Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma

Abstract

Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) – a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

Key Words: Monogenic diabetes; Maturity-onset diabetes of the young; Neonatal diabetes; Mitochondrial diabetes; Insulin resistance syndromes; Genetic testing; Next generation sequencing

Core Tip: Monogenic diabetes forms a spectrum of single gene disorders, characterized by distinct patterns of inheritance, accounting for about 1%–2% of diabetes mellitus burden in the world. Although more than 50 unique genetic mutations associated with these disorders have been identified to date, the diagnosis and management of monogenic diabetes are still inadequate globally because of the poor awareness and professional inertia among physicians. Prompt suspicion and diagnostic evaluation of these disorders are of paramount importance from the management and genetic counselling perspectives. A clinical update review in the World Journal of Diabetes empowers physicians to have a better understanding about this disease.

INTRODUCTION

Monogenic diabetes encompasses a spectrum of clinical disorders resulting from single genetic defects with a distinct pattern of inheritance, constituting about 1%-2% of the global burden of diabetes mellitus (DM)[1,2]. Despite over 50 types of genetic disorders linked to diabetes development, a limited number of patients receive accurate diagnoses and management, highlighting insufficient awareness among clinicians[2,3]. Accounting for over 3% of diabetes cases in young individuals, monogenic diabetes is categorized into maturity-onset diabetes of the young (MODY), neonatal DM (NDM), and rare syndromic forms, based on genetic abnormalities and clinical presentation[3]. Correct diagnoses of these disorders are of paramount importance to ensure proper prognostication, appropriate management, and counseling on inheritance. Identifying the genetic defect is essential for precision medicine in monogenic DM. The adoption of a nomenclature using the standard abbreviation for the pathogenic gene followed by the clinical phenotype (e.g., GCK-MODY and KCNJ11-PNDM) underscores the importance of recognizing genetic defects in defining MODY, NDM, and other monogenic forms of DM.

EPIDEMIOLOGY

Monogenic diabetes is relatively less prevalent than the commonly recognized type 1 DM (T1DM) or type 2 DM (T2DM). Additionally, many cases of monogenic diabetes are mistakenly classified as either T1DM or T2DM, leading to underreporting of its prevalence[4]. MODY, the most frequent form of monogenic diabetes, constitutes 1%-5% of diabetes cases, with varying estimates depending on clinical criteria, population, and testing methods[5-8].

Prevalence from population-based studies

Population-based studies to define the prevalence of monogenic diabetes are few. Data from diabetes registries in the United Kingdom where provisions for centralized genetic testing exist, reveal a prevalence of 2.5% for monogenic diabetes, with the MODY type estimated at 68-108 cases per million population[6]. The estimated prevalence in Australian population is 89 per million for MODY and 45 per million for neonatal diabetes[9].

Registry data

Monogenic diabetes registries of the University of Chicago revealed GCK mutations in 59% followed by HNF1A mutations in 28%. NDM was commonly caused by mutations in KCNJ11 (35%) and INS (16%)[10]. Trends in MODY diagnoses show regional variations, such as increased HNF1A-MODY in Northern Europe and predominant GCK-MODY in Southern Europe[11].

Developing countries

Though data from Asia, Africa and South America is relatively sparse, monogenic diabetes registries have recently been established in several countries of these continents. GCK mutation is again most common, followed by HNF1A mutation in Brazil[12]. The most common varieties identified in a tertiary care center in India were HNF1A-MODY, followed by HNF4A-MODY, ABCC8-MODY, GCK-MODY and HNF1B-MODY[13].

Limitations of population-based screening

Cost-effectiveness studies indicate that testing young adults with a diagnosis of T2DM for the HNF-1A, HNF-4A and GCK, the three common MODY mutations, might be worthwhile[14]. While centralized genetic testing remains the effective strategy, implementing population-based genetic testing poses significant financial challenges, emphasizing the need for increased physician awareness and appropriate screening strategies, particularly in resource-limited settings.

