The diagnosis and management of monogenic diabetes in children Compiled by Andrew Hattersley, Jan Bruining, Julian Shield &

Pal !olstad "efinition Monogenic diabetes results from the inheritance of a mutation or mutations in a single gene. It may be dominantly or recessively inherited or may be a de novo mutation and hence a spontaneous case. In children, almost all monogenic diabetes results from mutations in genes that regulate beta-cell function although diabetes can rarely occur from mutations resulting in very severe insulin resistance (C) 1. "iagnosis #hy diagnose monogenic diabetes$ The majority of patients with genetically proven monogenic diabetes are initially incorrectly diagnosed as Type 1 or Type 2 diabetes2 (C). It is important to correctly diagnose monogenic diabetes as it can predict the clinical course of the patient, explain other associated clinical features and most importantly guide the most appropriate treatment. In addition, ma ing a diagnosis !ill have implications for other family members often correcting the diagnosis and treatment for other diabetic family members as !ell as allo!ing appropriate genetic counseling. Clinical presentation of monogenic diabetes Clinical presentations in children when a diagnosis of monogenic diabetes should be considered and are discussed below include: 1. eonatal diabetes and diabetes diagnosed within the first ! months of life. 2. "amilial diabetes with an affected parent #. Mild $%.%&'.% mmol(l) fasting hyperglycaemia especially if young or familial *. +iabetes associated with e,tra pancreatic features #hen to suspect a diagnosis of Type % diabetes in children may not be correct$ "eatures in children initially thought to have Type 1 diabetes that should suggest a possible diagnosis of monogenic diabetes are shown below. one of these are absolute and should be considered as together rather than in isolation$C) #. The appro,imate percentage of patients with Type 1 diabetes is given in brac-ets i) ii) iii) . diagnosis of diabetes before ! months $/) $011 Type 1 Iafusco2 2332 42%1* ) "amily history of diabetes with a parent affected $C) $2&*1*) "vidence of endogenous insulin production outside the #honeymoon$ phase (after % years of diabetes) !ith detectable C peptide (&2''nmol(l) !hen glucose & ) mmol(l ("). (1-*+ ,ype 1). -hen pancreatic islet autoantibodies are absent, especially if measured at diagnosis (%-%'+ ,ype 1 patients *-. (C)). ,he great variation in

iv)

antibody prevalence in series probably represents differences in assays and means it is hard to apply published series directly into clinical practice. /bsent antibodies should lead to other investigation(consideration rather than leading directly to genetic tests("), #hen to suspect a diagnosis of Type & diabetes in children may not be correct$ "eatures in children initially thought to have Type 2 diabetes that should suggest a possible diagnosis of monogenic diabetes are shown below. ote most Type 2 diabetes in youth will meet former classification for M5+6 $diagnosed 02%2 autosomal dominant inheritance and non& insulin dependent $C) )-11). /n approximate percentage of children or adolescents !ith ,ype 2 diabetes are given in brac ets i) ii) iii) i) ot mar-edly obese or diabetic family members who are normal weight $231 11) /canthosis nigricans not detected (1'+ ') 7thnic bac-ground from a low prevalence Type 2 diabetes race e.g. 7uropean Caucasian $3&*%1'&11) 0o evidence of insulin resistance !ith fasting C peptide !ithin the normal range ('-2'+)-11)

'a(ing a diagnosis of monogenic diabetes .s well as having clinical features that are unusual for Type 1 and Type 2 diabetes a patient in whom a diagnosis of monogenic diabetes should also have the features of a specific genetic subtype of monogenic diabetes $7). The features of the commoner monogenic diabetes are given below. 8hile in Type 1 and Type 2 diabetes there is no single diagnostic test, this is not the case in monogenic diabetes !here in &)'+ of cases a molecular genetic diagnosis can be made by 10/ testing (C). 2olecular genetic testing is offered in most "uropean countries and the 34/ but many labs !ill test patients from other countries (for example www.diabetesgenes.org and www.mody.no ). ,hese tests are expensive (up to 5*'' ( 67'') but can have a big impact on management of the proband and other family members !ho !ill be cheaper as the mutation is no!n (51'' ( 612'). 4ome recently described monogenic diabetes genes li e 8ir7.2 testing in patients diagnosed less than 7 months may be available as research tests for no charge (see www.diabetesgenes.org). /pproval from the patient$s insurance company should be sought prior to sending 10/ !hen applicable. 9iven the limited resources available it is vital that these tests are used in situations !here they are li ely to be positive and !ill alter clinical care. ,his !ill involve careful clinical selection and performing physiological tests li e C peptide and autoantibody measurement as !ell as testing other family members before doing molecular genetic tests (").

