Lenz-Majewski syndrome and recurrent otitis media: Are they related or not?

Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features, brachydactyly, symphalangism and cutis laxa. Nineteen cases have been reported in the literature so far, eleven of them with PTDSS1 mutations. Although studies have had clinically similar findings, in some cases the authors have reported even rarer features such as hydrocephalus, facial paralysis, and cleft palate. We, hereby, report the case of the first patient with Lenz-Majewski syndrome (LMS) with molecular confirmation from Turkey. Although our patient had characteristic features described in the literature, she also had immunodeficiency, which has not been reported before. Although there is no established phenotype-genotype correlation, molecular mechanisms can be explained with the reporting of more patients.

Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy.

OBJECTIVE: Childhood epilepsy is a common neurological disorder with a prevalence of 300-600 cases per 100,000 people. It is associated with refractory epilepsies, global developmental delay, and epileptic encephalopathies, causing epileptic syndromes characterized by cognitive and behavioral disorders. METHODS: In this retrospective cohort study, patients with refractory epilepsy and global developmental delay, defined as epileptic encephalopathy, who applied to the Aydin 7Maternity and Children's Hospital Genetic Diagnosis Center and were followed in the pediatric neurology clinic of our hospital, between July 2018 and July 2021, were included. RESULTS: Targeted next-generation sequencing molecular genetics results were reviewed, and 3 ALDH7A1, 1 AARS, 3 CACNA1A, 1 CTNNB1, 1 DCX, 2 DBH, 2 DOCK7, 1 FOLR1, 2 GABRB3, 2 GCH1, 1 VGRIN2B, 1 GUF1, 3 KCNQ2, 2 KCNT1, 1 NECAP1, 1 PCDH19, 1 PNPO, 1 SCN8A, 1 SCN9A, 4 SCN1A, 2 SLC25A22, 1 SLC2A1, 2 SPTAN1, 2 SZT2, 4 TBC1D24, 2 TH, and 1 PCDH19 (X chromosome) mutations were detected in three of the patients using the next-generation sequencing method. CONCLUSION: Although the development of gene panels aids in diagnosis, there are still unidentified disorders in this illness category, which is highly variable in genotype and phenotype. Understanding the genetic etiology is vital for genetic counseling and, maybe, the future development of remedies for the etiology.

Case of twin achondroplasia and autism coexistence and literature review.

Achondroplasia and autism spectrum disorder (ASD) are two genetically based disorders. The coexistence of autism with chromosomal abnormalities such as Down syndrome, monogenic syndromes such as tuberous sclerosis, Fragile X, and Rett syndrome, and microdeletion syndromes such as Phelan-McDermid syndrome helps to shed light on the genetic basis of autism spectrum disorder. The association between ASD and achondroplasia has been reported twice in the literature. In this article, we report Turkish patients who were born as identical twins from IVF pregnancy of 34 and 36-year-old parents, clinically and molecularly diagnosed with achondroplasia, and diagnosed with ASD at the age of 39 months. Our case is the first twin patient with the coexistence of achondroplasia and autism. We discuss environmental and genetic factors contributing to the development of ASD.

Assessment of whole-exome sequencing results in neurogenetic diseases.

Neurogenetic diseases are rare genetic diseases in which neurological findings are prominent. Whole exome sequencing (WES) has led to great advances in the understanding of the causes of neurogenetic diseases. Etiological research ends with the WES method in many patients. This etiological research is called a "diagnostic odyssey" for many families. Here, we present the results of 168 patients who were previously undiagnosed and underwent WES with the suspicion of neurogenetic disease. A total of 168 cases, 94 males and 74 females, with suspected undiagnosed neurogenetic disease were included in the study. We presented the WES results of the patients. The mean age of patients at the time of WES request was 11 years (range 0.25-68 years). Seventy percent (n = 117) of the patients were born from consanguineous marriage. Most of the patients were children (n = 145). Patients were grouped according to age at the time of examination. Patients younger than 18 years of age at the time of examination were classified as children, otherwise adults. Seventy-eight patients had either a pathogenic variant or a likely pathogenic variant so the diagnostic rate for WES in our cohort was %46. Our experience showing the high diagnostic rate of WES, supports its use in undiagnosed neurogenetic diseases. It also affects medical treatment, prognosis and family planning by enabling early diagnosis in patients.

