CLINICAL BRIEF

Clinical Suspicion of Maturity Onset of Diabetes of the Youngin Pediatric Patients Diagnosed with Diabetes Mellitus

Shruti Chakrabarti Ramesh & Ian Marshall

Received: 10 February 2011 /Accepted: 28 November 2011 /Published online: 10 December 2011# Dr. K C Chaudhuri Foundation 2011

Abstract Type 1 diabetes remains the predominant form ofdiabetes in the pediatric population, while the incidence oftype 2 diabetes has increased, paralleling the increase inobesity. Another form of diabetes, Maturity Onset Diabetesof the Young (MODY), should also be considered especiallyin those whose clinical presentation is atypical for type 1and type 2 diabetes. Although testing for MODY is a chal-lenge, testing in appropriate patients and family membersshould be standard of care. Knowledge of the genetic etiol-ogy of the type of diabetes will enable appropriate treatmentand optimize outcomes, allow more accurate prediction ofdisease progression, as well as allow screening for and thediagnosis of MODY in family members.

Keywords Diabetes mellitus . MODY.Maturity onsetdiabetes of the young . Clinical presentation . Genetic testing

Introduction

While type 1 immune mediated diabetes mellitus continues toaccount for majority of cases of diabetes in the pediatricpopulation, the increased prevalence of obesity has resultedin more adolescents diagnosed with type 2 diabetes. Anotherform of diabetes, called type 1.5 or double diabetes, has beensuggested to occur in a subset of patients with characteristicsof both type 1 and type 2 diabetes [1].

However, these diabetes types do not account for all casesof diabetes in this population. Maturity Onset Diabetes of theYoung (MODY) is proposed to account for 2–5% of all casesof diabetes. [2] A PubMed search revealed multiple articlesdescribing the various MODY types and their respectivegenetic etiologies.

Due to the scarcity of information about the presentationof individuals with MODY in the clinical setting, the authorsdecided to report the clinical presentation of the patients intheir clinic who were suspected of and subsequently diag-nosed with MODY after evaluation for diabetes, or forimpaired fasting glucose or impaired glucose tolerance.

Case Reports

A summary of the clinical and biochemical presentation ofthe 8 patients diagnosed with MODY is illustrated inTable 1.

Only one patient presented with symptoms consistentwith hyperglycemia, with the majority essentially asymp-tomatic. Four patients were referred after glycosuria wasnoted on routine urinalysis performed by their generalphysicians. One patient was screened based on her sister’sdiagnosis of MODY. Another patient had a fasting fingerstick blood glucose tested at home by her mother because ofa 3-mo history of tiredness and lethargy (her mother wasbeing treated for gestational diabetes).

Four patients had a family history of diabetes mellitusnot obviously type 1 or 2. None of the patients had clinicalsigns of insulin resistance. Based on their respective BMIplotted for age and sex, 2 patients plotted in the overweightand 2 in the obese range, with the remainder within thenormal range.

S. C. Ramesh : I. Marshall (*)Division of Pediatric Endocrinology, Department of Pediatrics,UMDNJ-Robert Wood Johnson Medical School,Child Health Institute of New Jersey,89 French Street,New Brunswick, NJ 08901, USAe-mail: marshaia@umdnj.edu

Indian J Pediatr (July 2012) 79(7):955–958DOI 10.1007/s12098-011-0633-4

Tab

le1

Clin

ical

andbiochemical

presentatio

nof

8patientswith

MODY

Case

Age

atpresentatio

n(y)

Ethnicity

Clin

ical

presentatio

nBMIpercentile

forageandsex

Initial

fasting

plasmaglucose

level(m

g/dL

)a

Initial

HbA

1C(normal

<6.5%

)Fam

ilyhistory

ofdiabetes

mellitus,no

tob

viou

slytype

1or

2

MODY

type

111

Mexican

Latino

tiredness

andlethargy

25th

139

6.3

Yes

3

210

Mexican

Latino

nonspecific

abdo

minal

pain

50th

133

9.8

Yes

3

314

Ashkenazi

Jewish

routineurinalysis

10th

172

7.0

No

3

48

Caucasian

ofWestern

Europ

eandescent

routineurinalysis

25th

133

6.2

No

2

57

Caucasian

ofWestern

Europ

eandescent

weigh

tloss,with

questio

nable

polydipsia

andpo

lyuria

85–95

th13

26.5

Yes

2

610

Caucasian

ofWestern

Europ

eandescent

screening(sister,case

5,with

MODY2)

85–95

th110

6.0

Yes

2

714

Caucasian

ofItaliandescent

routineurinalysis

>95

th12

57.1

No

2

814

Caucasian

ofItaliandescent

routineurinalysis

>95

th118

6.9

No

2

ano

rmal

fastingplasmaglucoselevel<10

0mg/dL

;im

paired

fastingglucoselevel10

0–12

5mg/dL

;diabetes

mellitus

≥126

mg/dL

Tab

le2

Genetic

mutations

associated

with

differentMODY

types,clinical

presentatio

n,andtreatm

ent

MODY

type

Genelocus

Genename

Frequ

ency

Onset

ofdiabetes

Severity

ofdiabetes

Riskof

microvascular

disease

Treatment

MODY1

20q

HNF4α

Rare

Ado

lescence

andearlyadulthoo

dSevere

Frequ

ent

Oralhy

poglycem

ics;insulin

MODY2

7pGCK

10–65

%Early

child

hood

Mild

Rare

Dietandexercise

MODY3

12q

TCF1/HNF1α

20–75

%Ado

lescence

andearlyadulthoo

dSevere

Frequ

ent

Oralhy

poglycem

ics;insulin

MODY4

13q

IPF1

Rare

Early

adulthoo

dSevere

Frequ

ent

Oralhy

poglycem

ics;insulin

MODY5

17q

TCF2/HNF1β

Rare

–Severe

Frequ

ent

Insulin

MODY6

2q32

NEUROD1

Rare

Early

adulthoo

dSevere

Frequ

ent

Insulin

956 Indian J Pediatr (July 2012) 79(7):955–958

Fasting plasma glucose levels were elevated in all patients,ranging from 110 to 172 mg/dL, and were consistent witheither impaired fasting hyperglycemia or with diabetes melli-tus. Testing for diabetes autoimmune markers (insulin, isletcell, GAD 65 and IA-2 antibodies) was negative in all thepatients. Genetic analysis forMODYwas performed at AthenaDiagnostics, Worcester, Massachusetts, USA.

