Genetic Disorders Research Articles

Anesthetic management of a 9-year-old girl with Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay syndrome: airway difficulties and postoperative apnea during tendon surgery

Background: This case report described the anesthetic management and postoperative challenges of a patient diagnosed with Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) syndrome who underwent tenomyotomy of the right hand tendons. This syndrome, characterized by facial dysmorphisms, musculoskeletal abnormalities, and respiratory disturbances, including central apnea, is caused by a mutation in the NALCN gene.Case: A 9-year-old girl diagnosed with CLIFAHDD syndrome underwent tenomyotomy of the right hand tendon. General anesthesia was administered. Despite stable intraoperative conditions, the patient experienced inadequate ventilation with multiple episodes of apnea after extubation, necessitating assisted ventilation using a face mask.Conclusions: This case highlights the challenges and considerations in the anesthetic management of patients with CLIFAHDD syndrome, emphasizing the need for tailored approaches and vigilant postoperative monitoring to mitigate the potential respiratory complications associated with this rare genetic disorder.

Population-based, first-tier genomic newborn screening in the maternity ward.

The rapid development of therapies for severe and rare genetic conditions underlines the need to incorporate first-tier genetic testing into newborn screening (NBS) programs. A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes. The prospective observational BabyDetect pilot project was launched in September 2022 in a maternity ward of a public hospital in the Liege area, Belgium. In this ongoing observational study, 4,260 families have been informed of the project, and 3,847 consented to participate. To date, 71 disease cases have been identified, 30 of which were not detected by conventional NBS. Glucose-6-phosphate dehydrogenase deficiency was the most frequent disorder detected, with 44 positive individuals. Of the remaining 27 cases, 17 were recessive disorders. We also identified one false-positive case in a newborn in whom two variants in the AGXT gene were identified, which were subsequently shown to be located on the maternal allele. Nine heterozygous variants were identified in genes associated with dominant conditions. Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs. Challenges must be addressed in variant interpretation within a presymptomatic population and in result reporting and diagnostic confirmation.

Newborn with Refractory Seizures due to Hemimegalencephaly and Tuberous Sclerosis Complex: Case Report and Literature Review.

Hemimegalencephaly (HME) is a rare congenital disorder that is initiated during embryonic development with abnormal growth of one hemisphere. Tuberous sclerosis complex (TSC), a genetic disorder, is rarely associated with HME.We present a case of a newborn with HME with a confirmed mutation in the TSC-1 gene and describe the clinical course, findings on amplitude-integrated electroencephalography (aEEG), cranial ultrasound (CUS), MRI, and the postmortem evaluation. Furthermore, we conducted a comprehensive literature review of all reported newborns with HME and a genetically confirmed TSC mutation.This infant experienced therapy-resistant seizures after birth despite treatment with multiple antiseizure medications. CUS and MRI revealed HME of the left hemisphere. Early functional hemispherectomy, around the age of 3 months, was considered but dismissed after multidisciplinary evaluation, medical ethical consultation, and multiple discussions with the parents. Care was redirected due to worsening clinical and neurologic conditions, increasing respiratory insufficiency, and ongoing therapy-resistant seizures. Postmortem evaluation of the brain revealed hamartomatous brain changes and irregular gyration of the enlarged hemisphere. in addition, these changes were also present in the previously considered unaffected side, raising thoughts about the potential effectiveness of functional hemispherectomy.This case report illustrates that in cases with TSC abnormalities might not be confined solely to the initially considered affected side. This can have important therapeutic implications.

Polycystic Ovarian Syndrome: A Review of Multi-omics Analyses.

Polycystic Ovary Syndrome(PCOS) is among the most prevalent endocrinological abnormalities of young females, posing a grave public health challenge to the society. The objective of the present literature review is to analyze the enormous amount of information available by way of numerous multi-omic studies, and to explore a meaningful relationship between various factors such as genetic, proteomic, environmental etc. to understand the multifactorial metabolic disorder in a proper manner. Detailed literature search was done in various science article repositories and biomedical databases such as PubMed, Google Scholar, BioMed Central, Embase etc. by using several keywords in whole gamut of combinations. PCOS is a heritable disease. It manifests as a result of a combination of several intricately inter-linked symptoms such as anovulation, obesity, type II diabetes, hyperandrogenism, polycystic ovaries etc., the last one being the main manifestation of the disease, thus leading to infertility among several other complications. Such a multifactorial metabolic disorder with extreme symptomatic heterogeneity cannot be fully explained solely based on symptoms or genetic variations; thus, giving some space of thought to other factors such as epigenetic, microbiomic factors etc. playing a role in the causation of the disease. The present scientific survey of literature extensively reviews various aspects of PCOS by critically looking into the vast multi-omic data, and concluded with suggesting treatment options as well as lifestyle changes required to deal with the psychological/ emotional impacts of the condition on affected women.