DISEASE SPECTRUM

Monogenic diabetes refers to a group of uncommon forms of diabetes characterized by a single gene defect that affects insulin secretion or action. The frequently encountered groups are MODY and NDM, with several other rare varieties also identified (Table 1).

Table 1 Types of monogenic diabetes and the affected genes.

MODY	NDM	Mitochon-drial DM	Autoimmune monogenic DM	Insulin resistance syndromes	Lipodystrophy
MODY1 -HNF4A	Abnormal pancreatic development	MELAS	IPEX	Type A insulin resistance syndrome	Congenital generalized lipodystrophy
	PLAGL1	DMDF	FOXP3	Donohue and Rabson-Mendenhall syndromes – INSR
	HYMAI	MIDD
	ZFP57	Leigh syndrome SNHL
	PDX1	MM - m.3243A>G
	PTF1A
	PTF1A
	enhancer
	HNF1B
	RFX6
	GATA6
	GLIS3
	NEUROG3
	NEUROD1
	PAX6
MODY2 -GCK	MNX1				CGL1 - AGPAT2
MODY3 - HNF1A	NKX2-2	MELAS; possible atherosclerosis risk - m.3256C>T			CGL2 – BSCL2
MODY4 -PDX1	CNOT1	MMC/MELAS - m.3260A>G			CGL3 – CAV1
MODY5 - HNF1B	ONECUT1	MELAS/DM - m.3271T>C	Autoimmune polyglandular syndrome type 1 -AIRE	SHORT syndrome - PIK3R1	CGL4 - PTRF
MODY6 - NEUROD1	Abnormal beta-cell function	MERRF - m.8344A>G	IPEX-like” phenotype CTLA4	Other genetic abnormalities	Familial partial lipodystrophy
	KCNJ11		IL2RA	AKT2 TBC1D4
	ABCC8		ITCH	PRKCE
	INSC		LRBA
MODY7 -KLF11	GCK		Other autoimmune diabetes		FPLD2 - LMNA
MODY8 -CEL	SCLC2A2 (GLUT2)	MIDD, renal insufficiency - m.9155A>G	STAT1		FPLD3 - PPARG
MODY9 -PAX4	SLC19A2		STAT3		FPLD4 – PLN1
MODY10 -INS	KCNMA1		STAT5B		FPLD5 - CIDEC
MODY11 -BLK	Destruction of beta-cells	DMDF/RP + SNHL - m.12258C>A			FPLD6 - LIPE
	INS
	IER3IP1
	EIF2B1
	YIPF5
MODY12 -ABCC8	Wolcott-Rallison syndrome -EIF2AK3	MM + DMDF/Encephalomyopathy/Dementia + diabetes + ophthalmoplegia - m.14709T>C			FPLD7 – CAV1
MODY13 -KCNJ11	Wolfram syndrome - WFS1
MODY14 -APPL1

MODY: Maturity-onset diabetes of the young; CGL: Congenital generalized lipodystrophy; FPLD: Familial partial lipodystrophy; MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; DMDF: Diabetes mellitus and deafness; MIDD: Mitochondrial diabetes and deafness, MM: Mitochondrial Myopathy; MERRF: Myoclonic epilepsy and ragged red muscle fibers; MMC: Maternal myopathy and cardiomyopathy; RP: Retinitis pigmentosa; SNHL: Sensorineural hearing loss; NDM: Neonatal diabetes mellitus; IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked.

MODY

MODY, the most prevalent form of monogenic diabetes, typically demonstrates autosomal dominant inheritance. Current MODY classification identifies 14 distinct group of genes[15]. The mutations in MODY are diverse and can broadly affect transcription, glucose sensing, protein folding, ion channel function and signal transduction[16].

