Two siblings with a rare type of maturity-onset diabetes of the young (MODY)
- Fatima Riyadh Alhakim and
- Haya AlKhayyat
- Pediatrics, Bahrain Defence Force Royal Medical Services, Riffa, Bahrain
- Correspondence to Dr Fatima Riyadh Alhakim; fatima.alhakim@gmail.com
Abstract
Maturity-onset diabetes of the young (MODY) is a type of diabetes that does not entirely fit the usually encountered type 1 or type 2 diabetes. It is a monogenic, familial and non-autoimmune diabetes among children and young adults resulting from autosomal dominant gene mutations.
MODY diagnosis is confirmed by molecular genetic testing, which is costly. Therefore, it is rarely done.
Nearly 1%–6% of diabetes has a monogenic cause but this is frequently misclassified as type 1 diabetes mellitus due to the lack of genetic testing. Therefore, a correct diagnosis of MODY is crucial for determining the plan of management. Furthermore, having a patient with MODY in a family indicates screening other family members. In this case report, we highlight that paediatric diabetes cases are not always type 1 or type 2 diabetes mellitus since two siblings incidentally presented with hyperglycaemia and a confirmed diagnosis of MODY type 10 was ultimately made. Moreover, their mother who was previously labelled as a case of type 1 diabetes mellitus was diagnosed later as MODY after genetic testing.
Background
Diabetes mellitus is a common disease in paediatrics and the numbers of the new cases are rapidly increasing every year. Maturity-onset diabetes of the young (MODY) is a unique type of diabetes where its precise diagnosis is vital in order to provide favourable treatment and hence the best long-term outcome, especially since diabetes requires a long-running lifestyle modification to the child and his family. MODY is usually caused by a single gene mutation and it constitutes 1%–6% of all diabetes cases in children.1
The aim of this case report is to think broadly about the diagnosis of diabetes in children, as it can be easily missed and that genetic testing is to be considered whenever it is indicated.
Case presentation
First sibling
At early childhood, a previously healthy boy presented to our emergency department with high blood glucose reading which was checked by his mother at home. At that time, his infant younger brother was admitted for an upper respiratory tract infection and was found to have hyperglycaemia. A week prior to his presentation, he had symptoms of reduced activity, cough and low-grade fever. The mother denied any symptoms of polyuria and polydipsia. Moreover, there was no noticeable weight loss, significant poor appetite or abdominal pain. Developmental milestones were appropriate for his age and he was fully vaccinated.
He was born at term by vacuum extraction and discharged home after routine 48 hours’ observation. His mother was diagnosed to have type 1 diabetes at early childhood and was treated with single daily dose of insulin in the morning. This has contributed to poor glycaemic control, as her glycosylated haemoglobin (HbA1c) was about 11%. At early adolescence, she was started on multiple daily doses of insulin and was diagnosed to have diabetic retinopathy. Thereafter, her HbA1c improved and her glucose has been maintained within normal values. The family history was negative for diabetes and no history of consanguinity (figure 1).
This is a three-generation family pedigree of our cases of maturity-onset diabetes of the young type 10 diabetes mellitus (DM). The genetic study result reported the mother and both her sons having the heterozygous INS gene mutation (c.188-31G>A). It is a pathogenic type; the mother is on multiple daily injections of insulin while both sons are managed with insulin pumps. Onset age: II-2, early childhood; III-1, early childhood; III-2, infancy. N; Normal allele, M,; mutant allele.
His initial laboratory investigations showed random blood glucose level of 20 mmol/L, without ketosis, and autoantibodies were negative. His HbA1c was 13.7%. As part of the screening for other associated autoimmune diseases, thyroid function test was normal and thyroid antibodies and coeliac screen were negative. He was initially treated with multiple daily injections (MDIs) of rapid-acting and long-acting insulin. A month after diagnosis, he was started on insulin pump therapy. His blood glucose has been well controlled with an HbA1c ranging between 6% and 6.9%.
