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