Specific subtypes of monogenic diabetes and their management eonatal diabetes and diabetes diagnosed within the first ) months of life There is good evidence that diabetes diagnosed in the first ! months is not Type 1 diabetes as neither autoantibodies nor an e,cess of high Type 1 9:. susceptibility are found in these patients$/) 12. eonatal diabetes is another area which has rapidly moved from a clinical to a molecular genetic classification 1# 1*. eonatal diabetes is insulin re;uiring diabetes which is usually diagnosed in the first three months of life. Clinically two subgroups were recognised: transient neonatal diabetes mellitus $T +M) that resolved at a median of 12 wee-s and then did not re;uire any treatment although as many as %31 of cases would ultimately relapse $/) 1% 1!< in contrast permanent neonatal diabetes mellitus $= +M) re;uired continual insulin treatment from diagnosis. "or most patients with both types of neonatal diabetes the molecular aetiology can now be defined. The majority of patients with T +M have an abnormality of imprinting of the ZAC and HYMAI genes on chromosome !; $/)1* 1% while the commonest -nown cause of = +M are mutations in the KCNJ11 gene encoding the >ir!.2 subunit of the beta&cell >.T= channel $/)1? 1' . If both parents are glucose intolerant2 homo@ygous or compound hetero@ygous mutations in gluco-inase are most fre;uent 1A 23 "ifferential diagnosis 8hen diabetes is diagnosed in the neonatal period it is difficult to tell if it is li-ely to be transient or permanent although the features in table 1 can help differentiate the possible different subtypes and can be used to guide molecular genetic testing.

Table % Characteristics of "iabetes presenting in the first ) months of life *modified from reference %+,
Bene Clinical syndrome Inheritance D.C(96.MI imprinting defect on !;2* >ir!.2 $>C F11) Cpontaneous dominant $131) 7I"2.># 8olcott& Gallison syndrome recessive "5I=# I=7I syndrome I lin-ed = +M 1* Gare 2'!3 &1.2 !$3&#3) H T +M = +M( T +M umber of cases described 1 in Consanguineous or isolated populations 1%3 rare = +M T +M $131) 133 rare 2.%'3g $&1.?#) !$3&2!3) ormal +evelopmental delay $231) 7pilepsy $!1) +>. $#31) 7piphyseal dysplasia $A31) 5steopenia $%31). acute liver failure $?%1)2 developmental delay $'31)2 hypothyroidism $2%1) 5nly boys affected Chronic diarrhoea with villous atrophy $A%1)< =ancreatic and thyroid autoantibodies $?%1) Thyroiditis $231)2 ec@ema $%31)< anaemia $#31)often die young $1st yr) ormal =arents have fasting hyperglycaemia as hetero@ygotes =arents may have early& onset diabetes as hetero@ygotes Genal developmental disorders Median birth weight $C+C) .ge of diagnosis in wee-s. Median $range) =ancreatic appearance 5ther features

22133g $&2.A*)

3.% $3 E *)

ormal

Macroglossia $2#1)

= +M

#3 A31

1#$!&!%)

.trophy of pancreas $H)2 7,ocrine dysfunction $2%1)

BC> $gluco-inase) recessive I="1 recessive 9 "&1 dominant $!31) spontaneous =T"1. recessive

= +M

! '%1

1?23 &2.?% 21*3 &2.A? 1A33 &#.21

= +M

2 %31

.bsent

T +M

2 Gare

.trophy

= +M

# 1331

1#A3 &#.'