Second sibling
Five months after the older sibling’s diagnosis, the younger brother at infancy presented to our emergency department with high blood glucose reading. His symptoms began 3 days prior to his presentation with an upper respiratory tract infection, accompanied by 1 day of wetting diapers more than his usual. On the other hand, there was no significant history of abnormal breathing, weight loss, fever or lethargy. Regarding his medical history, at infancy, he was admitted with a viral fever and incidentally was found to have glucosuria and transient hyperglycaemia that required insulin infusion for short time over 2 days. Then, his blood glucose normalised and was discharged home after being normoglycaemic without insulin (this is when his older brother was incidentally found to be hyperglycaemic and diagnosed with diabetes). A diagnosis of transient neonatal diabetes was therefore established at that time.
He was born at term by spontaneous vaginal delivery, stayed for 48 hours for routine care and during that time all his blood glucose readings were within normal values.
His laboratory investigations showed blood glucose level of 12 mmol/L, without ketosis, and autoantibodies were negative. However, his HbA1c was 6%. As part of screening for other autoimmune diseases, thyroid and coeliac screening were negative. He was started on insulin pump therapy upon diagnosis and his blood glucose remained within normal values, with HbA1c ranging between 5.9% and 6.7%.
Further investigations
Subsequently, as the second sibling presented with neonatal diabetes, genetic testing was done for the two siblings and their parents. The results of the genetic testing of the siblings and their mother confirmed a gene mutation of the INS gene (insulin gene) located at intron 2 with DNA description of c.188-31G>A.
Differential diagnosis
For the first sibling, as his insulin and C peptide levels were low, a diagnosis of type 1 diabetes mellitus was established initially. However, along with the younger sibling’s presentation of hyperglycaemia on a couple of occasions all within infancy, in addition to normal C peptide and insulin values, a working diagnosis of neonatal diabetes versus MODY was suspected. Following which a diagnosis of MODY 10 was eventually confirmed after the genetic testing.
Treatment
The older sibling was started initially on MDIs of rapid and long-acting insulin. A month later from the diagnosis, he was started on insulin pump therapy.
However, as the younger infant sibling was diagnosed at infancy and his insulin requirements were very small, he was started immediately on insulin pump therapy. Initially, he only required food boluses. Three months later, his pump settings were adjusted to deliver basal insulin as well.
As for the mother, she had been on a single daily dose of insulin since the age of diagnosis in her early childhood, then changed to MDIs by early adolescence to date.
A team consisting of a paediatric endocrinologist, diabetic educators and dietitians was involved in caring for these siblings.
Outcome and follow-up
The siblings are routinely followed up in our insulin pump clinic, as their pumps are uploaded regularly and the pump settings are adjusted accordingly. During the pandemic, their pumps’ uploads were sent by their mother to the treating team and remote adjustments were made with the mother’s help. Figures 2 and 3 show the pump uploads over a 2-week period for the two siblings, respectively. Both uploads are suggestive of very good glucose control with 74% and 84% of the blood glucose readings within the normal range for the first sibling and the younger sibling, respectively. This is in spite of very low basal insulin doses ranging between 10% and 15% of the total daily dose of insulin. Furthermore, their growth and development have been monitored closely and are within normal limits for their ages.
First sibling download over 2-week period and showed very good control with 74% of the blood glucose (BG) readings within the normal range. This is in spite of very low basal insulin dose ranging between 10% and 15% of the total daily dose of insulin. SG ; Sensor glucose.
Second sibling download over 2-week period and showed very good control with 82% of the blood glucose (BG) readings within the normal range. This is in spite of very low basal insulin dose ranging between 10% and 15% of the total daily dose of insulin. SG ; Sensor glucose.
