Causal variants in Maturity Onset Diabetes of the Young (MODY) – A systematic review

Background Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date. Methods We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes. Results The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries. Conclusions We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.

Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip

Background: Developmental dysplasia of the hip (DDH) is one of the most prevalent skeletal disorders. DDH is considered a pathologic condition with polygenic background, but environmental and mechanic factors significantly contribute to its multifactorial etiology. Inheritance consistent with autosomal dominant type has also been observed. Single-nucleotide polymorphisms (SNPs) in various genes mostly related to formation of connective tissue are studied for a possible association with DDH. Methods: We genotyped three SNPs, rs1800796 located in the promoter region of the IL6 gene, rs143383 located in the 5′ untranslated region (UTR) of the GDF5 gene and rs726252 located in the fifth intron of the PAPPA2 gene. The study consisted of 45 subjects with DDH and 85 controls from all regions of Slovakia. Results: Association between DDH occurrence and studied genotypes affected by aforementioned polymorphisms was confirmed in the case of rs143383 in the GDF5 gene (p = 0.047), where the T allele was over-expressed in the study group. Meanwhile, in the matter of IL6 and PAPPA2, we found no association with DDH (p = 0.363 and p = 0.478, respectively). Conclusions: These results suggest that there is an association between DDH and GDF5 polymorphisms and that the T allele is more frequently presents in patients suffering from DDH.

Imaging studies used as aid in the diagnosis of cleidocranial dysplasia. A review

Cleidocranial dysplasia (CCD), also known as Marie-Sainton syndrome, is a rare disorder of autosomal dominant type that presents specific characteristics at the skeletal and dental level. The diagnosis of CCD is based on clinical and radiographic findings. Panoramic, cephalometric, and anterior poster radiographs have been used for its diagnosis in dentistry. However, these radiological techniques have limitations, and advances in technology with new imaging studies such as magnetic resonance imaging (MRI) and ultrasound have emerged, contributing to the diagnosis of CCD. Therefore, the aim of this review was to identify and describe current imaging studies that contribute to both the diagnosis and adequate and efficient treatment planning of CCD and describe the clinical and radiographic characteristics of patients with this syndrome.

Experience in use of L­-carnitine in treatment of patients with epidermolysis bullosa

Objective — to study the effectiveness of L-carnitine in patients with various forms of congenital epidermolysis bullosa (CEB).Materials and methods. We observed 120 patients with CEB aged 1 to 12 years. A simple form of the disease was diagnosed in 60, dystrophic form — in 60 children. According to genealogical maps, 17 (28.3 %) of 60 patients with dystrophic CEB had an autosomal dominant type of inheritance, and 43 (71.7 %) of 60 had autosomal recessive inheritance. In the autosomal dominant type, the multiple blisters, miliums and atrophic scarrings, mainly on the extremities, as well as anonychias were dominant as clinical manifestations. In the autosomal recessive type, multiple blisters, erosions, crusts, atrophic scars, onychodystrophy, pseudosyndactylies on the upper and lower extremities, as well as disabling contractures of the hands, feet, elbows and knees were observed.L-carnitine at a dose of 1 ml/kg during 3 months was prescribed as part of the complex therapy to patients with CEB. The standard treatment for patients with CEB was the correct use of external means and dressings to reduce trauma to the foci and accelerate the epithelialization of erosive rashes.Results and discussion. For clinical evaluation of the efficacy of L-carnitine, patients with CEB were divided into groups comparable by sex, age, duration and form of the disease: group I consisted of 30 patients with simple CEB who received standard treatment, group II — of 30 patients with simple CEB who received standard treatment in combination with L-carnitine, group III — of 30 patients with dystrophic form of CEB who received standard treatment, group IV — of 30 patients with dystrophic form of CEB who received standard treatment in combination with L-carnitine. The positive result of therapy (epithelialization of erosions and the absence of new rashes) was achieved in 19 (63.3 %) of 30 patients of group I, in 26 (86.7 %) of 30 patients of group II, in 11 (36.7 %) of 30 patients of group III, in 16 (53.3 %) of 30 patients of group IV. This confirms the effectiveness and feasibility of using L-carnitine in various forms of CEB.Conclusions. The use of L-carnitine in the complex therapy of patients with CEB allows accelerating the epithelialization of erosive formations on the skin and visible mucous membranes.

