Teeth and trauma: res ipsa loquitur in a case of intubation

Autosomal dominant periodic fevers constitute a range of syndromes characterised by recurrent attacks of fever and abdominal pain. Familial Hibernian fever (FHF) has been described in only one United Kingdom based family, but two other Irish families have been found with similar clinical features. FHF resembles familial Mediterranean fever (FMF) in several clinical features, but the mode of inheritance of FHF is dominant whereas FMF is recessive. We have investigated whether autosomal dominant periodic fevers, in particular FHF, map to the FMF susceptibility locus (MEFV) on chromosome 16p13.3. We have used informative microsatellite markers flanking this locus to genotype members of the three families mentioned above. Two point and multipoint lod scores definitively excluded linkage to MEFV in the two larger families. A haplotype study confirmed these findings, indicating that FHF is genotypically as well as phenotypically distinct from FMF.     

Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health

Regarded as the most common and best understood of the hereditary periodic fever syndromes, familial Mediterranean fever (FMF) is a recessively inherited disease of episodic fever with some combination of severe abdominal pain, pleurisy, arthritis, and a characteristic ankle rash. The flares typically last for up to 3 days at a time, and most patients are completely asymptomatic between attacks; if untreated with prophylactic colchicine, some patients later develop amyloidosis and renal failure. The recent cloning of the FMF gene on the short arm of chromosome 16p, and the subsequent finding that its tissue expression is limited to granulocytes, has helped to explain the dramatic accumulation of neutrophils at the symptomatic serosal sites; the wild-type gene likely acts as an upregulator of an anti-inflammatory molecule or as a downregulator of a pro-inflammatory molecule. For nearly half a century, FMF was thought to cluster primarily in non-Ashkenazi Jews, Arabs, Armenians, and Turks, although the screening of the 8 known mutations in an American cohort has identified substantial numbers of people from the Ashkenazi Jewish and Italian populations in the United States who also have this disease. Nevertheless, the symptoms often go unrecognized and patients remain undiagnosed for years, not receiving the highly efficacious colchicine therapy; their histories often include multiple laparotomies, laparoscopies, and psychiatric evaluations. The combinations of clinical manifestations among FMF patients are quite heterogeneous, but our American cohort did not establish any connections between individual mutations and specific clinical pictures--as is seen in other diseases like cystic fibrosis, in which distinct genotypes target certain organ systems. Specifically, the data from our American series are insufficient to evaluate the hypothesis that the M694V/M694V genotype confers a more severe phenotype, or increases the risk of amyloidosis; but both our data and the recent literature (160) indicate that amyloidosis can occur in FMF patients with only 1 copy, or no copies, of the M694V mutation. It appears that specific MEFV mutations are probably not the sole determinants of phenotype, and that unknown environmental factors or modifying genes act as accomplices in this disease. Although we hope the discovery of the FMF gene will allow the diagnosis of FMF to become genetically accurate, the reality is that both clinical and genetic tools must still be used together unless mutations are identified on both of a patient's chromosomes. Physicians should be careful not to rule out the diagnosis in patients of high-risk ethnic backgrounds just because of atypical clinical features, as our data indicate that MEFV mutations are sometimes demonstrable in such patients. At the same time, physicians cannot yet rely solely on a genetic diagnosis because we have not yet identified a sufficient spectrum of mutations, and it is not currently feasible to examine every patient's full DNA sequence for the entire gene; screening an ethnically consistent and clinically positive patient for the 8 known mutations frequently identifies a mutation on only 1 chromosome, and genetic analysis of other classic cases will often reveal none of the 8 mutations. Still, our data suggest that ethnic background is an important predictor of finding 1 of the presently known mutations, and the knowledge of ancestries atypical for FMF can suggest the diagnosis of other hereditary periodic fever syndromes. As the list of FMF-associated MEFV mutations is expanded, and/or new sequencing technologies permit more rapid screening, the value and interpretation of genetic testing for FMF will become more straightforward. Moreover, as the pathophysiology of this disorder becomes less of a hypothesis and more of an understood entity, it is likely that treatment options will broaden beyond the use of daily prophylactic colchicine. (ABSTRACT TRUNCATED)     

Familial Mediterranean fever and hyperimmunoglobulinemia D syndrome: two diseases with distinct clinical, serologic, and genetic features

