A Novel SEMA3G Mutation in Two Siblings Affected by Syndromic GnRH Deficiency.

INTRODUCTION: Gonadotropin-releasing hormone (GnRH) deficiency causes hypogonadotropic hypogonadism (HH), a rare genetic disorder that impairs sexual reproduction. HH can be due to defective GnRH-secreting neuron development or function and may be associated with other clinical signs in overlapping genetic syndromes. With most of the cases being idiopathic, genetics underlying HH is still largely unknown. OBJECTIVE: To assess the contribution of mutated Semaphorin 3G (SEMA3G) in the onset of a syndromic form of HH, characterized by intellectual disability and facial dysmorphic features. METHOD: By combining homozygosity mapping with exome sequencing, we identified a novel variant in the SEMA3G gene. We then applied mouse as a model organism to examine SEMA3Gexpression and its functional requirement in vivo. Further, we applied homology modelling in silico and cell culture assays in vitro to validate the pathogenicity of the identified gene variant. RESULTS: We found that (i) SEMA3G is expressed along the migratory route of GnRH neurons and in the developing pituitary, (ii) SEMA3G affects GnRH neuron development, but is redundant in the adult hypothalamic-pituitary-gonadal axis, and (iii) mutated SEMA3G alters binding properties in silico and in vitro to its PlexinA receptors and attenuates its effect on the migration of immortalized GnRH neurons. CONCLUSION: In silico, in vitro, and in vivo models revealed that SEMA3G regulates GnRH neuron migration and that its mutation affecting receptor selectivity may be responsible for the HH-related defects.

Colchicine Therapy for Glenohumeral Osteoarthritis: A Case Report.

Osteoarthritis management primarily focuses on targeting pain. Conventional modalities for pain management include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and intra-articular corticosteroid injections. However, these approaches may provide minimal pain relief and can be contraindicated for some patients, highlighting the ongoing need for alternative pain management. Colchicine, commonly used in the management of gout, has emerged as a potential option for pain management in osteoarthritis. There are implications of colchicine use for knee and hand osteoarthritis but remains inconclusive. In this context, we present a case of a 68-year-old diabetic woman with glenohumeral osteoarthritis and associated right shoulder pain. Due to minimal pain relief from previous treatments, the patient was given a combination trial of colchicine and acetaminophen for three months. After completion of this treatment, the patient experienced significant pain relief and improved functionality. The aim of this case is to highlight the efficacy of colchicine as a possible treatment option for managing shoulder pain in osteoarthritis.

Various Doses of Tanezumab in the Management of Chronic Low Back Pain (CLBP): A Pooled Analysis of 4,514 Patients.

Chronic low back pain (CLBP) is a persistent and debilitating condition characterized by pain and discomfort in the lower back region that lasts more than 12 weeks. This review aims to determine the efficacy and safety of various doses of tanezumab for managing CLBP. The present meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Intervention standards. We searched multiple databases, including PubMed, Cochrane Library, Excerpta Medica Database (EMBASE), Scopus, and Web of Science, to identify randomized controlled trials comparing tanezumab to placebo or different dosage regimens for CLBP in adult patients. The primary outcome was the mean change in low back pain intensity (LBPI) score baseline to the end of treatment. Secondary outcomes included adverse events and the degree of disability or impairment. A total of six studies were included in the meta-analysis. Analysis of the data showed that tanezumab 5 mg significantly reduced LBPI compared to placebo at all time points (mean deviation (MD) ranging from -0.31 to -0.5). Similarly, tanezumab 10 mg showed a significant reduction in LBPI compared to placebo at all time points (MD ranging from -0.48 to -0.84). However, tanezumab 5 mg showed significantly less reduction of LBPI compared to 10 mg at two, four, eight, and 12 weeks (MD ranging from 0.19 to 0.32). These findings suggest that tanezumab is an effective treatment for CLBP, with 5 mg and 10 mg doses providing clinically meaningful reductions in LBPI.

Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis

Objective: Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by nonautoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing. Methods: Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. Results: Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Conclusion: Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I.

BACKGROUND AND AIMS: Vitamin D-dependent rickets type I (VDDR1) is an autosomal recessive disorder caused by mutations in the 25-hydroxyvitamin D 1-alpha-hydroxylase gene (CYP27B1). Mutations in CYP27B1 disrupt or lead to a total loss of the 1-α-hydroxylase activity and require treatment with physiological doses of calcitriol. PATIENTS AND METHODS: A genetic analysis of the CYP27B1 gene was conducted in 22 Turkish patients with VDDR1 from 13 families. Presenting characteristics, biochemical features, treatment, and results from the genetic analysis are described. RESULTS: A splice donor site mutation c.195 + 2T>G was found in 10 patients. The novel missense p.192K>E (c.574A>G) mutation was detected in 5 patients, and a novel missense p.197G>D (c.590G>A) mutation was found in 4 patients. A previously reported 7-bp duplication 1319-1325dupCCCACCC (Phe443Profs*24) in exon 8 was detected in 1 patient, and 1 patient was a compound heterozygote for the novel p.192K>E and the previously described 1319-1325dupCCCACCC mutations. A novel single base pair deletion, c.171_171delG, leading to a frameshift, was found in 1 patient. CONCLUSIONS: We identified 3 novel and 2 previously described mutations in the CYP27B1 gene. A marked phenotypical diversity was observed between families that carried identical mutations, suggesting phenotypical heterogeneity.

