manual - spedp · cortisol and/or growth hormone, or defects in the meta-bolism of glucose,...

COORDENAÇÃO: Dra. Luísa Barros | Dra. Sandra PaivaDra. Isabel Dinis | Dra. Rita Cardoso

COIMBRA | 21 NOVEMBRO 2019

MANUAL

CURSO TEÓRICO-PRÁTICOPATOLOGIA ENDÓCRINA

NO PRIMEIRO ANO DE VIDA

PARTE 1

ÍNDICE

Diabetes NeoNatal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Dr. Ricardo Capitão

HiperiNsuliNismo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Dra. Ana Laura Fitas

HipotiroiDismo CoNgéNito . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Dra. Brígida Robalo

HipertiroiDismo NeoNatal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Dra. Susana Pacheco

HipoCalCemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Dra. Catarina Diamantino

Hiperplasia CoNgéNita Da suprarreNal . . . . . . . . . . . . . . . 117 Dra. Maria João Oliveira

DeseNvolvimeNto sexual DifereNte . . . . . . . . . . . . . . . . . . 173 Dra. Adriana Lages

3Manual 2019 | Curso TeóriCo-PráTiCo PaTOlOGIa EnDÓCRIna nO PRIMEIRO anO DE VIDa

Diabetes NeonatalRiCARDO CAPitãO

Manual 2019 | Curso TeóriCo-PráTiCo PaTOlOGIa EnDÓCRIna nO PRIMEIRO anO DE VIDa

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23Manual 2019 | Curso TeóriCo-PráTiCo PaTOlOGIa EnDÓCRIna nO PRIMEIRO anO DE VIDa

HiperinsulinismoAnA LAuRA FitAS


HiPerinsulinismo | AnA lAurA FiTAs

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Recommendations from the Pediatric Endocrine Society for Evaluationand Management of Persistent Hypoglycemia in Neonates, Infants,

and ChildrenPaul S. Thornton, MB, BCh1, Charles A. Stanley, MD2, Diva D. De Leon, MD, MSCE2, Deborah Harris, PhD3,

Morey W. Haymond, MD4, Khalid Hussain, MD, MPH5, Lynne L. Levitsky, MD6, Mohammad H. Murad, MD, MPH7,

Paul J. Rozance, MD8, Rebecca A. Simmons, MD9, Mark A. Sperling, MBBS10, David A. Weinstein, MD, MMSc11,

Neil H. White, MD12, and Joseph I. Wolfsdorf, MB, BCh13

During the first 24-48 hours of life, as normal neonatestransition from intrauterine to extrauterine life, theirplasma glucose (PG) concentrations are typically

lower than later in life.1-3 Published guidelines for screeningat-risk newborns andmanaging low PG concentrations in ne-onates focus on the immediate neonatal period, but do notaddress the diagnosis and management of disorders causingrecurrent and prolonged hypoglycemia.4-6 Distinguishingbetween transitional neonatal glucose regulation in normalnewborns and hypoglycemia that persists or occurs for thefirst time beyond the first 3 days of life is important forprompt diagnosis and effective treatment to avoid seriousconsequences, including seizures and permanent braininjury.

Moreover, the evaluation and management of pediatrichypoglycemia differ in several respects from that in adults,for whom guidelines were recently published.7 First, persis-tent hypoglycemiamost often results from a congenital or ge-netic defect in regulating secretion of insulin, deficiency ofcortisol and/or growth hormone, or defects in the meta-bolism of glucose, glycogen, and fatty acids. Second, it maybe difficult to identify and distinguish newborn infantswith a persistent hypoglycemia disorder from those withtransitional low glucose levels in the initial 48 hours of life,as detailed in the separate document on transitional neonatalhypoglycemia prepared by our committee.3 Third, the firstfew months of life are the most vulnerable period for devel-opmental disability, which occurs in �25%-50% of childrenwith congenital hyperinsulinism. Early recognition and treat-ment are crucial for preventing these sequelae.8-10

To address these deficiencies, the Pediatric Endocrine So-ciety convened an expert panel of pediatric endocrinologistsand neonatologists to develop guidelines for managing hypo-glycemia in neonates, infants, and children, but excludingchildren with diabetes. The goals of these guidelines are to

help physicians recognize persistent hypoglycemia disorders,guide their expeditious diagnosis and effective treatment, andprevent brain damage in at-risk babies.

Methods

Evidence Retrieval and RatingThe committee searched for existing evidence synthesis re-ports, systematic reviews, and meta-analyses. The committeealso evaluated guidelines published by the Endocrine Society,American Academy of Pediatrics, Canadian Pediatric Society,and others, and reviewed their bibliographies.4-7 Committeemembers identified additional individual studies.The committee adopted the framework of the Grading of

Recommendations Assessment, Development, and Evalua-tion (GRADE) Working Group,11 in which guideline devel-opers rate their confidence in the evidence as very low(+000), low (++00), moderate (+++0), or high (++++).Randomized trials start as high, and observational studiesstart as low.11

Grading the Strength of RecommendationsThe guideline developers considered the quality of the evi-dence. They also considered the balance between benefitsand harms, patients’ values and preferences, cost andresource utilization, and other societal and contextual fac-tors, such as availability of technology and health servicesand implementation barriers. The recommendations accord-ing to the GRADE framework are either strong (GRADE 1),stated as “we recommend,” or weak (GRADE 2), stated as“we suggest.”

From the 1Division of Endocrinology, Cook Children’s Medical Center, Fort Worth,TX; 2Division of Endocrinology, The Children’s Hospital of Philadelphia, Philadelphia,PA; 3Newborn Intensive Care Unit, Waikato District Health Board, Hamilton, NewZealand; 4Children’s Nutrition Research Center, Texas Children’s Hospital, Houston,TX; 5Department of Endocrinology, Great Ormond Street Hospital for Children NHSFoundation Trust, London, United Kingdom; 6Pediatric Endocrine Unit,Massachusetts General Hospital, Boston, MA; 7Division of Preventive Medicine,MayoClinic, Rochester,MN; 8Division of Neonatology, University of ColoradoSchoolof Medicine, Aurora, CO; 9Division of Neonatology, The Children’s Hospital ofPhiladelphia, Philadelphia, PA; 10Division of Endocrinology, Diabetes andMetabolism, Children’s Hospital of Pittsburgh, Pittsburgh, PA; 11Glycogen StorageDisease Program, University of Florida College of Medicine, Gainesville, FL;12Department of Pediatrics and Medicine, Washington University in St Louis, StLouis, MO; and 13Division of Endocrinology, Boston Children’s Hospital, Boston, MA

The authors declare no conflicts of interest.

0022-3476/Copyright ª 2015 The Authors. Published by Elsevier Inc. This is an open access article

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

http://dx.doi.org/10.1016/j.jpeds.2015.03.057

BOHB Beta-hydroxybutyrate

FFA Free fatty acid

GRADE Grading of Recommendations Assessment, Development,

and Evaluation

GSD Glycogen storage disease

HAAF Hypoglycemia-associated autonomic failure

IV Intravenous

PG Plasma glucose

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Section 1: Which Neonates, Infants, andChildren to Evaluate for Hypoglycemia

1.1. For children who are able to communicate their symp-toms, we recommend evaluation and management only ofthose in whom Whipple’s triad (see below) is documented.GRADE 1++++.

1.2. For infants and younger children who are unable to reli-ably communicate symptoms, we suggest evaluation andmanagement only of those whose PG concentrations aredocumented by laboratory quality assays to be below thenormal threshold for neurogenic responses (<60 mg/dL[3.3 mmol/L]). GRADE 2+++0.

1.3. For those neonates who are suspected to be at high riskof having a persistent hypoglycemia disorder, we suggestevaluation when the infant is $48 hours of age so that theperiod of transitional glucose regulation has passed andpersistent hypoglycemia may be excluded before dischargehome. GRADE 2++00.

Clinical Definition of HypoglycemiaClinical hypoglycemia is defined as a PG concentration lowenough to cause symptoms and/or signs of impaired brainfunction.7 Hypoglycemia may be difficult to recognizebecause the signs and symptoms are nonspecific, and a singlelow PG concentration may be an artifact. For these reasons,guidelines in adults emphasize the value of Whipple’s triadfor confirming hypoglycemia: symptoms and/or signs consis-tent with hypoglycemia, a documented low PG concentra-tion, and relief of signs/symptoms when PG concentrationis restored to normal. Young infants and children oftencannot dependably recognize and/or communicate theirsymptoms, however; therefore, recognition of hypoglycemiamay require confirmation by repeated measurements of PGconcentration and formal testing. Nevertheless, suspectedhypoglycemia should be treated promptly to avoid potentialadverse consequences.

Hypoglycemia cannot be defined as a specific PG concen-tration, because: (1) thresholds for specific brain responses tohypoglycemia occur across a range of PG concentrations, andthese thresholds can be altered by the presence of alternativefuels, such as ketones, and by recent antecedent hypoglyce-mia; (2) it is not possible to identify a single PG value thatcauses brain injury, and the extent of injury is influencedby other factors, such as duration and degree of hypoglyce-mia; and (3) potential artifacts and technical factors thatlead to inaccuracies in glucose determinationmay complicatethe interpretation of any single PG value.