OBJECTIVE: To determine whether the 2 periodic febrile syndromes familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS) are distinct diseases. METHODS: Clinical manifestations of the diseases were analyzed by physicians experienced with FMF and HIDS. Serum immunoglobulin (Ig) levels were studied in 70 patients with FMF using nephelometry or ELISA and compared with Ig levels in 50 patients with HIDS. Genetic linkage of HIDS with the chromosome 16 polymorphic locus RT70, currently used for refined localization of the FMF susceptibility gene (MEFV), was studied in 9 HIDS families (18 patients) using polymerase chain reaction amplification and gel electrophoresis. RESULTS: The main clinical features distinguishing FMF from HIDS were lymphadenectomy, skin eruption, and symmetrical oligoarthritis in HIDS, and monoarthritis, peritonitis, and pleuritis in FMF. Increased IgG levels were found in 12 patients with FMF (17%), IgA in 16 (23%), IgM in 9 (13%), and IgD in 9 (13%), significantly lower than the prevalence reported for HIDS. We found no evidence for genetic linkage between HIDS and the chromosome 16 marker RT70. CONCLUSION: HIDS and FMF are different entities, clinically, immunologically, and genetically.     

Gene localization for an autosomal dominant familial periodic fever to 12p13

We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses.     

Optimizing form and function with the direct posterior composite resin: a case report

The human testis determining factor (SRY) has been cloned from the Y chromosome. This gene is a dominant inducer of male differentiation. Mutations in the SRY gene result in an XY individual developing as a sex reversed phenotypic female. Sex reversal in humans can also be caused by mutations located in autosomal or X-linked loci. One such sex-reversing locus (SRAI) is associated with the developmental disorder campomelic dysplasia (CD). Both these syndromes were mapped to human chromosome 17q by the identification of balanced reciprocal translocations in five unrelated patients. The translocation breakpoint of one such XY-female CD patient was mapped and the region surrounding it cloned. The closest distal marker used to map the translocation breakpoint was the SOX9 gene. Because of the close proximity of this gene to the breakpoint, it was subjected to mutation analysis in patients without overt chromosome rearrangements. Analysis of DNA from these patients and their parents identified de novo mutations in the SOX9 gene in patients with both autosomal sex reversal and CD. This showed that mutations in the SOX9 gene are responsible for both syndromes.     

Genetic testing in presymptomatic diagnosis of multiple endocrine neoplasia

Multiple endocrine neoplasias (MEN) are familial diseases characterized by endocrine neoplasms and transmitted in an autosomal dominant manner. In MEN type 1, the major lesions affect parathyroid glands, pancreatic islet cells and anterior pituitary. The MEN-1 gene has been mapped to chromosome 11q13 and a set of DNA-polymorphic markers localized close to this region provides a useful tool for presymptomatic diagnosis in MEN-1 families. MEN type 2 refers to the inherited forms of medullary thyroid carcinoma (MTC) associated or not with pheochromocytoma and hyperparathyroidism. In MEN-2, germinal mutations of the C-RET proto-oncogene which is localized on chromosome 10q11 have been found in the three clinical and allelic forms of the syndrome respectively, MEN-2 type A, B and familial isolated MTC. Mutations of C-RET are found in more than 90% of MEN-2 patients and genetic screening leads to accurate risk evaluation in families and consequently a preventive treatment of MTC and adrenal neoplasms. Recent discoveries on MEN syndromes and related familial endocrine disorders have a major clinical impact and allow a better understanding of the physiological pathways involved in familial as well as in sporadic endocrine tumor pathogenesis.     

Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma

Vestibular schwannoma occurs both as a sporadic tumour and in the dominantly inherited familial cancer syndrome neurofibromatosis type 2 (NF2). The gene for NF2 has recently been isolated on chromosome 22, and the demonstration of inactivating germline mutations in NF2 patients and NF2 associated tumours suggests that it act as a tumour suppressor. We have investigated 85 sporadic and 2 NF2 associated vestibular schwannomas, and one vagal schwannoma for chromosome 22 allele loss and NF2 gene mutations. A further 7 vestibular schwannomas were investigated for NF2 mutations only. Chromosome 22 allele loss was detected in 34 of 87 vestibular schwannomas and in the vagal nerve schwannoma. Six exons of the NF2 gene were investigated by SSCP analysis in all 95 tumours. Somatic NF2 gene mutations were detected in 13 non-familial vestibular schwannomas and in one of the NF2 vestibular schwannomas. Seven non-familial tumours with an NF2 gene mutation also displayed a chromosome 22 allele loss. Thirteen of the mutations were predicted to produce truncation of the NF2 protein. These results suggest that somatic mutations of the NF2 tumour suppressor gene are a critical step in the pathogenesis of both familial and non-familial vestibular schwannoma and that the mechanism of tumourigenesis complies with a 'two-hit' mutation model.     

A new locus for hemiplegic migraine maps to chromosome 1q31

A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease.     