Approval was granted by authors’ institution’s IRB andconsent from the patents’ families to collect and publish thisdata.

Discussion

MODY refers to a familial form of monogenic diabetes thatpresents during childhood, adolescence, or early adulthood.It is characterized by abnormal insulin secretory functiondue to inactivating mutations in genes that regulate pancre-atic β-cell function. MODY is typically inherited in anautosomal dominant fashion, although mutations can arisede novo, resulting in spontaneous cases [3].

While 6 types of MODY have been associated with well-characterized single gene mutations (Table 2), a total of 11

types of MODY have been reported. 10–20% of these, whopresent with the classic MODY phenotype, do not demon-strate mutations in any of the known MODY genes [4].

Based on the estimate that MODYaccounts for at least 2–5% of patients diagnosed with diabetes, clinical guidelineshave been suggested for the molecular diagnosis of MODY.[4, 5] These guidelines apply to any individual diagnosedwith either type 1 or type 2 diabetes with atypical featuresfor these disorders, including the following: (1) the clinicaldiagnosis of type 1 diabetes with (a) absence of autoimmunemarkers at the time of diagnosis, (b) evidence of continuedendogenous insulin beyond the honeymoon period, and/or(c) a two or three generation family history of diabetes; (2) ayoung individual with the diagnosis of type 2 diabetes whois (a) not significantly overweight, or (b) lacks the clinicaland biochemical hallmarks of insulin resistance, includingacanthosis nigricans and/or fasting hyperinsulinemia; and(3) the diagnosis of diabetes in (a) 2 or more consecutivegenerations in an autosomal dominant pattern, (b) who areantibody negative at diagnosis, and (c) especially if endog-enous beta cell function is preserved. Figure 1 summarizes aclinical approach to the diagnosis of MODY in the pediatricand general population.

Diagnosis of T1DM in a patient with 1 of the following:

1) absence of diabetes autoimmune markers

2) persistence of pancreatic ß cell function beyond the honeymoon period

3) 2 or 3 generation family history of diabetes

GENETIC TESTING FOR MODY

Diagnosis of T2DM in a patient with 1 of the following:

1) absence of overweight and obesity

2) clinical and/or biochemical features of insulin resistance, including acanthosis nigricans and/or fasting hyperinsulinemia

Consider testing for MODY2 (GCK mutation) in a patient with stable hyperglycemia, presenting in childhood and well controlled with lifestyle changes only

Consider testing for MODY3 (TCF1/HNF1αmutation) in a patient presenting in adolescence and well controlled with sulphonylureas only

Fig. 1 Approach to genetictesting in suspected MODY

Indian J Pediatr (July 2012) 79(7):955–958 957

While MODY patients demonstrate evolution of hyper-glycemia and response to treatment distinct from types 1and 2 diabetes, each MODY type itself is different inpresentation and in therapeutic response (as demonstratedin Table 2). Although a small sample, the present casesreflect published data that MODY types 2 and 3 accountfor majority of cases of MODY, [6] and the presentationis typically in childhood and puberty. [3] Further, whileall patients with MODY2 were well controlled on life-style changes only, those with MODY3 demonstratedexcellent control on a sulphonylurea only.

Various obstacles for MODY testing were identified forboth the patient and for family members. Although occa-sionally there was limited access to family members, themain obstacle was denial of coverage of the costs of thegenetic testing by the health insurance companies. Thereasons for denial provided by these companies includedthat not only MODY was similar to type 2 and not a distinctform of diabetes, but that the genetic testing would not alterthe management of these patients.

Despite these challenges, the authors recommend thatMODY testing in the appropriate setting should be regardedas the standard of care, to enable optimization of treatment

and more accurate prediction of disease progression in thepatient and family.

Conflict of Interest None

Role of Funding Source None

References

1. Purushothaman R, Ramchandani N, Kazachkova I, Ten S.Prevalence and clinical features of type 1.5 diabetes mellitusin children. J Pediatr Endocrinol Metab. 2007;20:981–7.

2. Vaxillaire M, Froguel P. Genetic basis of maturity-onset diabetes ofthe young. Endocrinol Metab Clin North Am. 2006;35:371–84.

3. Rubio-Cabezas O, Argente J. Current insights into the genetic basisof diabetes mellitus in children and adolescents. J Pediatr EndocrinolMetab. 2008;21:917–40.

4. Naylor R, Philipson LH.Who should have genetic testing forMODY?Clin Endocrinol. 2011; doi:10.1111/j.1365-2265.2011.04049.x

5. Murphy R, Ellard S, Hattersley AT. Clinical implications of amolecular genetic classification of monogenic β-cell diabetes. NatClin Pract Endocrinol Metab. 2008;4:200–13.

6. Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharma-cogenetics and relevance to multifactorial forms of type 2 diabetes.Endocr Rev. 2008;29:254–64.

958 Indian J Pediatr (July 2012) 79(7):955–958