A 45-year-old man with sudden cardiac death, cutaneous abnormalities and a rare desmoplakin mutation: a case report and literature review.

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a rare, heritable myocardial disorder that is a leading cause of ventricular arrhythmia and sudden cardiac death (SCD) in young people. Desmoplakin (DSP) mutations account for 3-20% of AC cases. However, the number of patients with DSP mutations is extremely small in all published reports and genotype-phenotype correlations are scant and mostly non-gene-specific. CASE PRESENTATION: A 45-year-old man was admitted after an out-of-hospital cardiac arrest, with documented ventricular fibrillation. He had no previous history of heart disease or family history of SCD or cardiomyopathy. The cardiac magnetic resonance showed a mildly dilated left ventricle with an ejection fraction of 30% and a non-dilated right ventricle with mildly depressed systolic function, and extensive subepicardial late gadolinium enhancement. Genetic screening identified a heterozygote nonsense mutation in DSP (NM_004415.2: c.478 C > T; p.Arg160Ter). Cascade genetic screening of the relatives revealed a high prevalence of the genotype and cutaneous phenotype, but a very low penetrance of the cardiac phenotype. CONCLUSIONS: We report a case of SCD and an autosomal dominant mutation in DSP that causes arrhythmogenic dilated cardiomyopathy/AC. Like the recessive mutation in DSP known to cause Carvajal syndrome, Arg160Ter may be associated with cutaneous abnormalities.

Palmoplantar keratoderma, oral involvement, and homozygous CTSC mutation in two brothers from Cambodia.

Haim-Munk syndrome (HMS) and Papillon-Lefevre syndrome (PLS) are phenotypic variants of palmoplantar keratoderma (PPK) with progressive early-onset periodontitis and dental caries. HMS and PLS have been associated with homozygous or compound heterozygous mutations in the lysosomal protease gene Cathepsin C (CTSC). There have been only a few documented cases of CTSC mutations in patients from South-East Asia. We report the clinical findings of two Cambodian brothers who presented with diffuse, demarcated PPK with transgrediens extending to the elbows and knees, as well as pachyonychia and dental caries. Arachnodactyly and periodontitis were also found in the older brother. Next-generation sequencing unveiled a homozygous missense variant in CTSC (NM_001814.5: c.1337AC: p.(Asp446Ala)) in both brothers. Both parents were heterozygous for the variant, while an unaffected older brother was homozygous for the wild-type allele. Our study adds to the spectrum of mutations and associated clinical presentations for this rare genodermatosis.

FAM83G/Fam83g genetic variants affect canine and murine hair formation.

FAM83G/Fam83g genetic variants have been described in dogs, mice and recently also in humans. They are associated with palmoplantar keratoderma and altered hair or coat phenotype, reported as wooly phenotype in mice. FAM83G/Fam83g is an unexplored effector of temporally and spatially coordinated Wnt and BMP signalling which are key pathways in pre- and postnatal hair follicle morphogenesis and differentiation. The aim of this study was to unravel phenotypic consequences of FAM83G/Fam83g variants on hair coat formation in dogs and mice. Our results show differences in hair types and hair shaft structures in both species. Additionally, mice exhibit deregulated hair cycle progression which timely correlates with defective Wnt signalling (Axin2) and Bmp2/4 expression. These results affirm the involvement of FAM83G in hair morphogenesis, hair follicle differentiation and cycling.

Oro-dental characteristics of three siblings with Papillon-Lefevre syndrome.

Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder, showing oral and dermatological manifestations in the form of aggressive periodontitis, leading to the premature loss of both primary and permanent teeth at a very young age and palmar-plantar hyperkeratosis. It was first described by two French physicians, Papillon and Lefevre in 1924. Immunologic, genetic, or possible bacterial etiologies have been thought to account for etiopathogenesis of PLS. Severe gingival inflammation and periodontal destruction occurred after the eruption of primary teeth. This condition should warn the physicians and dentists as a one of the important sign for the diagnosis of PLS. There have been over 250 cases reported in literature about PLS, but a few of these were in the same family. This study presents oro-dental characteristics, dental treatments, and follow-up of three siblings (age of sisters are 13, 6, and 4 years) with PLS, which is rarely seen in the same family.

Generalized woolly hair with diventricular arrythmogenic cardiomyopathy: a rare variant of Naxos disease.

