Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects

Caetano, Lílian Araújo; Jorge, Alexander A L; Malaquias, Alexsandra C.; Trarbach, Ericka Barbosa; Queiroz, Márcia Silva; Nery, Márcia; Teles, Milena Gurgel

doi:10.1590/s0004-27302012000800010

Cited by 8 publications

(13 citation statements)

References 29 publications

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“…These data allow us to estimate the number of MODY cases in Brazil as approximately 140 000 to 280 000. However, until 2016, around 200 subjects of about 50 Brazilian families diagnosed with the 2 most common subtypes of MODY ( GCK and HNF1A ) have been described . Hence, MODY cases are clearly underestimated in Brazil.…”

Section: Introductionmentioning

confidence: 99%

“…However, until 2016, around 200 subjects of about 50 Brazilian families diagnosed with the 2 most common subtypes of MODY (GCK and HNF1A) have been described. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Hence, MODY cases are clearly underestimated in Brazil. Besides that, there is a great racial diversity in Brazilian people, contributing to a wide genetic background, an important difference from countries with more homogeneous population.…”

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confidence: 99%

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Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

et al. 2017

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Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

et al. 2017

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“…Maturity Onset Diabetes of the Young (MODY) is the most common form of monogenic diabetes, resulting from β pancreatic cell and insulin secretion dysfunction [2-4]. MODY includes a clinically and genetically heterogeneous group of diabetes subtypes characterized by an autosomal dominant pattern of inheritance [2,3] with early onset of hyperglycemia in individuals, typically younger than 25 years of age [2,5,6]. MODY accounts for 2%–5% of all cases of diabetes [7].…”

Section: Introductionmentioning

confidence: 99%

“…The first gene causally implicated was the glucokinase gene ( GCK ) [8]. Currently, 14 genes are associated with MODY: HNF4A , GCK , HNF1A , PDX1 , HNF1B , NEUROD1 , KLF11 , PAX4 , CEL , INS , and BLK , corresponding respectively to MODY types 1 to 11, with 3 more recently discovered new genes: ABCC8 , KCNJ11 , and APPL1 [6,9-11]. Depending on the genetic etiology, the different subtypes present with different clinical presentations [4].…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia in pediatric age: could it be maturity onset diabetes of the young? Case reports and review of the literature

Cascais¹,

Pereira²,

Vieira³

et al. 2019

Ann Pediatr Endocrinol Metab

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Maturity Onset Diabetes of the Young (MODY) includes a clinically and genetically heterogeneous group of diabetes subtypes with MODY-2 being the second most prevalent form. We report 2 cases of MODY-2 identified during the investigation of asymptomatic hyperglycemia. A 12-year-old girl with a familiar history of diabetes (mother, maternal aunt, and maternal grandfather) was referred due to hypercholesterolemia, abnormal fasting glucose (114 mg/dL), and increased levels of glycated haemoglobin (HbA1c) (6%) presenting with negative β-cell antibodies. A glucokinase (GCK) heterozygous missense mutation c.364C>T (p.Leu122Phe) in exon 4 was identified in the index patient and in the 3 family members. An obese 9-year-old boy was investigated for elevated fasting glycemic levels (99–126 mg/dL), HbA1c rise (6.6%–7.6%), and negative β-cell antibodies. The patient’s father, paternal aunt, and paternal grandfather had a history of diabetes during their childhood. A GCK heterozygous missense mutation c.698G>A (p.Cys233Tyr) in exon 7 was identified in the index patient. This variant was only described in another family strongly affected by both MODY and classic autoimmune mediated diabetes, contrary to our case. MODY-2 should be suspected in the presence of early onset of persistent mild fasting hyperglycemia and negative β-cell antibodies associated with a positive family history of diabetes. These cases illustrate the challenging aspects of MODY diagnosis due to possible phenotypic overlap with other types of diabetes. The diagnosis requires a high level of suspicion and GCK genetic screening should be performed in the presence of compatible features. An early diagnosis allows for appropriate management, genetic counselling, and the identification of affected family members.