Symptoms of HypoglycemiaThe symptoms of hypoglycemia reflect responses of the brainto glucose deprivation and have been well delineated inadults.12 Neurogenic (autonomic) symptoms result fromthe perception of physiological changes caused by the sympa-thetic nervous discharge triggered by hypoglycemia; these

include adrenergic responses (eg, palpitations, tremor,anxiety) and cholinergic responses (eg, sweating, hunger,paresthesias). Neuroglycopenic signs and symptoms,including confusion, coma, and seizures, are caused by braindysfunction resulting from a deficient glucose supply to sus-tain brain energy metabolism. Awareness of hypoglycemiadepends chiefly on perception of the central and peripheraleffects of neurogenic (as opposed to neuroglycopenic) re-sponses to hypoglycemia. Brain glucose utilization becomeslimited at a PG concentration of approximately 55-65 mg/dL (3.0-3.6 mmol/L).12 Neurogenic symptoms are perceivedat a PG concentration <55 mg/dL (<3.0 mmol/L), which inolder children and adults triggers a search for food or assis-tance, an important defense against hypoglycemia. Cognitivefunction is impaired (neuroglycopenia) at a PG concentra-tion <50 mg/dL (<2.8 mmol/L).

Glucose UtilizationThe adult brain accounts for more than one-half of totalglucose consumption. Because of their disproportionatelylarger brain size relative to body mass, infants and youngchildren have a 2- to 3-fold higher glucose utilization rate(4-6 mg/kg/min) per kilogram of body weight comparedwith adults.13 Although the brain has an obligate requirementfor glucose, it also can use plasma ketones and lactate asenergy sources if the concentrations of these substances aresufficiently elevated.14 However, in hypoketotic conditions,such as hyperinsulinism or fatty acid oxidation disorders,ketones and lactate are not available in sufficiently highconcentrations to substitute for glucose, and the risk of brainenergy failure is greater.

Neuroendocrine Defenses against HypoglycemiaIn normal individuals, the maintenance of normal PGconcentrations is highly protected. The first defense is sup-pression of insulin secretion when PG concentration fallsbelow the normal postabsorptive mean of �85 mg/dL(4.9 mmol/L).15 A further reduction of PG to 65-70 mg/dL(3.6-3.9 mmol/L) elicits glucagon secretion and activationof the sympathoadrenal system (reflected by increasedepinephrine concentration), which increases glucose releasefrom liver glycogen stores to raise the PG concentration. Ata PG concentration <65 mg/dL (3.6 mmol/L), levels ofplasma cortisol and growth hormone, important for mainte-nance of glucose during prolonged fasting, increase as well.Because the brain has only a few minutes worth of storedfuel reserves in the form of glycogen,12 interruption ofglucose delivery can have devastating consequences. Whereasrecovery from brief periods of hypoglycemia is usuallycomplete, severe and prolonged hypoglycemia can causepermanent brain injury.8-10,16

Metabolic Defenses against HypoglycemiaIn the postabsorptive phase, the liver supplies the brainand other tissues with glucose by releasing glucose fromthe breakdown of stored glycogen and by gluconeogenesis,principally from gluconeogenic amino acids, such as

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alanine, and recycled lactate. With longer fasting andfurther suppression of insulin secretion, glucose utilizationis restricted to the brain and a few glycolytic tissues, suchas erythrocytes. Adipose tissue lipolysis releases glycerol, agluconeogenic substrate, and free fatty acids (FFAs) thatcan replace glucose as an energy substrate in skeletal andheart muscle, but not in brain. FFAs are also convertedby the liver to beta-hydroxybutyrate (BOHB) and acetoa-cetate for use by the brain. BOHB is the predominant ke-toacid, and its plasma level serves as a measure ofketogenesis. As ketoacid concentrations rise, they canpartly support the brain’s energy needs. The changes infuel metabolism during fasting in normal neonates after2-3 days of age and in infants and children do not differsubstantially from those in adults, except that PG concen-trations decrease more rapidly and hyperketonemia de-velops sooner, because of the energy needs of theirrelatively larger brains.17 Measurement of BOHB, FFA,and lactate at the time of hypoglycemia provides impor-tant information for diagnosing the cause of hypoglycemia(Figure).

Altered Hypoglycemia AwarenessPrevious exposure to an episode of hypoglycemia can blunt,and repeated episodes can eliminate, neurogenic responsesto subsequent hypoglycemic episodes.18 This leads toreduced or absent awareness of hypoglycemia and impairs

hepatic glucose release, perpetuating hypoglycemia. Thiscombination of events has been termed hypoglycemia-associated autonomic failure (HAAF).18 HAAF can persistfor >24 hours after a single episode of hypoglycemia oreven longer after repeated episodes of hypoglycemia. Asimilar impairment in neuroendocrine responses to hypo-glycemia also occurs during sleep and exercise.18 Thus,exposure to recurrent hypoglycemia can shift the usualglucose threshold for recognition of neurogenic symptomsof 55 mg/dL (3.0 mmol/L) to a lower level. Although previ-ous exposure to hypoglycemia lowers the glucose thresholdfor neurogenic responses, the threshold for neuroglycopenicsymptoms is not altered acutely; whether adaptation occurswith repeated exposure to hypoglycemia is unknown. Fea-tures of HAAF have been demonstrated in infants as youngas age 10-13 weeks.19

Potential Artifacts in Measurements of PGConcentrationTo diagnose hypoglycemia, PG concentration should bemeasured using a clinical laboratory method.12 Importantconsiderations are that whole blood glucose values are�15% lower than PG concentrations, and that because ofred cell glycolysis, delays in processing and assaying glucosecan reduce the glucose concentration by up to 6 mg/dL/hour (0.3 mmol/L/hour). Point-of-care meters provide aconvenient screening method for detecting hypoglycemia,

Metabolic Clues to Hypoglycemia DiagnosisHypoglycemia

HCO3, BOHB , Lactate, FFA

No AcidemiaAcidemia

BOHB↓FFA ↑

OHB

Acidem

BOHB

Gluconeogenesis Defects

Fa y Acid Oxida on Defects

Gene c HyperinsulinismHypopituitarism in newborns

Transi onal Neonatal HypoglycemiaPerinatal Stress Hyperinsulinism

BOHB↑BOHB↓FFA ↓

Lactate ↑

Keto c HypoglycemiaGlycogenoses GH deciency

Cor sol deciency

Figure. Algorithm showing how the major categories of hypoglycemia can be determined with information from the criticalsample. GH, growth hormone.

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 167, No. 2

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but their accuracy is limited to approximately�10-15 mg/dL(0.6-0.8 mmol/L) in the range of hypoglycemia. Therefore,before establishing a diagnosis of hypoglycemia in neonates,infants, and children, it is essential to confirm low PG con-centration using a clinical laboratory method.

Normal PG Concentrations in Neonates Aged >48Hours, Infants, and ChildrenAfter the first 48 hours of life, PG concentration and thephysiology of glucose homeostasis do not differ to any greatextent with age. Mean PG concentration in the postabsorp-tive state in normal neonates after �2 days of age and ininfants and children does not differ from that in adults(70-100 mg/dL [3.9-5.5 mmol/L])17,20,21; however, childrenunder age 4 years may have a PG concentration <70 mg/dL(3.9 mmol/L) and hyperketonemia after overnight fastingbecause of limited fasting tolerance.17,20,21 Other evidencethat the normal PG concentration in children does not differfrom that in adults include the following: (1) fasting hyper-ketonemia develops at a similar PG concentration in infants,children, and adults21,22 (hyperketonemia does not occurduring transitional neonatal hypoglycemia in normal new-borns in the first 1-2 days of life3); (2) plasma lactate risesas PG falls below �70 mg/dL (�3.9 mmol/L) in childrenwith glucose-6-phosphatase deficiency23; and (3) lethargyand tachycardia are observed in patients with defects of fattyacid oxidation when PG decreases to 60-70 mg/dL (3.3-3.9 mmol/L).

PG Concentrations in Neonates Aged <48 HoursIn normal newborn infants, PG concentration commonly de-creases immediately after birth to levels below those in olderinfants and children. The interpretation and response to PGconcentration during the first 2 days of life have been contro-versial.24Whether the brain of newborn infants has greater orlesser susceptibility to hypoglycemic injury is controversial aswell.25,26 As discussed previously,3 the committee’s review ofavailable data on transitional neonatal hypoglycemia innormal newborns (ie, hypoketonemic hypoglycemia withinappropriately large glycemic responses to glucagon or

epinephrine stimulation) suggests that it is a mild and tran-sient form of hyperinsulinism in which the mean PGthreshold for suppression of insulin secretion is �55-65 mg/dL (3.0-3.6 mmol/L) shortly after birth, comparedwith �80-85 mg/dL (4.4-4.7 mmol/L) in older infants, chil-dren, and adults. As the glucose stimulated-insulin secretionmechanismmatures, mean PG concentration in normal new-borns increases and by 72 hours of age is similar to those inolder infants and children1,2; therefore, the standards fornormal neonates must never be extrapolated beyond2-3 days after birth. Because of the difficulty in distinguishinga suspected persistent hypoglycemia disorder from transi-tional neonatal glucose concentrations during the first48 hours of life, we suggest delaying diagnostic evaluationsuntil 2-3 days after birth.