Woolly hair may occur as an isolated problem of cosmetic concern or can be a part of a systemic disease (woolly hair syndrome) with underlying fatal cardiomyopathy. Two characteristic associations of woolly hair syndrome are Naxos disease and Carvajal syndrome. Naxos disease is characterized by woolly hair, palmoplantar keratoderma, and arrythmogenic right ventricular cardiomyopathy.In this report we describe a case of a young girl who presented with heart failure and was subsequently diagnosed as a case of generalized woolly hair with biventricular arrythmogenic cardiomyopathy.Our case represented a rare variant of Naxos disease in the advanced stage of arrythmogenic right ventricular cardiomyopathy; biventricular failure may occur with involvement of the interventricular septum and left ventricle causing congestive heart failure.

An unusual form of Naxos disease and its improvement by adjuvant low-dose colchicine therapy.

We evaluated a female patient with an unusual form of Naxos disease, who presented with central cyanosis and clubbing, simulating congenital heart disease. Adjuvant low-dose colchicine therapy (0.5 mg once daily) showed positive effects and has been continued for six months. Colchicine has anti-inflammatory and anti-fibrotic properties. It inhibits mitosis by disrupting tubulin assembly and enhances cellular apoptosis. Follow-up showed improvement in the patient's clinical status, with a dramatic disappearance of the electrical storm and reductions in cyanosis and palmoplantar hyperkeratosis. Low-dose colchicine may be safe and effective in patients with Naxos disease and may reduce related complications.

A case of arrhythmogenic right ventricular cardiomyopathy-Naxos disease.

We present a case of arrhythmogenic right ventricular cardiomyopathy (ARVC)-Naxos disease. The patient is 21-year-old male with no history of previous heart disease admitted in a private hospital for rhythm disorder in heart. The condition was diagnosed as ventricular tachycardia (VT) and was treated with cardioversion. The patient was referred to our hospital for further evaluation. On examination patient had palmoplantar keratoderma, wooly hair, and dystrophic nails. The cardiovascular system examination was clinically normal. His electrocardiogram showed epsilon wave in lead V1; echocardiography showed hypo-echogenic tissues in the right ventricular (RV) apex and free wall; magnetic resonance imaging (MRI) investigation revealed fibrofatty replacement of RV free wall and dyskinetic RV wall with diastolic outbulging.

Howel-Evans syndrome: a variant of ectodermal dysplasia.

Howel-Evans syndrome is a rare form of palmoplantar keratoderma associated with esophageal cancer and is inherited in an autosomal dominant fashion. First described in 2 kindreds in the United Kingdom, Howel-Evans syndrome has subsequently been reported in only one American family. We present a previously unreported case of Howel-Evans syndrome from this American kindred demonstrating a distinct clinical phenotype. The patient manifests both cutaneous and ectodermal abnormalities, supporting the reclassification of Howel-Evans syndrome as a variant of ectodermal dysplasia.

Naxos disease - a narrative review.

INTRODUCTION: Naxos disease is a rare entity that manifests with woolly hair, keratosis of extremities, and cardiac manifestations that resemble arrhythmogenic right ventricular cardiomyopathy. It is inherited in an autosomal recessive pattern and mutations affecting plakoglobin and desmoplakin have been identified. There is an increased risk of arrhythmias, including sudden cardiac death at a young age. Right ventricular systolic dysfunction often progresses and left ventricular involvement may also occur. AREAS COVERED: This article reviews historic background, epidemiology, clinical characteristics, genetics, and pathogenesis as well as therapeutic management and future perspectives. EXPERT OPINION: The principles of evaluation and treatment are based on arrhythmogenic right ventricular cardiomyopathy (ARVC) and general heart failure guidelines, because specific data on Naxos disease are limited. Therefore, larger registries on Naxos disease are welcome in order to gain more knowledge about clinical course and risk stratification. Translational research on pathophysiological mechanisms has evolved, including promising approaches using stem cells for novel targets.

A genetic model of CEDNIK syndrome in zebrafish highlights the role of the SNARE protein Snap29 in neuromotor and epidermal development.

