Acquired von Willebrand Syndrome Hiding Inherited von Willebrand Disease Can Explain Severe Bleeding in Patients With Aortic Stenosis.

OBJECTIVE: Aortic stenosis may be complicated by an acquired von Willebrand syndrome that rarely causes significant bleeding, raising the question of why it does so in a few cases. To seek an explanation, we studied 5 severe bleeder aortic stenosis patients in a cohort of 49 patients, using the flowchart for inherited von Willebrand disease. Approach and Results: All 5 patients were lacking in large and intermediate VWF (von Willebrand factor) multimers, 3 had reduced plasma and platelet VWF levels, and none showed PFA100 closure. Two patients (those with most multimers missing) also had a short VWF half-life. Genetic analyses on the 3 patients with reduced platelet VWF levels revealed that one carried both the c.1164C>G and the c.7880G>A mutations, and another carried the c.3390C>T mutation, while the third had one of the 2 VWF alleles relatively less expressed than the other (25% versus 75%). No genetic alterations emerged in the other 2 patients. Successful replacement of the stenotic aortic valve, performed in the 2 patients with VWF mutations, did not correct their abnormal VWF multimer picture-unlike what happened in the aortic stenosis patients without bleeding symptoms. CONCLUSIONS: Our findings suggest that acquired von Willebrand syndrome can develop in patients with hitherto-undiagnosed inherited von Willebrand disease. Since von Willebrand disease is the most common bleeding disorder, this possibility should be considered in aortic stenosis patients-especially those with a more severe bleeding history and more disrupted VWF laboratory patterns-because they risk hemorrhage during aortic valve replacement.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

The p.R1819_C1948delinsS mutation makes von Willebrand factor ADAMTS13-resistant and reduces its collagen-binding capacity.

This report concerns abnormal ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) and collagen interactions coinciding with the p.R1819_C1948delinsS von Willebrand factor (VWF) mutation associated with the deletion of the C-terminus of the A3 domain (amino acids 1819-1947) in a patient with a history of bleeding. The von Willebrand disease (VWD) phenotype of the patient featured low plasma and platelet VWF, multimers with smears extending over the highest normal oligomers in plasma, but not platelets, and an impaired collagen-binding capacity. In vitro full-length p.R1819_C1948delinsS VWF expression showed impaired VWF release, increased cellular content with normally-multimerized VWF and impaired collagen binding. The recombinant p.R1819_C1948delinsS VWF fragment, extending from domains A2 to B3 (p.R1819_C1948delinsS A2-B3 VWF), was completely resistant to proteolysis by ADAMTS13 in the presence of 1·5 mol/l urea, unlike its normal counterpart. The defect stems from impaired ADAMTS13 binding to p.R1819_C1948delinsS A2-B3, analysed under static conditions. Partial deletion of the C-terminus of the A3 domain thus makes VWF resistant to ADAMTS13, interfering with ADAMTS13 binding to VWF, and impairing the collagen-binding capacity of VWF. The p.R1819_C1948delinsS mutation has both haemorrhagic features (defective collagen binding, reduced VWF levels) and prothrombotic (ADAMTS13 resistance) features, and the latter probably mitigate the patient's bleeding symptoms.

Spontaneous hemarthrosis in combined Glanzmann thrombasthenia and type 2N von Willebrand disease.

Glanzmann thrombasthenia is a rare autosomal recessive inherited bleeding disorder characterized by the lack of platelet aggregation, caused by deficiencies and/or abnormalities of platelet GPIIb-IIIa receptor. We report a case of Glanzmann thrombasthenia combined with type 2N von Willebrand disease (VWD), a variant characterized by an impaired capacity of FVIII to bind von Willebrand factor (VWF), which results in an autosomally transmitted reduction in circulating FVIII levels. Glanzmann thrombasthenia stems from compound T1214C and G1234A mutations in the ITGA2B gene; the type 2N VWD is due to a heterozygous G2561A mutation in the VWF gene (R854Q). The haemostatic phenotype of a 48-year-old female patient was unusually characterized by a severe chronic arthropathy with loss of cartilage and the presence of subchondrial cysts involving both ankles. The arthropathy was quantified with the compatible MRI scoring system (currently used to assess arthropathy in haemophilia), reaching almost the highest score. These haemorrhagic complications are very rare in Glanzmann thrombasthenia and resemble those seen in severe haemophilia; for such, a reason we decided to explore the patient's FVIII and VWF parameters. Our findings suggest that the type 2N R854Q mutation, which is normally asymptomatic at the heterozygous level, may be expressed in the presence of a combined impairment of primary haemostasis.

A common ancestor more than 10,000 years old for patients with R854Q-related type 2N von Willebrand's disease in Italy.

The impaired capacity of von Willebrand factor to carry factor VIII is identified as type 2N von Willebrand's disease. R854Q is the most common type 2N mutation, and almost the only one identified in Italy. This aim of this study was to ascertain whether R854Q mutations in a cohort of Italian patients with type 2N von Willebrand's disease originated from a single event or recurrent events. Thirteen unrelated Italian families were investigated, analyzing the von Willebrand factor gene haplotype associated with the R854Q mutation. A common haplotype emerged in all the families, extending from single nucleotide polymorphisms rs2166902 to rs216293 over 48.2 kb and including five intragenic markers. This haplotype is infrequent in the healthy Italian population (17% versus 100%, P<0.0001) and each genetic marker within the said haplotype is similarly rare. These data strongly suggest a founder effect, with a single R854Q mutation event being the cause of the type 2N von Willebrand's disease in our cohort of patients. Using DMLE+ software and the mathematical model of Bengtsson and Thomson, it was estimated that the R854Q mutation occurred from 10,000 to 40,000 years ago, which is consistent with the short dimension of the haplotype shared by our patients. Together with the fact that the R854Q mutation seems to be limited to Caucasian populations, these findings suggest that a single mutational event took place after human populations moved from Africa towards Europe.

The homozygous ganglioside-induced differentiation-associated protein 1 mutation c.373C > T causes a very early-onset neuropathy: case report and literature review.

Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene may cause severe early-onset inherited neuropathies. Here, the authors report a clinical and neurophysiological follow-up of a Pakistani child with a very early-onset neuropathy carrying a novel homozygous mutation in the GDAP1gene. They discuss the relationship between the several forms of Charcot-Marie-Tooth disease presenting in the first months of life and focus on the literature of GDAP1-associated early-onset neuropathy. This case further expands on the clinical spectrum and the genetic heterogeneity of early-onset inherited neuropathy due to GDAP1 gene mutations.

Novel mutations in the L1CAM gene support the complexity of L1 syndrome.

X-linked hydrocephalus, MASA syndrome, X-linked complicated Spastic Paraplegia Type I and X-linked partial agenesis of the corpus callosum are the four rare diseases usually referred to L1 syndrome, caused by mutations in the L1CAM gene. By direct sequencing of L1CAM in 16 patients, we were able to identify seven mutations, five of which were never described before. Patients' phenotype evaluation revealed a correlation between the number of clinical features typical of L1 syndrome and the chance to find causative mutation. Our findings support that L1CAM mutations are associated with widely heterogeneous phenotypes, however the occurrence of several clinical features remains the best criterion for planning molecular testing both in familial and apparently sporadic cases.