Neonates Aged >48 Hours Who May Be at Risk forPersistent Hypoglycemia DisordersSome neonates can be identified by various clinical features asbeing at high risk for severe hypoglycemia during the first48 hours after delivery,16,26 and a subset of those neonatesare also at increased risk for persistent hypoglycemia beyond48 hours of life (Table).27-30 These include not only the rareinfants with genetic hypoglycemia disorders, such ascongenital hyperinsulinism or hypopituitarism,31 but alsothose with relatively more common prolonged neonatalhyperinsulinism (also referred to as perinatal stresshyperinsulinism) associated with birth asphyxia,intrauterine growth restriction, or toxemia.27,28,30

To provide a practical guide and in the light of scarce ev-idence in this area, the committee used a consensus processto make the following technical suggestions:For neonates with a known risk of a genetic or other persis-

tent form of hypoglycemia (eg, congenital hyperinsulinism,glucose-6-phosphatase deficiency, fatty acid oxidation disor-der), consultation with a specialist should be consideredbefore planning discharge from the nursery. Diagnostic testsmay be available to exclude the possibility of a specific disor-der within a few weeks (eg, genetic mutation analysis, plasmaacyl-carnitine profile). In these cases, a “safety” fasting test

Table. Recognizing and managing neonates at increased risk for a persistent hypoglycemia disorder

Neonates at increased risk of hypoglycemia and require glucose screening:1. Symptoms of hypoglycemia2. Large for gestational age (even without maternal diabetes)3. Perinatal stress

a. Birth asphyxia/ischemia; cesarean delivery for fetal distressb. Maternal preeclampsia/eclampsia or hypertensionc. Intrauterine growth restriction (small for gestational age)d. Meconium aspiration syndrome, erythroblastosis fetalis, polycythemia, hypothermia

4. Premature or postmature delivery5. Infant of diabetic mother6. Family history of a genetic form of hypoglycemia7. Congenital syndromes (eg, Beckwith-Wiedemann), abnormal physical features (eg, midline facial malformations, microphallus)Neonates in whom to exclude persistent hypoglycemia before discharge:1. Severe hypoglycemia (eg, episode of symptomatic hypoglycemia or need for IV dextrose to treat hypoglycemia)2. Inability to consistently maintain preprandial PG concentration >50 mg/dL up to 48 hours of age and >60 mg/dL after 48 hours of age3. Family history of a genetic form of hypoglycemia4. Congenital syndromes (eg, Beckwith-Wiedemann), abnormal physical features (eg, midline facial malformations, microphallus)

August 2015 MEDICAL PROGRESS

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia inNeonates, Infants, and Children

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should be done before discharge from the nursery to ensurethat PG concentration can be maintained above 70 mg/dLif a feeding is missed (ie, a minimum of 6-8 hours). If nodefinitive test is available (which is often the case with hyper-insulinism), then the fasting test should be extended toexclude diagnostic features of the suspected disorderfollowing the paradigm shown in the Figure.

For at-risk neonates without a suspected persistent hypo-glycemia disorder and in whom hypoglycemia is consideredlikely to resolve within a short time, a “safety” fastof 6-8 hours should be considered before discharge, todetermine whether a PG concentration >60 mg/dL can bemaintained, or whether additional management or investiga-tions may be required.

ValuesHypoglycemia disorders in older infants and children are un-common. Thus, the recommendation to require the presenceof Whipple’s triad before undertaking an evaluation avoidsexposing patients without a specific disorder to unnecessaryprocedures, potential risks, and expense without any likelybenefit. For neonates, infants, and younger children inwhomWhipple’s triad cannot be applied, unnecessary inves-tigation can be avoided by confirming a PG concentration ator below the range at which neurogenic symptoms usuallyoccur. The recommendations regarding which neonates toevaluate for hypoglycemia focus on those high-risk neonateswho require close monitoring and/or intervention, such asintravenous (IV) dextrose, for treatment of hypoglycemia(Table). They take into account that transitionalhypoglycemia in normal newborns should be completelyresolved before the usual time for discharge from thenursery at 2-3 days. The committee emphasizes thenecessity of carefully excluding persistent hypoglycemiadisorders before discharge to home in the small subset ofhigh-risk neonates (Table) to ensure recognition andfacilitate treatment.

Section 2. Workup/Investigation ofPersistent Hypoglycemia

2.1. We recommend that investigations be carried out to di-agnose the underlying mechanism of persistent hypoglyce-mia disorders to provide specific management. GRADE1++++.

In patients with hypoglycemia, a thorough history shouldinclude the episode’s timing and its relationship to food,birth weight, gestational age, and family history. Physical ex-amination should include looking for evidence of hypopitu-itarism (eg, micropenis or cleft lip or palate, short stature),glycogenosis (eg, hepatomegaly), adrenal insufficiency (eg,recurrent abdominal pain, hyperpigmentation, anorexia,weight loss), or Beckwith-Wiedemann syndrome (eg, om-phalocele, hemihypertrophy, macroglossia).

Whenever possible, specimens (a “critical sample”) foridentifying the etiology of hypoglycemia should be obtainedat the time of spontaneous presentation and before treatment

that may rapidly alter the levels of BOHB, FFA, and insulin.Assays for PG, bicarbonate, BOHB, and lactate are readilyavailable and useful for distinguishing categories of hypogly-cemia disorders (Figure). Extra plasma can be held in reservefor specific tests (eg, plasma insulin, FFA, and C-peptide forsuspected hyperinsulinism; plasma total and free carnitineand acyl-carnitine profile for a suspected disorder of fattyacid oxidation). Laboratory reference ranges for some ofthese tests (eg, insulin, BOHB) may be inappropriatefor interpreting values obtained during childhoodhypoglycemia.In the absence of a “critical sample,” a provocative fasting

test is the most informative method for identifying the etiol-ogy of hypoglycemia disorders.20,32 The duration of fastingand the specimens obtained should be tailored to the sus-pected diagnosis. With few exceptions, blood tests performedwhile glucose concentrations are normal are not informative.For safety, a fasting test should be done with frequent moni-toring of vital signs, PG, and BOHB concentrations. A PGconcentration of 50 mg/dL (2.8 mmol/L) is sufficiently lowto elicit the metabolic and neuroendocrine responsesrequired for diagnosis. After appropriate specimens havebeen obtained, the fast may be terminated. The fast alsocan be stopped earlier for signs or symptoms of distress ora plasma BOHB measurement of >2.5 mmol/L.For suspected hyperinsulinism, the fasting test can be

terminated when the PG concentration is <50 mg/dL(<2.8 mmol/L) with administration of glucagon (1 mg IV,intramuscularly, or subcutaneously) to evaluate the glycemicresponse. An exaggerated glycemic response (>30 mg/dL[>1.7 mmol/L]) is nearly pathognomonic of hyperinsulin-ism.33 Because plasma insulin concentration is sometimesnot above the lower limit of detection,34 it is important toinclude the following tests when assessing the possibility ofhypoglycemia due to hyperinsulinism: plasma BOHB andFFA (both inappropriately low; BOHB <1.5 mmol/L[<15 mg/dL] and FFA <1.0-1.5 mmol/L [<28-42 mg/dL]),and an increased glycemic response to glucagon. Based onthe suspected diagnosis, additional tests performed on spec-imens obtained at the time that fasting is terminated shouldbe considered, such as growth hormone, cortisol, total andfree carnitine, acyl-carnitine profile, C-peptide, proinsulin,and drug screening.Adrenal insufficiency, congenital or acquired, may mani-

fest with hypoglycemia. Simultaneous measurement ofplasma adrenocorticotropic hormone and cortisol is recom-mended if primary adrenal insufficiency is suspected. An ad-renocorticotropic hormone stimulation test may be neededto confirm suspected secondary or tertiary adrenal insuffi-ciency.The possibility of drug administration (accidental or sur-

reptitious) or a toxin may need to be considered. Specimensof plasma and urine obtained at the time of an acute episodemay be informative. High plasma insulin level but lowC-peptide level during hypoglycemia suggest exogenous in-sulin administration. The drugs most commonly associatedwith hypoglycemia include insulin, sulphonylureas, alcohol,


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beta-blockers, and salicylates. Not all commercially availableinsulin assays measure the insulin analogues; thus, thefinding of low insulin and C-peptide levels at time of hypo-glycemia might not rule out surreptitious insulin administra-tion. (Consultation with the testing laboratory should beconsidered if clinical suspicion is high.)

