scholarly journals MON-LB120 MODY3 With Insulin Coding Gene Mutation and Craniofacial Microsomia: A Case Report

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Chenxiang Cao ◽  
Xueyao Han ◽  
Yumin Ma ◽  
Victor Joseph Bernet ◽  
Jianzhong Xiao
Keyword(s):  
Insulin Therapy ◽  
Gene Mutation ◽  
Internal Auditory Canal ◽  
Gene Mutations ◽  
Maternal Diabetes ◽  
Abnormal Development ◽  
Hemifacial Microsomia ◽  
Coding Region ◽  
Chromosome 11 ◽  
C Peptide

Abstract Background: Maturity onset diabetes in young 3 (MODY 3) is caused by mutation of the hepatic nuclear factor 1 alpha (HNF-1A) gene. Craniofacial macrosomia (CFM) is associated with an abnormal development of craniofacial structures during the embryonic period. Maternal diabetes and genetic predisposition have been associated with CFM1. There are rare reports about an association of MODY 3 and CFM. Clinical case: An 11-year-old male patient presented with right side CFM (mild mandibular hypoplasia, internal auditory canal absence, severe pinna hypoplasia, abnormal orbital size and location, O3.M0.E3.N0.S02) noted at 8 months of age. Preoperative examination revealed A1c at 10.9%. After short term intensive insulin therapy, he had standard bread meal test: fasting glucose 8.11 mmol/L, insulin 13.9 mIU/L (3-25), C-peptide 1.25 ng/ml (0.81-3.85); 1 hour glucose 10.05 mmol/L, insulin 27 mIU/L, C-peptide 2.42 ng/ml; 2 hour glucose 8.17 mmol/L, insulin 16.09 mIU/L, C-peptide 2.11 ng/ml. GADA, IAA and ICA were negative. The mother was diagnosed diabetes at age 27years, when the patient was 8-month-old, and received insulin therapy. The mother was blind by age 35years due to diabetic retinopathy and died of DKA at 38-years-old. The patient’s 16-year-old brother had left side CFM (O2.M1.E2.N0.S0) and his OGTT was normal. The father was diagnosed with impaired glucose tolerance. The family had whole genome sequencing by Sanger technique, and resequenced the mutation with side primers. The CGA to CAA mutation was present at the 686 loci of exon 3 of HNF1A gene in the patient and mother. The HNF1A exon 3 mutation of CGA to CAA resulted in the change of arginine to glutamine which by the HGMA database is recognized as a reported MODY3 gene mutation. There was a mutation of G to A in the 4 loci of exon 1 of the insulin coding region in chromosome 11 in both the patient and elder brother. Neither elder brother nor father had the CGA mutation of HNF1A. Conclusion: There has not been a previous report of a relationship between HNF1A and CFM. In this case, the elder brother had CFM without a HNF1A mutation which does not support a connection between CFM and HNF1A. The two brothers both had CFM and insulin coding gene mutations which would represent a new association not previously described. Further testing is needed to confirm a relationship between the two. Reference: 1. Chen Q, Zhao Y, Shen G, Dai J. Etiology and Pathogenesis of Hemifacial Microsomia. J Dent Res 2018; 97(12): 1297-305. 2. Gougoutas AJ, Singh DJ, Low DW, Bartlett SP. Hemifacial microsomia: clinical features and pictographic representations of the OMENS classification system. Plast Reconstr Surg 2007; 120(7): 112e-20e.

scholarly journals MON-057 MODY Diagnosis: Missed Opportunity to Avert Insulin Therapy. A Case Series

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Remberto Paulo ◽  
Salman Kirmani ◽  
Kristal Anne Matlock ◽  
Deborah A Bowlby ◽  
Terry Headley
Keyword(s):  
Genetic Testing ◽  
Insulin Therapy ◽  
Gene Mutation ◽  
Health Care Providers ◽  
Diabetes Management ◽  
Case Series ◽  
Care Providers ◽  
C Peptide ◽  
Bolus Insulin ◽  
Basal Bolus