A TTPA deletion is associated with Retinopathy with Vitamin E Deficiency (RVED) in the English Cocker Spaniel Dog.

Retinopathy with Vitamin E Deficiency (RVED) is a familial disease in the English Cocker Spaniel (ECS) dog breed. Ophthalmic abnormalities observed in RVED-affected ECS include lipofuscin granule deposition within the tapetal fundus and subsequent retinal degeneration resulting in visual deficits. Affected dogs may also exhibit neurological signs that include ataxia and hindlimb proprioceptive deficit. In all cases, circulating plasma concentrations of α-tocopherol are low. This study sought to investigate the genetic basis of RVED in the ECS breed. We undertook a genome-wide association study comprising 30 ECS with normal fundic examinations aged 6 years or older (controls) and 20 diagnosed with RVED (cases) and identified a statistically associated signal on chromosome 29 (Praw = 1.909×10-17). Whole genome sequencing (WGS) of two cases identified a 102bp deletion in exon 1 of the Alpha Tocopherol Transfer Protein gene (TTPA), truncating the protein by 34 amino acids. The c.23_124del variant segregated with RVED in a total of 30 cases and 43 controls. Variants in TTPA are causal for Ataxia with Vitamin E Deficiency (AVED) in humans which is a phenotypically similar disease to RVED. The identification of the canine variant is extremely significant as the availability of a DNA test will allow for identification of presymptomatic dogs and early therapeutic intervention which may prevent development of retinopathy and improve neurological signs. Breeders can also use the DNA test to efficiently eradicate the disease from this breed.

Development of HEK293T cell reference materials for β-thalassemia genetic testing using prime editing

Abstract Objectives β-thalassemias, caused by mutations in HBB, are hereditary blood disorders that impose a significant global health burden. Detecting these mutations through accurate genetic analysis is essential. This study aimed to create a panel of cell type reference materials for β-thalassemia genetic testing using prime editing (PE), a flexible and precise genomic editing method. Methods PE3 systems were designed to target specific HBB mutations, including single nucleotide variants (SNVs) (−32 (C>A), CD 17 (A>T)), insertions (CD 14/15 (+G), CD 71–72 (+A)), and deletions (CD 31 (−C), CD 41/42 (−TTCT)). HEK293T cells were edited to carry these mutations. Sanger sequencing was performed to confirm the accurate introduction of homozygous and heterozygous mutations. The cell lines were further verified using commercial reverse dot-blot hybridization and melting curve assays. Results We successfully constructed 12 stable HEK293T cell lines carrying the intended homozygous or heterozygous HBB mutations using PE3 systems. No off-target mutations in the HBB were detected by Sanger sequencing in these stable cell lines, even after more than 10 weeks of culturing. Additionally, all target mutations were accurately and consistently detected using two reverse dot-blot hybridization kits and one melting curve assay kit. Conclusions The 12 stable cell lines exhibited accurate and stable HBB mutations, making them valuable reference materials for β-thalassemia genetic testing. PE3 systems show potential for generating a comprehensive panel of HBB mutations, particularly those that are clinically rare.

Understanding the Support Needs of People with Autosomal Dominant Polycystic Kidney Disease: A Qualitative Phenomenological Descriptive Study.

Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary kidney disease and the fourth most common cause of kidney failure. Patients may be aware of their condition from an early age or discover it unexpectedly, with varying levels of familial knowledge about the disease. This chronic condition presents significant challenges for healthcare professionals. The study aimed to investigate how people with ADPKD experience their participation in a dedicated ADPKD clinic and to investigate their support needs in managing their disease in everyday life. A qualitative phenomenological descriptive study was conducted, involving semi-structured telephone interviews with patients who attended a newly established dedicated ADPKD clinic between March and April 2023. The data were analyzed using Malterud's principles of systematic text condensation. In total, 18 out of 22 patients agreed to participate in the interviews. Six themes emerged from the interviews. Participants expressed feelings of uncertainty about their future and highlighted the necessity for personalized care tailored to their individual circumstances. They reported challenges in coping with emotions associated with the disease and sought assistance in making difficult decisions. Maintaining control over their health and illness was a significant theme, alongside a desire for increased knowledge about their condition. Our study supports existing knowledge in this area. In this study, the participants experienced satisfaction with the dedicated ADPKD clinic, feeling well informed, listened to, and more at ease after the check-up. Investing in a dedicated ADPKD clinic could help alleviate the uncertainty that many people with ADPKD experience.