Postprandial hypoglycemia in infants and children is usu-ally a complication of fundoplication for gastroesophagealreflux (incidence 25%-30%) or gastric bypass bariatric sur-gery for morbid obesity. In these patients, a meal may triggerhypoglycemia 1-3 hours later. Postprandial hypoglycemia isoften preceded by exaggerated glucose, glucagon-like pep-tide-1, and insulin responses, which can be detected on anoral glucose or mixed-meal tolerance test.35

ValuesFailure to investigate a neonate, infant, or child with sus-pected hypoglycemia increases the risk of delaying a defini-tive diagnosis and instituting effective treatment.Expeditiously identifying the specific cause of hypoglycemia,as outlined above, will enable prompt institution of appro-priate treatment and decrease the risk of permanent braininjury from persistent and recurrent severe hypoglycemia.The decision to subject an infant or child to a diagnosticinvestigation for suspected hypoglycemia, which includes amonitored assessment of fasting adaptation that may exposethe patient to the risk of another episode of hypoglycemia,places a higher value on achieving diagnostic certainty anda lower value on avoiding the discomfort, inconvenience,and cost of such procedures.

Section 3. Management of Neonates, Infants,and Children with a Persistent HypoglycemiaDisorder

3.1. For neonates with a suspected congenital hypoglycemiadisorder and older infants and children with a confirmed hy-poglycemia disorder, we recommend that the goal of treat-ment be to maintain a PG concentration >70 mg/dL(3.9 mmol/L). GRADE 1++00.

3.2. For high-risk neonates without a suspected congenitalhypoglycemia disorder, we suggest the goal of treatment beto maintain a PG concentration >50 mg/dL (>2.8 mmol/L)for those aged <48 hours and >60 mg/dL (>3.3 mmol/L)for those aged >48 hours. GRADE 2+000.

3.3. We recommend an individualized approach to man-agement with treatment tailored to the specific disorder, tak-ing into account patient safety and family preferences.Ungraded best practice statement.

Neonates, Infants, and Children with HypoglycemiaDisordersNeurogenic and neuroglycopenic symptoms usually occurwhen the PG concentration decreases to 50-70 mg/dL(2.8-3.9 mmol/L). Recurrent PG levels in this range may

result in the development of HAAF, which increases therisk of subsequent hypoglycemia and attenuates its recogni-tion.7,36 Therefore, treatment targets are generally aimed atavoiding activation of neuroendocrine responses andHAAF by maintaining PG concentration within the normalrange of 70-100 mg/dL (3.9-5.6 mmol/L).7 For this reason,we recommend that the same goal for treatment of adultsand children with diabetes (ie, PG >70 mg/dL [>3.9 mmol/L]) be used for neonates with a confirmed hypoglycemia dis-order and for infants and children with a persistent hypogly-cemia disorder.For disorders such as hyperinsulinism, the aim is to pre-

vent recurrent hypoglycemia that increases the risk of subse-quent, possibly unrecognized, hypoglycemic episodes. Fordisorders such as defects in glycogen metabolism and gluco-neogenesis, maintenance of PG concentration in the normalrange prevents metabolic acidosis and growth failure, andpossibly the development of long-term complications.Any episode of severe symptomatic hypoglycemia should

be rapidly corrected with IV dextrose infusion. The initialdose is 200 mg/kg, followed by infusion of 10% dextrose ata maintenance rate for age. In cases of hyperinsulinism,glucagon can be expected to raise PG concentration tonormal or above within 10-15 minutes and to maintainthat concentration for at least 1 hour. Doses of 0.5-1.0 mg(independent of weight), given IV, intramuscularly, or sub-cutaneously, are usually effective; lower doses (0.03 mg/kg)may carry less risk of transient nausea and vomiting, butmay be ineffective unless given IV.Long-term therapy for hypoglycemia disorders should be

based on the specific etiology of the disorder, in consultationwith a physician experienced in the diagnosis and manage-ment of hypoglycemia in infants and children and with care-ful consideration of patient and family preferences.Medications are available for some disorders, such as hyper-insulinism, and for cortisol and growth hormone deficiency.Surgery may be necessary in some children with hyperinsu-linism who are unable to maintain PG concentration in asafe range through medical therapy. Nutritional therapy isthe cornerstone of treatment for some disorders, such as dis-orders of glycogen metabolism or hereditary fructose intoler-ance. Some milder disorders may be treated adequately byavoidance of prolonged fasting. Patients diagnosed withketotic hypoglycemia who have recurrent episodes shouldbe reevaluated for other specific disorders, such as glycogensynthase deficiency (GSD 0), GSD type VI, GSD type IX(especially in males), and MCT1 gene deficiency.37,38

Nonspecific treatment with glucocorticoids for neonateswith hypoglycemia is discouraged.

High-Risk Neonates without a SuspectedCongenital Hypoglycemia DisorderThe mean PG concentration in normal newborns during thefirst hours after birth (�55-60 mg/dL [�3 mmol/L]) issimilar to the threshold for neurogenic symptoms of hypo-glycemia in older children and adults, but above thethreshold for neuroglycopenic symptoms. This appears to



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be tolerated during the first few hours after birth. In normalnewborns, the mean PG concentration rises to >70 mg/dL(3.9 mmol/L) after 48 hours of age.1 This is similar to themean glucose concentration in older children and adults.There is no evidence that the concentration at which PG be-comes limiting for brain function is different in neonatesthan in older children and adults. Of concern, as noted pre-viously,3 plasma ketone levels are suppressed during hypogly-cemia in high-risk neonates, making them particularlyvulnerable to hypoglycemia-induced brain damage, andthere is no assurance the plasma lactate level will be suffi-ciently elevated to compensate for low glucose.27,28,30,39

Given the absence of evidence on the short-term or long-term consequences of different treatment targets, the com-mittee focused on evidence related to physiology, etiology,and mechanism, and balanced the risks and benefits of in-terventions. The committee also focused on postnatal age,because ongoing hypoglycemia beyond the first 48 hoursof life (and particularly beyond the first week) increasesthe concern for an underlying hypoglycemia disorder,such as prolonged neonatal hyperinsulinism,30 or a geneticdisorder. The committee’s consensus was that during thefirst 48 hours of life, for a high-risk neonate without a sus-pected congenital hypoglycemia disorder and on normalfeedings, a safe target PG concentration should be close tothe mean for healthy newborns on the first day of life andabove the threshold for neuroglycopenic symptoms(>50 mg/dL [2.8 mmol/L]). The committee recommendedraising the glucose target after 48 hours of age (>60 mg/dL [3.3 mmol/L]) to above the threshold for neurogenicsymptoms and close to the target for older infants and chil-dren, because of the increased concern for an underlyinghypoglycemia disorder. The suggested target glucose con-centrations were considered adequate while assessingwhether hypoglycemia will resolve over time. Because at-risk neonates who require interventions beyond normalfeedings, such as IV dextrose, to treat hypoglycemia in thefirst 48 hours of life are likely to have more severe and pro-longed hypoglycemia, the initial treatment target should beabove the thresholds for both neurogenic and neuroglyco-penic symptoms (>60 mg/dL [3.3 mmol/L]). For neonateswho require dextrose infusion, transitioning to normalfeedings alone can be attempted once PG concentration isstabilized at >60 mg/dL (>3.3 mmol/L).

The committee’s consensus to accept a lower PG target inhigh-risk neonates without a suspected congenital hypogly-cemia disorder (Section 3.2) than in those with a suspectedcongenital hypoglycemia disorder (Section 3.1) was basedon balancing the risks of intervention compared with a briefperiod of undertreatment in this group. Higher treatmenttargets (Section 3.1) should be considered for those with asuspected genetic hypoglycemia disorder and for symptom-atic neonates, because the risks of undertreatment outweighthose of overtreatment in these patients. n

Submitted for publication Aug 8, 2014; last revision received Mar 3, 2015;

accepted Mar 31, 2015.

Reprint requests: Paul S. Thornton,MD, Cook Children’s Medical Center, 1500

Cooper St, Second Floor, Fort Worth, TX 76104. E-mail: Paul.thornton@

cookchildrens.org

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32

R E S E A R CH R E V I EW

Congenital hyperinsulinism disorders: Genetic and clinicalcharacteristics

Elizabeth Rosenfeld1 | Arupa Ganguly2 | Diva D. De Leon1,3

1Division of Endocrinology and Diabetes, The

Children's Hospital of Philadelphia,

Philadelphia, Pennsylvania

2Department of Genetics, The Perelman

School of Medicine at the University of

Pennsylvania, Philadelphia, Pennsylvania

3Department of Pediatrics, The Perelman

School of Medicine at the University of

Pennsylvania, Philadelphia, Pennsylvania

Correspondence

Diva D. De Leon, Division of Endocrinology

and Diabetes, The Children's Hospital of

Philadelphia, Room 12128, Buerger Building,

3500 Civic Center Blvd, Philadelphia,

PA 19104.

