Genetic Heterogeneity Of Disease Research Articles

Primary ciliary dyskinesia associated with a novel DNAH11 genetic variant: a case report

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic disorder associated with abnormalities in ciliary structure and function. Here, we report A 22-year-old non-smoking Chinese man with recurrent episodes of respiratory tract infections and sinusitis since high school period. The diagnosis is more complicated by the atypical symptoms and the late age of onset. We summarized the clinical characteristics of this case and literature review. This report aimed to improve the clinical understanding of primary ciliary dyskinesia.

Oral health management in children with severe congenital neutropenia with periodontitis: Case report.

Severe congenital neutropenia (SCN) is a rare and heterogeneous genetic disease. By describing the diagnosis and treatment of a child with SCN and periodontitis, this case provides a reference for the oral health management of a child with SCN and periodontitis. We describe a boy with clinical manifestations of oral bleeding, neutropenia, recurrent fever, and other recurrent infections. The absolute neutrophil count (ANC) was <0.50 × 109/L most of the time. Morphological examination of bone marrow cells showed active granulocyte hyperplasia and dysmaturation. According to the clinical manifestations, hematological examination and gene detection results, the child was diagnosed as SCN with chronic periodontitis. Periodontal treatment was performed after informed consent was obtained from the child guardian. These included supragingival and subgingival cleaning, hydrogen peroxide and saline irrigation, placement of iodoglycerin in the gingival sulcus, and oral hygiene instruction. Hematopoietic stem cell transplantation (HSCT) was performed later. One month after initial periodontal treatment, oral hygiene was well maintained and gingival swelling had subsided. Probing depth (PD) index on periodontal probing and bleeding was significantly reduced. However, there was no significant change in blood routine and other indicators before and after periodontal treatment. Once SCN is diagnosed, individualized treatment plans can be developed according to the characteristics of the disease and its impact on oral health, which can effectively control the interaction between SCN and periodontal disease and reduce the occurrence of serious infection.

Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.

Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.

Intellectual Disabilities and Neurocognitive Impairment in Adult Patients with Inherited Metabolic Diseases: A UK Single Centre Experience.

Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% (n = 357), with patients with LSDs accounting for 23.5% (n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes.

Mavacamten: a novel avenue towards hypertrophic obstructive cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HCM) is the most common heterogeneous genetic cardiovascular disorder. Its pathophysiology involves left ventricular hypertrophy, increased fibrosis, hypercontractility, and reduced compliance. The symptomatic obstructive HCM presents as dyspnoea, syncope, chest pain, palpitations, arrhythmias, or sudden death, usually after provocative manoeuvres like exercise. Until April 2022, treatment options were disease non-specific like Beta blockers, Cardio-selective Calcium Channel Blockers, Dipyridamole, and Ranolazine. Mavacamten is a first-in-class, FDA-approved drug molecule for HCM. It works by selective and reversible inhibition of the cardiac myosin ATPase thereby decreasing the formation of actin- myosin cross- bridges in systole and diastole. The excessive actin-myosin cross-bridging is the hallmark of disease and is responsible for the compromised functioning of the heart in both the systole and diastole phase due to left ventricular outflow tract (LVOT) obstruction and increased ventricular filling pressure respectively. Mavacamten acts by producing super-relaxed state of heart which is then translated into decreased LVOT obstruction and improved cardiac filling pressures thereby improving the functional capacity and symptoms in patients with New York Heart Association (NYHA) stage II, and III symptomatic or obstructive heart failure. Mavacamten is administered orally 2.5-15 mg per day with titration guided by lab investigations and clinical symptoms. Its bioavailability is 85%, undergoes metabolism by CYP2C19 and CYP3A4 and is excreted mainly in urine. It is also an enzyme inducer and shows considerable drug interactions. Common adverse effects are dizziness and syncope. Sometimes the drug may worsen heart failure or completely block ventricular function. Mavacamten has raised hopes for the possibility of managing this potentially lethal intrigue disorder with medicines alone.