Surgical Outcomes in Unicoronal Synostosis-A 23-Year Experience From a Single Supraregional Craniofacial Unit.

Unicoronal synostosis is a rare condition leading to anterior plagiocephaly with facial scoliosis and deformation of the anterior cranial fossa. Fronto-orbital advancement and remodelling (FOAR) is the standard of care for management, aiming to normalise the brow shape and position while ameliorating the risk of raised intracranial pressure (ICP) throughout childhood. Published long-term surgical outcome data for unicoronal synostosis is lacking. The authors present our series of 151 cases of FOAR for unicoronal synostosis between January 2000 and January 2023. The average age at surgery was 22.7 months, with an average follow-up of 87 months. Ninety-six patients (66.2%) had no comorbidity. Nineteen (13.1%) had named genetic or chromosomal disorders. There was a 33.1% dural tear rate with no related postoperative CSF leak. Ninety-three patients (67.8%) had a blood transfusion with average donor exposure <1. The total early complication rate was 8.6% most commonly infection and wound dehiscence at 3.4% and 2.8%, respectively. The most common late complication was temporal recession in 30 (20.1%) patients and 3 of these patients required revision surgery. None of our patients required investigation for, or treatment of, raised ICP after the primary surgery. There were no life-threatening complications or mortalities. The authors compare our results to a previous publication on trigonocephaly patients and other available published data. The authors present our recommendations, which include support for a supraregionalized service that encompasses high-volume workload and multidisciplinary care.

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

Transforming Medicine: Advances in Gene Therapy, Immunotherapy, and Targeted Cures.

In recent years, novel therapeutic approaches have revolutionized the landscape of medicine, offering promising avenues for the cure of various diseases. The novel approaches explore advancements in gene therapy in pharmaceuticals, immunotherapy, RNA-based therapeutics, cell-based therapies, and targeted tumor therapies. Gene therapy has emerged as a groundbreaking approach, leveraging genetic material to cure or prevent diseases by targeting defective genes. In pharmaceuticals, gene therapy holds immense potential for addressing genetic disorders, offering a personalized approach to medicine. Immunotherapy, on the other hand, harnesses the body's immune system to combat diseases, including tumors, by enhancing immune responses or directly targeting malignant cells. RNA-based therapeutics have gained prominence due to their ability to modulate gene expression, offering targeted and precise interventions for a wide range of diseases. Cell-based therapies involve the transplantation or manipulation of cells to restore or enhance their function, offering innovative solutions for diseases such as neurodegenerative disorders and cardiovascular diseases. Furthermore, targeted tumor therapies have revolutionized tumor cure by specifically targeting molecular alterations driving tumor growth and minimizing damage to healthy cells. Overall, these novel therapeutic approaches represent a paradigm shift in medicine, offering tailored and precise interventions with the potential to significantly improve patient outcomes and quality of life.

Genomic profiling at a single center cracks the code in inborn errors of immunity.

Inborn errors of immunity (IEI) entail a diverse group of disorders resulting from hereditary or de novo mutations in single genes, leading to immune dysregulation. This study explores the clinical utility of next-generation sequencing (NGS) techniques in diagnosing monogenic immune defects. Eight patients attending the immunodeficiency clinic and with unclassified antibody deficiency were included in the analysis. Clinical records, immune characteristics, and family histories were reviewed, and a target gene panel (TGP) sequencing was performed to identify pathogenic variants. TGPs identified seven variants in TNFRSF13B (TACI), CARMIL2, STAT1, STAT3, and ORAI1 genes. These findings provided definitive diagnoses and proper prognostic assessment. Patients exhibited a wide range of clinical manifestations, including recurrent infections, autoimmune cytopenias, and organ-specific complications. The genetic diversity observed highlights the importance of genetic testing in diagnosing IEIs and tailoring treatments. This study underscores the role of TGPs in diagnosing IEIs, revealing significant genetic heterogeneity and phenotypic variability. They offer a precise tool for identifying underlying genetic defects, facilitating personalized medicine approaches, and eventually improving patient outcomes. The findings emphasize the need for comprehensive genetic testing to uncover novel pathogenic variants, enhancing our understanding of immune system dysfunction. NGS is a critical tool for the management of IEI, enabling precise diagnosis and personalized treatment strategies. Despite resource limitations, the progressive affordability is likely to expand its clinical utility, ultimately improving patient care and advancing the field of immunology. In the meantime, accurate phenotypic assessment is essential for resource optimization and case prioritization.