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“…GCK mutations are more commonly diagnosed in countries where glucose screening in asymptomatic people is a routine procedure (such as Germany, France, Spain and Italy), whereas HNF1A-MODY is more commonly diagnosed were routine glucose screening is seldom done (12,13). There also some reported MODY cases in Brazilian literature (14)(15)(16)(17)(18).…”

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confidence: 99%

Maturity onset diabetes of young type 2 due to a novel de novo GKC mutation

Afonso¹,

Ferraria²,

Carvalho³

et al. 2014

Arq Bras Endocrinol Metab

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SUMMARYMaturity Onset Diabetes of Young (MODY) is a heterogeneous group of monogenic disorders that result in β-cell dysfunction, with an estimated prevalence of 1%-2% in industrialized countries. MODY generally occurs in non-obese patients with negative autoantibodies presenting with mild to moderate hyperglycemia. The clinical features of the patients are heterogeneous, depending on the different genetic subtypes. We pretend to report a case of MODY type 2 caused by a novel de novo CGK mutation, highlighting the importance of the differential diagnosis in pediatric diabetes. A 13-year-old, healthy and non-obese girl was admitted for investigation of recurrent hyperglycemia episodes. She presented with persistent high levels of fasting blood glycemia (> 11.1 mmol/L) and had no familial history of diabetes. The blood glucose profile revealed an impaired fasting glucose of 124 mg/dL (6,9 mmol/L) with a normal oral glucose tolerance test. Fasting insulinemia was 15 mg/dL (90.1 pmol/L), HOMA-IR was 3.9 and hemoglobin A1c was 7.1%. Pancreatic autoantibodies were negative. Genetic testing identified a novel missense heterozygous mutation in exon 5 of GCK gene c.509G > T (p.Gly170Val), not present on the parents. This result established the diagnosis of MODY type 2. Clinical identification of patients with MODY remains a diagnostic challenge, especially when familial history is absent. Molecular diagnosis is very important for establishing an individualized treatment and providing a long term prognosis for each type of MODY. Arq Bras Endocrinol Metab. 2014;58(7):772-5 SUMáRioO diabetes da maturidade com início na juventude (MODY) é um grupo heterogêneo de doenças monogênicas que resultam em disfunção das células β, com uma prevalência estimada de 1-2% nos países industrializados. O MODY geralmente ocorre em pacientes não obesos, negativos para autoanticorpos e que apresentam hiperglicemia de leve a moderada. As características clínicas dos pacientes são heterogêneas e dependem do subtipo genético. Pretende-se relatar um caso de MODY tipo 2 causado por uma mutação GKC de novo não descrita anteriormente, demonstrando a importância do diagnóstico diferencial no diabetes pediátrico. Uma menina de 13 anos de idade, saudável e não obesa, foi admitida em um hospital para investigação de episódios recorrentes de hiperglicemia. Ela apresentava níveis altos e persistentes de glicemia de jejum (> 11,1 mmol/L) e não havia histórico familiar de diabetes. O perfil glicêmico sanguí-neo revelou glicose de jejum de 124 mg/dL (6,9 mmol/L), com resultados normais no teste oral de tolerância à glicose. O resultado da insulinemia de jejum foi 15 mg/dL (90,1 pmol/L), do HOMA-IR foi 3,9 e da hemoglobina A1c foi de 7,1%. Os autoanticorpos pancreáticos foram negativos. A análise genética identificou uma nova mutação heterozigota missense no éxon 5 do gene GCK c.509G > T (p.Gly170Val), não encontrada nos país. Esse resultado estabeleceu o diagnóstico de MODY tipo 2. A identificação clínica dos pacientes com MODY permanece um desafio diagnóstic...

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Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects

Cited by 8 publications

References 29 publications

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

Hyperglycemia in pediatric age: could it be maturity onset diabetes of the young? Case reports and review of the literature

Maturity onset diabetes of young type 2 due to a novel de novo GKC mutation

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