Molecular genetic analysis of candidate genes for glutaric aciduria type II in a cohort of patients from Queensland, Australia

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.

Production of an induced pluripotent stem cell line CSSi018-A (14192) from a patient with hypomyelinating leukodystrophy 7 (HLD7) carrying biallelic variants of POLR3A (c.1802 T > A; c.4072G > A)

Hypomyelinating leukodystrophies (HLD) are a group of heterogeneous genetic disorders characterized by a deficit in myelin deposition during brain development. Specifically, 4H-Leukodystrophy is a recessive disease due to biallelic mutations in the POLR3A gene, which encodes one of the subunits forming the catalytic core of RNA polymerase III (PolIII). The disease also presents non-neurological signs such as hypodontia and hypogonadotropic hypogonadism. Here, we report the generation of a human induced pluripotent stem cell (hiPSC) line from fibroblasts of the first identified carrier of the biallelic POLR3A variants c.1802 T > A and c.4072G > A.

Concurrent Collection of Fetal Murine Brain and Serum to Assess Effects of Maternal Diet on Nutrition and Neurodevelopment in Neurofibromatosis Type 1.

Maternal diet-induced obesity has been demonstrated to alter neurodevelopment in offspring, which may lead to reduced cognitive capacity, hyperactivity, and impairments in social behavior. Patients with the clinically heterogeneous genetic disorder Neurofibromatosis Type 1 (NF1) may present with similar deficits, but it is currently unclear whether environmental factors such as maternal diet influence the development of these phenotypes, and if so, the mechanism by which such an effect would occur. To enable evaluation of how maternal obesogenic diet exposure affects systemic factors relevant to neurodevelopment in NF1, we have developed a method to simultaneously collect non-hemolyzed serum and whole or regionally micro-dissected brains from fetal offspring of murine dams fed a control diet versus a high-fat, high-sucrose diet. Brains were processed for cryosectioning or flash frozen to use for subsequent RNA or protein isolation; the quality of the collected tissue was verified by immunostaining. The quality of the serum was verified by analyzing macronutrient profiles. Using this technique, we have identified that maternal obesogenic diet increases fetal serum cholesterol similarly between WT and Nf1-heterozygous pups.

Genotype-Phenotype Correlations in Alport Syndrome-A Single-Center Experience.

Alport syndrome (AS) is a common and heterogeneous genetic kidney disease, that often leads to end-stage kidney disease (ESKD). This is a single-center, retrospective study that included 36 adults with type IV collagen (COL4) mutations. Our main scope was to describe how genetic features influence renal survival. A total of 24 different mutations were identified, of which eight had not been previously described. Mutations affecting each of the type IV collagen α chains were equally prevalent (33.3%). Most of the patients had pathogenic variants (61.1%). Most patients had a family history of kidney disease (71%). The most prevalent clinical picture was nephritic syndrome (64%). One-third of the subjects had extrarenal manifestations, 41.6% of patients had ESKD at referral, and another 8.3% developed ESKD during follow-up. The median renal survival was 42 years (95% CI, 29.98-54.01). The COL4A4 group displayed better renal survival than the COL4A3 group (p = 0.027). Patients with missense variants had higher renal survival (p = 0.023). Hearing loss was associated with lower renal survival (p < 0.001). Patients with COL4A4 variants and those with missense mutations had significantly better renal survival, whereas those with COL4A3 variants and those with hearing loss had worse prognoses.