Long-Lasting Auditory and Vestibular Recovery Following Gene Replacement Therapy in a Novel Usher Syndrome Type 1c Mouse Model.

Usher syndrome type 1C (USH1C) is a genetic disorder caused by mutations in the USH1C gene, which encodes harmonin, a key component of the mechanoelectrical transduction complex in auditory and vestibular hair cells. USH1C leads to deafness and vestibular dysfunction in humans. An Ush1c knockout (KO) mouse model displaying these characteristic deficits is generated in our laboratory. To examine gene replacement therapy (GT) in this model, a synthetic adeno-associated viral vector, Anc80L65, driving harmonin expression is administered, to the inner ears of Ush1c KO mice at postnatal day 2 (P2). Remarkably, this single treatment significantly improved auditory brainstem response (ABR) thresholds and balance motor function at 1 month post-injection, with these effects persisting for up to 10 months. At 12 months post-treatment, the vestibular function is assessed using the vestibular-ocular reflexes (VOR) and single vestibular afferent recordings. The GT treatment significantly restored both the canal and otolith VORs and increased vestibular afferent spontaneous firing rates and responses to head rotation and translation. These findings provide the first evidence of long-lasting restoration of both the auditory and vestibular functions by GT in a novel mouse model of Usher syndrome, highlighting the potential of GT for treating deficits associated with USH1C.

P-18 THREE BODY PROBLEM PATIENT: EHLER DANLOS SYNDROME COMBINED WITH HYPOPHOSPHATASIA AND FATTY ACID OXIDATION DEFECT

Abstract Introduction Ehler-Danlos syndrome (EDS) is a genetic disorder that affects connective tissues, including the skin, joints, and blood vessel walls. EDS can be accompanied by postural tachycardia syndrome, acid reflux, mast cell activation disorder, migraine, or early disc degeneration. We present a case with EDS associated with hypophosphatasia, a genetically defined fatty acid deficiency, and mastocytosis. Clinical Case A 27-year-old male visited an endocrinology clinic with a complaint of low libido that started six months ago. He was diagnosed with hypothyroidism, celiac disease, and testicular torsion at the age of 13. He was also diagnosed with autosomal dominant hypophosphatasia (ALPL heterozygous mutation) at the same age, following spontaneous tooth loss. He had no prior history of bone fractures. He did not get any medications to address hypophosphatasia. He had no family history of any disorder. He was diagnosed with EDS at the age of 22. He had mandible, patella, and shoulder dislocations as a result of joint hypermobility. He began to experience symptoms of hypoglycemia after the diagnosis of EDS. His blood glucose levels were about 52 mg/dL. Hyperinsulinism was excluded and genetic analysis resulted as a heterozygous mutation in the medium chain acylcoa dehydrogenase gene. The recommendations were L-Carnitine, Coenzyme Q, and Omega-3. Attacks of hypoglycemia became exceedingly uncommon. Since infancy, he had suffered from urticaria. His multiple allergies, elevated tryptase levels (35 and 22 ng/ml), and positive blood c-kit (CD117) mutation suggested mastocytosis. Omalizumab was implemented to alleviate urticarial symptoms. The patient underwent an evaluation for his premature ejaculation, low libido, and reduced hair growth. The testicular measure was normal. Gynecomastia and onychoid structure were not present. Hypogonadotropic hypogonadism was detected during the evaluation. The following hormone levels were: follicle-stimulating hormone: 1.9 mIU/ml (1.5-12), luteinizing hormone: 3.8 mIU/ml (1.2-7.8), total testosterone: 2.5 ng/ml (3-10), estradiol: 11.8 pg/ml (10-50), dehydroepiandrosterone sulfate: 437 ug/dl (18-391), and progesterone: 0.13 ng/ml (0.27-0.9). Subcutaneous choriogonadotropin-alpha was implemented as a substitute for androgens after the occurrence of urticaria in response to intramuscular and transdermal testosterone treatment. The femur neck bone mineral density (BMD) was 0.749 (Z score: 1.3), whereas the L1-L4 vertebra BMD was 0.977 (Z score: 1.0). No pathology was detected in the echocardiogram. We assessed the patient's osteogenesis imperfecta (OI) Type 1 or Type 2 due to the coexistence of EDS Type 7A and Type 7B. However, no known mutation for OI was identified. Conclusion Due to the overlapping clinical features of muscle hypotonia and joint complaints, as well as early tooth loss, these two diagnoses may be disregarded in a patient. Enzyme replacement therapy may alleviate symptoms in patients with these conditions.

