Recessive Manner Research Articles

Exome sequence analysis identifies a homozygous, pathogenic, frameshift variant in the MAN2B1 gene underlying clinical variant of α-mannosidosis.

α-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions' impairment followed by facial asymmetry. We studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function. Re-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel α-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant. Patients in both the families have manifested peculiar set of clinical symptoms associated with α-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to α-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of α-mannosidosis.

In silico characterization and identification of compound heterozygous variants in H/ACA Ribonucleoprotein Assembly Factor (SHQ1) from Indian population.

H/ACA small nucleolar ribonucleoproteins (snoRNP) form a complex with multiple proteins to accomplish the pseudouridylation of rRNA. The assembly of H/ACA small nucleolar ribonucleoproteins (snoRNP) is initiated by H/ACA ribonucleoprotein Assembly factor, that is, SHQ1. Mutations in SHQ1 have been reported to cause two disorders namely, dystonia-35 childhood onset (OMIM*619921) and neurodevelopmental disorder with seizures and dystonia (OMIM*619922), both of which are inherited in an autosomal recessive manner. Considering the high genetic and clinical diversity of SHQ1-related clinical features and the importance of SHQ1 in the assembly of the H/ACA snoRNP complex, it is important to take a systematic approach to delineate the genetic diagnosis and impact of mutations on protein structure and stability. Whole exome sequencing followed by Sanger validation was performed in an individual with the clinical features of neurodevelopmental disorder with seizures and dystonia (OMIM*619922). Protein modeling studies of all the reported SHQ1 variants to date were performed using freely available web servers Interactive Tree of Life, String, BioGrid, ShinyGO, DAVID, and Pathvix. Protein structures were visualized using Pymol. We identified compound heterozygous variants, one known frameshift deletion c. 828_831del, p.(Asp277Serfs*27) and the other novel missense variant c. 1157A>C, p.(Tyr386Ser) found in an individual with neurodevelopmental disorder, seizures, movement disorder, and hypomyelination leukodystrophy on neuroimaging. Protein-interactome studies identified potential genetic interactors that include GAR1, NAF1, TRUB1, UTP15, DKC1, NOP10, NPHOSPH 10, KRR1, NOP58, NOP56, FBL, RRP9, NHP2, RUVBL1, and RUVBL2. Ribosome biogenesis in eukaryotes, RNA polymerase, RNA transport, spliceosome, ribosome, cytosolic DNA-sensing pathway, DNA replication, mismatch repair, base excision repair, nucleotide excision repair, and basal transcription factors process were identified as the linked pathways with the prioritized genes. In conclusion, a sophisticated genotype and phenotype correlation followed by linking the genes to the key biological pathways opens new avenues to understand disease pathology and plan for therapeutic interventions.

Understanding CFTR Functionality: A Comprehensive Review of Tests and Modulator Therapy in Cystic Fibrosis.

Cystic fibrosis is a genetic disorder inherited in an autosomal recessive manner. It is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7, which leads to abnormal regulation of chloride and bicarbonate ions in cells that line organs like the lungs and pancreas. The CFTR protein plays a crucial role in regulating chloride ion flow, and its absence or malfunction causes the production of thick mucus that affects several organs. There are more than 2000 identified mutations that are classified into seven categories based on their dysfunction mechanisms. In this article, we have conducted a thorough examination and consolidation of the diverse array of tests essential for the quantification of CFTR functionality. Furthermore, we have engaged in a comprehensive discourse regarding the recent advancements in CFTR modulator therapy, a pivotal approach utilized for the management of cystic fibrosis, alongside its concomitant relevance in evaluating CFTR functionality.