Email: [email protected]

Funding information

National Institute of Diabetes and Digestive

and Kidney Diseases, Grant/Award Numbers:

R01 DK056268, T32 DK063688; National

Institutes of Health, Grant/Award Numbers:

R01DK056268, T32DK063688

Abstract

Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglyce-

mia in infants and children. Delays in diagnosis and initiation of appropriate treatment

contribute to a high risk of neurocognitive impairment. HI represents a heteroge-

neous group of disorders characterized by dysregulated insulin secretion by the pan-

creatic beta cells, which in utero, may result in somatic overgrowth. There are at least

nine known monogenic forms of HI as well as several syndromic forms. Molecular

diagnosis allows for prediction of responsiveness to medical treatment and likelihood

of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus

become standard of care. However, despite significant advances in our understanding

of the molecular basis of this disorder, the number of patients without an identified

genetic diagnosis remains high, suggesting that there are likely additional genetic loci

that have yet to be discovered.

K E YWORD S

beta-cell, hypoglycemia, insulin, KATP channel, pancreas

1 | INTRODUCTION

Congenital hyperinsulinism (HI) is the most common cause of persis-

tent hypoglycemia in infants and children. To date, at least nine mono-

genic forms of HI have been identified in addition to several

syndromic forms. Prompt identification of congenital HI is crucial to

minimize the risk of permanent neurological damage that results from

untreated hypoglycemia. Despite significant advances which have

expanded our understanding of the pathophysiology of this disorder,

the cause of HI remains unknown in up to 50% of patients suggesting

the role of additional genetic loci that have yet to be discovered

(Kapoor et al., 2013; Martinez et al., 2016; Snider et al., 2013). In this

article, we review the known monogenic and syndromic forms of HI

as well as the approach to genetic testing.

2 | CLINICAL DIAGNOSIS

Infants with congenital hyperinsulinism typically present with persis-

tent hypoglycemia shortly after birth, but they can also present later

in infancy. Clinical clues to the diagnosis of HI include increased

glucose utilization requiring high glucose infusion rates to maintain

euglycemia and large-for-gestational age birth weight. The latter

results because fetal insulin secretion induces cellular hyperplasia via

insulin-like growth factor 1 receptor (IGF1R) mediated signaling and

by promoting anabolic metabolism (Hill, 1982) and is thus a major

determinant of in utero growth.

The diagnosis of HI is made based upon the critical sample, the

blood specimen obtained at the time of spontaneous or provoked

hypoglycemia, and the glycemic response to glucagon. The threshold

plasma glucose for obtaining the critical sample is <50 mg/dl to permit

investigation of the biochemical counter-regulatory response to hypo-

glycemia and to limit the likelihood of false positive results. Biochemi-

cal findings consistent with inappropriate insulin action (Table 1)

include inappropriately low plasma beta-hydroxybutyrate and free

fatty acid concentrations, and a glycemic response to glucagon of

30 mg/dl or more at the time of hypoglycemia (Finegold, Stanley, &

Baker, 1980). While a detectable insulin level at the time of hypogly-

cemia is inappropriate and consistent with insulin excess, the absence

Received: 20 April 2019 Revised: 13 July 2019 Accepted: 29 July 2019

DOI: 10.1002/ajmg.c.31737

Am J Med Genet. 2019;1–11. wileyonlinelibrary.com/journal/ajmgc © 2019 Wiley Periodicals, Inc. 1



33

of measurably elevated insulin does not exclude a diagnosis of HI. In

many cases, increased insulin levels are not observed because the

serum insulin concentration is below the detection threshold of the

insulin assay utilized (Palladino, Bennett, & Stanley, 2008). Hemolysis

of the blood sample may also result in undetectable insulin concentra-

tion (De Leon & Stanley, 2013). Conversely, due to improvements in

assay sensitivity and differences in laboratory reporting practices,

serum insulin may be reported as detectable in the absence of hyper-

insulinism. Thus, accurate diagnosis requires a comprehensive inter-

pretation of biochemical markers of insulin action, and does not rely

solely upon an insulin level.

3 | THERAPEUTIC APPROACH

The primary goal for hyperinsulinism treatment is to maintain plasma

glucose >70 mg/dl, above the threshold for activation of neuroendo-

crine responses to hypoglycemia. This target is supported by physiology

and reflects current consensus opinion recognizing an absence of out-

comes data comparing different therapeutic thresholds (Thornton et al.,

2015). Diazoxide, which acts to open pancreatic β-cell ATP-sensitive

potassium (KATP) channels and decrease insulin secretion, is the first-line

therapeutic agent. However, diazoxide is ineffective in treating hyperin-

sulinism caused by inactivating mutations in the genes encoding the

KATP channel. Diazoxide responsiveness is typically the starting point for

distinguishing congenital hyperinsulinism phenotypes and it is defined

operationally as the demonstration that the cardinal features of hyper-

insulinemic hypoglycemia (i.e., fasting hypoketotic hypoglycemia) are

corrected while on treatment with diazoxide at doses ≤15 mg/kg/day.

Practically, this is assessed by demonstrating: (a) appropriate beta-

hydroxybutyrate elevation (>2 mmol/L) prior to the decline of plasma

glucose concentration below 50–60 mg/dl during a provocative fasting

test and (b) correction of protein-induced hypoglycemia, when present.

Treatment options for diazoxide-unresponsive cases are limited.

Second-line medical therapy for hyperinsulinism includes octreotide

and the longer-acting somatostatin analogs, which act downstream of

the KATP channel to inhibit insulin secretion (Hosokawa et al., 2017;

Modan-Moses, Koren, Mazor-Aronovitch, Pinhas-Hamiel, & Landau,

2011). As explained later, the treatment of choice for focal hyperinsu-

linism is localized surgical excision. For nonfocal cases unresponsive

to medical therapy, subtotal pancreatectomy may be required. That

the optimal management of hyperinsulinism is dependent upon the

underlying cause accentuates the importance of early ascertainment

of a genetic diagnosis.

4 | MONOGENIC FORMS OFCONGENITAL HI

The incidence of congenital HI is estimated at 1 in 40,000 live births

in the general population and as high as 1 in 2,500 in populations with

high rates of consanguinity (Mathew et al., 1988; Otonkoski et al.,

1999). Defects in key genes involved in regulating pancreatic β-cell

insulin secretion cause this heterogeneous clinical condition charac-

terized by recurrent hyperinsulinemic hypoglycemia (Figure 1). Nota-

bly, several of the genes associated with monogenic congenital HI are

also involved in the pathogenesis of monogenic diabetes.

4.1 | KATP-HI

The most common and severe form of monogenic HI is caused by

inactivating mutations in ABCC8 and KCNJ11 located on chromosome

11p15.1, which respectively encode the two subunits, SUR-1 (sulfo-

nylurea receptor) and Kir6.2 (potassium pore), of the hetero-octameric

β-cell plasma membrane KATP channel (Thomas, Ye, & Lightner, 1996;

Thomas et al., 1995). KATP-HI mutations are inherited in either a

recessive or dominant manner. Biallelic inheritance of recessive KATP

channel mutations result in complete absence of plasma membrane

KATP channels and therefore diazoxide-unresponsiveness (Cartier,

Conti, Vandenberg, & Shyng, 2001). Monoallelic paternally inherited

recessive KATP channel mutations in combination with a somatic loss

of maternal 11p15 result in absence of plasma membrane KATP chan-

nels only in a localized area of the pancreas (see later description of

focal hyperinsulinism; Verkarre et al., 1998). Monoallelic dominant

KATP channel mutations allow for normal protein trafficking but result

in the incorporation of mutant subunits into the KATP channel complex

and impaired channel function. Mutations that severely diminish chan-

nel activity cause diazoxide-unresponsive HI. In contrast, mutations

that permit residual KATP activity result in a diazoxide-responsive form

(Macmullen et al., 2011; Pinney et al., 2008). Biallelic recessive and

dominant diazoxide-unresponsive KATP-HI are clinically indistinguish-

able from each other at presentation. Affected neonates are born

large-for-gestational age and present with severe hypoglycemia in the

first few days of life (De Leon & Stanley, 2012). Both fasting and

protein-induced hypoglycemia are observed; the latter likely results

from glutamine-mediated amplification of glucagon-like peptide

1 (GLP-1) receptor signaling (De Leon et al., 2008). Near-total pancre-

atectomy is frequently required to control hypoglycemia. Dominant

diazoxide-responsive forms typically manifest with milder hypoglyce-

mia due to retained partial KATP function. Presentation may be

TABLE 1 Sensitivity and specificity of critical sample laboratoryvalues for the diagnosis of hyperinsulinism (Ferrara, Patel, Becker,Stanley, & Kelly, 2016)

Sensitivity, % Specificity, %

Detectable insulin 82.2 100

Elevated C-peptide (≥0.5 ng/ml) 88.5 100

Suppressed IGFBP1 (≤ 110 ng/ml) 85 97

Suppressed β-hydroxybutyrate(<1.8 mM)

100 100

Suppressed free fatty acids (<1.7 mM) 86.9 100

Positive glycemic response to 1 mg

glucagon injection (Δ plasma

glucose ≥ 30 mg/dl)

88.9 100

Abbreviation: IGFBP1, insulin-like growth factor binding protein 1.