Cribriform-morular thyroid carcinoma

Along with classic papillary thyroid cancer, there are rare histological variants with special clinical features, and often physicians are not well informed about them. We present a clinical case of 25 years-old female, who was diagnosed with papillary thyroid cancer based on neck ultrasound and fine needle aspiration biopsy followed by thyroidectomy. The histological and immunohistochemical investigation (expression of cytokeratin-19, CD 56, thyroglobulin, β-catenin) were performed and cribriform-morular carcinoma was identified. It’s believed that this type of papillary thyroid cancer in the majority of cases is associated with familial adenomatous polyposis of the colon. This disease with an autosomal dominant type of inheritance is caused by the mutation of the APC suppressor gene and characterized by the presence of multiple adenomatous polyps in the colon with a 100% risk of malignancy and colon cancer. The patient underwent an additional examination with colonoscopy which revealed polyps in all parts of the colon ranging in size from 1 mm to 3.5 cm. We identified mutation in gene APC — p.S1104X and performed a preventive coloproctectomy. The histological examination verified tubular and tubulovillous adenomas with moderate epithelial dysplasia. During 6 years of follow-up of patient, structural and biochemical remission of thyroid cancer was observed.

The Variable Expression of a Novel MBD5 Gene Frameshift Mutation in an Italian Family

Haploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene is reported as a cause of an autosomal dominant type of cognitive disability (MRD1) and autism spectrum disorder through large deletions involving multiple genes or point mutations, ultimately leading to haploinsufficiency in both cases. However, relatively few reports have been published on the phenotypical spectrum resulting from point mutations.We report here on a novel heterozygous frameshift variant in the MBD5 gene [c.2579del; p.(Lys860Argfs*11)] in a family in which the typical signs associated with pathogenic variants were expressed with different degrees of severity in the clinical presentation of the carrier individuals.Our findings, adding a novel mutation to the mutational spectrum, further support the relevance of the MBD5 gene as one of the main molecular mechanisms involved in the pathogenesis of intellectual disability and contribute to the characterization of the genotype–phenotype correlations.

A rare case of Vohwinkel’s syndrome

Keratoderma hereditarium mutilans or Vohwinkel’s syndrome is a rare autosomal dominant type of palmoplantar keratoderma characterized by honeycomb appearance, pseudoainhum leading to auto-amputation and stellate keratosis on knuckles. It’s mode of inheritance is autosomal dominant with mutation in loricrin and connexin 26 genes. We report the case of a 35-year-old female with alopecia universalis since birth and transgradient palmoplantar keratoderma, impaired hearing and pseudoainhum formation since childhood. This case is being reported to highlight the association of Vohwinkel’s syndrome with sensorineural hearing loss and alopecia universalis.

Porokeratosis: clinical manifestations and treatment options

Porokeratosis is a rare disease with an autosomal dominant type of inheritance. It is customary to distinguish classic Mibelli porokeratosis, as well as disseminated and localized variations of the course of dermatosis, which differ in genetic predisposition, trigger factors, and treatment approaches. The article describes the variants of the disease – eruptive itchy papular malformation that occurs on the extremities against the background of microcirculation disorders and giant, developed on the skin of the trunk. The main methods of treatment of porokeratosis are also described.

Search for new genetic factors associated with the development of hypertrophic cardiomyopathy in the Russian population

Гипертрофическая кардиомиопатия (ГКМП) - самая распространённая форма наследственных заболеваний сердца с преимущественно аутосомно-доминантным типом наследования. Однако до сих пор не выявлены все гены, которые могут быть связаны с патогенезом ГКМП. В связи с этим, целью данной работы стали изучение и поиск новых генетических факторов, связанных развитием ГКМП в российской популяции. Hypertrophic cardiomyopathy (HCM) is the most common form of inherited heart disease with a predominantly autosomal dominant type of inheritance. However, all genes that may be associated with the pathogenesis of HCMP have not yet been identified. In this regard, the aim of this work was to search for new genetic factors associated with the development of HCM in the Russian population.