.trophy

Cevere neurological dysfunction and cerebellar

hypoplasia

Transient neonatal diabetes from imprinting anomalies on )-&. Imprinted anomalies of the !;2* locus involving the D.C and 96.MI genes are the most common cause of neonatal diabetes and result in T +M $/)1* 1% 21. The commonest !;2*anomalies are inherited paternal duplications or paternal uniparental disomy although methylation anomalies are being more fre;uently identified $7)1!. +iabetes associated with this is typically diagnosed within the first wee- and resolves around 12 wee-s $/) 1%. In appro,imately %31 of cases diabetes will reoccur during the paediatric age range $/) 1%. .part from macroglossia seen in 2#1 there are no non&pancreatic features $/) 1%. Initial glucose values can be very high $range12&%?mmol(l) and so insulin is used initially although the dose can rapidly be reduced. 5nce patients have relapsed patients should remain under annual follow up due to the ris- of diabetes relapsing. 5n relapse patients are not insulin dependent and can be treated with diet initially although subse;uently often need insulin $7) 1*. The response to oral treatment such as sulphonylureas or metformin is uncertain. Permanent neonatal diabetes, Transient neonatal diabetes and diabetes diagnosed in the first ) months of life due to /ir)0& mutations >ir!.2 mutations are the second commonest cause of mutations in patients with diabetes diagnosed in the first ! months of life $/) 1? 1'. 8hile some $131) have a remitting form of diabetes that may latter relapse the majority have permanent neonatal diabetes $C) 22. Most patients have isolated diabetes although neurological features are seen in 231 of patients. +espite being a hetero@ygous mutation most have no family history as A31 of cases are spontaneous mutations. The most severe defect is very mar-ed developmental delay of motor and social function and generalised epilepsy often with hypsarrhythmia as seen in 8est syndrome $C)1?. This has been called +evelopmental delay2 7pilepsy and eonatal +iabetes $+7 +) syndrome 1'. More common is the intermediate +7 + syndrome where patients have less severe developmental delay and do not have epilepsy 1'. :atients !ith 8ir7.2 mutations have all the clinical features of insulin dependency as %'+ present !ith etoacidosis and they usually do not have detectable C peptide and so !ere treated !ith insulin (C) 1). It has recently been sho!n that these patients can not only be successfully treated !ith oral sulphonylureas but can also get better glycaemic control !ithout an increase in hypoglycaemia. ,he doses needed are high !hen calculated on a per g body !eight basis compared to adults !ith patients typically needing '.*mg( g(glibenclamide(day although some may need as much as 1mg( g(day (C) 2%-2). -ith time many patients have been able to reduce their doses of sulphonylureas but maintain excellent glycaemic control ("). WolcottRallison syndrome 8olcottEGallison syndrome is a rare autosomal recessive condition characterised by early onset diabetes2 epiphyseal dysplasia2 renal impairment2 acute hepatic failure2 and developmental delay $/) 2A #3. It is associated with mutations in EIF2AK3 #1. +iabetes usually presents in infancy2 but may be latter2 and is associated with J cell loss2 leading to insulin deficiency without autoimmune

pathology. Insulin treatment is re;uired. 8olcottEGallison syndrome should be considered in any patient with diabetes in the first # years who has epiphyseal dysplasia or acute severe hepatic failure $C2 7) 2A. 1ther causes of neonatal diabetes In Table 1 the clinical features of other causes of neonatal diabetes are outlined. Ccanning the pancreas to assess if it is present and its si@e2 chec-ing for e,ocrine pancreatic function and pancreatic autoantibodies $found in I=7I syndrome) are the most useful diagnostic tests before proceeding to molecular genetic testing $7). .ll other causes need to be treated with insulin. Come paediatricians consider these patients are easiest managed on subcutaneous insulin pumps. In patients with pancreatic aplasia e,ocrine pancreatic supplements will be re;uired. 2amilial diabetes The commonest causes of familial diabetes or familial hyperglycaemia are shown in the table 2 below:
3nheritance umber of families identified in 4/ 1A? Typical age of presentation in paediatric clinic *range, 1* $*&1') Typical glucose at presentation *range, mmol5l 1? $11&2!) 1ther clinical features

;0<-1

+ominant

*'1"6+,

:arge increment in an 5BTT $2hr &3hr usually K%mmol(l) :ow renal threshold =rogressive hyperglycaemia with age Censitive to sulphonylureas

;0<-=

+ominant

22

1? $%&1')

1% $A&23)

*'1"6%,
9luco inase (2>1?2) +ominant $may not be diagnosed in parents as mild) 1%2 13 $3&1') 11 $%.%&1!)

