Mutation in Nav 1.7 causes high olfactory sensitivity.

Mutations in the sodium-channel Nav 1.7, encoded by the gene SCN9A, are known to cause pain disorders. In particular, gain-of-function missense mutations in Nav 1.7 have been shown to be causal in primary erythromelalgia. We present a patient with erythromelalgia, pain attacks and hyperosmia with a mutation within the sodium-channel gene SCN9A. A 50-year-old woman presented with burning pain in both feet and abdominal pain attacks developed over the course of 10 years. Furthermore, this patient experienced a hypersensitivity for odours. Clinical investigation as well as serum/cerebrospinal fluid laboratory findings and electrophysiological testing were unremarkable. Olfactory testing showed high olfactory acuity for all screened modalities and good intranasal sensitivity. Furthermore, quantitative sensory testing within the trigeminal area revealed very low thresholds for thermal, tactile and pain detection. In addition, quantitative sensory testing at the lower legs showed hyperalgesia and, as the disease progresses, thermal sensory function loss. Skin biopsies of the proximal and distal lower limbs revealed reduced epidermal nerve fibre density indicating small fibre neuropathy. Genetic analysis of the SCN9A gene demonstrated a heterozygous mutation in Exon 20 - c.3734A>G (p.N1245S). Treatment with clinically available sodium-channel inhibitors did not result in significant pain relief. Local application of the sodium-channel blocker ambroxol however, reduced pain intensity. Continuous odour exposure stabilised mood and induced a short-term pain relief. This clinical note illustrates the course of middle-age onset erythromelalgia and points to clinical findings related to a likely pathogenic missense mutation affecting the sodium-channel Nav 1.7. SIGNIFICANCE: This case report illustrates the course of middle-age onset erythromelalgia with presumed gain-of-function in olfactory and pain sensation associated with a Nav1.7 channel mutation.

Multiple trichoepitheliomas--a novel mutation in the CYLD gene.

BACKGROUND: Trichoepitheliomas are benign neoplasms with follicular differentiation. They may present as a solitary lesion or as multiple lesions. Multiple trichoepitheliomas are inherited in an autosomal dominant pattern within families, with both variable penetrance and expressivity. Recent investigations support that mutations in CYLD, the gene affected in familial cylindromatosis as well as in Brooke-Spiegler syndrome, are also responsible for multiple trichoepitheliomas. OBJECTIVE: The authors report the case of a 9-year-old African girl with multiple facial trichoepitheliomas in whom a mutation in the CYLD gene was hypothesised. MATERIALS AND METHODS: After genomic DNA extraction from the peripheral blood, a molecular analysis of the CYLD gene was performed by PCR, DHPLC and automated sequencing. RESULTS: A novel heterozygous mutation in exon 18 of the CYLD gene (c.2449delT) was identified, with a deletion of one nucleotide resulting in a premature translational termination codon at amino acid position 831 on the affected allele (p.Cys817Valfs X15). CONCLUSIONS: The predominating tumours define the classification of these three entities. Nevertheless, studies suggest that they can simply represent phenotypic variations of the same disease spectrum, sharing common genetic mutations.

TGFBI (BIGH3) gene mutations in German families: two novel mutations associated with unique clinical and histopathological findings.

BACKGROUND: To report the clinical, histopathological and immunohistochemical findings of two novel mutations within the TGFBI gene. METHODS: The genotype of 41 affected members of 16 families and nine sporadic cases was investigated by direct sequencing of the TGFBI gene. Clinical, histological and immunohistochemical characteristics of corneal opacification were reported and compared with the coding region changes in the TGFBI gene. RESULTS: A novel mutation Leu509Pro was detected in one family with a geographic pattern-like clinical phenotype. Histopathologically we found amyloid together with non-amyloid deposits and immunohistochemical staining of Keratoepithelin (KE) KE2 and KE15 antibodies. In two families and one sporadic case the novel mutation Gly623Arg with a late-onset, map-like corneal dystrophy was identified. Here amyloid and immunohistochemical staining of only KE2 antibodies occurred. Further, five already known mutations are reported: Arg124Cys Arg555Trp Arg124His His626Arg, Ala546Asp in 13 families and five sporadic cases of German origin. The underlying gene defect within the TBFBI gene was not identified in any of the four probands with Thiel-Behnke corneal dystrophy. CONCLUSIONS: The two novel mutations within the TGFBI gene add another two phenotypes with atypical immunohistochemical and histopathological features to those so far reported.

Evidence for a founder effect of the germline fumarate hydratase gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer (HLRCC).

We report on the results of clinical investigation, pedigree analysis, mutation screening and haplotyping in a family with the syndrome of multiple cutaneous and uterine leiomyomas (MCUL1) and a germline missense mutation (R58P) in the fumarate hydratase gene (FH). We provide evidence for a founder effect for the identified mutation and distant relationship of our family to another familial case of MCUL1 associated with renal cell cancer, which was recently published with the same mutation.