2 ROSENFELD ET AL.



34

delayed beyond infancy, and in some cases, hypoglycemia remains

unrecognized until adulthood (Pinney et al., 2008). Children treated

with near-total pancreatectomy are at high risk of progression to

insulin-dependent diabetes mellitus; incidence rates exceed 90% by

early adolescence (Beltrand et al., 2012; Lord et al., 2015). Further-

more, development of both gestational and insulin-dependent diabe-

tes has been reported in nonsurgically treated patients. Based upon

findings in transgenic KATP-HI mice, hyperglycemia in these cases

likely results from increased β-cell apoptosis; however, the pathophys-

iology in humans has not been fully determined (Huopio et al., 2000).

KATP-HI can be classified into two distinct histological forms: a dif-

fuse form with functional abnormality of all pancreatic β-cells and a

focal form with localized islet cell adenomatous hyperplasia. Diffuse

hyperinsulinism results from monoallelic dominant or biallelic recessive

mutations in ABCC8 or KCNJ11. Focal KATP-HI occurs via a “two-hit”

mechanism of paternal transmission of a monoallelic recessive loss of

function mutation in ABCC8 or KCNJ11 followed by a somatic loss of

maternal 11p15 compensated by paternal uniparental disomy (Verkarre

et al., 1998). Loss of maternally expressed genes involved in tumor sup-

pression results in the histological findings of localized islet hyperplasia,

while reduction to homozygosity of the paternally inherited recessive

mutation within the lesion results in diazoxide-unresponsiveness

(Figure 2). Clinically, focal KATP-HI presents similarly to the diffuse

diazoxide-unresponsive KATP forms. While focal disease is more likely to

present at an older age and with hypoglycemic seizures than diffuse,

the observed differences are sufficiently subtle to preclude clinical

differentiation between these histologic forms (Lord, Dzata, Snider,

Gallagher, & De Leon, 2013). However, identification of focal cases is

extremely important as surgical excision of the discrete lesion results in

cure in 97% of patients (Adzick et al., 2018). Conversely, surgery can

help ameliorate severe hypoglycemia, but does not cure diffuse disease.

Over 180 unique mutations causing KATP-HI have been identified

since the initial description of the molecular basis of the disorder in

1995 with ABCC8 mutations comprising the majority. KATP defects

account for ~90% of identified mutations in diazoxide-unresponsive

HI and 50% of these cases are focal. These findings highlight the para-

mount importance of mutation analysis in determining therapeutic

options and prognostication.

4.2 | GK-HI

Glucokinase, encoded by GCK on chromosome 7p13, functions as the

pancreatic β-cell glucose sensor responsible for regulation of glucose-

Focal lesionNormal pancreas

Chromosomes 11Chromosomes 11

within the focal lesion

H19 CDKN1C

IGF2

(a) (b)

F IGURE 2 “Two-hit” mechanism of focal hyperinsulinism.(a) The paternally inherited chromosome is depicted in blue and thematernally inherited chromosome in orange. The paternally inheritedmutation in the ABCC8 or KCNJ11 gene (red) is present in all cells. Theblack circle highlights the imprinted 11p15 region normally containingmaternally expressed tumor suppressor genes, H19 and CDKN1C, andpaternally expressed growth promoting factor IGF2. (b) Somatic lossof the maternal 11p15 region is compensated by paternal uniparentaldisomy resulting in the focal pancreatic lesion

F IGURE 1 Genetic causes of congenital HI. Pancreatic β-cellinsulin secretion is predominately controlled by oxidation of glucoseand amino acids. Glucose is transported into the β-cell by an insulin-independent glucose transporter (GLUT), predominantly GLUT1, andis phosphorylated by glucokinase (GCK). Glucose metabolism leads toan elevated intracellular ATP/ADP ratio resulting in sequential closureof plasma membrane ATP-sensitive KATP channels (composed ofSUR1 and Kir6.2 subunits), membrane depolarization, activation ofvoltage-gated calcium channels, elevation of cytosolic calcium, andrelease of insulin from storage granules into the circulation. Aminoacids stimulate insulin secretion via a variety of mechanisms. Leucinestimulates insulin secretion by allosterically activating glutamate

dehydrogenase (GDH), increasing the oxidation of glutamate to alpha-ketoglutarate which increases the ATP/ADP ratio and triggers theinsulin secretion cascade. GDH is allosterically inhibited by GTP andSCHAD. Diazoxide activates KATP channels thereby inhibiting insulinsecretion. Defects in the triggering pathway for insulin secretioncause monogenic HI. Genes associated with congenital HI arehighlighted in bold and include: SUR1 (sulfonylurea receptor), Kir6.2(inwardly rectifying potassium channel), GCK (glucokinase), HK1(hexokinase 1), GDH (glutamate dehydrogenase), SCHAD (short-chain3-OH acyl-CoA dehydrogenase), HNF4a (hepatocyte nucleartranscription factor 4alpha), and HNF1a (hepatocyte nucleartranscription factor 1alpha), MCT1 (monocarboxylate transporter 1),UCP2 (uncoupling protein 2)

ROSENFELD ET AL. 3



35

stimulated insulin secretion. Dominant activating mutations lower the

glucose threshold for insulin release resulting in hyperinsulinemic

hypoglycemia of varying severity (Glaser et al., 1998). Affected chil-

dren are often born large-for-gestational age and may present with

severe hypoglycemia at birth. However, presentation in adulthood is

not uncommon and clinical phenotype may differ markedly, even

between affected individuals within the same family (Challis et al.,

2014; Martinez et al., 2017). The majority of cases are unresponsive

to diazoxide therapy. Among those treated with near-total pancrea-

tectomy, many continue to require medical management to prevent

hypoglycemia (Sayed, Matschinsky, & Stanley, 2012). In these

difficult-to-manage cases, combined therapy with diazoxide and a

long-acting somatostatin analogue has been employed with some suc-

cess (Wabitsch et al., 2007). For patients requiring dietary manage-

ment, continuous enteric feeds may prove superior to treatment with

intragastric dextrose.

4.3 | GDH-HI

Dominant activating mutations in GLUD1 cause the hyperinsulinism

hyperammonemia (HI/HA) syndrome, the second most common form

of congenital HI and most common form of diazoxide-responsive HI

(Snider et al., 2013; Stanley et al., 1998). GLUD1, located on chromo-

some 10q23.3, encodes glutamate dehydrogenase (GDH) a mitochon-

drial matrix enzyme expressed in liver, kidney, brain, and pancreatic

ß-cells. Disease-causing mutations in GDH result in impaired sensitiv-

ity to allosteric inhibition by guanosine triphosphate (GTP). Conse-

quently, normal leucine-mediated allosteric activation is uninhibited

leading to the clinical phenotype of fasting and protein-induced hyp-

erinsulinemic hypoglycemia (Kelly et al., 2001) (Figure 1). In addition

to HI, affected patients have persistent hyperammonemia due to the

effects of the activating mutation in the kidney (Treberg, Clow,

Greene, Brosnan, & Brosnan, 2010). Ammonia levels are typically ele-

vated two to five times the normal range but are not associated with

the classical signs of lethargy, headaches, or vomiting observed in

other hyperammonemic disorders (Palladino & Stanley, 2010). How-

ever, a high rate of neurological abnormalities, including epilepsy,

learning disabilities, and behavioral disorders are observed in affected

patients (Bahi-Buisson et al., 2008; Kelly & Stanley, 2008). These

symptoms are unrelated to hypoglycemia and may reflect GDH over-

activity in the brain. HI/HA syndrome is associated with a normal

birthweight, milder fasting hypoglycemia, and later age of presenta-

tion (median age 4–5 months) as compared to KATP-HI (Kapoor et al.,

2009; Stanley et al., 2000). Hypoglycemia is usually easily controlled

by diazoxide and dietary modification, including avoiding the con-

sumption of protein without concomitant carbohydrate intake.

4.4 | SCHAD-HI

Inactivating mutations of short-chain, 3-hydroxyacyl-coA dehydroge-

nase (SCHAD) encoded by HADH on chromosome 4q25 cause a rare,

autosomal recessive form of HI. SCHAD is a mitochondrial enzyme

highly expressed in the pancreas with dual roles of catalyzing fatty

acid β-oxidation and inhibitory regulation of GDH (Li et al., 2010). Loss

of inhibitory regulation of GDH by SCHAD results in a similar pheno-

type of fasting and protein-induced hypoglycemia as in GDH-HI but

without associated hyperammonemia or neurodevelopmental abnor-

malities (Heslegrave & Hussain, 2013). An abnormal pattern of ele-

vated fatty acid metabolites, 3-hydroxybutyryl-carnitine in plasma and

3-hydroxyglutaric acid in urine, was noted in the first reported cases

but has not been universally observed in subsequent reports possibly

due to varying degrees of enzyme deficiency (Clayton et al., 2001;

Popa et al., 2012). Notably, affected children do not exhibit hepatic,

cardiac, or skeletal muscle dysfunction characteristic of fatty acid oxi-

dation disorders. Over 40 cases have been reported in the literature

to date with variable clinical presentation ranging from severe neona-

tal hypoglycemia presenting in the first few days of life to mild

infancy-onset hypoglycemia (Camtosun et al., 2015; Flanagan et al.,

2011). The majority of cases had normal birth weights and all have

been responsive to diazoxide.