Discussion
Diabetes mellitus is among the most common chronic illnesses of childhood. There are three main known forms of paediatric diabetes which include type 1 diabetes mellitus, type 2 diabetes mellitus and monogenic diabetes.1
Both type 1 and 2 diabetes are considered to be polygenic conditions as they are caused by genetic and environmental factors.2
Monogenic diabetes is caused by a single gene mutation, inherited in an autosomal dominant manner, and occasionally caused by a de novo pathogenic mutation.2–5 It is estimated to be about 1%–6% of total diabetes cases in the paediatric age group.1 6–8 It is divided into three main groups: neonatal diabetes, mitochondrial diabetes and MODY.1
Most of the reported cases are in Europe; regrettably, no accurate statistics have been published among other people in East Asia, Africa, the Middle East and South America.9
MODY has 14 known gene variants identified to date; alteration in each gene can produce different forms.1 4 5 8 9
Ninety per cent of MODY cases are due to a gene mutation in hepatocyte nuclear factor 1 alpha (HNF1A) which is type 3 MODY, and the second common gene is glucokinase which is MODY type 2.8–10
Our two siblings were diagnosed as MODY type 10, which is a rare heterozygous INS gene mutation located at chromosome 11p15.5. The underlying pathogenesis is a protein-misfolding disorder causing insulin biosynthesis defect.4 9 11
MODY type 10 is caused by gene mutations affecting beta-cells leading to dysregulation in the INS gene and improper glucose sensing.1 6 10 11 INS-MODY causes beta-cell mass reduction leading to the ongoing loss of insulin secretions, and the varying onset of hyperglycaemia and diabetes commence.9
This explains the increasing insulin requirements for both siblings over time.
INS gene mutation is estimated to be less than 1% of total MODY types.7 It is a well-known cause of a permanent neonatal form of diabetes that typically manifests during the first 6 months of life. Affected patients still have some residual insulin in the body but it is insufficient to sustain the full body requirement.12 13 Our younger sibling had a similar presentation at early infancy.
Patients with MODY present with mild symptoms of hyperglycaemia, polyuria, polydipsia younger than 25 years of age and a history of diabetes in a first-degree family member.9 14 It is infrequent to have gastrointestinal symptoms or diabetic ketoacidosis in this affected group. Besides that, a family history of autosomal dominant diabetes is almost always present.14 15
To differentiate between the three types of diabetes, MODY differs from type 1 diabetes mellitus by the lack of islet cell antibodies and from type 2 diabetes mellitus by absence of the signs of insulin resistance such as obesity, acanthosis nigricans, dyslipidaemia and hypertension.1 5 9 14 Both siblings and their mother were negative for insulin antibodies and had no signs of insulin resistance.
Routine investigations of blood glucose level, HbA1c, islet cell antibodies and C peptide are always done in any patient with diabetes. However, the final diagnostic tool is directed toward gene sequencing.14
A C peptide value of >200 pmol/L denotes some degree of conserved beta-cell function.7
Confirming the final diagnosis of MODY needs genetic testing either by serial single-gene testing, a MODY multigene panel or exome sequencing.15
It is reported that some add-on tests have been used to aid in the diagnosis of MODY, such as high-density lipoprotein level and high-sensitivity C reactive protein, and the body mass index as a biomarker was also used, which all helped in diagnosing HNF1A-MODY.16
The INS gene heterogeneous mutation (c.188-31G>A) was first reported by Garin et al as permanent neonatal diabetes mellitus, in a daughter at infancy and her father who had neonatal diabetes since he was in his 30s. The insulin autoantibodies were negative in both the daughter and her father. They both required insulin therapy.17
This INS gene is one of the rarest types of MODY 10 and is predicted to be pathogenic. In our case, Sanger sequencing of INS exon 3 and the flanking intronic regions to test for the familial mutation (NM_000207.2) resulted in heterozygous INS gene mutation, DNA description c.188-31G>A, protein description p., consequence: Aberrant splicing.