[Molecular genetic and histopathological examinations for genotype-phenotype analysis in patients with TGFBI-linked corneal dystrophy]. / Molekulargenetische und histopathologische Untersuchungen zur Genotyp-Phänotyp-Analyse bei Patienten mit TGFBI-gekoppelten Hornhautdystrophien.

PURPOSE: Different missense mutations in the TGFBI gene cause granular (Groenouw CDGG1, Avellino CDA, Reis-Bücklers CDB1) and lattice (Type I; Biber-Haab-Dimmer; CDL1) corneal dystrophies and, in some reports, corneal dystrophy Thiel-Behnke (CDB2). We report on the mutation spectrum and the genotype-phenotype correlations on the basis of clinical and histopathological examinations of 13 German families with TGFBI-linked corneal dystrophies. METHODS: In 31 patients with different corneal dystrophies, DNA was extracted from leukocytes of the peripheral blood and mutation analysis was performed by direct sequencing of the TGFBI gene. Clinical and histopathological findings were compared with the molecular genetic findings for genotype-phenotype correlations. RESULTS: In 6 patients (2 families/one single person) with clinical and histopathological CDL1 we found a Missense mutation Arg124Cys and in 7 patients (3 families/one single person) with clinical and histopathological CDA we found a Missense mutation Arg124His in the exon 4 of the TGFBI gene. In 12 patients (4 families/2 single persons) with clinical and histopathological CDGG1 we found a Missense mutation Arg555Trypt in the codon 12 of the TGFBI gene. In all five patients (1 family/4 single persons) with clinical and histopathological CDB2 we could not find any mutation in the TGFBI gene. In one patient with exceptional clinical and histopathological findings we found a Missense mutation Ala546Asp, which was reported before only twice in connection with polymorphous corneal amyloidosis. CONCLUSIONS: In comparison of our clinical and histopathological findings and the molecular genetic results we found a strong genotype-phenotype correlation in patients with TGFBI-linked corneal dystrophies. Rare mutations can lead to exceptional clinical and histopathological findings which cannot be classified into the different groups of corneal dystrophies. In our patients with CDB2 we could not find any molecular genetic correlation to the TGFBI gene.

[Hereditary multiple exostoses. Molecular genetic analysis of the EXT1 gene in an unusual family]. / Hereditäre multiple Exostosen. Molekulargenetische Analyse des EXT1-Gens in einer ungewöhnlichen Familie.

Hereditary multiple exostosis (HME), a disorder inherited in an autosomal dominant manner, is characterized by multiple projections of bone, mainly at the extremities. The risk of malignant transformation of the exostoses is estimated to be up to 2%. The most common underlying cause of the disease involves mutations in either the EXT1 or the EXT2 gene. We report on the clinical and molecular findings in a family affected with HME.A mother and her three children from different partnerships, all clinically diagnosed with HME, were referred for genetic counseling. Subsequently, molecular analysis of the EXT1 gene was performed according to standard procedures. We identified a mutation in the EXT1 gene in all four affected family members (delA in codon 133). This mutation has not been previously described and is suggested to cause the disease in this family. Identification of disease causing mutations in patients with HME and their relatives can help to improve the clinical management of tumor prevention, early tumor detection, and orthopedic therapy.

Another case of autosomal dominant exstrophy of the bladder.

OBJECTIVE: Exstrophy of the bladder is a rare malformation due to an anterior midline defect. Most cases of this condition with variable expression occur sporadically, but there are some cases indicative of a strong genetic component apart from environmental factors. This is a report about another rare mother-child pair with bladder exstrophy. METHODS: We present the clinical data of a familial case of bladder exstrophy with an affected mother and her equally affected male fetus. RESULTS: Prenatal diagnosis of bladder exstrophy in the fetus was assessed by ultrasound at the 19th gestational week and was confirmed after termination of pregnancy at the 21st gestational week. CONCLUSION: The present case may be additional evidence for an autosomal dominant inherited variant of this malformation complex with implication for counselling of affected patients.

[Molecular genetic mutation analysis of the PTPN11 gene in the multiple lentigines (LEOPARD) syndrome]. / Molekulargenetischer Mutationsnachweis im PTPN11-Gen beim Multiple-Lentigines- (LEOPARD-)Syndrom.

BACKGROUND AND OBJECTIVE: LEOPARD syndrome (MIM #151100) is a rare autosomal dominant condition with characteristic skin anomalies, facial dysmorphism, hypertelorism, cardiac anomalies, and occasional conductive hearing loss. Mutations in the PTPN11 gene are described as the causal gene defect for the clinical features of Noonan syndrome (MIM #163950), but also for LEOPARD syndrome. For confirmation of the clinical diagnosis of multiple lentigines syndrome, the molecular genetic mutation analysis in the PTPN11 gene could be helpful. PATIENTS/METHODS: We report on a family with LEOPARD syndrome in which the mutation analysis in the father and his daughter in the PTPN11 gene was carried out us:ng PCR, DHPLC, and automated sequencing. RESULTS: We could identify both father and daughter as carriers of the mutation Y279C in the PTPN11 gene, which is known as a disease-related mutation. CONCLUSIONS: The allelic affinity to Noonan syndrome could thus be further supported.