#104 : Live Birth Rate After Preimplantation Genetic Testing for Monogenic Disorders (PGT-M) for Thalassemia in Vietnamese Patients

Background and Aims: Thalassemia is a hereditary blood disorder with diverse clinical manifestation inherited by autosomal recessive manner which affected 1.5% of the population. Clinically, there are two major forms: [Formula: see text]-thalassemia and [Formula: see text]-thalassemia. Palliative treatment of the severe forms by blood transfusion is eventually compromised by the concomitant problems of iron overload, alloimmunization, and bloodborne infections. In Vietnam, there are approximately 13.8% cases of thalassemia carriers in the entire population. PGT-M aims to characterize the genetic status of embryos resulting from in vitro fertilization (IVF) cycles. Herein, we report the clinical outcome of using PGT-M in couples who are thalassemia carriers. Methods: This was a case series report conducted at IVFMD, My Duc Hospital, Vietnam between April 2019 and April 2022. A total of 38 couples who underwent IVF cycle in combination with PGT-M were enrolled in this study. Trophectoderm biopsy samples undergone whole-genome amplification, followed by next-generation sequencing (NGS) via the MiSeq platform for aneuploidy screening. Specific-targeted genes were performed for thalassemia detection in the next step. Results: PGT-M was performed on a total of 128 blastocysts from 38 couples. Among 128 blastocysts, 92 (71.9%) were euploid. The rate of unaffected blastocysts was 38.0% and heterozygous blastocysts was 27.2% among euploid blastocysts. Single blastocyst transfer was performed in 30 couples and underwent 34 cycles. The clinical pregnancy rate was 50.0% and the overall live birth rate was 41.2%. Conclusion: Data from this study showed a favorable live birth rate after PGT-M for thalassemia. We should encourage carrier couples to undergo PGT-M to eliminate the transfer of this disorder through the next generation.

A Fatal Case of Hemophagocytic Lymphohistiocytosis Triggered By Babesiosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by hyperactivation of macrophages and T lymphocytes. While HLH is primarily inherited in a recessive manner among children, in adults, it is more commonly associated with underlying infections, autoimmune disorders, and malignancies. However, the association between HLH and Babesia infection remains exceptionally uncommon, with only a few reported cases in the medical literature. In this report, we present a unique case of HLH in the context of babesiosis, shedding light on the crucial clinical features and risk factors. By raising awareness of this rare differential diagnosis, we aim to contribute to early recognition and timely treatment, potentially reducing mortality from this treatable illness. Case Presentation: A 77-year-old male with history of deep vein thrombosis (DVT), Parkinson's disease, and lumbar radiculopathy on chronic prednisone, presented for progressive generalized weakness, leg pain, and confusion. Initial labs showed normocytic anemia, thrombocytopenia, low fibrinogen and elevated INR and liver enzymes (Table 1). Multiple ischemic signs were noted including acute on chronic DVT, as well as findings of marked splenomegaly with wedge infarcts and periportal lymphadenopathy on abdominal ultrasound and CT (Figure 1). The underlying etiology of these findings was unclear and broad differential work up was pursued. Given the anemia and thrombocytopenia on presentation, the patient received multiple blood products including platelets, red blood cells, fresh frozen plasma and cryoprecipitate, in addition to vitamin K. No schistocytes were seen peripherally, and DIC/TTP workup was negative. Multidisciplinary teams evaluated the risk versus benefit of anticoagulation with heparin drip considering evidence of multi-organ ischemic damage. It was briefly initiated, but later held due to persistent thrombocytopenia and abnormal liver function. Further work up only revealed hemolysis with a low haptoglobin and elevated LDH (Table 1). However, the follow up Coombs test was negative, ruling out immune mediated hemolysis. While symptomatic management continued, blood parasite screen obtained on admission indicated Babesia microti infection. Upon repeat testing, no evidence of babesia was identified on labs or blood smear. However, this finding was skewed by the multiple transfusions the patient received. Unfortunately, the clinical course rapidly declined, and the patient's family elected a transition to comfort care measures whereby the patient expired within two days of presentation. Remaining work up resulted posthumously, with CD25 levels elevated at 38,354.0 pg/mL. Coupled with the previously established splenomegaly, pancytopenia, hypertriglyceridemia, and elevated ferritin, these findings indicate a diagnosis of HLH, likely triggered by Babesia microti infection. Conclusion: HLH should be strongly suspected in patients from endemic regions, especially with additional risk factors such as age, genetics, and immunosuppression. Tools such as the HScore and the HLH-2004 criteria can aid in further patient risk stratification. Urgent treatment with steroids and addressing underlying babesiosis with atovaquone, azithromycin, and potentially red blood cell exchange transfusion, remains crucial for preventing decompensation and improving outcomes.