According to the American College of Medical Genetics and Genomics guidelines, the mutation variant is being pathogenic and labelled within the pathogenicity as a very strong category, since the (NM_000207.2) that resulted in heterozygous INS gene mutation demonstrates a damaging effect—as the variant leads to the inclusion of 29 base pairs and an altered reading frame. Also, the in silico analysis, which includes splice predictors and evolutionary conservation, suggests that this variant is pathogenic and may impact on gene splicing causing permanent neonatal diabetes mellitus. Thus, the outcome is expected to be pathogenic, particularly when occurred through altered protein function. Therefore, and as published earlier by Garin et al, the INS gene mutation is pathogenic as it turns the dinucleotide (Y)nGG into (Y)nAG, creating a typical consensus 3’ splice site, as in silico analysis prediction.17 18
Later on, Dusatkova et al published a case report with the same gene mutation beyond the age of 6 months. They reported a daughter who was diagnosed with diabetes as a toddler. Initially requiring insulin for 2 weeks only, she was in a remission until early childhood after which insulin was restarted. Her mother was diagnosed with diabetes mellitus in her middle childhood years; at first she was started on oral hypoglycaemic therapy, then switched to insulin. Both the daughter and her mother had positive auto-insulin antibodies but GAD antibodies were negative.19
Moreover, Matsuno et al identified the INS gene mutation in a mother with her two daughters; the older daughter was found to have diabetes mellitus during her infancy and later her younger sister was diagnosed when she was a toddler. The mother had diabetes mellitus since early childhood. The mother and her two daughters had negative tests for insulin autoantibodies and they required insulin. The mother is receiving MDIs of insulin, while the two daughters are both on insulin pump.20
A summary of our cases and the previously reported cases is shown in table 1.
A summary of our cases with the previously published cases of INS gene mutation c.188-31G>A
| Participants | Age at diagnosis | Autoantibodies | Treatment | |
| Our cases | Older son | Early childhood | Negative | Insulin |
| Younger son | Infancy | Negative | Insulin | |
| Mother | Early childhood | Negative | Insulin | |
| Garin et al 17 | Daughter | Infancy | Negative | Insulin |
| Father | Infancy | Negative | Insulin | |
| Dusatkova et al 19 | Daughter | Toddler | Positive for insulin autoantibodies Negative for GAD |
Initially insulin for 2 weeks (achieved remission until early childhood then required insulin) |
| Mother | Middle childhood | Positive for insulin autoantibodies Negative for GAD |
Initially oral hypoglycaemic therapy then insulin | |
| Matsuno et al 20 | Older daughter | Infancy | Negative | Insulin |
| Younger daughter | Toddler | Negative | Insulin | |
| Mother | Early childhood | Negative | Insulin |
Almost 80% of individuals with MODY have been labelled as type 1 or 2 diabetes mellitus and it was also estimated to have a 15-year lag in confirming the diagnosis as MODY from other diabetes forms.7
The mother of the two siblings was diagnosed as type 1 diabetes mellitus in early childhood and her diagnosis was confirmed as MODY type 10 about 25 years from the initial presentation. The earlier the diagnosis, the better is the outcome for the patient.
Treatment of INS-MODY is variable; some may initially require only diet modifications or oral antidiabetic agents. Yet, eventually, affected individuals will necessitate the use of insulin. Some patients might need only a small dose, which is best provided through an insulin pump similar to our cases.5 8
Learning points
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Paediatric diabetes cases are not always type 1 or type 2 diabetes mellitus. Maturity-onset diabetes of the young (MODY) is rare and variable in the onset and can present during neonatal and childhood phases.
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Genetic testing is the only confirmatory tool to diagnose patients with MODY.
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Knowing the exact type of diabetes will help in providing the precise treatment required.
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Screening other family members of patients with MODY will lead to early diagnosis and proper management.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to extend our appreciation to the Molecular Genetics Laboratory at the University of Exter Medical School for providing the genetic testing for our patients. Also, special thanks to the patient’s mother for her consent.
Footnotes
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Contributors Report was written by FRA. Supervised by HA.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
References
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