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Cited by 255Diabetes and associated disordersPancreatic function and diabetesDiabetes Management and Research

The diagnosis and management of monogenic diabetes in children and adolescents

Hattersley, Andrew, Bruining, Jan, Shield, Julian, Njolstad, Pal, Donaghue, Kim C·2009·Pediatric Diabetes
DOI 10.1111/j.1399-5448.2009.00571.x
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Abstract

Monogenic diabetes results from the inheritance of a mutation or mutations in a single gene. It may be dominantly or recessively inherited or may be a de novo mutation and hence a spontaneous case. In children, almost all monogenic diabetes results from mutations in genes that regulate beta-cell function although diabetes can rarely occur from mutations resulting in very severe insulin resistance (C) 1. The majority of patients with genetically proven monogenic diabetes are initially incorrectly diagnosed as Type 1 or Type 2 diabetes 2 (C). It is important to correctly diagnose monogenic diabetes as it can predict the clinical course of the patient, explain other associated clinical features and most importantly guide the most appropriate treatment. In addition, making a diagnosis will have implications for other family members often correcting the diagnosis and treatment for other diabetic family members as well as allowing appropriate genetic counseling. Clinical presentations in children when a diagnosis of monogenic diabetes should be considered and are discussed below include: Neonatal diabetes and diabetes diagnosed within the first 6 months of life. Familial diabetes with an affected parent Mild (5.5–8.5 mmol/l) fasting hyperglycaemia especially if young or familial Diabetes associated with extra pancreatic features Features in children initially thought to have Type 1 diabetes that should suggest a possible diagnosis of monogenic diabetes are shown below. None of these are absolute and should be considered as together rather than in isolation (C) 3. A diagnosis of diabetes before 6 months (B) (in Type 1: < 1% 4) Family history of diabetes with a parent affected (C) (in Type 1: 2–4% 5) Evidence of endogenous insulin production outside the 'honeymoon' phase (after 3 years of diabetes) with detectable C peptide (> 200 nmol/l) when glucose > 8 mmol/l (E) (in Type 1 DM: 1–5%). When pancreatic islet autoantibodies are absent, especially if measured at diagnosis (C) (in Type 1: 3–30% 6-8). The great variation in antibody prevalence in series probably represents differences in assays and means it is hard to apply published series directly into clinical practice. Absent antibodies should lead to other investigation/consideration rather than leading directly to genetic tests (E). Features in children initially thought to have Type 2 diabetes that should suggest a possible diagnosis of monogenic diabetes are shown below. Note most Type 2 diabetes in youth will meet former classification for MODY (diagnosed < 25, autosomal dominant inheritance and non-insulin dependent (C) 9-12). Not markedly obese or diabetic family members who are normal weight (in Type 2: 20% 12) Acanthosis nigricans not detected (in Type 2: 10% 9) Ethnic background has a low prevalence of Type 2 diabetes race e.g. European Caucasian (in Type 2: 0–45%) No evidence of insulin resistance with fasting C peptide within the normal range (in Type 2: 0-20% 9-12) As well as having clinical features that are unusual for Type 1 and Type 2 diabetes a patient in whom a diagnosis of monogenic diabetes should also have the features of a specific genetic subtype of monogenic diabetes (E). The features of the commoner monogenic diabetes are given below. While in Type 1 and Type 2 diabetes there is no single diagnostic test, this is not the case in monogenic diabetes where in > 80% of cases a molecular genetic diagnosis can be made by DNA testing (C). Molecular genetic testing is offered in most European countries and the USA but many labs will test patients from other countries (for example www.diabetesgenes.org and www.mody.no). These tests are expensive (up to €500/$600) but can have a big impact on management of the proband and other family members who will be cheaper as the mutation is known (€100/$120). Some recently described monogenic diabetes genes like Kir6.2 testing in patients diagnosed less than 6 months may be available as research tests for no charge (see www.diabetesgenes.org). Approval from the patient's insurance company should be sought prior to sending DNA when applicable. Given the limited resources available it is vital that these tests are used in situations where they are likely to be positive and will alter clinical care. This will involve careful clinical selection and performing physiological tests like C peptide and autoantibody measurement as well as testing other family members before doing molecular genetic tests (E). There is good evidence that diabetes diagnosed in the first 6 months is not Type 1 diabetes as autoantibodies are rare and HLA genotyping is actually protective for Type 1 in these patients (B) 4. Neonatal diabetes is another area which has rapidly moved from a clinical to a molecular genetic classification 13, 14. Neonatal diabetes is insulin requiring diabetes which is usually diagnosed in the first three months of life. Clinically two subgroups were recognised: transient neonatal diabetes mellitus (TNDM) that r

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  • A subset of individuals within type 1B diabetes have monogenic forms of diabetes, such as maturity onset diabetes of the young (MODY).

    “A subset of individuals within this latter group have monogenic forms of diabetes, such as maturity onset diabetes of the young (MODY).43”

    From Type 1 diabetes (2014) · cites this paper as [43]

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Authors
Hattersley, A., Bruining, J., Shield, J., Njolstad, P., & Donaghue, K. C.
Affiliations
  • University of Exeter (GB)
  • Erasmus MC - Sophia Children’s Hospital (NL)
  • The University of Sydney (AU)
Corresponding author
Hattersley, Andrew
ORCID
Venue
Pediatric Diabetes
Publisher
Wiley
Published
2009-09
Volume
10
Pages
33-42
ISSN
  • 1399-543X (ISSN-L)
  • 1399-5448
DOI
10.1111/j.1399-5448.2009.00571.x
OpenAlex
W2113745162
Cited by
255
References
167
Citations by year
2026: 2 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 25 · 2020: 18 · 2019: 10 · 2018: 9 · 2017: 21 · 2016: 26 · 2015: 28 · 2014: 20 · 2013: 20 · 2012: 19
FWCI
1.57
Type
journal article
Language
en
Open access
closed
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2191 d)
Locations
  • Pediatric Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
monogenic diabetes, children and adolescents, neonatal diabetes, maturity-onset diabetes of the young, KCNJ11, HNF1A, HNF4α, KCNN4, KCNQ1, KCNQ2, KCNQ3, KCNQ5, KCNN3
MeSH terms
Adolescent, Child, Diabetes Mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Ethnicity, Family, Genes, Dominant, Genes, Recessive, Humans, Medical History Taking, Mutation

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