A Case of Diabetes Mellitus Type MODY5 as a feature of 17q12 Deletion Syndrome.

Maturity onset diabetes of the young (MODY) is characterized by noninsulin-dependent diabetes diagnosed at a young age (<25 years) with an autosomal dominant inheritence. Rare mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that resemble MODY and about half of patients diagnosed with MODY5 (HNF1B mutation) have a a whole gene deletion, called as 17q12 deletion syndrome, is a rare chromosomal anomaly and is typified by deletion of the more than 15 genes including HNF1B resulting in kidney abnormalities and renal cysts and diabetes syndrome and neurodevelepmental or neuropsychiatric disorders. A 12-year-old girl was referred to our clinic, after high blood sugar was detected in the hospital where she suffered with the complaints of poliuria and polydipsia for the last 1 month. Her serum magnessium level was low (1.5 mg/dl) (normal value 1.6-2.6) and HbA1c level was 14% (normal value 3.6-5.8) and c-peptide level was 1.54 ng/ml (normal value 0.8-4). MODY5 was suspected and followed NGS gene panel (ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEURODD1, PAX4, PDX1, RFX6, ZFP57, GLIS3, FOXP3, NEUROG3, G6PC2) analysis revealed that there was no any mutation. On follow-up period, her serum magnessium level was low (1.2 mg/dl) and her urinary magnessium excretion was high at 172.5 mg/day. HNF1B gene mutation was considered in the patient with chronic hypomagnesemia with increased basal C peptide level. Abdominal CT and MR imagings revealed that there was a 43 mm diameter cystic lesion in the head of the pancreas, and agenesis of the pancreatic neck, trunk and tail as well. Because of there is no mutation in HBF1B gene in NGS panel, microarray analysis was performed, heterozygous deletion at 17q12 including HNF1B was detected. The HNF1B mutation is difficult to diagnose and has a large phenotypic variation . In case of clinical suspicion,further genetic examination (MLPA, array CGH) may be required since deletions and duplications can not be detected even if mutations in the HNF1B gene are not detected with NGS.

Comprehensive Genetic Analysis of RASopathy in the Era of Next-Generation Sequencing and Definition of a Novel Likely Pathogenic >KRAS Variation.

Introduction: Germline pathogenic variations of the genes encoding the components of the Ras-MAPK pathway are found to be responsible for RASopathies, a clinically and genetically heterogeneous group of diseases. In this study, we aimed to present the results of patients genetically investigated for RASopathy-related mutations in our Genetic Diagnosis Center. Methods: The results of 51 unrelated probands with RASopathy and 4 affected relatives (31 male, 24 female; mean age: 9.327 ± 8.214) were included in this study. Mutation screening was performed on DNA samples from peripheral blood of the patients either by Sanger sequencing of PTPN11 hotspot regions (10/51 probands), or by a targeted amplicon next-generation sequencing panel (41/51 probands) covering the exonic regions of BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RASA2, RIT1, SHOC2, SOS1, SOS2, SPRED1, and KAT6B genes. Results: Pathogenic/likely pathogenic variations found in 22 out of 51 probands (43.13%) and their 4 affected family members were located in PTPN11, BRAF, KRAS, NF1, RAF1, SOS1, and SHOC2 genes. The c.148A>C (p.Thr50Pro) variation in the KRAS gene was a novel variant detected in a sibling in our patient cohort. We found supportive evidence for the pathogenicity of the NF1 gene c.5606G>T (p.Gly1869Val) variation which we defined in an affected boy who inherited the mutation from his affected father. Conclusion: Although PTPN11 is the most frequently mutated gene in our patient cohort, as in most previous reports, different mutation distribution among the other genes studied motivates the use of a next-generation sequencing gene panel including the possible responsible genes.

The efficiency of cinacalcet treatment in delaying parathyroidectomy in a case with neonatal severe hyperparathyroidism caused by homozygous mutation in the CASR gene.

Neonatal severe hyperparathyroidism (NSHPT) causes severe hypercalcaemia, metabolic bone disease, and potential neurodevelopmental deficits, all of which can be life-threatening. The use of calcimimetic agents can prevent or delay technically difficult parathyroidectomy in the newborn period. We present a 6-day-old male infant who presented with poor feeding, weight loss, and severe hypotonia. His total serum calcium and parathyroid hormone levels were very high (23.6 mg/dl and 1120 ng/dl, respectively). Based on these findings, the patient was diagnosed with NSHPT and was started on cinacalcet therapy until the genetic analysis results were available. Genetic analysis revealed a previously reported homozygous mutation in the CASR gene that was unresponsive to cinacalcet therapy in the literature. However, a normocalcaemic state unexpectantly occurred, which could be maintained with low calcium formula and cinacalcet therapy up to 13 months of age in the patient. Nevertheless, hypercalcaemia developed 2 months after he started a normal calcium-containing diet. Therefore, the patient underwent total parathyroidectomy at 17 months of age. We would like to emphasize, in light of this case, that cinacalcet treatment may be considered as first-line therapy for delaying parathyroidectomy in all cases with NSHPT, even in those who have an unresponsive cinacalcet CASR gene mutation.

A 17-year-old boy who presented with acute mononeuropathy was found to have Type 1 diabetes.

Diabetic neuropathy in children and adolescents with Type 1 diabetes mellitus is rare and is usually subclinical and a complication of the late diabetes period. A 17-year-old boy admitted with a right foot drop of sudden onset was diagnosed with peroneal nerve palsy. He had had osmotic polyuria, polydipsia and weight loss for the past 2 months; his blood glucose was 25 mmol/L (<7.8), HbA1c 15.2% (4.0-5.6) and vitamin B12 125 pg/ml (180-914). The peroneal nerve palsy resolved within 3 months with blood glucose regulation and B12 supplementation. Diabetes should be borne in mind in the differential diagnosis of unusual cases of mononeuropathy.Abbreviations: DCCTS: Diabetes Control and Complications Trial Study; DM: diabetes mellitus; DN: diabetic neuropathy; GAD: glutamic acid decarboxylase; PN: peripheral neuropathy; T1DM: Type 1 diabetes mellitus.

The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region

Objective: The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey. Methods: A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses. Results: In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel. Conclusion: This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY.

Exogenous Cushing syndrome due to misuse of potent topical steroid.

We report an infant with exogenous Cushing syndrome after being treated for 2 months with a potent topical corticosteroid via the mother's application of topical clobetasol for diaper rash without a prescription. We emphasize that potent topical steroids should be used with great caution, especially when used under occlusion (e.g., diaper area) and that parents should be warned about potential side effects of these medications, particularly when used in infants.