Prevalence of Rare Bleeding Disorders in the Central California Cohort: A Retrospective Single Institution Analysis

Abstract Rare bleeding disorders (RBD) constitute 3- 5% of all inherited clotting factor deficiencies and include inherited deficiencies of fibrinogen (FI), factors II, V, VII, X, XI and XIII, and combined factor V and VIII, and affect both sexes in an autosomal recessive manner. Rare platelet disorders can also present with bleeding diathesis which are recessively inherited. Significant clinical heterogeneity is present in these disorders with varying bleeding symptomatology causing diagnostic and therapeutic challenges. The objective of this study was to analyze the prevalence, characteristics, and treatment of rare bleeding disorders at the Valley Children's Hemophilia Treatment Center(HTC) in Central California.We conducted a retrospective analysis of all individuals who were referred for abnormal bleeding to our institution from 2018- 2023. We analyzed the clinical features, laboratory variables, and treatment of patients identified with RBD. Rare platelet disorders were included in this study. We excluded factor VIII, IX deficiencies and Von Willebrand disease (VWD) from this analysis. Results We identified a total of 157 patients (age range 18 months-46 years old) with RBD, 46% were of female gender (Table 1). Majority of the patients (n=92, 58%) were of Hispanic ethnicity. Major RBD in the cohort was Factor 7 (F7) deficiency (n= 96, 60.4%). F11 deficiency constituted 10.1%, followed by fibrinogen deficiency (6.3%), and F13 deficiency (5.7%). F2 and Plasminogen activator inhibitor-1 (PAI-1) deficiency was identified in one individual each. Glanzmann thrombasthenia was the most common platelet disorder noted in our population (n=7, 4.4%), followed by giant platelet disorder (n=6, 3.8%). MYH9- related disorder was identified in 5 (3.1%) individuals with macrothrombocytopenia and bleeding. Wiskott-Aldrich Syndrome was detected in 3 (1.9%) cases of RBD. Combined bleeding disorders (CBDs) were observed in 15 individuals (9.5%) (Table 2). These disorders were distinguished by genotyping, factor activity, and chromogenic activity assays. F7 and Type 1 VWD combined disorder was observed in 46.7% (n=7) of these individuals. Genetic testing was done in 38% (n=60) of the affected individuals. Genetic analysis was done through American Thrombosis & Hemostasis Network (ATHN 10) in 19% (n=30). F7 gene mutation was the most commonly identified mutation and variants c.1238G>A (p.Arg413Gln), c.1172G>A (p.Arg353Gln), and c.1091G>A (p.Arg364Gln) were observed in those with F7 deficiency. All individuals with F7 deficiency with variants of uncertain significance were presumed to be positive. Treatment was specific to the factor deficiency. Most individuals received additional anti-fibrinolytic therapy during acute bleeding episodes. Recombinant F7 was used in platelet disorders for bleeding. Major bleeding events and death in the cohort was 1.2% (n= 2), and 2 individuals with F13 deficiency developed inhibitors to F13 concentrate. These individuals have been managed with recombinant F7 and anti-fibrinolytic therapy. Conclusion Ethnically diverse distribution of rare bleeding disorders was evident in our Central California cohort. Similar to previous reports, F7 deficiency was of the highest prevalence. A high prevalence of CBDs was also observed in this cohort. Genetic testing enabled diagnosis in some complex cases and needs to be used more widely to facilitate timely and accurate identification, and treatment of CBDs, and RBD in general. Further, these results help to identify novel mutations in different ethnicities, and provide additional information in understanding the clinical impact of new mutations.