The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges.

Homologous recombination is a largely error-free DNA repair mechanism conserved across all domains of life and is essential for the maintenance of genome integrity. Not only are the mutations in homologous recombination repair genes probable cancer drivers, some also cause genetic disorders. In particular, mutations in the Bloom (BLM) helicase cause Bloom Syndrome, a rare autosomal recessive disorder characterized by increased sister chromatid exchanges and predisposition to a variety of cancers. The pathology of Bloom Syndrome stems from the impaired activity of the BLM-TOP3A-RMI1-RMI2 (BTRR) complex which suppresses crossover recombination to prevent potentially deleterious genome rearrangements. We provide a comprehensive BTRR proximal proteome, revealing proteins that suppress crossover recombination. We find that RAD54L2, a SNF2-family protein, physically interacts with BLM and suppresses sister chromatid exchanges. RAD54L2 is important for recruitment of BLM to chromatin and requires an intact ATPase domain to promote non-crossover recombination. Thus, the BTRR proximity map identifies a regulator of recombination.

P-06 WHEN IS GENDER SELECTION IN CONGENITAL ADRENAL HYPERPLASIA?

Abstract Introduction Congenital adrenal hyperplasia (CAH) is one of the most common (classical type; nonclassical type) genetic diseases and is inherited in an autosomal recessive manner. This disease can lead to adrenal insufficiency, fluid-electrolyte disorder, and ambiguous genitalia as a result of axis dysfunction in cortisol biosynthesis. The optimal time for gender identity formation is between the ages of 18 and 36 months. The gender assignment of patients with CAH should be done as soon as possible before people around them know about it. Clinical Case A 23-year-old patient with known CAH due to 21-hydroxylase deficiency was referred to our clinic by a psychiatrist 1 year ago with the diagnosis of gender dysphoria. In his history, the patient was admitted first to the hospital with complaints of nausea and vomiting only one month after birth by his family. During examination at that time, BP was 70/40mmHg, and genital examination revealed ambiguous genitalia. In laboratory tests, Na:128mEq/l, K:5.1 mEq/l, DHEA-SO4: 4mcg/dl, basal cortisol: 1.18 mcg/dl and 17-OH progesterone: 6.8 ng/ml were found, and Karyotype analysis was reported as 46 XX. According to these results, the patient was diagnosed with CAH. Genetic analysis revealed CYP21A2 IVS2-13 C&amp;gt;G homozygous mutation. The patient who has classical type CAH was accepted as a phenotypically and genetically female child by her family and had undergone 2 correction operations since the age of 1 due to ambiguous genitalia. Between 2003 and 2013, he continued his follow-up in the pediatric endocrinology department and used Hydrocortisone + Fludrocortisone treatment in varying doses. He expressed that he did not go for regular check-ups and did not use his medications until 2018. Due to being untreated for a long time, his testosterone levels were high as male normal ranges, and his phenotype was male. The Ferriman-Gallwey score was determined as 22, and reconstruction scars and narrow vaginal opening were observed in the genital examination. In the laboratory test without any treatment were 17-OH-progesterone &amp;gt; 20ng/ml, basal cortisol: 7.8 mcg/dl, ACTH: 570 pg/ml, total testosterone: 524 ng/L, estradiol: 42 ng/L, DHEAS:252 mcg/dl, FSH:4.5 IU/L, LH: 0.76 IU/L, Na:136 mEq/L, K:4.3 mEq/L. The patient, who had simple virilizing CAH and gender dysphoria together, was first planned to start steroid replacement therapy in terms of CAH treatment. According to his clinical course, a decision was made to re-evaluate him in terms of identity change and testosterone replacement therapy. Conclusion The majority of CAH patients were raised as chromosomally female-identifying and living as female despite masculinized gender behaviors. Only 5.2% of these patients experienced gender dissatisfaction. Recent studies have shown that rather than intrauterine hormone exposure, regular treatment during the growth period and gender orientation during follow-up are more accurate and important regarding psychosocial satisfaction.Figure 1Possesses a masculine phenotype without using any testosterone