Abstract BACKGROUND Prevalence of MODY is 1.2% in pediatric diabetes population. SEARCH study reported most of these patients were misdiagnosed as T1DM or T2DM up to 36% and 51% respectively (1). GCK (MODY 2) and HNF1A/HNF4A (MODY3) are the most common forms of MODY. Despite improvement in testing strategy (panel testing instead of step-wise approach) and cost, MODY testing remains underutilized. These conditions do not require insulin therapy, and MODY 2 patients may even be discharged from clinic after diagnosis. We present 4 cases and valuable lessons learned. MODY 2 Case 1. 4 yo M referred for hyperglycemia in the 300s during surgery. A1c 6.4%. FBG at home 150s, asymptomatic. MGM and MGM’s siblings have diabetes. Diabetes autoantibodies (DAA) negative. C-peptide 5.4 (NL 0.78 - 5.19 ng/ml). MODY panel (GeneDx) showed heterozygous mutation in GCK gene (c.70 C>T). Patient remains off insulin, family reassured and advised to undergo genetic testing. MODY 2 Case 2. 8 yo M diagnosed at local ED with “T1DM” after presenting with polyuria, polydipsia, and random BG 237. A1c 6.7%, C-peptide 1.9, started on basal-bolus insulin. MODY panel (sent a year later when patient was found to have low insulin requirement, negative DAA) showed pathogenic variant in GCK gene. Weaned from insulin, A1c unchanged (6.3–7%). Mother found to have same mutation. MODY 3 Case 1. 16 yo F referred by PCP who started her on insulin a year prior after an incidental finding of hyperglycemia. A1c was 7.5% at diagnosis. Mom, MGM have diabetes, unknown type (MGM thin by report). DAA neg, C-Peptide 1.74. MODY Panel showed HNF1A heterozygous gene mutation for RI31Q. She was switched to Glyburide, blood glucose 90s. MODY 3 Case 2. 10 yo M referred from the ED for “T1DM” (weight loss, fatigue, A1c 7.6%) started on basal-bolus insulin, but lost to follow up for a year. Brother has MODY 3. DAA neg, C-Peptide 3.1. Targeted gene sequencing showed HNF1A gene mutation. He was switched to Glyburide, A1c improved to 6.7%. However, patient became noncompliant as teenager, A1c now 9.3%. CONCLUSION MODY remains underdiagnosed. A high index of suspicion should be maintained in nonobese, DAA-negative patients diagnosed with DM before 25yo. Although DAA and genetic testing can be costly, diagnosis can dramatically alter diabetes management as illustrated in all 4 cases, and overall cost of management may be lower in the end. Patients with MODY 2 do not develop vascular complications associated with diabetes, nor require pharmacotherapy. MODY 3 patients may be safely switched to sulfonylurea monotherapy, though degree of diabetes control depends on compliance with medication. Testing gives relatives previously misdiagnosed the opportunity to improve their own quality of life. More education for health care providers is warranted for prompt diagnosis and appropriate management of this condition. Reference:1. Pihoker, et al. JCEM 2013; 98:4055–62

Central Diabetes Insipidus Caused by Arginine Vasopressin Gene Mutation: Report of a Novel Mutation and Review of Literature

2020 ◽  
Vol 52 (11) ◽  
pp. 796-802
Author(s):  
Lara L.I. Feldkamp ◽  
Elke Kaminsky ◽  
Tina Kienitz ◽  
Marcus Quinkler
Keyword(s):  
Diabetes Insipidus ◽  
Gene Mutation ◽  
Arginine Vasopressin ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Coding Region ◽  
Exon 2 ◽  
German Family ◽  
Gene Coding ◽  
Avp Gene

AbstractFamilial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant hereditary disorder characterized by severe polydipsia and polyuria that usually presents in early childhood. In this study, we describe a new arginine vasopressin (AVP) gene mutation in an ethnic German family with FNDI and provide an overview of disease-associated AVP-gene mutations that are already described in literature. Three members of a German family with neurohypophyseal diabetes insipidus were studied. Isolated DNA from peripheral blood samples was used for mutation analysis by sequencing the whole coding region of AVP-NPII gene. Furthermore, we searched the electronic databases MEDLINE (Pubmed) as well as HGMD, LOVD-ClinVar, db-SNP and genomAD in order to compare our cases to that of other patients with FNDI. Genetic analysis of the patients revealed a novel heterozygote missense mutation in exon 2 of the AVP gene (c.274T>G), which has not yet been described in literature. We identified reports of more than 90 disease-associated mutations in the AVP gene in literature. The novel mutation of the AVP gene seems to cause FNDI in the presented German family. Similar to our newly detected mutation, most mutations causing FNDI are found in exon 2 of the AVP gene coding for neurophysin II. Clinically, it is important to think of FNDI in young children presenting with polydipsia and polyuria.