Most individuals with MODY fall into two phenotypic groups. The first group comprises HNF1A-MODY and HNF4A-MODY, characterized by beta-cell dysfunction with insulin secretory defects, impaired glucose-mediated insulin secretion, initial therapeutic response to low-dose sulfonylurea, gradual progression to insulin dependency, and susceptibility to typical DM complications. In contrast, GCK-MODY is characterized by mild fasting hyperglycemia with preserved insulin secretion. Individuals with GCK mutations typically do not require treatment, except during pregnancy[15,16].

Neonatal diabetes

The next broad group of monogenic diabetes comprise permanent or transient varieties of NDM. NDM is again a heterogenous group of disorders characterized by severe hyperglycemia usually occurring before six months of age. The frequency of NDM is approximately 1 in 90000-160000 live births, and around 80% are identified to have a specific genetic defect[17,18]. Nearly 40 genetic mutations inducing abnormal pancreatic development, beta-cell dysfunction, or beta-cell destruction have been identified in infants with NDM[19].

Permanent NDM is commonly caused by mutation in the K_ATP channel genes and the insulin (INS) genes. Activating mutations in KCNJ11 or ABCC8, coding for the inner subunit (Kir6.2) and the outer subunit (SUR1), respectively, prevent K_ATP channel closure and diminish insulin response to hyperglycemia. Babies with the disease often develop intrauterine growth retardation (IUGR), and are small-for-gestational age. The classic neurological association with KCNJ11 includes developmental delay and epilepsy, and along with NDM, labelled as DEND syndrome, although milder forms with less developmental delay and without epilepsy are more common. Diabetic ketoacidosis is present at diagnosis in 30%-75%, and initial stabilization often requires insulin[18].

Around two-thirds of transient NDM can be attributed to abnormalities in an imprinted region on chromosome 6q24. Severe IUGR is a hallmark, and one-third of these cases exhibit macroglossia. Early-onset, severe but nonketotic hyperglycemia is typically observed within the first week of life. Although the need for insulin or sulfonylurea is short-term, there is a high risk of developing diabetes in the future. The majority of the remaining cases of transient NDM are caused by activating mutations of the KCNJ11 or ABCC8 genes[19].

Other forms of monogenic diabetes

Mitochondrial diabetes, a form of maternally inherited diabetes, commonly arises from MT-TL1 (m.3243A>G) genotype, presenting as maternally inherited diabetes and deafness or mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. Diminished glucose-stimulated insulin secretion results from reduced amount of oxidative phosphorylation due to defects in the tricarboxylic acid cycle and the mitochondrial electron transport chain[20].

Mutations in several immune regulatory genes such as AIRE, CTLA4, FOXP3, IL2RA, ITCH, LRBA, STAT1, STAT3, and STAT5B can lead to early-onset DM including NDM[19]. The prototype disorder is immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome resulting from mutation of FOXP3 gene[21]. Mutations in the INS receptor (INSR) gene cause insulin-resistance syndromes of varying severity, such as Donohue syndrome, Rabson-Mendenhall syndrome, and type A insulin resistance[22]. Single gene mutations are also responsible for generalized and partial lipodystrophies characterized by generalized or localized fat loss, insulin resistance, and youth-onset diabetes[23]. Additionally, rare syndromic forms like Wolcott-Rallison syndrome, characterized by early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation, have been described[24].

SCREENING AND DIAGNOSIS

A universal genetic screening strategy for all early-onset diabetes cases is unfortunately impractical, and identifying eligible candidates is best achieved through a combination of phenotypic and biochemical variables.

MODY

Several deviations from the original diagnostic triad of MODY, based on onset before 25 years of age, autosomal dominant inheritance, and noninsulin-dependent physiology, are now recognized. Given the diversity in clinical features, phenotypic characterization of MODY into homogeneous subgroups for identifying candidates for screening is prudent. A diagnostic algorithm for the three common types of MODY is presented in the Figure 1.

Figure 1 The diagnostic algorithm based on phenotype and biochemical characteristics for testing for maturity-onset diabetes of the young. MODY: Maturity-onset diabetes of the young; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin; OGTT: Oral glucose tolerance test; HDL: High density lipoprotein; hs-CRP: High sensitivity C-reactive protein; GDM: Gestational diabetes mellitus.