Cimilar to 9 "&1

but renal threshold normal0

Lsually incidental finding at diagnosis. "asting glucose in range %.%& 'mmol(l Cmall increment in an 5BTT $2hr &3hr usually 0#.%mmol(l) :ittle deterioration in glycaemia with age

Children and young adults with diabetes and a strong family history of diabetes7 hepatocyte nuclear factor % alpha *H 28%, gene mutations *'1"6+,0 The possibility of monogenic diabetes should be considered when ever a parent has diabetes even if they are thought to have Type 1 or Type 2 diabetes $7). The most common form of monogenic diabetes which results in familial diabetes (known in the past as Maturityonset diabetes of the young (MODY)) are H !-" mutations $/) #$% The clinical characteristics of patients with H !-" mutations are: i) 6oung&onset diabetes that shows characteristics of not being insulin&dependent e.g. not developing -etoacidosis in the absence of insulin2 good glycaemic control on a small dose of insulin2 or detectable C&peptide measured when on insulin with glucose K 'mmol(l outside a normally e,pected honeymoon period $# years) $7). "amily history of diabetes. This may be insulin treated and considered to be Mtype 1N diabetes. This would typically be diagnosed in the 23s2 #3s or *3s. There may also be an affected grandparent although often these are diagnosed after *% yrs $C). 5ral glucose tolerance tests in early stages tend to show a very large glucose increment usually K% mmol(l ##. Come subjects may have a normal fasting value but still rise into the diabetic range at 2hrs ## $/). Blycosuria at relatively normal blood glucose levels are often seen as these patients have a low renal threshold $/) ##. Mar-ed sensitivity to sulphonylureas resulting in hypoglycaemia despite poor glycaemic control before starting sulphonylureas$C) #* #%%

ii)

iii)

iv) v)

Treatment &atients with H !-" gene mutations can initially be treated with diet although they will have mar-ed post prandial hyperglycaemia high carbohydrate food as the beta&cell defect results in insufficient increase in insulin secretion with hyperglycaemia#!. Most patients will need pharmacological treatment as they show progressive deterioration in glycaemic control throughout life and are at ris- of considerable micro&vascular and macro& vascular complications$/2C) #?. ,he first treatment to be used in children !ho are not controlled on insulin should be lo! dose sulphonylureas !hich results in a = fold greater lo!ering of glucose than metformin (/) %). ,hese patients are extremely sensitive to sulphonylureas and as long as they do not have problems !ith hypoglycaemia can be maintained on these for many decades (C) %=. 9lycaemic control in sulphonylureas is often better than that achieved on insulin especially in children and young adults %@. ,he dose of sulphonylureas should initially be lo! (A - of the normal starting dose in adults) to avoid hypoglycaemia ("). If there is hypoglycaemia despite dose titration of a once or t!ice daily sulphonylurea preparation such as 9liclaBide a slo! release preparation or meal time doses !ith a short acting agents li e nateglinide may be considered (C) ='.