Etiology and Pathogenesis of Hemifacial Microsomia

2018 ◽  
Vol 97 (12) ◽  
pp. 1297-1305 ◽  
Author(s):  
Q. Chen ◽  
Y. Zhao ◽  
G. Shen ◽  
J. Dai
Keyword(s):  
Molecular Mechanisms ◽  
Maternal Diabetes ◽  
Abnormal Development ◽  
Future Research ◽  
Hemifacial Microsomia ◽  
Vascular Abnormality ◽  
Intrinsic Factors ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Genetic Interventions

Hemifacial microsomia (HFM) is a common congenital malformation of the craniofacial region. There are 3 possible pathogenic models of HFM—vascular abnormality and hemorrhage in the craniofacial region, damage to Meckel’s cartilage, and the abnormal development of cranial neural crest cells—and the most plausible hypothesis is the vascular abnormality and hemorrhage model. These 3 models are interrelated, and none of them is completely concordant with all the variable manifestations of HFM. External environmental factors (e.g., thalidomide, triazene, retinoic acid, and vasoactive medications), maternal intrinsic factors (e.g., maternal diabetes), and genetic factors (e.g., the recently reported mutations in OTX2, PLCD3, and MYT1) may lead to HFM through ≥1 of these pathogenic processes. Whole genome sequencing to identify additional pathogenic variants, biological functional studies to understand the exact molecular mechanisms, and additional animal model and clinical studies with large stratified samples to elucidate the pathogenesis of HFM will be necessary. Small-molecule drugs, as well as CRISPR/CAS9-based genetic interventions, for the prevention and treatment of HFM may also be a future research hotspot.

Stimulation of residual insulin secretion by glibenclamide in insulin dependent diabetics

1980 ◽  
Vol 95 (3) ◽  
pp. 372-375 ◽  
Author(s):  
B. J. Burke ◽  
R. J. Sherriff
Keyword(s):  
Insulin Secretion ◽  
Insulin Therapy ◽  
Metabolic Control ◽  
C Peptide ◽  
Beneficial Effects ◽  
Insulin Dependent ◽  
Serum And Urine ◽  
Stimulation Of

Abstract. Residual insulin secretion, reflected by the presence of C-peptide in serum and urine, has been demonstrated in 5 of 10 insulin-requiring diabetics of less than 10 years' duration tested. The C-peptide response, in the C-peptide secretors, showed a significant increase in both serum and urine after 4 weeks' treatment with 15 mg glibenclamide daily in addition to their usual insulin regime although no beneficial effects in metabolic control were detected. It is suggested that glibenclamide might be a useful adjunct to insulin therapy in insulinrequiring diabetics who still secrete C-peptide.

scholarly journals The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

2020 ◽  
Vol 21 (21) ◽  
pp. 8403
Author(s):  
Erkut Ilaslan ◽  
Renata Markosyan ◽  
Patrick Sproll ◽  
Brian J. Stevenson ◽  
Malgorzata Sajek ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Signaling Pathway ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Androgen Insensitivity Syndrome ◽  
Homologous Gene ◽  
Gene Encoding ◽  
Androgen Insensitivity ◽  
Disorder Of Sexual Development ◽  
Partial Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

Evaluation of the tshr gene reveals polymorphisms associated with typical symptoms in primary congenital hypothyroidism

2016 ◽  
Vol 29 (1) ◽  
Author(s):  
Erik Artur Cortinhas Alves ◽  
Raissa Coelho Andrade ◽  
Carlos Eduardo de Melo Amaral ◽  
Milena Coelho Fernandes Caldato ◽  
Adriana Maria Rocha Bastos ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Peripheral Blood ◽  
Genomic Dna ◽  
Gene Mutations ◽  
Molecular Heterogeneity ◽  
Coding Region ◽  
Blood Samples ◽  
Live Births ◽  
Tshr Gene ◽  
Inactivating Mutations