Facing the Challenge: Hormonal hurdles, Olfaction Obstacles in Kallmann Syndrome

Kallmann syndrome (KS) is an uncommon disorder that was first defined in 1856 and designed by Kallmann in 1944. It is also referred to as olfactogenital dysplasia and is characterized by hypogonadism and the agenesis of the olfactory bulb. The prevalence of KS is not well understood, with the incidence in males ranging from 1 in 8000 to 1 in 10,000 and being less common in females. Kallmann syndrome exhibits genetic heterogeneity, with the inheritance of the trait occurring in an autosomal recessive, autosomal dominant, or X-linked manner. Over 24 genes have been determined to be responsible for Kallmann syndrome, which is thought to be caused by mutations that inhibit the formation of cell markers necessary for the migration of olfactory and GnRH (gonadotropin-releasing hormone) neurons to the forebrain during foetal development. Kallmann syndrome is characterised by hypogonadotropic hypogonadism and hyposmia or anosmia. Other less common symptoms include osteoporosis, cleft lip and palate, cryptorchidism, unilateral renal agenesis, and cardiovascular problems. Magnetic resonance imaging (MRI) can help detect anomalies in the olfactory system and other forebrain regions, as well as pituitary disorders. The treatment for Kallmann syndrome typically involves hormone replacement therapy (HRT) with both testosterone and gonadotropin-releasing hormone (GnRH) analogues to stimulate puberty and promote secondary sexual characteristics.

Unraveling the Mysteries of Cystic Fibrosis: Causes, Symptoms, and Treatment Strategies

In this work we present the most relevant and important data, so that the reader will be able to identify the disease "Cystic Fibrosis", regardless of the fact that in Mexico this disease is not common, thanks to the fact that in Mexico and in the world newborns are screened. In this way the rate of this disease in Mexico and the world was reduced. In Mexico, there are 350 new cases every year, said the General Director of the National Center for Gender Equity and Reproductive Health, Dr. Ricardo García Cavazos. Thanks to this data, the purpose of this work is to guide readers in the identification of this disease and in this way generate a positive and active influence in the identification of this disease. This disease is a disease that has its historical antecedents since the year 1595, when with the thought of a spell on a girl during her autopsy, the first clinical data that are characteristic of this disease were given. Being in the 70's where with the passage of time and as new knowledge came to what we know today. Cystic fibrosis is an inherited multisystem disorder of children and adults, it is the leading cause of severe chronic lung disease in children. Cystic fibrosis occurs most often in white populations in Northern Europe, North America and Australia/New Zealand and is inherited in an autosomal recessive manner.

A rare case of Noonan syndrome associated with biallelic variants 
 in the LZTR1

Introduction. Noonan syndrome is a clinically and genetically heterogeneous disease with multiple organ involvement associated with mutations in the genes of the RAS/MAPK signalling pathway. Most patients with Noonan syndrom (up to 50–80%) have disorders of the cardiovascular system, presented by a wide range of congenital heart defects and/or cardiomyopathy, predominantly hypertrophic phenotype. Thanks to the introduction of high-throughput sequencing, knowledge of the genetic causes of Noonan syndrome has expanded significantly, so since 2014, the LZTR1 gene (OMIM 601247) has been included in the list of genes responsible for the development of Noonan syndrome. The nucleotide variants of this gene are known to be inherited both in an autosomal dominant and autosomal recessive manner. However, the number of reports describing the clinical and genetic characteristics of patients with LZTR1 gene mutations is scarce in the world scientific literature.
 Objective. To describe the clinical features of Noonan syndrome with an autosomal recessive type of inheritance caused by biallelic variants c.1259A>G (p.Q420R) and c.2051T>C (p.I684T) in the LZTR1 gene.
 Materials and methods. A detailed analysis of the history data, the results of clinical, laboratory, and instrumental studies, a molecular genetic study using high-throughput sequencing technology and direct Sanger sequencing was carried out. After verifying the biallelic variants in the proband, a search was made for the identified nucleotide substitutions in the venous blood samples of the parents and sibs.
 Results. The article presents the data of a clinical observation of a rare case of Noonan syndrome caused by pathogenic variants in the LZTR1 gene with an autosomal recessive type of inheritance by the Department of Cardiology of the National Medical Research Center for Children’s Health of the Ministry of Health of Russia.
 Conclusion. The diversity of clinical manifestations makes it difficult to diagnose Noonan syndrome based on phenotype alone. The possibility of using high-throughput sequencing improves the quality of diagnostics, contributes to the replenishment of data on new pathogenic variants and the establishment of genotype-phenotypic correlations.