Children and young adults with diabetes and a strong family history of diabetes7 hepatocyte nuclear factor . alpha *H 28., gene mutations *'1"6%,0 +iabetes due to mutations of the 9 "&* gene are considerably less common *Table &, than diabetes due to mutations of the H 28% gene but has similar characteristics e9cept there is not a low renal threshold and the age of diagnosis may be later *C, =1. ;0<-= mutations should be considered when H 28% se-uencing is negati:e but the clinical features were strongly suggesti:e of H 28% =1. :atients are often sensitive to sulphonylureas (C) =2 1ther causes of familial diabetes . handful of families with autosomal dominant non&insulin dependent diabetes have been described with mutations in I="1 $M5+6*)=%, 0euro11 (2>1?7) == =*and recently the carbo,yl ester lipase $C7:) gene $M5+6?)*! but these are so unusual they do not need to be tested for in children with diabetes e,cept in a research setting $7) or when there are additional phenotypes such as pancreatic e,ocrine dysfunction*!. 'ild fasting hyperglycaemia7 due to gluco(inase mutations *'1"6&, The finding of raised fasting blood glucose in the range of %.% E '.% mmol(l is unusual in children and young adults. This always raises concern that they may be about to develop type 1 diabetes or the patient has Type 2 diabetes. 9owever a considerable proportion of these patients with persistent mild fasting hyperglycaemia will have a hetero@ygous mutation in the gluco-inase gene. The phenotype associated with gluco-inase mutations is remar-ably similar for all mutations. The following features suggest a diagnosis of a gluco-inase mutation:& i) ii) iii) The fasting hyperglycaemia is persistent and stable over a period of months or years## 9b.1c is typically just below or just above the upper limit of normal $%.%&%.?1) In an oral glucose tolerance test the increment $2hr glucose E fasting glucose) is small $typically 0#.% mmol(l) although because of the variability of the oral glucose tolerance test this should not be considered an absolute criteria ##. =arents may have Mtype 2 diabetesN or may not be diabetic. On testing one parent will have a mildly raised fasting blood glucose2 in the range of %.% E '.% mmol(l2 as this is an autosomal dominant condition $C) ##) . Testing of apparently unaffected parents fasting glucose is important when considering a diagnosis of a gluco-inase mutation $7).

iv)

Treatment The fasting hyperglycaemia does not deteriorate significantly and the glucose is regulated at the higher set point ##. This is rarely associated with any microvascular or macrovascular complications even when no treatment is given throughout life $C) *?. .n important point is that these patients do not need treating in the paediatric age range. There is very little if any response to either oral hypoglycaemic agents or insulin $7). 7,ogenous insulin results in reduction of endogenous insulin secretion and so the degree of glycaemia will be

maintained .e,plaining why these children can be treated with insulin without significant hypoglycaemia.

;enetic syndromes associated with diabetes 8hen diabetes in a child is associated with other multi&system disease the possibility of a monogenic syndrome that e,plains all features should be considered. The online Mendelian inheritance in Man $5MIM) website $access through the C/I website http:((www.ncbi.nlm.nih.gov(entre@(;uery.fcgi) can help with clinical features and to -now if the gene has been defined and hence molecular genetic testing is available. "or described and previously undescribed syndromes help can be obtained through the IC=.+ rare diabetes collection $contact through lin- on the IC=.+ web page or through www.diabetesgenes.org ). The most common genetic syndromes which include diabetes are listed below: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness (DIDMOAD) syndrome (Wolfram syndrome) 8olfram syndrome is an autosomal recessive syndrome in which the association of diabetes with progressive optic atrophy under 1! years of age is diagnostic *'. The syndrome is more common in races where consanguineous marriages are fre;uent. 5ther features are bilateral sensorineural deafness2 diabetes insipidus2 dilated renal tracts2 and truncal ata,ia or more protean neurological signs2 with the complete phenotype seen in ?%1 of patients with increasing prevalence with age. The order of appearance of the neurological symptoms may vary even within families. The median age of death in 8olfram syndrome is #3 years *'. Mutations in the gene for 8olfram syndrome $8"C1) are present in at least A31 of patients with clinical 8olfram syndrome *A&%1. The diabetes is non&autoimmune and insulin deficient and presents at a mean age of si, years *'. =atients re;uire insulin treatment from the time of diagnosis but autoantibodies are not present $C) *'. Thiamine responsi e me!aloblastic anaemia (Ro!er"s syndrome) Thiamine responsive megaloblastic anaemia $TGM.) is a rare recessive2 genetic syndrome of early onset megaloblastic anaemia $which responds to thiamine) is associated with diabetes and sensorineural deafness. This results from mutations in the gene C:C1A.2 %2. The diabetes2 which is insulin deficient in nature2 is responsive to thiamine in some patients2 although all seem to develop an insulin re;uirement in the long term $C) %#. +eafness is unresponsive to thiamine. <enal Cysts and "iabetes syndrome due to a Hepatic uclear 2actor %8 mutation .lthough initially described as a subgroup of familial diabetes $M5+6%) it is now clear that patients with mutations in 9 "&1 rarely present with isolated diabetes%*. Genal developmental disorders especially renal cysts and renal dysplasia are present in almost all patients with mutations or gene deletions%%2 may be diagnosed in utero and precede the diagnosis of diabetes $/). 5ther features which may be present in children include uterine and genitalia developmental anomalies2 hyperuricaemia2 gout and abnormal liver function tests%* . diagnosis of 9 "&1 should be considered in any child with diabetes who also has non&diabetic renal disease. =atients with 9 "&1 mutations2 unli-e patients with 9 "&1 mutations2 are not sensitive to sulphonylureas and so usually re;uire insulin treatment%!. =ancreatic si@e is reduced reflecting a reduction in both the endocrine and e,ocrine pancreas and sub&clinical e,ocrine deficiency is present in most patients%? but it is uncertain if this should be treated if it is asymptomatic.