Inherited neuropathies: Charcot-Marie-Tooth disease and related disorders

Collectively, the inherited disorders of peripheral nerves represent a common group of neurological diseases and are frequently encountered in the clinical setting. Recent advances in molecular genetics have not only provided improved diagnosis and counselling, but may ultimately lead to specific, rational therapies for the various forms of inherited neuropathy. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17p (CMT1A), chromosome 1q (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or may occasionally result from a point mutation in the peripheral myelin protein 22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with defects in the connexin 32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One locus for CMT2 has been assigned for chromosome 1p (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset, demyelinating polyneuropathy which may be associated with point mutations in the P0 or PMP22 genes. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal cross-over during germ-cell meiosis.     

Antimicrobial resistance in staphylococci and enterococci in 10 Portuguese hospitals in 1996 and 1997. POSGAR. Portuguese Study Group of Antimicrobial Resistance

Nephropathic cystinosis, an autosomal recessive disorder resulting from defective lysosomal transport of cystine, is the most common inherited cause of renal Fanconi syndrome. The cystinosis gene has been mapped to chromosome 17p13. We found that the locus D17S829 was homozygously deleted in 23 out of 70 patients, and identified a novel gene, CTNS, which mapped to the deletion interval. CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. Eleven different mutations, all predicted to cause loss of function of the protein, were found to segregate with the disorder.     

Targeting lurking pathogens in acute traumatic and chronic wounds

Calcium homeostasis by the kidneys and parathyroids is mediated by the calcium-sensing receptor (CaSR), which is located on 3q21-q24 and belongs to family C of the superfamily of G-protein coupled receptors that includes those for metabotropic glutamate, certain pheromones, and gamma-amino butyric acid (GABA-B). Inactivating CaSR mutations result in familial benign hypercalcemia (FBH), or familial hypocalciuric hypercalcemia (FHH), whereas activating mutations result in hypocalcemic hypercalciuria. However, not all FBH patients have CaSR mutations, which, together with the mapping of another FBH locus to 19p13.3, suggests that additional CaSRs or second messengers may be involved. These may be identified by positional cloning, and we therefore performed a genomewide search, using chromosome-specific sets of microsatellite polymorphisms, in an Oklahoma family with an FBH variant (FBHOk), for which linkage to 3q and 19p had been excluded. Linkage was established between FBHOk and eight chromosome 19q13 loci, with the highest LOD score, 6.67 (recombination fraction.00), obtained with D19S606. Recombinants further mapped FBHOk to a <12-cM interval flanked by D19S908 and D19S866. The calmodulin III gene is located within this interval, and DNA sequence analysis of the coding region, the 5' UTR, and part of the promoter region in an individual affected with FBHOk did not detect any abnormalities, thereby indicating that this gene is unlikely to be implicated in the etiology of FBHOk. This mapping of FBHOk to chromosome 19q13 will facilitate the identification of another CaSR or a mediator of calcium homeostasis.     

Ethical aspects of resuscitation

OBJECTIVE: To evaluate whether basal levels of circulating cytokines and selectins exhibit a distinct profile in attack-free, non-colchicine taking familial Mediterranean fever (FMF) patients compared to normal healthy controls, and to determine the effect of colchicine treatment on these parameters. METHODS: Serum levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, and soluble P-, E-, and L-selectin in attack-free, asymptomatic, non-colchicine using FMF patients (n = 11) and in normal controls (n = 10) were studied. Following 2 months of colchicine treatment the same parameters were evaluated again in the FMF patients. RESULTS: Before colchicine treatment the serum levels of all parameters except soluble P-selectin were significantly higher in FMF patients than in controls. After two months of treatment statistically significant decreases were observed in these parameters (p < 0.05). CONCLUSION: A distinct profile of IL-6, IL-8, TNF-alpha, and soluble E- and L-selectin levels was observed in FMF patients, which could reflect the presence of sustained inflammation in attack-free FMF patients. The effect of colchicine on these parameters suggests its therapeutic potential.     