Global carrier frequency and predicted genetic prevalence of patients with pathogenic sequence variants in autosomal recessive genetic neuromuscular diseases

Genetic neuromuscular diseases are clinically and genetically heterogeneous genetic disorders that primarily affect the peripheral nerves, muscles, and neuromuscular junctions. This study aimed to identify pathogenic variants, calculate carrier frequency, and predict the genetic prevalence of autosomal recessive neuromuscular diseases (AR-NMDs). We selected 268 AR-NMD genes and analyzed their genetic variants sourced from the gnomAD database. After identifying the pathogenic variants using an algorithm, we calculated the carrier frequency and predicted the genetic prevalence of AR-NMDs. In total, 10,887 pathogenic variants were identified, including 3848 literature verified and 7039 manually verified variants. In the global population, the carrier frequency of AR-NMDs is 32.9%, with variations across subpopulations ranging from 22.4% in the Finnish population to 36.2% in the non-Finnish European population. The predicted genetic prevalence of AR-NMDs was estimated to be 24.3 cases per 100,000 individuals worldwide, with variations across subpopulations ranging from 26.5 to 41.4 cases per 100,000 individuals in the Latino/Admixed American and the Ashkenazi Jewish populations, respectively. The AR-NMD gene with the highest carrier frequency was GAA (1.3%) and the variant with the highest allele frequency was c.-32-13 T>G in GAA with 0.0033 in the global population. Our study revealed a higher-than-expected frequency of AR-NMD carriers, constituting approximately one-third of the global population, highlighting ethnic heterogeneity in genetic susceptibility.

Family-based genetic analysis in schizophrenia by whole-exome sequence to identify rare pathogenic variants.

Schizophrenia (SCZ) is influenced by a combination of genetic and environmental factors. Although several studies have been conducted to identify the causative loci and genes, few of these loci or genes can be repeated due to the high phenotypic and genetic heterogeneity of disease, and their mechanisms are not fully understood. There may be some "missing heritability" that has not yet been found. In order to investigate the deleterious heritable mutations, whole-exome sequencing (WES) in pedigrees with SCZ was used in the current work. Two unrelated pedigrees with SCZ were recruited to perform WES. Genetic analysis was next performed to find potential variants in accordance with the prioritized strategy. Followed by genetic analysis to detect candidate variants according to the prioritized strategy. Next, a series of algorithms was used to predict the pathogenicity of variants. Sanger sequencing was finally conducted to verify the co-segregation. Recessive mutations in six genes (TFEB, SNAI2, TFAP2B, PRKDC, ST18 in Pedigree 1 and PKHD1L1 in Pedigree 2) that co-segregated with SCZ in two families were discovered through genetic analysis by WES. Sanger sequencing verified that all of the mutations in the affected siblings were homozygous. These results corroborated the hypothesis that SCZ exhibits strong heterogeneity and complex inheritance patterns. The newly discovered homozygous variations deepen our understanding of the mutation spectrum and offer more proof for the involvement of TFEB, SNAI2, TFAP2B, PRKDC, ST18, and PKHD1L1 in the development of SCZ.

Overview of epidemiology and management hypertrophic cardiomyopathy among children

Hypertrophic cardiomyopathy is the most common form of cardiomyopathy. It is a heterogeneous genetic cardiac muscle disorder characterized by inappropriate left ventricular hypertrophy, malalignment of the myocardial fibers, and myocardial fibrosis.

Medical Treatment Strategies for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart disease inherited in an autosomal dominant pattern with an estimated prevalence of 0.6% in the general population. Clinical manifestations of HCM vary considerably, with symptoms ranging from none or mild exercise intolerance to severe lifestyle-limiting symptoms, advanced heart failure, and sudden cardiac death. Current management options for HCM include lifestyle modifications, familial screening with genetic counseling, pharmacotherapy for symptom control, sudden cardiac death risk stratification with or without defibrillator implantation, septal reduction therapy, and, in some cases, heart transplantation. Only recently have strongly targeted medical therapies for HCM, such as myosin inhibitors, been studied in multicenter randomized controlled trials. In this report, we review the currently available medical treatments for HCM and the future directions of HCM pharmacotherapy, and we highlight important unmet needs in this population.