4.5 | HNF4A-HI and HNF1A-HI

Dominant inactivating mutations in HNF4A and HNF1A, the genes

encoding transcription factors hepatocyte nuclear factors 4α (HNF4α)

and 1α (HNF1α), respectively, cause congenital hyperinsulinism

followed by monogenic diabetes later in life (Pearson et al., 2007;

Stanescu, Hughes, Kaplan, Stanley, & De Leon, 2012). HNF4A, located

on chromosome 20q13.2, and HNF1A, located on chromosome

12q24.31, have been shown to co-regulate expression of each other

in addition to forming a regulatory network important for both

glucose-stimulated insulin secretion and maintenance of the fully dif-

ferentiated β-cell phenotype (Mitchell & Frayling, 2002). However,

the mechanism by which these mutations result in a biphasic pheno-

type of hyperinsulinism early in life and diabetes in adulthood has not

been elucidated. HI due to mutations in these genes is classically char-

acterized by macrosomia, early neonatal presentation, and diazoxide

responsiveness. Importantly, consideration of this diagnosis should

not be excluded among those with normal birth weight; large-

for-gestational age birth weight was recently reported among 30% of

children with HNF1A-HI and 40% with HNF4A-HI in the largest case

series to date (Tung, Boodhansingh, Stanley, & De Leon, 2018). The

severity and natural history are clinically heterogeneous, ranging from

transient hypoglycemia that does not necessitate pharmacologic treat-

ment to the persistence of hyperinsulinism into late childhood

(McGlacken-Byrne et al., 2014; Tung et al., 2018). Recently, a

mutation-specific phenotype associated with the p.Arg63Trp muta-

tion in HNF4A has been identified. Nine patients with this mutation

have been described, all with proximal renal tubular dysfunction (atyp-

ical Fanconi syndrome) in addition to the recognized β-cell phenotype

(Hamilton et al., 2014; Improda et al., 2016; Stanescu et al., 2012).

4.6 | MCT1-HI

Dominant mutations in the regulatory regions of SLC16A1 on chromo-

some 1 encoding the pyruvate transporter monocarboxylate transporter

4 ROSENFELD ET AL.



36

1 (MCT1) result in exercise-induced hyperinsulinism (EIHI). Normally,

pancreatic β-cell expression of MCT1 is suppressed to prevent stimula-

tion of insulin secretion by pyruvate and lactate. Mutations in the pro-

moter region of SLC16A1 lead to aberrant MCT1 expression and

inappropriate insulin secretion in response to rising intracellular pyruvate

concentrations during anaerobic exercise. Thirteen patients from three

families have been identified thus far with severity of symptoms ranging

from mild to recurrent hypoglycemic syncope (Meissner et al., 2001;

Otonkoski et al., 2007). This disorder is best treated by carbohydrate

intake surrounding periods of vigorous exercise because the response

to diazoxide is often incomplete.

4.7 | UCP2-HI

Dominant loss of function mutations in UCP2, located on chromo-

some 11q13.4, encoding the mitochondrial carrier protein uncoupling

protein 2 (UCP2) were first described to result in diazoxide-responsive

hyperinsulinism in 2008. Since then, a total of nine patients with this

disorder have been identified (Gonzalez-Barroso et al., 2008; Laver

et al., 2017; Snider et al., 2013). The majority of affected children

were born appropriate for gestational age and presented with hypo-

glycemic seizure. Profound postprandial hypoglycemia due to ampli-

fied β-cell glucose-stimulated insulin secretion has been described as

a distinguishing feature (Ferrara et al., 2017). More recently, the role

of UCP2 as a monogenic cause of HI has been questioned based upon

the high prevalence of UCP2 variants identified in the general popula-

tion utilizing data from the Genome Aggregation Database (gnomAD)

(Laver et al., 2017).

4.8 | HK-1

The HK1 gene encodes hexokinase 1 (HK1), a glucose-phosphorylating

enzyme with high affinity for glucose. Its expression is normally

suppressed in β-cells. Impaired silencing of HK1 expression lowers the

glucose threshold for insulin secretion, resulting in hyperinsulinemic

hypoglycemia (Henquin et al., 2013). Variants in the noncoding regions

of HK1 have been proposed as the cause of a dominant form of

diazoxide-responsive HI based upon analysis of a large, four-generation

pedigree with congenital hyperinsulinism (Pinney et al., 2013).

5 | SYNDROMIC FORMS OF HI

Hyperinsulinism is a feature of several developmental syndromes

(Table 2). The most common syndrome associated with HI is

Beckwith–Wiedemann syndrome, which is discussed in detail else-

where in this issue. In some syndromes, such as Kabuki syndrome,

congenital hyperinsulinism may be the presenting feature (Yap et al.,

2018). HI is observed in up to 70% of infants with Kabuki syndrome

and is often diazoxide-responsive. While the genetic basis for many of

these disorders has been discovered, the mechanisms responsible for

hyperinsulinism remain unknown.

6 | MIMICKERS OF CONGENITAL HI

Activating mutations in the PI3K-AKT–mTOR insulin signaling pathway

genes including AKT2, AKT3, and PIK3CA cause hypoinsulinemic hypo-

glycemia albeit with a phenotype similar to HI characterized by severe,

recurrent hypoketotic hypoglycemia and inappropriately low free fatty

acids indicative of excess insulin action. This phenotype results from

constitutive, autonomous activity of the downstream signaling pathway

in the absence of the normal physiological ligand, insulin (Arya et al.,

2014; Hussain et al., 2011). Affected children often require continuous

intragastric feedings to maintain euglycemia. All three mutations are

associated with asymmetric somatic overgrowth; AKT3 and PIK3CA

mutations are additionally associated with megalocephaly (Leiter

et al., 2017).

7 | PERINATAL STRESS-INDUCED HI

In contrast to the rarity of monogenic congenital HI, prolonged neona-

tal hyperinsulinism due to perinatal stress is quite common. Risk factors

are conditions associated with fetal distress and include intrauterine

growth restriction, perinatal asphyxia, meconium aspiration, and mater-

nal toxemia, among others. While most infants have an apparent pre-

disposition based upon birth history, this may not be obvious in all

cases. The etiology of perinatal stress-induced HI remains unknown; a

persistence of fetal patterns of insulin regulation has been hypothe-

sized. Affected neonates are, with rare exception, diazoxide-responsive

and hyperinsulinism typically resolves within the first few weeks of life

although may persist for several months (Hoe et al., 2006).

8 | STRATEGIC APPROACH TO GENETICTESTING

Genetic testing for hyperinsulinism is performed in a two-tier

approach (Figure 3). Children who are unresponsive to medical

therapy with diazoxide undergo Tier 1 testing which includes genes

involved in diazoxide-unresponsive HI (ABCC8, KCNJ11, GCK). Tier

1 testing is performed by direct sequencing of exons and flanking

introns for all genes. This testing also includes deletion/duplication

analysis for all genes as well as screening for the deep intronic muta-

tion in ABCC8 identified as a founder mutation in the Irish population.

Tier 1 testing is performed with a rapid turnaround time of 5–7 days,

and includes parental testing of identified variants. This rapid turn-

around time with simultaneous parental testing is crucial for identify-

ing children who likely have a focal lesion and thus can be cured of

their hypoglycemia following surgical resection. The presence of a sin-

gle recessive KATP mutation has been shown to predict focal HI with

97% sensitivity and 90% specificity (Snider et al., 2013).

Children who are responsive to medical therapy with diazoxide

undergo Tier 2 testing which includes testing for nine genes (ABCC8,

KCNJ11, GLUD1, GCK, HADH, UCP2, HNF4A, HNF1A, MCT1). Tier

2 testing is performed by next generation sequencing of exons and

ROSENFELD ET AL. 5



37

TABLE 2 Syndromic forms of HI

Gene Locus Inheritance Associated features

Overgrowth syndromes

Beckwith–Wiedemann syndrome

Kalish et al. (2016)

IGF2, H19, CDKN1C,

KCNQ1

11p15.4 Sporadic Macrosomia, macroglossia, hemihypertrophy,

visceromegaly, abdominal wall defects, ear

creases/pits, embryonal tumors

Sotos-like syndromes

Sotos syndrome

Malan syndrome

Grand et al. (2019); Matsuo et al.

(2013); Tatton-Brown et al.

