Monogenic diabetes: An evidence-based clinical approach

Table 1 Various categories of monogenic diabetes with genes involved in the pathogenesis and the clinical features, with special emphasis on monogenic diabetes other than maturity-onset diabetes of the young and neonatal diabetes mellitus

Types	Subtypes/varieties	Gene/protein	Clinical features	Inheritance
MODY	MODY 1 to 14	See Table 2		See Table 2
Neonatal diabetes	Permanent NDM	See Table 2		See Table 2
	Transient NDM	See Table 2		See Table 2
Other monogenic diabetes with defective insulin synthesis and secretion	Mitochondrial DM	m.3243A > G	Maternally inherited diabetes and deafness	Maternal
	Wolfram syndrome 1 or 2	WFS1 or CISD2	DIDMOAD 1 or 2 diabetes insipidus, diabetes mellitus, optic atrophy and deafness	AR
	Rogers syndrome	SLC19A2	Thiamine-responsive megaloblastic anaemia, deafness, and diabetes	AR
	H or PHID syndrome	SLC29A3	H syndrome: Hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomaly, hearing loss, low height, hypogonadism and hyperglycaemia; PHID syndrome	AR
Monogenic autoimmune diabetes syndromes	IPEX syndrome	FOXP3	IPEX syndrome	XR
		LRBA	Common variable immunodeficiency 8	AR
		STAT3	Infancy-onset multi-system autoimmune disease type 1	AD
	APECED syndrome	AIRE	Autoimmune polyendocrinopathy syndrome type 1	AR
		IL2RA	Immunodeficiency 41 with lymphoproliferation and autoimmunity	AR
	IPEX-like syndrome	STAT1	IPEX-like syndrome	AD
		STAT5B	Growth defect, primary immunodeficiency, and endocrine abnormalities	AR
Insulin resistance syndromes	Congenital generalized lipodystrophy (Seip-Berardinelli syndrome)	AGPAT2	CGL1-acromegalic features	AR
		BSCL2	CGL2-cardiomyopathy, polyneuropathy, mental retardation	AR
		CAV1	CGL3-short stature, pulmonary arterial hypertension, and vitamin D resistance	AR
		PTRF	CGL4-congenital myopathy, pyloric stenosis, cardiomyopathy, atlantoaxial instability	AR
	Partial lipodystrophy	LMNA	FPLD2-fat loss from limbs; fat deposition in face, neck and perineum (Dunnigan variety)	AD
		PPARG	FPLD3-loss of subcutaneous fat from distal extremities	AD
		PLIN1	FPLD4-loss of subcutaneous fat from extremities	AD
		AKT2	AKT2 linked FPLD-loss of subcutaneous fat from extremities	AD
		CIDEC	FPLD5-fat loss of lower limbs and abdomen, and multilocular lipid droplets	AR
		LIPE	FPLD6-upper body pseudo-lipomatosis, fat loss from limbs, and muscle atrophy in some cases	AR
		LMNA	Mandibuloacral dysplasia A syndrome-skeletal anomaly, loss of extremity fat, neuropathy, premature ageing	AR
		ZMPST24	Mandibuloacral dysplasia B syndrome-skeletal anomaly, loss of fat, premature renal failure, progeroid	AR
		PIK3R1	SHORT syndrome	AD
		POLD1	MDPL syndrome	De novo
		WRN	Werner syndrome-progeria and cataract	AR

MODY: Maturity-onset diabetes of the young; DM: Diabetes mellitus; NDM: Neonatal diabetes mellitus; IPEX syndrome: Immuno-dysregulation, polyendocrinopathy, enteropathy, X-linked; PHID: Pigmented hypertrichosis and insulin-dependent diabetes mellitus; APECED: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; DIDMOAD: Diabetes insipidus, diabetes mellitus, optic atrophy and deafness; AD: Autosomal dominant; AR: Autosomal recessive; XR: X-linked recessive; CGL: Congenital generalized lipodystrophy; FPLD: Familial partial lipodystrophy; SHORT: Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly and teething delay; MDPL: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome.