'itochondrial "iabetes Maternal transmission of mutated or deleted mitochondrial + . $mt+ .) can result in maternally inherited diabetes although they are not usually in the paediatric age range. .lthough several mutations and deletions have been implicated2 the strongest evidence relates to a point substitution at nucleotide position #2*# $. to B) in the mitochondrial tG . $leu$LLG)) gene $/) %'. .n identical mutation occurs in the M7:.C syndrome $mitochondrial myopathy2 encephalopathy2 lactic acidosis2 and stro-e&li-e syndrome)< and there may be some overlap between these syndromes in family members. Mitochondrial diabetes is commonly associated with sensorineural deafness and short stature. The diabetes is characterised by progressive non&autoimmune beta&cell failure and may progress to needing insulin treatment rapidly. 3nsulin resistance syndromes7 Type A 3nsulin <esistance, =eprechaunism, <abson8 'endenhall Syndrome and lipodystrophy The -ey feature of all insulin resistance syndromes are acanthosis nigricans2 androgen e,cess and massively raised insulin concentrations in the absence of obesity 1. The more severe the insulin resistance and the earlier the onset the more li-ely is diabetes $C) 1. . summary of some of the -ey clinical features is shown below $adapted from Musso et al 1).
Cyndrome 5nset Clinical features .bnormal facies. :arge genitalia. CB. and growth retardation Garely survive infancy 7,treme Browth retardation .bnormal dentition IG in absence of obesity .canthosis igricans 6es E mar-ed .ndrogen 7,cess O 9ypertrichosis =C5 Insulin levels Bene involved Insulin receptor Lsually Gecessive

:eprechaunism

Congenital

Gabson& Mendenhall

Congenital

6es E mar-ed

=C5

Insulin receptor Lsually Gecessive

Type .

.dolescence

6es E mar-ed

=C5

Insulin receptor Lsually Gecessive

:ipodystrophy

Congenital or .dolescence

:oss of subcutaneous fat E partial or total

6es E may be mar-ed

=C5 P(&

Total: Ceipin O .B=.T2 $recessive) =artial : :amin .C O ==.GB

$dominant)

Treatment of severe insulin resistance is very difficult and most patients with diabetes have poor glycaemic control and fre;uently develop long term complications$C) 1. .pproaches used include the use of the insulin sensitisers metformin and glita@ones but their impact is limited when the insulin resistance is very severe. Insulin is the main stay of treatment and L%33 insulin and insulin pumps are usually re;uired1. In partial lipodystrophy Metformin may have benefit and insulin is not re;uired in the early stages $C) %A. In total lipodystrophy the response of diabetes to recombinant lipodystrophy !3 can be dramatic but is only available on a research basis. Summary 8 when is genetic testing recommended$ .dvances in molecular genetics have led to the identification of the genes associated with many clinically identified subgroups of diabetes. The identification of genes has e,plained clinical heterogeneity in conditions defined on the basis of when they were diagnosed e.g. neonatal diabetes and M5+6. ow molecular genetics is being used as a diagnostic test which can help define the diagnosis and treatment of children with diabetes. .s these tests are e,pensive genetic testing should be limited to those who on clinical grounds are li-ely to be positive.

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