Genotype-phenotype correlations of neurofibromatosis type 1: a cross-sectional study from a large Chinese cohort.

Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype-phenotype associations in a large Chinese cohort of NF1 patients. We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains. A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy. Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.

Erythrocyte Disorders Mimicking Congenital Dyserythropoietic Anemia Based on Bone Marrow Pathology Exposed By Genetic Evaluation

Congenital dyserythropoietic anemias (CDAs) are a rare group of heterogeneous genetic diseases characterized by hemolysis, ineffective erythropoiesis predisposing to iron overload, and the pathologic finding of bi- and multinucleated erythroblasts in the bone marrow (BM). With the identification of causative genetic mutations over the last two decades, the current classification includes the following types with the causative gene in parenthesis: Ia ( CDAN1), Ib ( CDIN1); II ( SEC23B); IIIa ( KIF23), IIIb ( RACGAP1); IV ( KLF1) ; and XLTD ( GATA1). Clinical presentation can vary widely even within the same type, ranging from mild cases of anemia to severe cases in which patients are subject to lifelong transfusion dependency. The CDA registry (CDAR) in North America (NCT02964494) was established to allow natural history studies on patients with CDA. Participants without a genetic diagnosis are offered whole genome sequencing (WGS) for patients and parents and may elect to provide samples to the CDAR biorepository to support collaborative mechanistic studies. Currently 169 subjects from 73 different families are enrolled in CDAR (85 patients, 84 unaffected family members). After genetic evaluation, 13 patients were found to be affected not by CDA, but rather by other causes of hereditary hemolytic anemia with secondary dyserythropoiesis. Three patients were diagnosed with pyruvate kinase deficiency (PKD). Patient (pt) 1 had a history of chronic anemia requiring sporadic transfusions since birth and was diagnosed with CDA-II based on BM studies. WGS revealed that the patient was heterozygous for a known PKLR pathogenic variant c.1022G&amp;gt;C p.(Gly341Ala)and for a novel variant of uncertain significance (c.695-3C&amp;gt;G).PK activity assay confirmed the diagnosis of PKD and the patient is now treated with the PK activator mitapivat. Pt 2 had severe transfusion dependent anemia since birth and iron overload. The patient underwent splenectomy at the age of 4 with mild improvement of symptoms. He was diagnosed with CDA II based on BM pathology. Genetic testing was performed and he was found to be compound heterozygous for 2 pathogenic variants in PKLR: c.644dup p.(Arg216fs) and c.994_1003dup p.(Val335fs). Pt 3 had a history of anemia and jaundice since birth; she has not had frequent transfusions but was splenectomized at age 17. The patient was found to be homozygous for c.1436G&amp;gt;A p.(Arg510Gln), a known pathogenic variant in PKLR. Four patients were diagnosed with HBB pathogenic variants causing frameshift and transcription of an elongated β-globin chain, i.e. unstable hemoglobinopathy. Pt 4 was first diagnosed with CDA II at 12 years of age based on BM studies performed due to chronic hemolytic anemia. After enrolling in CDAR, WES revealed heterozygous HBB p.(Lys96Asnfs*63). Pts 5, 6, and 7 are all symptomatic participants from the same family (mother and children). The mother (Pt 5) had frequent transfusion requirement, misdiagnosed in childhood as CDA IV due to BM dyserythropoiesis and the finding of high fetal hemoglobin. Her children had a similar phenotype requiring episodic transfusions initially, transitioning to scheduled transfusions by 8 y.o. WES in pt 5 revealed heterozygous HBB c.348_349delinsG (Hb Grand Junction) with follow-up HBB sequencing confirming that the children also carry the same variant . Three more patients were diagnosed with SPTA1 variants causing RBC membrane disorders. Pt 8 was found to have homozygous c.4339-99C&amp;gt;T (alpha-LEPRA) and heterozygous c.4347G&amp;gt;T p.(Lys1449Asn) with a phenotype of hereditary spherocytosis. Pts 9 and 10 are sisters, who presented with chronic, transfusion-dependent anemia since birth. They were diagnosed with CDA-II based on binucleated erythroblasts in BM studies performed in early childhood. They had splenectomy at 5 years of age and became transfusion-independent but continued to have mild anemia and reticulocytosis. WGS performed for them and their parents revealed a novel homozygous intronic variant in SPTA1 c.5834-18A&amp;gt;G. Phenotypic analysis was compatible with hereditary spherocytic pyropoikilocytosis. Hemolytic anemias with stress erythropoiesis may mimic the clinical presentation and pathologic findings of CDAs, making the phenotypic diagnosis challenging. Including genetic evaluation in the diagnostic workup of these patients can improve accuracy, timing of diagnosis, and management by specific therapy, if available.