AbstractPrimary congenital hypothyroidism (PCH) has an incidence of approximately 1 in each 3000–4000 live births. In the last two decades, nearly 50 types of the distinct inactivating mutations have already been described in the coding region of the tshr gene. The aim of present study was to investigate tshr gene mutations in patients with primary congenital hypothyroidism, analyzing a sample of 106 patients that were diagnosed with PCH. Genomic DNA was isolated from peripheral blood samples, and 10 exons from the TSH receptor were automatically sequenced. Five nucleotide alterations (P52T, N187N, A459A, L645L, and D727E. N187N and D727E polymorphisms) were associated with positive medical history. In view of the clinical, biochemical and molecular heterogeneity of the etiology of the PCH, the study of polymorphisms is critical for investigating the possible associations with prevailing symptoms of this disorder.

scholarly journals The association of CYP2D6 gene polymorphisms in the full-length coding region with higher recurrence rate of vivax malaria in Yunnan Province, China

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Herong Huang ◽  
Ying Dong ◽  
Yanchun Xu ◽  
Yan Deng ◽  
Canglin Zhang ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Gene Mutation ◽  
Dna Sequences ◽  
Vivax Malaria ◽  
Yunnan Province ◽  
Reference Sequence ◽  
Radical Cure ◽  
Coding Region ◽  
Cyp2d6 Gene ◽  
Genotype 4

Abstract Background Accumulating evidence suggest that compromised CYP2D6 enzyme activity caused by gene mutation could contribute to primaquine failure for the radical cure of vivax malaria. The current study aims to preliminarily reveal the association between the recurrence of vivax malaria in Yunnan Province and CYP2D6 gene mutation by analysing polymorphisms in the entire coding region of human CYP2D6 gene. Methods Blood samples were collected from patients with vivax malaria, who received "chloroquine and 8-day course of primaquine therapy" in Yunnan Province. The suspected relapsed cases were determined by epidemiological approaches and gene sequence alignment. PCR was conducted to amplify the CYP2D6 gene in the human genome, and the amplified products were then sequenced to compare with the non-mutation “reference” sequence, so as to ensure correct sequencing results and to determine 9 exon regions. Subsequently, the DNA sequences of 9 exons were spliced into the coding DNA sequence (CDS), which, by default, is known as maternal CDS. The paternal CDS was obtained by adjusting the bases according to the sequencing peaks. The mutation loci, haplotypes (star alleles), genotypes and odds ratios (OR) of all the CDSs were analysed. Results Of the119 maternal CDS chains in total with 1491 bp in length, 12 mutation sites in the 238 maternal and paternal CDS chains were detected. The c.408G > C mutation was most frequently detected in both suspected relapsed group (SR) and non-relapsed group (NR), reaching 85.2% (75/88) and 76.0% (114/150), respectively. The c.886C > T mutation was most closely related to the recurrence of vivax malaria (OR = 2.167, 95% CI 1.104–4.252, P < 0.05). Among the 23 haplotypes (Hap_1 ~ Hap_23), Hap_3 was non-mutant, and the sequence structure of Hap_9 was the most complicated one. Five star alleles, including *1, *2, *4, *10 and *39, were confirmed by comparison, and CYP2D6*10 allele accounted for the largest percentage (45.4%, 108/238). The frequency of CYP2D6*2 allele in the SR group was significantly higher than that in the NR group (Χ2 = 16.177, P < 0.05). Of the defined 24 genotypes, 8 genotypes, including *4/*4, *4/*o, *2/*39, *39/*m, *39/*x, *1/*r, *1/*n, and *v/*10, were detected only in the SR group. Conclusion Mutation of CYP2D6*10 allele accounts for the highest proportion of vivax malaria cases in Yunnan Province. The mutations of c. 886C > T and CYP2D6*2 allele, which correspond to impaired PQ metabolizer phenotype, are most closely related to the relapse of vivax malaria. In addition, the genotype *4/*4 with null CYP2D6 enzyme function was only detected in the SR group. These results reveal the risk of defected CYP2D6 enzyme activity that diminishes the therapeutic effect of primaquine on vivax malaria.

scholarly journals NPHS2 gene mutation, atopy, and gender as risk factors for steroid-resistant nephrotic syndrome in Indonesians