Hereditary thrombocytopenia with familial novel mutation in MYH9 gene: A familial case report.

One of the rarest types of hereditary thrombocytopenia is the MYH9-related disorder. This spectrum of disorders is characterized by large platelets with or without leukocyte inclusion bodies, a decrease in the total number of platelets, and autosomal dominant inheritance. Proteinuric nephropathy that frequently progresses to end-stage renal failure, as well as the beginning of progressive high-frequency sensorineural hearing loss in young adults, is also associated with MYH9-related disorder. In this case report, we presented three family members who had thrombocytopenia and in whom a heterozygous novel 22 bp deletion (c.4274_4295del) was detected which is located in exon 31 of the MYH9 gene. There was no evidence of bleeding in the family members we presented and thrombocytopenia was detected incidentally. Additionally, renal failure, hearing loss, presenile cataracts, and clinical symptoms were not detected in these family members. This novel mutation detected in the MYH9 gene has not been reported in the literature before.

A rare CALR variant mutation and efficient peginterferon alfa-2a response in a patient with essential thrombocythemia.

Calreticulin (CALR) is a calcium-binding protein chaperone that may be found throughout the extracellular matrix and membranes of cells. It regulates calcium homeostasis and ensures the appropriate folding of newly generated glycoproteins within the endoplasmic reticulum. A somatic mutation in JAK2, CALR, or MPL is responsible for the great majority of essential thrombocythemia (ET) cases. ET has a diagnostic and prognostic value because of the sort of mutation that causes it. ET patients with the JAK2 V617F mutation had more noticeable leukocytosis, higher hemoglobin levels, and lower platelet levels, but also more thrombotic problems and a higher risk of PV transition. CALR mutations, on the other hand, are linked to a younger age group, males, with lower hemoglobin and leukocyte counts, but higher platelet counts, and a higher risk of myelofibrosis transformation. There are two predominant types of CALR mutations in ET patients. Different CALR point mutations have been identified in recent years, but their involvement in the molecular pathogenesis of MPN, including ET, is still unknown. In this case report, we presented a rare CALR mutation in a patient who was diagnosed with ET and followed up.

Contribution of genotypes in Prothrombin and Factor V Leiden to COVID-19 and disease severity in patients at high risk for hereditary thrombophilia.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.

Importance of targeted next-generation sequencing in pediatric patients with developmental epileptic encephalopathy

SUMMARY OBJECTIVE: Childhood epilepsy is a common neurological disorder with a prevalence of 300-600 cases per 100,000 people. It is associated with refractory epilepsies, global developmental delay, and epileptic encephalopathies, causing epileptic syndromes characterized by cognitive and behavioral disorders. METHODS: In this retrospective cohort study, patients with refractory epilepsy and global developmental delay, defined as epileptic encephalopathy, who applied to the Aydın 7Maternity and Children's Hospital Genetic Diagnosis Center and were followed in the pediatric neurology clinic of our hospital, between July 2018 and July 2021, were included. RESULTS: Targeted next-generation sequencing molecular genetics results were reviewed, and 3 ALDH7A1, 1 AARS, 3 CACNA1A, 1 CTNNB1, 1 DCX, 2 DBH, 2 DOCK7, 1 FOLR1, 2 GABRB3, 2 GCH1, 1 VGRIN2B, 1 GUF1, 3 KCNQ2, 2 KCNT1, 1 NECAP1, 1 PCDH19, 1 PNPO, 1 SCN8A, 1 SCN9A, 4 SCN1A, 2 SLC25A22, 1 SLC2A1, 2 SPTAN1, 2 SZT2, 4 TBC1D24, 2 TH, and 1 PCDH19 (X chromosome) mutations were detected in three of the patients using the next-generation sequencing method. CONCLUSION: Although the development of gene panels aids in diagnosis, there are still unidentified disorders in this illness category, which is highly variable in genotype and phenotype. Understanding the genetic etiology is vital for genetic counseling and, maybe, the future development of remedies for the etiology.

Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey.

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.

Mild congenital myopathy due to a novel variation in SPEG gene.

Centronuclear myopathies (CNMs) are a subgroup of congenital myopathies (CMs) characterized by muscle weakness, genetic heterogeneity, and predominant type 1 fibers and increased central nuclei in muscle biopsy. Mutations in CNM-causing genes such as MTM1, DNM2, BIN1, RYR1, CACNA1S, TTN, and extraordinary rarely SPEG (striated muscle preferentially expressed protein kinase) have been identified for about 60-80% of patients. Herein, we report a case of CM due to a novel variation in the SPEG gene, manifested by mild neonatal hypotonia, muscle weakness, delayed motor milestones, and ophthalmoplegia, without dilated cardiomyopathy. We identified a novel variation [c.153C>T (p.Asn51=) in exon 1] in the SPEG gene with whole-exome sequencing and confirmed by Sanger sequencing. Mild intellectual disability has not been associated with SPEG-related CM in the previous reports. We suggest that this report expands the phenotypic spectrum of SPEG-related CM, and further case reports are required to expand the genotype-phenotype correlations.

A rare variant Klinefelter syndrome seen 40 years later: 47,X,del(Xq24),Y.

Patients with Klinefelter syndrome (KS) show a typically 47,XXY karyotype; however, some variations have been observed, including 47,XX,der(Y), 46,XY/47,XXY, 48,XXXY, 48,XXYY, and mosaicism or structural sex chromosome abnormalities in some patients. In the literature, a rare KS variant, 47,X,del(Xq),Y karyotype, was reported in only a few cases prior to 1981. A 40-year-old man (IV-3) was referred to our department due to infertility. His phenotype did not differ from the classic KS phenotype. He had two siblings (1-male; 1-female). His brother (IV-5) had mental retardation and died one year earlier at age 32. Additionally, his sister (IV-2) also had a history of infertility due to her husband's azoospermia. His mother had a history of 12 miscarriages. Karyotype analysis revealed the 47,X,del(Xq24),Y karyotype, and no deletions were seen in the AZF and SRY regions. We thought this chromosomal abnormality in the patient might have resulted from X-autosome translocation in one of his parents since his mother had recurrent pregnancy loss and his sibling had mental retardation. However, we could not confirm it due to his parents were not alive. This study shows the first case of a long-arm X-chromosome deletion after a long period and reviews current knowledge concerning variant KS (deletion Xq).

Status dystonicus associated with CLN8 disease.

BACKGROUND: Status dystonicus is an underdiagnosed condition, probably due to heterogeneous etiology, presentation and course. Herein, we report the first case of CLN8 disease in the literature presenting with status dystonicus who responded well to pharmacological intervention. CASE: A boy aged five years and three months presented with fever, loss of appetite, intermittent excessive dystonic contractions, opisthotonus with retrocollis, and irritability for three days. His developmental milestones were reported as normal up to the age of three years and six months. At this age, he developed seizures, ataxia, and vision problems. Deterioration in developmental milestones was observed from the age of four. Laboratory tests demonstrated leukocytosis, abnormal renal function, mild metabolic acidosis, elevated creatine kinase and transaminase levels. The brain magnetic resonance imaging demonstrated cerebral and cerebellar atrophy. Homozygous missense mutation of c.709G > A (p.G237R) in the CLN8 gene was revealed. With all these clinical and laboratory findings, he was diagnosed with status dystonicus associated with CLN8 disease. Antibiotherapy, anticonvulsant drugs, and intravenous hydration with alkaline fluids were initiated. Due to irregular breathing, dysphagia, and worsening of dystonic contractions, mechanical ventilation was performed, and baclofen, haloperidol, midazolam infusion and chloral hydrate were administered, respectively. Finally, serum creatine kinase levels decreased, and dystonic contractions improved on the 15th day of hospitalization. CONCLUSION: To the best of our knowledge, our case is the first report describing the status dystonicus in a patient with CLN8 disease. Our report suggested that neuronal ceroid lipofuscinoses should be kept in mind in the etiology of status dystonicus.

Investigation of the interchromosomal effects in male carriers with structural chromosomal abnormalities using FISH.