A Recurrent Nonsense Mutation in NECTIN4 Underlying Ectodermal Dysplasia-Syndactyly Syndrome with a Novel Phenotype in a Consanguineous Kashmiri Family.

EDSS1, a syndrome characterized by ectodermal dysplasia-syndactyly, is inherited in an autosomal recessive manner due to mutations in the NECTIN4/PVRL4 gene. Clinical manifestations of the syndrome include defective nail plate, sparse to absent scalp and body hair, spaced teeth with enamel hypoplasia, and bilateral cutaneous syndactyly in the fingers and toes. Here, we report a consanguineous family of Kashmiri origin presenting features of EDSS1. Using whole exome sequencing, we found a recurrent nonsense mutation (NM_030916: c.181C > T, p.(Gln61 ∗)) in the NECTIN4 gene. The variant segregated perfectly with the disorder within the family. The candidate variant was absent in 50 in-house exomes pertaining to other disorders from the same population. In addition to the previously reported clinical phenotype, an upper lip cleft was found in one of the affected members as a novel phenotype that is not reported by previous studies in EDSS1 patients. Therefore, the study presented here, which was conducted on the Kashmiri population, is the first to document a NECTIN4 mutation associated with the upper lip cleft as a novel phenotype. This finding broadens the molecular and phenotypic spectrum of EDSS1.

Recurrent Harlequin Ichthyosis in a Family: A Case Report

Introduction: Harlequin ichthyosis is a severe form of erythrodermic ichthyosis that manifests in a distinctive and distressing appearance at birth. The newborn baby is covered in thick, plate-like scales with distorted surface features, resulting in limited mobility. Fortunately, this condition is rare, with an estimated incidence of approximately 1 in 300,000 births. It is inherited in an autosomal recessive manner and is caused by a mutation in the adenosine triphosphate binding cassette subfamily A member 12 (ABCA12) gene. This mutation affects lipid transport, and the activity of ABCA12 is crucial to produce long-chain ceramides, which are essential for the development of a normal skin barrier. Methods: We present a case report of a newborn who presented with thick, firmly adherent dense plaques covering the entire body, accompanied by deep fissures that extended into the dermis. The facial features included severe ectropion, conjunctival chemosis, eclabium, tethered ears, and a rudimentary nose. In addition, there was flexion contracture of the arms, legs, and digits, along with hypoplastic nails. Results: The baby experienced respiratory difficulty, poor sucking, and a severe cutaneous infection. Unfortunately, the baby’s condition deteriorated and passed away on the 20th day after delivery. Conclusion: Previously considered universally fatal, harlequin ichthyosis now has reported cases of survivors, although it remains a challenging condition. It is crucial to provide parents and family with comprehensive information about the implications of the condition. They should be encouraged to explore all available options and receive psychological support throughout the process. It is essential for the neonatal intensive care unit staff to be trained in providing specialized care for these babies. In addition, parents should be offered the option of antenatal counseling, particularly in cases where there is a previously affected sibling or a history of consanguinity.

