) than in tumors with low mitotic activity (< 2 mitoses/HPF)-88% versus 56% (P < 0.01). A total of 26% (11 of 42) of all tumors demonstrated loss of all 22q sites analyzed, consistent with the loss of 1 copy of the entire long arm. Such tumors carried a 4.6-fold (95% confidence interval, 0.5 to 49.8) risk for recurrence compared with tumors with no LOH. LOH was frequently detected at the neurofibromatosis 2 (NF2) tumor-suppressor gene locus at 22q12. Sequencing of the NF2 gene from 5 GISTs did not reveal mutations, however. Furthermore, 16 of 19 tumors (84%) analyzed by immunohistochemistry were positive for the NF2 gene product, merlin. The findings suggest that allelic losses at 22q are associated with high mitotic activity and recurring disease, and that alterations in the NF2 gene are unlikely to participate in the pathogenesis of GIST.     

Identification of a small supernumerary ring chromosome 8 by fluorescent in situ hybridization in a child with developmental delay and minor anomalies

We report a 15-month-old female with developmental delay, hypotonia, and minor anomalies whose karyotype is 47,XX, + r. Due to its small size, the origin of the ring chromosome was indeterminate by standard G-banded karyotyping. Fluorescent in situ hybridization was performed, which indicated that the ring chromosome was derived from the pericentric region of chromosome 8. © 1994 Wiley-Liss, Inc.