OBJECTIVE: The interchromosomal effect (ICE) refers to the uncertainty during meiosis where the rearrangement of the chromosomes affects the segregation of the chromosomes that are not involved in the structural chromosomal abnormalities. The aim of this study is to investigate the existence of ICE in the sperm nuclei of the males who have structural chromosomal abnormalities. MATERIAL AND METHODS: Nine male individuals who are the carriers of the structural chromosomal abnormalities (patient group) and 14 male individuals who did not have any chromosomal abnormalities (control group) were diagnosed by the classical cytogenetic analysis. The aneuploidy of chromosomes 2, 3, 12, 13, 17, 18, 21, X, and Y in the sperm nuclei was investigated using the fluorescence in situ hybridization (FISH) method in these individuals. The patient group included 5 Robertsonian translocation (ROB) carriers, 3 reciprocal translocation (RCP) carriers, and 1 inversion carrier. RESULTS: A total of 51921 sperm nuclei were analyzed (19484 from the patient group and 32437 from the control group). While ICE was determined in 4 of 5 patients who were the carriers of ROB and an inversion carrier patient, it was not determined in the patient carrier of RCP. CONCLUSION: Our results suggest that there is ICE in the male carriers with a structural chromosomal abnormality, which appears to be translocation, breakpoint, chromosome, and patient dependent.

Male infertility associated with de novo pericentric inversion of chromosome 1.

Inversion occurs after two breaks in a chromosome have happened and the segment rotates 180° before reinserting. Inversion carriers have produced abnormal gametes if there is an odd number crossing- over between the inverted and the normal homologous chromosomes causing a duplication or deletion. Reproductive risks such as infertility, abortion, stillbirth and birth of malformed child would be expected in that case. A 54-year- old male patient was consulted to our clinic for primary infertility. The routine chromosome study were applied using peripheral blood lymphocyte cultures and analyzed by giemsa-trypsin-giemsa (GTG) banding, and centromer banding (C-banding) stains. Y chromosome microdeletions in the azoospermia factor (AZF) regions were analyzed with polymerase chain reaction. Additional test such as fluorescence in situ hybridization (FISH) was used to detect the sex-determining region of the Y chromosome (SRY). Semen analysis showed azoospermia. A large pericentric inversion of chromosome 1 46,XY, inv(1) (p22q32) was found in routine chromosome analysis. No microdeletions were seen in AZF regions. In our patient the presence of SRY region was observed by using FISH technique with SRY-specific probe. Men who have pericentric inversion of chromosome 1, appear to be at risk for infertility brought about by spermatogenic breakdown. The etiopathogenic relationship between azoospermia and pericentric inversion of chromosome 1 is discussed.

The effect of rs9939609 FTO gene polymorphism on weight loss after laparoscopic sleeve gastrectomy.

PURPOSE: Remarkable differences in weight loss have been observed in obese patients undergoing laparoscopic sleeve gastrectomy (LSG). These high variations might be partly explained by genetic factors. The rs9939609 fat mass and obesity-associated gene (FTO) polymorphism has been implicated in the susceptibility of obesity. We aimed to explore the effects of the rs9939609 FTO gene polymorphism on weight loss among severely obese patients applying for LSG. MATERIALS AND METHODS: All individuals were analyzed for the FTO rs9939609 gene polymorphism. A total of 74 morbid obese patients (20 male, 54 female) were operated. Body weight and body mass index (BMI) were measured at before LSG and after surgery at the sixth month. RESULTS: Twenty-eight patients (37.8%) had genotype TT (wild-type allel), 36 patients (48.6%) had genotype TA, and 10 patients (13.5%) had genotype AA. In both wild-type group and mutant group, BMI and weight levels decreased at the sixth month after surgery. Percent of excess weight loss (EWL) at 6 months of follow-up was similar in both groups. There were no differences between the mutant and wild-type groups percent of EWL at the sixth month after applying LSG. CONCLUSION: Our data showed that the rs9939609 FTO gene polymorphism is not a useful genetic test prior to LSG to help clinicians predicting the weight loss for severely obese patients in short-term follow-up.