Polygenic Risk Scores for Bipolar Disorder: Progress and Perspectives.

Bipolar disorder (BD) is a common and highly heritable psychiatric disorder, the study of BD genetic characteristics can help with early prevention and individualized treatment. At the same time, BD is a highly heterogeneous polygenic genetic disorder with significant genetic overlap with other psychiatric disorders. In recent years, polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) data have been widely used in genetic studies of various complex diseases and can be used to explore the genetic susceptibility of diseases. This review discusses phenotypic associations and genetic correlations with other conditions of BD based on PRS, and provides ideas for genetic studies and prevention of BD.

Congenital hyperinsulinism and surgical outcome in a single tertiary center in Brazil

ObjectiveCongenital hyperinsulinism (CHI) is a heterogeneous genetic disease characterized by increased insulin secretion and causes persistent hypoglycemia in neonates and infants due to dysregulation of insulin secretion by pancreatic β cells. Babies with severe hypoglycemia and for whom medical treatment has been ineffective usually require surgical treatment with near-total pancreatectomy. To evaluate the clinical and surgical aspects affecting survival outcomes in babies diagnosed with CHI in a single tertiary care center. MethodsRetrospective Cohort study involving a single university tertiary center for the treatment of CHI. The authors study the demographics, clinical, laboratory, and surgical outcomes of this casuistic. Results61 % were female, 39 % male, Birth weight: 3576 g (±313); Age of onset of symptoms: from the 2nd hour of life to 28 days; Time between diagnosis and surgery ranged between 10 and 60 days; Medical clinical treatment, all patients received glucose solution with a continuous glucose infusion and diazoxide. 81 % of the patients used corticosteroids, 77 %. thiazide, 72 % octreotide, 27 % nifedipine; Neurological sequelae during development and growth: 54 % had some degree of delay in neuropsychomotor development, 27 % obesity. Surgery was performed open in 6 and 12 minimally invasive surgery (MIS). Histopathology: 2 focal and 16 diffuse, Length of stay (days) was lower in MIS (p < 0.05). Survival was 100 %. ConclusionsCHI is a rare and difficult-to-manage tumor that must be performed in a multidisciplinary and tertiary center. Most surgical results are good and the laparoscopic approach to disease has been the best choice for patients.

Gorlin-Goltz Syndrome: A Comprehensive Analysis of the Clinical, Genetic and Therapeutic Manifestations of a Rare and Complex Disease

Gorlin-Goltz syndrome, also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, is a rare and heterogeneous genetic disease with a varied clinical presentation involving multiple systems and organs. This comprehensive review aims to provide an in-depth understanding of this syndrome from a medical and scientific perspective. Gorlin-Goltz syndrome is characterized by an inherited predisposition to the formation of skin and skeletal tumors, as well as the development of jaw cysts, cleft palates, facial deformities, ocular malformations and other anomalies. At the genetic level, this syndrome is linked to mutations in the PTCH1 gene, which regulates the hedgehog signaling pathway, playing a crucial role in the regulation of cell growth and differentiation. Early and accurate diagnosis of Gorlin-Goltz syndrome is essential to prevent serious complications, such as advanced basal cell carcinomas and facial disfigurement. Molecular diagnostic strategies and therapeutic options, including reconstructive surgery, hedgehog pathway inhibitor therapy, and multidisciplinary patient management will be addressed. This review will also explore the psychological and social impact on patients and their families, as well as advances in genetic and therapeutic research that may open new perspectives for the management and prevention of this complex disease. Ultimately, detailed knowledge of Gorlin-Goltz syndrome is essential to improve the quality of life of those affected and to promote future research in this evolving field.