B-262 Evaluation of the Genotypic Profile of the c.202 G>A Mutation in the G6PD Gene in Brazil

Abstract Introduction Glucose 6 phosphate dehydrogenase (G6PD) is an enzyme found in the cytoplasm of all human cells and plays an important role in preventing cellular damage to reactive oxygen species (ROS). G6PD deficiency is inherited in an X-linked recessive genetic disorder that can destroy red blood cells (hemolysis) leading to acute hemolytic anemia during periods of increased ROS production. The disease prevalence is more frequent in male individuals. To date, more than 400 G6PD variants have been identified, and molecular studies have shown that G6PD deficiency can be associated with different mutations. The c.202 G > A mutation (rs1050828; NM_000402.4) was described as the most frequent. The rapid and accurate diagnosis of this condition is extremely important in neonatal screening and cases of diagnostic suspicion. Therefore, this study aims to describe the genotypic profile of the c.202 G > A mutation in the G6PD gene in Brazilian samples by two molecular assays. Methods Genomic DNA samples from 130 individuals previously genotyped by Restriction Fragment Length Polymorphism PCR were used for validation. DNA isolation was performed in MagNA Pure 24 Total NA Isolation Kit at the automated platform MagNA Pure 24 System (Roche Diagnostics, Basel, Switzerland), according to manufacturer instructions. Genotyping for rs1050828 was performed using TaqMan SNP Genotyping Assays (Thermo Fisher, Foster City, CA) at 7500 Fast Real-Time PCR System (Thermo Fisher, Foster City, CA), according to manufacturer instructions. The results were analyzed using TaqMan Genotyper Software version 1.0.1. Results This study evaluated 130 blood samples, of which 81 were men (62.3%) and 49 were women (37.7%). Male carriers of rs1050828 A genotype (hemizygotes) predominated (56/81, 69.1%) and the remaining carriers for allele G (wild type) were 25/81 (30.9%). While female carriers of rs1050828 GG (wild type) predominated (39/49, 79.6%), heterozygotes were 5/49 (10.2%), and homozygotes also were 5/49 (10.2%). The number of male individuals with the presence of the mutation in hemi/homozygotes was considerably higher when compared to female individuals. This is explained by the fact that the mutation is inherited in an X-linked recessive manner. The results showed agreement and reproducibility of 100% for both methodologies. However, the qPCR assay sensibility and efficiency (>99%) were higher than the RFLP PCR assay. Conclusions Here, we described an efficient molecular method to detect the mutation c.202 G>A in the G6PD gene. The frequency of c.202 G>A described in this study was similar to that observed in others population studies in Brazil. Detection of the mutation target requests an additional evaluation of the G6PD activity level. Obtained results should be evaluated in association with the clinical aspects. The absence of the c.202 G>A in the G6PD gene does not exclude the existence of other mutations in the same region.

Curated incidence of lysosomal storage diseases from the Taiwan Biobank

Lysosomal storage diseases (LSDs) are a group of metabolic disorders resulting from a deficiency in one of the lysosomal hydrolases. Most LSDs are inherited in an autosomal or X-linked recessive manner. As LSDs are rare, their true incidence in Taiwan remains unknown. In this study, we used high-coverage whole-genome sequencing data from 1,495 Taiwanese individuals obtained from the Taiwan Biobank. We found 3826 variants in 71 genes responsible for autosomal recessive LSDs. We first excluded benign variants by allele frequency and other criteria. As a result, 270 variants were considered disease-causing. We curated these variants using published guidelines from the American College of Medical Genetics and Genomics (ACMG). Our results revealed a combined incidence rate of 13 per 100,000 (conservative estimation by pathologic and likely pathogenic variants; 95% CI 6.92-22.23) to 94 per 100,000 (extended estimation by the inclusion of variants of unknown significance; 95% CI 75.96–115.03) among 71 autosomal recessive disease-associated genes. The conservative estimations were similar to those in published clinical data. No disease-causing mutations were found for 18 other diseases; thus, these diseases are likely extremely rare in Taiwan. The study results are important for designing screening and treatment methods for LSDs in Taiwan and demonstrate the importance of mutation curation to avoid overestimating disease incidences from genomic data.

Arterial Tortuosity Syndrome: Unraveling a Rare Vascular Disorder.