2011 ◽  
Vol 51 (5) ◽  
pp. 272 ◽  
Author(s):  
Dedi Rachmadi ◽  
Danny Hilmanto ◽  
Ponpon Ijradinata ◽  
Abdurahman Sukadi
Keyword(s):  
Risk Factors ◽  
Nephrotic Syndrome ◽  
Gene Mutation ◽  
Significant Risk ◽  
Gene Mutations ◽  
Male Gender ◽  
Amplification Refractory Mutation System ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Nphs2 Gene

Background Steroid-resistant nephrotic syndrome (SRNS) often develops into end stage renal disease. Previous studies have reported that NPHS2 gene mutation, gender, and atopic history are risk factors associated with SRNS. Interethnic, sociocultural, and environmental differences have also been suggested to affect these mutations.Objective To analyze possible risk factors for SRNS, including NPHS2 gene mutations (412C→T and 419delG), gender and atopic history, in Indonesian subjects with SRNS.Methods A case-control study with 153 subjects, consisting of 88 SRNS patients and 65 control subjects, was undertaken in 10 Indonesian teaching centre hospitals from September 2006 to December 2007. Analysis of the NPHS2 gene mutation in 412 C→T was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), while that for the NPHS2 gene mutation in 419delG was performed by restriction fragment length polymorphism (RFLP). Data was analyzed by multiple logistic regression.Results In our Indonesian subjects, the significant risk factors for SRNS were male gender (OR=2.21; CI 95%:1.07-4.56, P=0.036), NPHS2 412C→T gene mutation (OR=18.07; CI 95%:6.76-48.31, P<0.001), and NPHS2 419delG gene mutation (OR=4.55; CI 95%:1.66-12.47, P=0.003). However, atopic history was not a significant risk factor for SRNS (OR=1.807; CI 95%:0.642-5.086, P=0.262).Conclusion NPHS2 412C→T and 419delG gene mutations, as well as male gender are risk factors for SRNS in Indonesian subjects. Atopic history was not significantly associated with SRNS in our subjects. [Paediatr Indones. 2011;51:272-6].

scholarly journals The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil

2018 ◽  
Vol 44 (5) ◽  
pp. 383-389
Author(s):  
Manuela Brisot Felisbino ◽  
Frederico Leon Arrabal Fernandes ◽  
Maria Cecília Nieves Maiorano de Nucci ◽  
Regina Maria de Carvalho Pinto ◽  
Emilio Pizzichini ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Respiratory Symptoms ◽  
Gene Mutations ◽  
Lower Lobe ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Referral Center ◽  
Patient Profile ◽  
Significant Difference ◽  
Alpha 1 Antitrypsin

ABSTRACT Objective: The clinical, functional, radiological and genotypic descriptions of patients with an alpha-1 antitrypsin (A1AT) gene mutation in a referral center for COPD in Brazil. Methods: A cross-sectional study of patients with an A1AT gene mutation compatible with deficiency. We evaluated the A1AT dosage and genotypic, demographic, clinical, tomographic, and functional characteristics of these patients. Results: Among the 43 patients suspected of A1AT deficiency (A1ATD), the disease was confirmed by genotyping in 27 of them. The A1AT median dosage was 45 mg/dL, and 4 patients (15%) had a normal dosage. Median age was 54, 63% of the patients were male, and the respiratory symptoms started at the age of 40. The median FEV1 was 1.37L (43% predicted). Tomographic emphysema was found in 77.8% of the individuals. The emphysema was panlobular in 76% of them and 48% had lower lobe predominance. The frequency of bronchiectasis was 52% and the frequency of bronchial thickening was 81.5%. The most common genotype was Pi*ZZ in 40.7% of participants. The other genotypes found were: Pi*SZ (18.5%), PiM1Z (14.8%), Pi*M1S (7.4%), Pi*M2Z (3.7%), Pi*M1I (3.7%), Pi*ZMnichinan (3.7%), Pi*M3Plowell (3.7%), and Pi*SF (3.7%). We did not find any significant difference in age, smoking load, FEV1, or the presence of bronchiectasis between the groups with a normal and a reduced A1AT dosage, neither for 1 nor 2-allele mutation for A1ATD. Conclusions: Our patients presented a high frequency of emphysema, bronchiectasis and bronchial thickening, and early-beginning respiratory symptoms. The most frequent genotype was Pi*ZZ. Heterozygous genotypes and normal levels of A1AT also manifested significant lung disease.

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