A novel ALMS1 homozygous mutation in two Turkish brothers with Alström syndrome.

BACKGROUND: Alström syndrome (AS) is an extremely rare, autosomal recessive disorder characterised by multi-organ features that typically manifest within the first two decades of life. AS is caused by mutations in the Alström syndrome 1 (ALMS1) gene located at 2p13.1. METHODS: In the current study, two brothers from a first-cousin consanguineous family presented with a complex phenotype and were suspected of having AS. RESULTS: Both brothers were found to be homozygous for a novel nonsense c.7310C>A (p.S2437X) mutation in exon-8 of ALMS1 gene. The consanguineous parents were sequenced and both were heterozygous for the same mutation. CONCLUSIONS: This particular mutation has never been reported before and confirmed the diagnosis of AS in the patients. Our work identifies a novel mutation in ALMS1 gene responsible for the complex phenotype of AS in these patients.

Dipeptidyl peptidase-4 expression in pancreatic tissue from patients with congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is caused by unregulated insulin release and leads to hyperinsulinaemic-hypoglycaemia (HH). Glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) and the enzyme; dipeptidyl peptidase-4 (DPP-4) all regulate appetite and glucose homeostasis. These proteins have been identified as possible contributors to HH but the mechanism remains poorly understood. We aimed to look at the expression pattern of pancreatic DPP-4 in children with focal and diffuse CHI (FCHI and DCHI, respectively). Using immunohistochemistry; we determined DPP-4 expression patterns in the pancreas of CHI patients. DPP-4 was found to be expressed in the pancreatic ß, α and δ-cells in and around the focal area. However, it was predominantly co-localised with ß-cells in the paediatric tissue samples. Additionally, proliferating ß-cells expressed DPP-4 in DCHI, which was absent in the FCHI pancreas. Insulin was found to be present in the exocrine acini and duct cells of the DCHI pancreas suggestive of exocrine to endocrine transdifferentiation. Furthermore, 6 medically-unresponsive DCHI pancreatic samples showed an up-regulation of total pancreatic DPP-4 expression. In conclusion; the expression studies have shown DPP-4 to be altered in HH, however, further work is required to understand the underlying role for this enzyme.

A novel homozygous SLC19A2 mutation in a Portuguese patient with diabetes mellitus and thiamine-responsive megaloblastic anaemia.

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare syndrome where patients present with early onset diabetes mellitus, megaloblastic anaemia and sensorineural deafness. This report describes a new case of TRMA syndrome in a female patient of Portuguese descent, born to unrelated parents. The patient was found to have a novel homozygous change R397X in exon 4 of the SLC19A2 gene, leading to a premature stop codon. The patient's diabetes and anaemia showed a good response to daily thiamine doses, reducing the daily insulin dose requirement. The report further indicates that TRMA is not only limited to consanguineous or ethnically isolated families, and should be considered as a differential diagnosis for patients presenting with suggestive clinical symptoms.

Familial isolated growth hormone deficiency due to a novel homozygous missense mutation in the growth hormone releasing hormone receptor gene: clinical presentation with hypoglycemia.

CONTEXT: Mutations in the growth hormone releasing hormone receptor (GHRHR) gene are a relatively rare cause of isolated growth hormone deficiency (IGHD). OBJECTIVE: This study aimed to understand the biochemical basis of hypoglycemia in the index case and the molecular basis of severe short stature in a large consanguineous family with IGHD. PATIENTS AND METHODS: The index case presented with a hypoglycemic convulsion, following which eight members in two related consanguineous Turkish families were identified with IGHD. Homozygosity mapping identified the homozygous regions shared only among the affected individuals. Sanger sequencing of GHRHR, which resided in the shared homozygous region, was performed. In silico analysis of the pathogenic GHRHR variant was performed. RESULTS: The clinical presentation and hormonal analysis confirmed GH deficiency in all affected individuals. Magnetic resonance imaging scan of the pituitary gland showed anterior pituitary hypoplasia in five affected individuals in which the youngest was only 0.4 years old, but with normal pituitary size in three affected individuals. Homozygosity mapping showed two large homozygous regions on chromosome 7 shared only among affected individuals. Sanger sequencing of GHRHR gene present in one of these shared regions identified a novel homozygous missense mutation (p.C64G) segregating with the disease phenotype. In silico analysis predicted the mutation to be deleterious and disease causing. CONCLUSIONS: We describe a large consanguineous Turkish kindred with IGHD due to a novel homozygous missense GHRHR mutation. This is the first description of presentation with hypoglycemia and the earliest reported occurrence of anterior pituitary hypoplasia in patients with GHRHR mutation.