Arterial tortuosity syndrome (ATS) is a rare genetic disorder characterized by abnormal twists and turns of arteries, leading to cardiovascular complications. This syndrome, first reported around 55 years ago, is inherited in an autosomal recessive manner and affects both genders. ATS manifests primarily in childhood, with arterial abnormalities disrupting blood circulation, increasing shear stress, and causing complications, such as atherosclerosis and strokes. This article reviews the genetics, etiology, pathophysiology, clinical presentation, diagnosis, associated conditions, management, and challenges of ATS. The syndrome's genetic cause is linked to mutations in the SLC2A10 gene, affecting collagen and elastin synthesis. Arterial tortuosity, a complex phenomenon, arises from factors such as vessel elongation, anatomic fixation, and vessel diameter. ATS is one of many conditions associated with arterial tortuosity, including Marfan syndrome and Loeys-Dietz syndrome. Recent studies highlight arterial tortuosity's potential as a prognostic indicator for adverse cardiovascular events. Management requires a multidisciplinary approach, and surveillance and prevention play key roles. Despite challenges, advancements in understanding ATS offer hope for targeted therapies and improved patient care.

Spinal Muscle Atrophy (SMA) in a 5 Years Old Girl from Macedonia: Case Report

Spinal muscular atrophies are inherited diseases in which nerve cells in the spinal cord and brainstem regress, causing progressive muscle weakness and wasting. There are five main types of spinal muscular atrophy, which are classified according to the severity of muscle weakness and wasting. Depending on the type, one may be confined to a wheelchair, and life expectancy may also be limited. Based on symptoms, the diagnosis can be proven through family history, muscle and nerve function studies, and blood tests to determine the location of the defective gene. Spinal muscular atrophies are usually inherited in an autosomal recessive manner. Thus, for a person to inherit the disease, two genes are necessary, one from each parent. The group of SMA disease in childhood can affect the brain and spinal cord as well as the peripheral nerves. We present a case of a 5 years old girl with spinal muscle atrophy and analyze the different new therapeutical options and future research in the field of spinal muscular atrophy in childhood.

Microcephaly and Chorioretinopathy Relevance as a Differential Diagnosis.

Microcephaly and chorioretinopathy are genetic disorders that are inherited in an autosomal recessive manner. The most frequent ocular manifestation is the presence of lacunar atrophy in the retina and choroid. The diagnosis of this condition can be challenging as several potential causes and related syndromes need to be ruled out. We present two cases of microcephaly and chorioretinopathy in Mexican patients, their clinical characterization, and discuss the differential diagnoses that should be considered. An 8-year-old girl was examined due to a history of decreased vision in both eyes. Fundus examination showed excavated, well-defined, sectorial, bilateral, and symmetrical areas of chorioretinal atrophy. An 18-year-old male had a history of poor vision since childhood. Previous ophthalmological examinations reported bilateral symmetric chorioretinal atrophy with pigment accumulation. Both patients had a prior diagnosis of microcephaly and language delay. Blood tests and a comprehensive systemic evaluation ruled out intrauterine infections. The electroretinogram showed decreased amplitude and increased implicit time in the photopic and scotopic responses. Genetic tests revealed mutations in the TUBGCP4 gene, leading to a diagnosis of microcephaly and chorioretinopathy. As observed in these cases, there was variability in retinal lesions. The presence of chorioretinal lacunae and genetic testing can help to correctly diagnose this disorder.