Characterization of cyanobacteria by SDS-PAGE of whole-cell proteins and PCR/RFLP of the 16S rRNA gene

Childhood neuroblastoma, an embryonal neoplasm of sympathetic nervous system progenitors, occurs in a familial form with an autosomal dominant mode of inheritance. Genetic susceptibility to this disorder is thought to arise via a germline mutation affecting a tumor suppressor gene, in accord with the two-hit model established for familial and sporadic retinoblastoma. Surprisingly, the familial neuroblastoma predisposition locus does not map to chromosome band 1p36, a genomic region likely to contain one or more neuroblastoma suppressor genes. We reasoned that inherited point mutations affecting one allele would be unmasked in many cases by somatically acquired deletions of the second allele that included the target gene in the tumor cells from these patients. Thus, to identify chromosomal regions that might contain suppressor genes important in hereditary neuroblastoma, we analyzed six familial tumors by comparative genomic hybridization. Recurrent losses of genetic material were detected on chromosome arms 3p (consensus region, 3p24-pter), 10p (consensus, 10p12-p13), 10q (consensus, 10q25-qter), 16q (consensus, 16q12-q22), and 20q (consensus, 20q13.3-qter), in addition to the regions commonly deleted in sporadic neuroblastomas (1p36 and 11q). These chromosomal sites may harbor novel tumor suppressor genes that could aid in our understanding of the predisposition to and pathogenesis of familial neuroblastoma and potentially sporadic tumors as well.     

Epithelial cyst in the cerebellopontine angle

Aase-Smith syndrome (ASS) is usually defined as a dominantly inherited combination of arthrogryposis, Dandy-Walker malformation and cleft palate. We describe a sporadic case of foetal akinesia with abnormal fossa posterior, fitting the diagnosis of ASS, and discuss the nosology of this entity among syndromes with distal arthrogryposis. ASS shows a "hybrid" phenotype: adults with mild ASS could be classified as distal arthrogryposis, whereas severely affected newborns overlap with the Marden-Walker phenotype, which is recessively inherited. The specificity of the disorder comes from the coexistence of both forms in the same pedigree, so that ASS appears impossible to diagnose with certitude in sporadic cases. We suggest that the severe expression of ASS is only the extreme but aspecific expression of a dominantly inherited form of distal arthrogryposis. Implications for genetic counselling in distal arthrogryposis are outlined.     

Frequency of familial inheritance among 488 index patients with idiopathic focal dystonia and clinical variability in a large family

Idiopathic torsion dystonia is characterized by involuntary twisting movements and postures. One molecularly defined form with generalized dystonia has been shown to be autosomal dominantly inherited with reduced penetrance in chromosome 9q34.1, especially in Ashkenazi Jewish families, while other generalized families from Europe and families with other subtypes of dystonia have been excluded from linkage to this locus. Genealogical studies suggest that the much more frequent focal dystonia follows an autosomal dominant inheritance with reduced penetrance as well. For our study, 488 patients with focal dystonia, without a tendency for generalization, were interviewed for their family history. Evidence for hereditary disposition was found in 88 individuals. In a second step, all available family members of 17 of the 488 index patients (chosen for cooperation) were clinically examined. Objective diagnosis of affected relative was established in 13 families, whereas only 4 of the 17 index patients had previously admitted a positive family history. Furthermore, a large three-generation family with focal dystonia linked to chromosome 18p (linkage data described elsewhere) was identified. The familial pattern of all reported families is compatible with autosomal dominant inheritance with reduced penetrance. Assessment only on patients' report leads to underestimation of the frequency of familial idiopathic focal dystonia.     

Mapping TNNC1, the gene that encodes cardiac troponin I in the human and the mouse

We have mapped the TNNC1 gene, whose protein product is the cardiac TnI protein. TnI is one of the proteins that makes up the troponin complex, which mediates the response of muscle to calcium ions. The human TNNC1 locus had been assigned to a large region of chromosome 19, and we have refined the mapping position to the distal end of the chromosome by amplification of DNAs from a chromosome 19 mapping panel. We have also mapped the mouse Tnnc1 locus, by following the segregation of an intron sequence through DNAs from the European Interspecific Backcross. Tnnc1 maps close to the centromere on mouse chromosome 7.     

Genetic mapping of lung cancer modifier loci specifically affecting tumor initiation and progression

Mouse inbred strains with inherited predisposition and resistance to lung cancer provide a tool for the dissection of the complex genetics of this disease. In the present report, we have crossed the BALB/c with the SWR/J strain and performed whole-genome scanning for loci affecting lung tumor development in their F2 progeny. Both parental strains carry the pulmonary adenoma susceptibility 1 (Pas1) locus, a major locus affecting predisposition to lung cancer in mice. On distal chromosome 18 and on centromere of chromosome 6, we have mapped two pulmonary adenoma resistance loci (Par2 and Par4, respectively), which reduce lung tumor multiplicity strongly, up to 15-fold. Par2 and Par4, however, do not affect lung tumor size, which is instead controlled by an additional locus that we have mapped on the central region of chromosome 4. We designated this locus as "pulmonary adenoma progression 1" (Papg1), because it specifically modifies lung tumor size but not multiplicity. The present results, therefore, provide evidence for the existence of cancer modifier loci acting on specific stages of lung tumorigenesis.     

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases

Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.