Table 2 Various types of maturity-onset diabetes of the young and neonatal diabetes mellitus with the genes involved in the pathogenesis and the clinical features

	Subtype	Gene	Frequency	Gene-disease	Clinical feature	Inheritance
MODY	MODY 1	HNF4A	14%	Classical MODY	Fetal macrosomia and/or neonatal hypoglycemia, respond to low-dose SU initially, progressive β-cell failure, require insulin later, risks of complications	AD
	MODY 2	GCK	22%		Mild fasting hyperglycemia does not require treatment except during gestation determined by the GCK mutation status of the foetus	AD, rarely AR
	MODY 3	HNF1A	33%		Disproportionate glucosuria (low renal threshold), response to low-dose SU initially, progressive β-cell failure, require insulin later, risks of complications	AD, rarely AR
	MODY 4	IPF1/PDX1	< 1%		A heterozygous mutation causing MODY or T2DM or homozygous mutation causing PNDM (see below)	AD
	MODY 5	HNF1B	6%	Syndromic MODY	Renal cysts and diabetes, pancreas hypoplasia, exocrine insufficiency, β-cell defect, low magnesium, gout, altered LFT, and autism; Require insulin; Risks of complications; 40% are de novo	AD
	MODY 6	NEUROD1	1%	Classical MODY	A heterozygous mutation causing MODY or homozygous mutation causing NDM (not mentioned below)	AD
	MODY 7	KLF11	< 1%	Evidence refuted	Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	MODY 8	CEL	< 1%	Syndromic MODY	Diabetes and pancreatic exocrine dysfunction; Pancreatic cysts may be present	AD
	MODY 9	PAX4	< 1%	Evidence refuted	Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	MODY 10	INS	2%	Classical MODY	Mild defects can present as MODY whereas severe defects can present as TNDM or PNDM (as below), insulin treatment preserves β-cell mass and insulin secretion	AD
	MODY 11	BLK	< 1%	Evidence refuted	Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	MODY 12	ABCC8	4%	Classical MODY	Manifest as relapse following TNDM or as isolated MODY with no history of TNDM, respond to low-dose SU	AD
	MODY 13	KCNJ11	2%		Manifest as relapse following TNDM or as isolated MODY with no history of TNDM, respond to low-dose SU	AD
	MODY 14	APPL1	< 1%	Evidence weak	Delayed onset MODY with low penetrance and less severity; Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	RFX6-MODY	RFX6	< 1%	Classical MODY	Significantly low penetrance; Likely to respond to DPP4 inhibitors or GLP-1 receptor agonists (low GIP levels are present in these patients)	AD
NDM	TNDM 45% NDM	ZAC and HYMAI	70% TNDM	TNDM1	6q24 abnormal uniparental disomy 40%, paternal duplication 40%, maternal hypomethylation 20%, macroglossia, umbilical hernia, cardiac/renal defect, hypothyroidism	Sporadic or AD
		ABCC8	15% TNDM	TNDM2	TNDM (early infancy), remission (early childhood), and/or relapse of diabetes (in adulthood), mild developmental features may be seen, marked response to low-dose SU	Sporadic or AD
		KCNJ11	10% TNDM		TNDM (early infancy), remission (early childhood), and/or relapse of diabetes (in adulthood), mild developmental features may be seen, marked response to low-dose SU	Sporadic or AD
		INS	5% TNDM		IUGR; Doesn’t respond to SU but responds to insulin therapy	AD, rarely AR
		HNF1B			Renal cyst and pancreatic hypoplasia	AD
		SLC2A2			TNDM, PNDM (rare), or Fanconi-Bickel syndrome (Fanconi syndrome, short stature, rickets, growth retardation, hepatomegaly, and glucose/galactose intolerance)	AR
	PNDM 45% NDM	KCNJ11	50% PNDM		DEND (developmental delay, epilepsy, NDM) or iDEND syndrome (mild developmental delay, no epilepsy), severe hyperglycemia, DKA frequent, response to high-dose SU	Sporadic or AD
		INS	30% PNDM		IUGR; Doesn’t respond to SU but responds to insulin therapy	AD
		ABCC8	15% PNDM		DEND (developmental delay, epilepsy, NDM) or iDEND syndrome (mild developmental delay, no epilepsy), severe hyperglycemia, DKA frequent, response to high-dose SU	Sporadic, AD or AR
		GCK	3% PNDM		IUGR; Homozygous mutations causing PNDM requiring lifelong insulin therapy	AR
		IPF1/PDX1	2% PNDM		Pancreatic hypoplasia causing PNDM (homozygous mutation)	AR
		HNF1B			Renal cyst and pancreatic hypoplasia	AD
	Syndromic NDM; 10% NDM	EIF2AK3	Rare		PNDM with spondyloepiphyseal dysplasia, and renal anomalies (Wolcott-Rallison syndrome)	AR
		FOXP3			IPEX syndrome	XR
		GATA4/6			Permanent neonatal diabetes with pancreatic agenesis and congenital heart defects	AD
		RFX6			Neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis, intestinal atresia (Mitchell-Riley syndrome)	AR
		GLIS3			Congenital hypothyroidism, glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay	AR
		PTF1A			Pancreatic and cerebellar hypoplasia	AR