SKIN CANCER IN CHILDREN WITH XERODERMA PIGMENTOSUM

Introduction: Xeroderma pigmentosum) is a rare disease, inherited in an autosomal recessive manner with disturbances in the repair of deoxyribonucleic acid (DNA) which often occur in malignancy. Irreversible DNA lesions and mutations also occur in the genes which regulate skin cancer development in Xeroderma Pigmentosum. Purpose: To explain the signs, symptoms, and management of skin cancer Xeroderma Pigmentosum. Case Report : A 6 year old girl with basal cell carcinoma arising from Xeroderma pigmentosum. The histopathological picture of the left nasolabial biopsy preparation was found to show basal cell carcinoma (BCC). The patient was treated with 5FU administration and were followed after 6 week In the second patient, a 3 year old boy, squamous cell carcinoma in the oocipital area. From the histopathological picture, moderately differentiated squamous cell carcinoma on the left frontalis occipital dextra and corresponds to mottled hypermegrance on the parietal dextra. In this patient, a wide excision of the occipital lump was performed and the defect was closed with a full-thickness skin graft. Provided education to the parents of both patients for direct prevention of sun exposure by using sunscreen/hats. Discussion and Conclusion: Xeroderma Pigmentosum patients who are Xeroderma Pigmentosum to ultraviolet radiation (UV) can result in the development of highly cancerous lesions consisting of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma (MM). Clinical management of Xeroderma Pigmentosum includes sun avoidance, minimizing UV eXeroderma Pigmentosumosure, early detection, skin lesions, and genetic counseling. Topical application of 5-fluorouracil or imiquimod is used for premalignant lesions, and surgical excision is performed for malignant neoplasms of the skin, tongue, eyelids, conjunctiva, and cornea.

Fabry’s Disease and Dysferlinopathy: co-occurence of two rare genetic disorders

Fabry’s Disease (FD) is a rare X-linked inherited disorder of glycosphingolipid metabolism due to absent or deficient activity of α-galactosidase A (GLA) enzyme that can present with multisystemic involvement, including painful small fiber neuropathy. Dysferlinopathy is a heterogeneous spectrum of neuromuscular disorders inherited in an autosomal recessive manner. In this report, we present a case of co-occurrence of these two rare genetic disorders

Identification and characterization of the compound heterozygous variants of TYR gene in a northern Chinese family with Oculocutaneous albinism type 1.

Oculocutaneous albinism (OCA) is a genetically heterogeneous disease and is most inherited in an autosomal recessive manner. The characteristic manifestation of OCA is due to disfunction of melanin synthesis. OCA1 is the most severe subtype of OCA and is caused by homozygous or compound heterozygous variants in tyrosinase (TYR) gene, which is the key gene for melanin synthesis. This study aimed to identify the genetic variants of a northern Chinese family with OCA1. Clinical information and peripheral blood samples were collected. PCR amplification and Sanger sequencing were used to detect the entire exons and adjacent flanking sequences of TYR gene. Functional prediction of variants was performed by various bioinformatic analyses, while the pathogenicity classification of variants was evaluated according to ACMG standards and guidelines. A missense variant NM_000372.5:c.107G > C;NP_000363.1:p.C36S was discovered in TYR gene which converted cysteine to serine. Another variant in intron, NM_000372.5:c.1037-7 T > A, also affected the function of TYR gene. We verified the pathogenicity of the intron variant with a pCAS2 mini-gene based splicing assay and found that c.1037-7 T > A led to an insertion of 5 bp upstream from the common acceptor site of exon 3, which caused a frameshift TYR:c.1037-7 T > A:p.G346Efs*11. The results showed that the compound heterozygous variants c.107G > C:p.C36S and c.1037-7 T > A:p.G346Efs*11 of TYR gene were the pathogenic variants for this OCA1 family.

Bruck syndrome – description of the first Polish infant with FKBP10 gene mutation

Background: Bruck syndrome is a very rare genetic disorder that combines features of congenital bone fragility and arthrogryposis. It is characterised by osteoporosis, increased susceptibility to bone fractures, progressive joint contractures, and short stature, among other features. Bruck syndrome is inherited in an autosomal recessive manner, and the mutation affects mainly the gene located on chromosome 17p12 (FKBP10 gene). Case presentation: The authors present the first description of an 18-month-old Polish boy diagnosed with Bruck syndrome. The management includes making a correct diagnosis based on the clinical picture, phenotypic features, and additional laboratory and imaging examinations. In the discussion, the authors touched upon the available treatment modalities and the differentiation of Bruck syndrome with similar diseases. Conclusions: Understanding the clinical spectrum of Bruck syndrome and providing appropriate medical interventions in the early stages of the disease enables the implementation of appropriate treatment and rehabilitation.