NDM

Infants diagnosed with diabetes in the first six months of life should undergo immediate molecular genetic testing. For those diagnosed between 6 and 12 months, genetic testing may be considered, especially if lacking islet autoantibodies or showing features suggestive of a monogenic cause. Genetic diagnosis of NDM provides crucial information on treatment options, associated comorbidities, and the course of diabetes. Genetic testing is indicated in the conditions summarized in Table 2[18,19]. Urine ketones, serum glucose, C-peptide, and insulin estimations, along with a pancreatic ultrasound, should be performed in all cases. Screening for antibodies will not alter the management approach before six months but is recommended for infants between 6 to 12 months. Additionally, congenital anomalies should be ruled out based on their association with genetic anomalies[18].

Table 2 Clinical conditions suggestive of neonatal diabetes mellitus and for ordering genetic analysis.

Rank	Clinical or laboratory context
1	Infant before 6 months of age with plasma glucoses persistently > 250 mg/dL (13.9 mmol/L) without an alternative etiology
2	Hyperglycemia persisting after seven to ten days of birth
3	Infants with extreme hyperglycemia i.e., plasma glucose > 1000 mg/dL (55.6 mmol/L)
4	Infants with diabetes diagnosed between 6 and 12 months, especially in those without islet autoantibodies or who have other features suggestive of a monogenic cause
5	Infants with transient diabetes mellitus1

¹Median age when treatment is not required is 12-14 wk in 6q24 anomalies.

Other monogenic forms of diabetes

Insulin resistance syndromes are characterized by hyperinsulinemia (fasting serum insulin level > 30 μU/mL) accompanied by juvenile-onset glucose intolerance, acanthosis nigricans, hypertrichosis, polycystic ovary, low birth weight, IUGR, and distinctive facial features. The diagnosis is confirmed by abnormalities in the insulin receptor (INSR) or genes related to insulin receptor signaling (PIK3R1, AKT2, TBC1D4, PRKCE)[25]. Maternal transmission, along with bilateral hearing impairment, progressive external ophthalmoplegia, and other organ involvement, are hallmarks of mitochondrial diabetes. The detection of the m.3243A>G mutation in mitochondrial DNA is used for confirmation of this most prevalent variety[26].

MANAGEMENT AND PROGNOSIS

Monogenic diabetes presents a unique opportunity for the application of precision medicine.

MODY

Individuals with GCK-MODY experience mild and stable fasting hyperglycemia, rarely developing chronic complications, and typically require no treatment, except during pregnancy[19]. For those with HNF1A-MODY or HNF4A-MODY, low doses of glibenclamide (or other sulphonylureas) show an excellent glucose-lowering response. A randomized controlled trial demonstrated similar efficacy of liraglutide and glimepiride in HNF1A-MODY, with liraglutide causing less hypoglycemia[27]. HNF1A inhibits sodium–glucose cotransporter 2 (SGLT2) expression in the kidney and causes glycosuria despite near-normal blood glucose levels. Given the effects of HNF1A on SGLT2 expression, caution should be observed in administering SGLT2 inhibitors in HNF1A-MODY[28].

NDM

Approximately 90% of children with K_ATP channel gene mutations can transition from insulin to sulfonylurea tablets, particularly glibenclamide. This switch significantly improves long-term glycemic control with minimal hypoglycemia. The dose requirement is higher compared to T2DM, typically around 0.5 mg/kg/d, occasionally reaching 2.3 mg/kg/d. Insulin requirement often goes down when glycemic control is maintained[19].

Others

Individuals with genetic insulin resistance exhibit a high requirement for insulin, and the administration of metformin and SGLT-2 inhibitors by insulin-independent mechanisms allow for a reduction in insulin dose[25]. Mitochondrial diabetes has its onset around fourth decade and though initially responds to oral agents, the need for insulin arises earlier than in T2DM. Metformin is contraindicated because of the risk of lactic acidosis[19].