P-67 TWO RARE GENETIC DISORDERS IN ONE CASE ‘’ALLAN-HERNDON-DUDLEY-SYNDROME’’ AND’ “TREACHER COLLINS SYNDROME’’:A CASE REPORT

Abstract Introduction Resistance to thyroid hormone syndrome (RTH), also named Refetoff Syndrome is an autosomal dominant or recessive rare genetic disease. It’s incidence is approximately 1:50.000 in newborns. Increasing awareness and knowledge about RTH will increase the diagnosis rate. So that other genetic diseases that accompany can be detected with early genetic consultation. Clinical Case A 45-year-old female patient was consulted to the endocrinology department for abnormal thyroid function tests. In her medical history, she had no known disease and no medication she used regularly. Her TSH level was 1,26 mıU/L(0,45-4,31), fT4:1,94ng/dl(0,85-1,70 ng/dl), fT3:5,73 ng/L(2-4,4). Thyroid autoantibodies were negative. In pituitary MRI, nodular formations that were hypointense compared to normal tissue were observed on the right and left sides of the pituitary (microadenoma?). Anterior pituitary hormones within the normal range. Heterophile antibody was negative. RTH or TSHoma was considered. She was admitted to the service for further examinations. Alpha subunit level could not measured. Basal TSH was found to be 1,49mU/L (0,54-4,31). A TRH stimulation test was performed on the patient and end of the test TSH was found to be 14.6 mıU/L. T3 supression test was performed. End of the test TSH was &amp;lt;0,1 mıU/L. Thyroid hormone resistance was considered. During the patient’s medical history there were no signs of hyperthyroidism other than fatigue. In patient's genetic analysis heterozygous c.401A&amp;gt;C:p variant detected in the THRB gene. NM_006517.5:C.401A&amp;gt;C:p.(Glu134Ala) missense variant heterozygous was detected in SLC16A2 gene and was associated with the ‘’Allan-Herndon-Dudley Syndrome’’ phenotype. The NM__001371623.1;C.2998G&amp;gt;A:p(Glu1000Lys)rs755763024 missense variant was observed heterozygous in the TCOF1 gene and was associated with the ‘’Treacher Collins Syndrome 1’’phenotype. Thyroid function tests were performed to the daughter and sons of the patient (table2). Genetic counseling was recommended to the patient and her family. There in no phenotypic features of ‘’Allan-Herndon-Dudley Syndrome ‘’ and Treacher Collins Syndrome ‘’ detected in the patient. Ophthalmology, otorhinolaryngology and cardiology examination was normal. The patient was diagnosed as RTH. She was clinically asymptomatic and discharged with plans to remain under medication-free monitoring. Conclusion As far as the literature is examined there is no previous case of the coexistence of TCS with RTH and other thyroid function test abnormalities. More case reports are needed to determine whether the coexistence of these two rare diseases is coincidental or related. According to previous literature information AHDS is usually clinically asymptomatic in women. But it is with RTH in the female patient in this case. As in the case, it is important to perform genetic screening and provide genetic counseling to the patients and family members.Table 1:Thyroid Function Tests of the Patient Table 2:Family Members Thyroid Function Test Results (1 daughter and 3 son of the patient)

Ide Copy Number Variant Does Not Influence Stroke Severity in 2 C57BL/6J Mouse Models nor in Humans: An Exploratory Study.