Drivers and high-molecular-risk mutations in Argentine patients with primary myelofibrosis

Primary myelofibrosis (PMF), a BCR-ABL negative myeloproliferative neoplasm, is a heterogeneous clinical and genetic disorder with a poor prognosis. We aimed to study the mutational profile of driver genes (JAK2, CALR, and MPL) and high-molecular-risk (HMR) genes (ASXL1, EZH2, IDH1/2, and SRSF2) and their prognostic impact in 65 Argentine patients with PMF. Mutually exclusive driver mutations were identified in 88% of the cases and HMR mutations were detected in 37% of patients, including 37.5% of triple negative cases. ASXL1 and SRSF2 were the most frequently mutated HMR genes, and a significant association between these mutations was observed (P = 0.04). Additionally, age &gt;65 years, lower hemoglobin level, constitutional symptoms, male sex, and bone marrow (BM) fibrosis grade ≥ 2 were correlated with ASXL1 mutations, and circulating blasts with SRSF2 mutations. HMR mutations were significantly associated with inferior overall survival (P &lt; 0.001). These mutations were more frequent with increasing risk of DIPSS score and allowed us to identify patients with poor survival in intermediate DIPSS groups. The application of the MIPSS70 score stratified our patients into three risk groups, with significant differences in overall survival (P &lt; 0.001). Interestingly, 85% of the patients who were upgraded to a higher risk category compared to the DIPSS score showed a HMR profile. In conclusion, our study contributes to the understanding of the mutational landscape in MFP, supports the integration of molecular data to improve prognostic models and reinforces the adverse prognostic impact of HMR mutations, particularly in ASXL1 and SRSF2 genes.

Prevalence and quality of temporomandibular disorders, chronic pain and psychological distress in patients with classical and hypermobile Ehlers-Danlos syndrome: an exploratory study

BackgroundThe Ehlers-Danlos syndromes are a group of clinically and genetically heterogeneous hereditary diseases affecting the connective tissue. They are characterized by hypermobility of the joints, hyperextensible skin and friable tissue. According to current classification, 13 subtypes can be distinguished, of which the hypermobile and the classical subtype are the most prevalent. This study aimed to evaluate patients with classical (cEDS) and hypermobile (hEDS) Ehlers-Danlos syndrome regarding temporomandibular disorder (TMD), chronic pain, and psychological distress.MethodsSupport groups from Germany, Austria, and Switzerland were contacted, and social media were used to recruit participants. Free text questions, the German version of the Depression Anxiety and Stress Scale (DASS), and the German version of the Graded Chronic Pain Status (GCPS) were used.Results259 participants were included (230 hEDS/29 cEDS). At least 49.2% of the participants had painful or restricted jaw movements, and at least 84.9% had pain in the masticatory muscles, with 46.3% already having a diagnosed TMD. Multivariate analysis showed a significant correlation between TMJ involvement and chronic pain with a 2.5-fold higher risk of chronic pain with a diagnosed TMD. 22.8% of participants had a critical score for depression, 53.3% had a critical score for anxiety, and 34.0% had a critical score for stress.ConclusionThere is a high prevalence of TMD problems and chronic pain in patients with cEDS and hEDS. The lack of knowledge about these problems can create psychological distress. More research is needed to provide adequate treatment for patients with EDS.