(2005)

NSD1

NFIX

5q35

19p13

Sporadic or

AD

Macrocephaly, distinctive facial features (broad and

prominent forehead, sparse frontotemporal hair,

long narrow face, and chin), learning disability,

advanced bone age

Simpson–Golabi–Behmel

Sajorda, Gonzalez-Gandolfi,

Hathaway, and Kalish (1993)

GPC3 Xq26 X-linked Pre- and postnatal overgrowth, macrocephaly,

coarse facial features, macrosomia, macroglossia,

palatal abnormalities, mild to severe intellectual

disability with or without structural brain

anomalies

Perlman syndrome

Morris, Astuti, and Maher (2013)

DIS3L2 2q37.1 AR Neonatal macrosomia, polyhydramnios, broad and

flat nasal bridge, everted V-shaped upper lip,

low-set ears, deep-set eyes, prominent forehead,

renal dysplasia, nephroblastomatosis, high

neonatal mortality rate

Postnatal growth failure syndromes

Kabuki syndrome

Adam et al. (2018)

KMT2D

KDM6A

12q13.12

Xp11.3

AR

Sporadic

Postnatal growth restriction, long palpebral fissures

with eversion of the lateral third of the lower

eyelid, arched and broad eyebrows, large,

prominent or cupped ears, short columella with

depressed nasal tip, persistent fingertip pads,

cardiac defects, intellectual disability

Costello syndrome

Gripp et al. (2016)

HRAS 11p15.5 AD

Sporadic

Failure to thrive, short stature; developmental delay

or intellectual disability, coarse facial features (full

lips, large mouth, full nasal tip), macrocephaly,

hypertrophic cardiomyopathy, solid tumor risk

Turner syndrome

Gibson et al. (2018)

KDM6A? X Sporadic Short stature, premature ovarian failure, low

posterior hairline, congenital heart defects, renal

and skeletal abnormalities, autoimmune thyroiditis

Congenital disorders of glycosylation (CDG)

CDG 1A

Sparks and Krasnewich (1993)

PMM2 16p13.2 AR Failure to thrive, hypotonia, inverted nipples,

abnormal subcutaneous fat distribution, cerebellar

hypoplasia, developmental delay

CDG 1B

Sparks and Krasnewich (1993)

MPI 15q24.1 AR Failure to thrive, cyclic vomiting, hepatic

fibrosis, protein-losing enteropathy,

coagulopathy

PGM-1 CDG (formerly CDG 1T)

Wong et al. (2016)

PGM1 1p31.3 AR Hepatopathy, cleft palate, bifid uvula, dilated

cardiomyopathy, growth retardation, myopathy

Other

Forkhead BOX A2

Giri et al. (2017); Vajravelu et al.

(2018)

FOXA2 20p11.21 Sporadic Hypopituitarism, hypertelorism, choroidal coloboma,

thin upper lip, low-set ears, widely spaced nipples

L-type voltage-dependent calcium

channel, ALPHA-1D SUBUNIT

Flanagan et al. (2017)

CACNA1D 3p21.1 Sporadic Congenital heart defects (aortic insufficiency,

ventricular septal defect, biventricular

hypertrophy), hypotonia, seizures, developmental

delay, primary hyperaldosteronism

Timothy syndrome

Napolitano, Splawski, Timothy,

Bloise, and Priori (1993)

CACNA1C 12p13.33 AD

Sporadic

Prolonged QT interval, congenital heart disease,

cutaneous syndactyly, low-set ears, depressed

nasal bridge, thin vermilion border of the upper lip,

developmental delay, autism

(Continues)

6 ROSENFELD ET AL.



38

flanking introns for all genes. Deletion/duplication analysis for all

genes is included in Tier 2 testing. Testing for the deep intronic muta-

tion in ABCC8 identified as a founder mutation in the Irish population,

as well as for the deep intronic mutation in HADH identified in the

Turkish population, are also included in this testing. The turnaround

time for Tier 2 testing is ~4 weeks and includes parental testing for

identified mutations.

Reporting laboratories rely on the American College of Medical

Genetics guidelines for variant interpretation, published literature, and

laboratory-specific internal knowledge to determine whether a given

variant detected in a causative gene should be classified as pathogenic

(Richards et al., 2015). The most difficult variants are those classified

as “unknown significance” where the burden of evidence does not

rule in/out a change as diseases causing. In these cases, our approach

includes evaluation of additional evidence from functional studies,

familial segregation, phenotyping of the proband and other family

members carrying the variant, which may help to reclassify the

changes as pathogenic or nonpathogenic.

Parental testing should be included in the genetic analysis for all

cases in which a mutation is identified. This information not only aids

in the clinical management for the affected child, but also can identify

other family members who may be at risk of hypoglycemia. Further-

more, parental testing can aid in counseling the families of recurrence

risk in future children.

Our approach has been to consider genetic testing for syndromic

forms of HI in cases where a mutation is not detected on the above

panels. Others have proposed that routine testing for syndromic HI in

patients without suggestive features is not warranted. Laver et al.

recently reported their findings on 82 infants with HI of unknown

genetic etiology without a clinical diagnosis of a known syndrome.

After genetic evaluation for 20 syndromes associated with HI, a path-

ologic KMT2D variant was identified in one patient. No pathogenic

variants were identified in the remainder of the cohort (Laver et al.,

2018). While not included in our congenital HI genetic panel, some

panels employed at other institutions include KMT2D and KDM6A, the

genes responsible for Kabuki syndrome. We anticipate that our

Diazoxide-ResponsiveN=317

Diazoxide-UnresponsiveN=497

Focal

Biallelic recessive KATP

No mutations

Monoallelic dominant KATP

GLUD1

F IGURE 3 Genetic etiologies of HI stratified by diazoxide responsiveness. Data from 814 children with hyperinsulinism treated at theChildren's Hospital of Philadelphia. Among those with diazoxide-unresponsive HI, KATP mutations were the most common etiology identified by

genetic testing: focal KATP (50%), biallelic recessive KATP (31%), monoallelic dominant KATP (7%), GCK (3%), no mutation identified (9.5%). Incontrast, the most common finding among those with diazoxide-responsive HI was no identified mutation (64.5%), followed by monoallelicdominant KATP (14.5%), GLUD1 (12%), HNF4A (3%), HNF1A (3%), UCP2 (2%), and HADH (0.6%)

TABLE 2 (Continued)

Gene Locus Inheritance Associated features

Trisomy 13

Tamame et al. (2004)

Trisomy 13 Sporadic Holoprosencephaly, microphthalmia, cleft lip/palate,

postaxial polydactyly, cardiac and urogenital

malformations, severe intellectual disability

Tyrosinemia Type 1

Baumann, Preece, Green, Kelly,

and McKiernan (2005)

FAH 15q25.1 AR Failure to thrive, liver failure, renal Fanconi

syndrome, neurologic crises, risk for hepatocellular

carcinoma

Usher syndrome, TYPE 1C

Al Mutair et al. (2013)

USH1C-ABCC8a 11p15.1 AR Congenital sensorineural deafness, vestibular

dysfunction, retinitis pigmentosa

Abbreviations: AD, autosomal dominant; AR, autosomal recessive.aContiguous gene deletion including ABCC8.

ROSENFELD ET AL. 7



39

recommended approach may change as our understanding of the

mechanisms underlying hyperinsulinism in these syndromic forms

develops.

Of note, the approach to genetic testing in other centers around

the world may differ to ours. The variety of gene testing arises from

various aspects of gene testing. For example, the panel of genes

included in the Targeted panel sequencing ranges from as few as four

genes (ABCC8, KCNJ11, GCK, and GLUD1) to nine genes (ABCC8,

KCNJ11, GCK, GLUD1, SLC16A1, UCP2, HNF1A, HNF4A, and HADH).

Some laboratories include syndrome associated HI genes such as

KMT2D, KDM6A for Kabuki syndrome. In many cases, parental testing

is not included as standard of care. However for diazoxide-

unresponsive cases, information on the parent of origin can inform on

the possibility of focal HI and therefore, potential benefits of surgical

management and can be crucial in clinical decision-making process.

It is important to recognize the limitations of genetic testing in

cases where a disease-causing mutation is not identified. De novo

mutations confined to the pancreas will not be detected by analysis of

peripheral blood (Henquin et al., 2013). Deep intronic or promoter

mutations may be missed as a consequence of the sequencing meth-

odology employed by a given laboratory. Lastly, mutations in novel

causative genes cannot be excluded.

9 | CONCLUSIONS

Timely identification of genotype is crucial to aid in prediction of clini-

cal phenotype, including determination of best therapeutic options, to

limit exposure to persistent hypoglycemia, and thus reduce risk of per-

manent brain damage in affected infants and children. Currently, the

number of cases without an identified genetic diagnosis remains high.

Thus, further research into the molecular genetics of congenital HI

including the development and utilization of newer sequencing tech-

nologies is needed.

ACKNOWLEDGMENTS

The authors thank Kara E. Boodhansingh, BS for reviewing the article.

This work was supported by National Institutes of Health grants

T32DK063688 (E.R.) and R01DK056268 (D.D.D.L. and A.G.).

CONFLICT OF INTEREST

The authors declared that they have no conflict of interest.

ORCID

Diva D. De Leon https://orcid.org/0000-0003-1225-8087

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How to cite this article: Rosenfeld E, Ganguly A, De

Leon DD. Congenital hyperinsulinism disorders: Genetic and

clinical characteristics. Am J Med Genet Part C. 2019;1–11.

https://doi.org/10.1002/ajmg.c.31737

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