Homozygous mutations in SNAP29, encoding a SNARE protein mainly involved in membrane fusion, cause CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis and Keratoderma), a rare congenital neurocutaneous syndrome associated with short life expectancy, whose pathogenesis is unclear. Here, we report the analysis of the first genetic model of CEDNIK in zebrafish. Strikingly, homozygous snap29 mutant larvae display CEDNIK-like features, such as microcephaly and skin defects. Consistent with Snap29 role in membrane fusion during autophagy, we observe accumulation of the autophagy markers p62 and LC3, and formation of aberrant multilamellar organelles and mitochondria. Importantly, we find high levels of apoptotic cell death during early development that might play a yet uncharacterized role in CEDNIK pathogenesis. Mutant larvae also display mouth opening problems, feeding impairment and swimming difficulties. These alterations correlate with defective trigeminal nerve formation and excess axonal branching. Since the paralog Snap25 is known to promote axonal branching, Snap29 might act in opposition with, or modulate Snap25 activity during neurodevelopment. Our vertebrate genetic model of CEDNIK extends the description in vivo of the multisystem defects due to loss of Snap29 and could provide the base to test compounds that might ameliorate traits of the disease.

Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome.

Synaptosomal-associated protein 29 (SNAP29) encodes a member of the SNARE family of proteins implicated in numerous intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). Moreover, bi-allelic SNAP29 mutations in patients are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome. A mouse model that recapitulates abnormalities found in these syndromes is essential for uncovering the cellular basis of these disorders. In this study, we report that mice with a loss of function mutation of Snap29 on a mixed CD1;FvB genetic background recapitulate skin abnormalities associated with CEDNIK, and also phenocopy neurological and ophthalmological abnormalities found in CEDNIK and a subset of 22q11.2DS patients. Our work also reveals an unanticipated requirement for Snap29 in male fertility and supports contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients.

Effect of debridement of plantar hyperkeratoses on gait in older people - An exploratory trial.

Hyperkeratoses are a common cause of foot pain due to the release of inflammatory mediators, which can have an impact on the mobility and independence of people suffering from them. However, the repercussions that hyperkeratoses have on gait parameters remain uncertain. AIM: The aim of this study is to analyze the repercussions that plantar hyperkeratosis debridement has on several kinematic and kinetic variables of gait in a group of older participants. METHODS: 98 older participants (75.1 ±â€¯6.7 years) were randomly assigned to two groups: Group A, Scalpel debridement of plantar hyperkeratoses; and Group B, Control group (Simulated debridement). Plantar hyperkeratotic pain was measured before and after treatment on a visual analog scale. Several kinematic and kinetic variables of gait were measured before and after treatment using a Win-Track pressure sensitive walkway. RESULTS: A significant difference was found in the level of pain between the treated group and the control group (p < 0.01 [8.55-18.15; 95% confidence interval]). Regarding the gait parameters, statistically significant reductions were found in peak pressures (p < 0.05; Cohen's d = 2.688) and maximum force (p < 0.04; d = 0.262). CONCLUSIONS: Data suggests that debridement of plantar hyperkeratosis may lead to a reduction in pain and appear to reduce peak maximum force and peak plantar pressure. No significant changes were observed in the kinematic variables analyzed. The duration of the benefits remain unknown.

Do plantar hyperkeratoses affect balance in people older than 65 years old?

Tactile information picked up by plantar receptors provides afferent sensory information that is fundamental for controlling body balance. Plantar hyperkeratoses may alter the quality and quantity of such information, thereby modifying balance. AIM: Analyse how plantar hyperkeratosis debridement affects static body balance in subjects of 65 years of age or older. METHODS: In order to analyse the impact of hyperkeratoses on balance, 50 older people took part in this study. Pain caused by plantar hyperkeratoses was measured on a visual analogue scale. Static balance was assessed on a pressure sensitive platform. The treatment was scalpel debridement of hyperkeratoses. RESULTS: Pain decreased significantly (p=0.03). Regarding the variables analysed, significant differences were found between pre- and post-treatment values in anteroposterior length (Length, mm) (p=0.032) and anteroposterior amplitude (Amp, mm) (p=0.044) of the centre of plantar pressure with eyes open. CONCLUSIONS: Plantar hyperkeratosis debridement is capable of interfering favourably with sensory afferent inputs, thereby improving control of stability and modifying stabilometric readings in the AP component when a subject balance with eyes open.