MODY: Maturity-onset diabetes of the young; NDM: Neonatal diabetes mellitus; TNDM: Transient neonatal diabetes mellitus; PNDM: Permanent neonatal diabetes mellitus; AD: Autosomal dominant; AR: Autosomal recessive; XR: X-linked recessive; SU: Sulfonylurea; LFT: Liver function test; T2DM: Type 2 diabetes mellitus; DPP4: Dipeptidyl peptidase-4; GLP: Glucagon-like peptide; IUGR: Intrauterine growth restriction; DEND: Developmental delay, epilepsy, neonatal diabetes mellitus; iDEND: Intermediate developmental delay, epilepsy, and neonatal diabetes syndrome; DKA: Diabetic ketoacidosis; IPEX syndrome: Immuno-dysregulation, polyendocrinopathy, enteropathy, X-linked.

Table 3 Conditions that can be mistaken for monogenic diabetes, the impact of misdiagnosis, and the clinical clues for suspecting appropriate diagnosis

	Stage of life	Misdiagnosis	Clinical clues	Impact of accurate diagnosis on the management plans
HNF1A and HNF4A related diabetes	Neonate and infancy	Congenital hyperinsulinism	Transient neonatal hypoglycaemia (diazoxide discontinued in the first decade in the majority). Progresses to hyperglycemia (usually < 25 years); Association with Fanconi syndrome; Family history of diabetes; Macrosomia independent of glycaemic control (HNF4A-MODY is a more likely cause than HNF1A-MODY)	Treatment with diazoxide; Natural history differs from other causes of congenital hyperinsulinism
	Childhood and adolescence	T1DM	Islet antibodies absent within 3-5 years of diagnosis	Stop insulin; Treat with low-dose sulfonylurea (respond initially); use other antidiabetics as necessary; avoid SGLT2i in HNF1A-MODY
			Diabetic ketoacidosis is usually absent even when omitting insulin; serum C-peptide > 0.6 ng/mL (> 0.2 nmol/L) after 3-5 years of onset; low insulin requirement (< 0.5 U/kg/day)
	Adults	T2DM	Absence of features of insulin resistance; BMI in the normal range	Treat with low dose SU (respond initially); use other antidiabetics as necessary; avoid SGLT2i in HNF1A-MODY; Aim to reduce CVD risk despite normal lipids in HNF1A-MODY
	Pregnancy	GDM	Insulin is recommended therapy, consider additional glyburide if control inadequate, especially in 1st trimester	Treat with insulin, fetal growth surveillance from 26 weeks
GCK related diabetes	Childhood and adolescence	T1DM	Stable nonprogressive mild fasting hyperglycemia; islet antibodies absent within 3-5 years of diagnosis; diabetic ketoacidosis absent on omitting insulin; strong family history	Stop insulin; pharmacological intervention is not needed
	Adults	T2DM	Stable nonprogressive mild fasting hyperglycemia; no features of insulin resistance or obesity; strong family history	Pharmacological intervention is not needed; screening for microvascular and macrovascular complications is not indicated
	Pregnancy	GDM	Stable nonprogressive mild fasting hyperglycemia; Minimal rise in plasma glucose levels after oral glucose or food	Insulin if the fetus does not have the mutation; no treatment if the fetus carries the mutation
Neonatal diabetes mellitus	Neonate and infancy	T1DM	Negative autoantibody testing; Extra-pancreatic features (gastrointestinal anomalies, congenital defects, and neurological disorders); unusual family history; small for gestational age	Should be transitioned to high-dose sulfonylurea from insulin
Mitochondrial diabetes	Adults	T2DM	Maternal inheritance; associated sensorineural hearing loss or progressive external ophthalmoplegia at an early age	Oral antidiabetics; may require insulin later; avoid metformin

MODY: Maturity-onset diabetes of the young; SU: Sulfonylurea; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; BMI: Body mass index; SGLT2i: Sodium-glucose co-transporter-2 inhibitor; GDM: Gestational diabetes mellitus; CVD: Cardiovascular disease.