WHAT THE REVIEW ADDS TO OUR KNOWLEDGE

A review by Sun and Lin[29] in the recent issue of the World Journal of Diabetes[29], provides us a comprehensive overview of the genetic aspects, diagnosis, and management of monogenetic diabetes. The authors emphasize the challenges in identifying this condition due to its clinical and genetic diversity but highlights the promise of advanced genetic testing methods such as next-generation sequencing (NGS) and machine learning algorithms. The shift towards personalized treatments, including gene-based therapies like CRISPR-Cas9, represents a significant advancement in managing monogenic diabetes. The review discusses breakthroughs in diagnosis, emphasizing the role of targeted gene sequencing, whole-exome sequencing (WES), and NGS. While Sanger sequencing remains crucial, WES has proven effective in identifying novel causal genes, and NGS allows for simultaneous analysis of multiple genes. The incorporation of nanotechnology in diabetes care, particularly in glucose sensing and non-invasive insulin delivery, is also explored. The review underscores that studying monogenic DM has the potential to uncover new gene mutations, understand disease subtypes, and drive precision medicine strategies, signaling a transformative era in pediatric diabetes care.

AREA OF UNCERTAINTY/EMERGING RESEARCH QUESTIONS

Monogenic diabetes research has significantly advanced our understanding of diabetes pathophysiology and the genetics of common diabetes. Notably, it has unveiled heterozygous pathogenic mutations in genes like ABCC8, KCNJ11, INS, HNF1B, GATA4, and GATA6, demonstrating their roles in both MODY and NDM, as well as shaping the risk for type 2 diabetes[30]. The recognition of a potential spectrum for non-autoimmune diabetes challenges traditional distinctions, suggesting a more continuous disease progression. However, uncertainties persist, particularly in the variability of penetrance and expressivity of mutations, emphasizing the need for further research to comprehend the full spectrum of associated diseases[31,32].

While advancements in genetic diagnosis through affordable NGS have enabled precise identification of monogenic diabetes, drug development directly resulting from this research remains elusive. However, induced pluripotent stem cells (iPSCs) generated from monogenic diabetes models is an important breakthrough. By differentiating iPSCs into pancreatic beta-like cells, researchers can delve into disease mechanisms such as impaired insulin secretion or beta-cell dysfunction in a controlled laboratory setting[33]. This understanding can serve as a cornerstone for developing novel treatments, not only for monogenic diabetes but also for advancing personalized medicine approaches in the broader context of type 1 and type 2 diabetes[34].

The current clinical knowledge of monogenic diabetes demands a graded approach to diagnosis, emphasizing the judicious use of genetic methods. Future priorities include developing cost-effective gene screening methods, advancing treatments for monogenic diabetes, and deepening our understanding of pancreatic beta-cell biology with appropriate use of iPSCs generated from monogenic diabetes. Regardless of the successes, continued exploration of genomic medicine and gene-based therapies is crucial to bridge existing knowledge gaps and enhance the quality of life for individuals with monogenic diabetes.

CONCLUSION

Despite significant advancements in understanding the genetic basis of monogenic diabetes, challenges persist in identifying these conditions, leading to misclassification as type 1 or type 2 diabetes. Screening strategies to identify candidates for genetic testing based on phenotype and biochemical parameters are needed. Management strategies tailored to specific genetic defects highlight the opportunities for precision medicine in monogenic diabetes. Ongoing research into advanced genetic testing methods and gene-based therapies fuels optimism for continued progress in our understanding and management of this diverse spectrum of diabetes disorders. The article by Sun and Lin[29] in the Journal issue is a good step towards filling our knowledge gaps of the genetic, diagnostic, and therapeutic landscapes of monogenic diabetes in children.

ACKNOWLEDGEMENTS

We thank Dr. Marina G Kudiyirickal for providing audio clip for the Core Tip of this paper.