Contrary to the common belief, the most commonly used laboratory C57BL/6J mouse inbred strain presents a distinctive genetic and phenotypic variability, and for several traits, the genotype-phenotype link remains still unknown. Recently, we characterized the most important stroke survival factor such as brain collateral plasticity in 2 brain ischemia C57BL/6J mouse models (bilateral common carotid artery stenosis and middle cerebral artery occlusion) and observed a Mendelian-like fashion of inheritance of the posterior communicating artery (PcomA) patency. Interestingly, a copy number variant (CNV) spanning Ide locus was reported to segregate in an analogous Mendelian-like pattern in the C57BL/6J colonies of the Jackson Laboratory. Given IDE critical role in vascular plasticity, we hypothesized Ide CNV may have explained PcomA variability in C57BL/6J inbred mice. We applied a combination of techniques (T2-weighted magnetic resonance imaging, time-of-flight angiography, cerebral blood flow imaging, and histology) to characterize the collaterome in 77 C57BL/6J bilateral common carotid artery stenosis, middle cerebral artery occlusion, naive, and sham mice and performed on these Taqman genotyping, exome sequencing, and RNA sequencing. We then investigated the hypothesis that IDE structural variants (CNVs, gain/loss of function mutations) may have influenced the cerebrovascular phenotype in a large cohort of 454 040 cases and controls (UK Biobank, Genomics England). We detected an Ide CNV in a bilateral common carotid artery stenosis mouse with 2 patent PcomAs (minor allele frequency, 1.3%), not segregating with the PcomA patency phenotype. In addition, 2 heterozygous IDE CNVs, resulting in loss of function were found in 1 patient with hereditary ataxia, a patient with hereditary congenital heart disease, and 2 healthy individuals (minor allele frequency 9×10-6). Moreover, we report 4 IDE loss of function point mutations (p.Leu5X, p.Met394ValfsX29, p.Pro14SerfsX26, p.Leu889X, minor allele frequency 0.02%) present also in controls or inherited from healthy parents. Ide CNV and loss of function variants are rare, do not crucially influence PcomA variability in C57BL/6J inbred mice, and do not cause a vascular phenotype in humans.

An Autoethnographic Account of Familial Mediterranean Fever: A Turkish Patient's Discovery of Spiritual Meaning.

Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disorder characterized by recurrent febrile episodes that are accompanied by pain in the abdomen, chest, or joints caused by peritonitis, pleuritis, skin lesions, arthritis, and pericarditis. This original article aims to provide an analytic autoethnographic account of a Turkish patient's experience of FMF, with a focus on the discovery of spiritual meaning. In addition to discussing the grief reactions to a loss of health, the article uses self-reflexive discourse and narrative-based analysis to explore four stages of discovery of spiritual meaning through FMF: "omnipotent me," "God's punishment," "God's test," and "God's mercy." The article provides an in-depth look at the experience of FMF, a chronic and lifelong disease, through a spiritual lens and offers suggestions for mental health professionals and rheumatologists providing holistic treatment to FMF patients that might improve treatment adherence.

Long-Term Risks of Living Kidney Donation: State of the Evidence and Strategies to Resolve Knowledge Gaps.

Living-donor kidney transplantation is the preferred treatment for kidney failure. In the United States, rates of living kidney donation have been stagnant, which is partly related to concerns over medical and financial risks. Recent research has better characterized the risks of living kidney donation, although the field is limited by a lack of robust registries. Available evidence supports small increases in the risks of end-stage kidney disease and hypertensive disorders of pregnancy in living donors. For most donors, the 15-year risk of kidney failure is less than 1%, but for certain populations this risk may be higher. New tools such as genetic kidney disease panels may assist with risk stratification. Living kidney donors generally have similar or improved psychosocial health following donation compared to prior to donation and nondonor experience. Postdonation care allows for preventative care measures to mitigate risk as well as ongoing surveillance of donor outcomes. Continuing efforts to capture and report outcomes of living donation are necessary to safely expand living donation worldwide.

Ataxia telangiectasia in a Bahraini child treated with intensive physiotherapy: A case report

Ataxia telangiectasia (AT) is a rare neurodegenerative condition with a prevalence of 1 in 40,000 to 1 in 300,000 worldwide. It involves a genetic mutation of chromosome 11q.26. The condition is inherited in an autosomal recessive manner causing atrophy of the cerebellum due to loss of Purkinje fibres. AT presents early in childhood and the clinical features depend on the type of mutation. The study is a case report of a rare genetic disorder of a 9-year-old female who came to the physiotherapy clinic with a diagnosis of AT. The patient was presented with progressively worsening gait problems with frequent falls, with complete dependence on assistance and impaired balance and coordination. The treatment program was 12 months divided into an intense physiotherapy program for two months followed by 10 months of two times per week of physiotherapy sessions. The program was divided into four elements which are: (1) Lifestyle changes, (2) Strengthening exercises, (3) Coordination exercises, and (4) Balance training exercises. The result showed a positive outcome in increasing the patient’s independence, increased muscle strength, reduced ataxia symptoms intensity, and the patient can carry out complex activities with the help of accessory orthosis devices.