Hypoglycaemia of Genetic Cause – Diagnostic Approach

A clinical finding shared by dozens of monogenic diseases — hyperinsulinisms, insulin signalling defects, hormone deficiencies, glycogen storage diseases, defects of gluconeogenesis and fructose metabolism, and defects of fatty acid oxidation, ketogenesis and ketolysis — whose diagnosis rests on the sample collected during hypoglycaemia, the timing of the episode in relation to meals, liver size and the presence or absence of ketosis and lactic acidosis.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

0.1. Class summary

0.2. Entities detailed in this article

1. Introduction

1.1. The clinical problem

Hypoglycaemia is one of the most frequent metabolic emergencies in paediatrics and, at the same time, one of the findings whose definition generates the most controversy, above all in the neonatal period [1]. In most newborns with low blood glucose the cause is not genetic: prematurity, low birth weight, sepsis, infant of a diabetic mother and perinatal stress account for most episodes in the first days [1]. Outside that context, persistent or recurrent hypoglycaemia signals a defect in one of the systems that maintain normoglycaemia — insulin secretion, counter-regulatory hormones, glycogenolysis, gluconeogenesis, fatty acid oxidation and ketogenesis — and almost all of these systems have known monogenic causes [1,15]. Congenital hyperinsulinism is the most frequent and most severe cause of persistent hypoglycaemia in the infant and child [10]; after the neonatal period, the most frequent causes become treated diabetes mellitus and idiopathic ketotic hypoglycaemia, which is a diagnosis of exclusion [12,43].

The aetiological diagnosis has immediate consequences. Brain injury from neuroglycopenia occurs in more than 30% of cases of severe neonatal hyperinsulinism with late diagnosis or inadequate treatment [3], and neurodevelopmental impairment affects 25–50% of children with congenital hyperinsulinism in the series cited by the Pediatric Endocrine Society (PES) [4]. Treatment differs radically between classes: glucagon raises blood glucose within minutes in hyperinsulinism and is ineffective in glycogen storage diseases and gluconeogenesis defects; IV fructose and sorbitol, harmless for most people, can be fatal in HFI and FBPase deficiency; L-carnitine is life-saving in primary carnitine deficiency; hydrocortisone is indispensable in cortisol deficiencies [1,8,13,44].

1.2. Definitions and thresholds

The PES defines clinical hypoglycaemia as a PG concentration low enough to cause symptoms or signs of brain dysfunction, and stresses that it cannot be defined by a single value: the thresholds of brain responses vary with the availability of alternative fuels (ketones, lactate) and with prior hypoglycaemia, there is no single value that causes injury (which depends on duration and degree), and measurement is subject to artefacts [4]. In children able to communicate symptoms, evaluation is justified only in the presence of documented Whipple's triad — compatible symptoms or signs, a measured low PG and relief with normalisation (recommendation 1.1, strong, high-quality evidence) [4]; the Endocrine Society applies the same criterion to adults [45]. In infants and young children who cannot communicate, a laboratory PG below the threshold of neurogenic responses, <60 mg/dL (3.3 mmol/L), is investigated (recommendation 1.2, weak, moderate-quality evidence) [4]. Physiological thresholds, delineated in adults, place the limitation of cerebral glucose utilisation at ~55–65 mg/dL (3.0–3.6 mmol/L), neurogenic symptoms at <55 mg/dL (<3.0 mmol/L) and neuroglycopenia at <50 mg/dL (<2.8 mmol/L) [4].

In the newborn, hypoglycaemia in the first 48 h mostly corresponds to a mild, transient form of hyperinsulinism: the mean threshold for insulin suppression is ~55–65 mg/dL (3.0–3.6 mmol/L) shortly after birth, compared with ~80–85 mg/dL (4.4–4.7 mmol/L) in the older infant, child and adult, and by 72 h mean PG is already similar to that of the child [4]. Hence the rule that standards for the normal newborn are not extrapolated beyond 2–3 days and the recommendation to evaluate newborns at high risk of a persistent disorder at ≥48 h of life, excluding that disorder before discharge (recommendation 1.3) [4]. The Oxford reference book defines hypoglycaemia, after 72 h in the term newborn and after the first week in the preterm infant, as glucose <2.6 mmol/L (some authors use <2.5 mmol/L) [1]. For the transitional period there is no agreement between societies: the American Academy of Pediatrics (AAP) states that the evidence does not support a specific concentration that distinguishes normal from abnormal or that causes neurological injury [46], and a 2026 systematic review shows that the AAP, the British Association of Perinatal Medicine (BAPM), the PES, the Canadian Paediatric Society (CPS, 2025), New Zealand (2025) and Australia differ in the timing of the first measurement, the frequency of screening and the minimum treatment threshold, although all require investigation of hypoglycaemia persisting beyond 48–72 h [47]. Table 7.14 summarises these divergences.

1.3. Historical overview

The modern clinical description of spontaneous hypoglycaemia in infancy is owed to McQuarrie (1954), who brought together "idiopathic spontaneous hypoglycaemia" of infancy and discussed its significance and treatment [48]; the 2024 international consensus refers to some 65 years of history of hyperinsulinism in children [10]. Fructose intolerance was described as "fructose idiosyncrasy" by Chambers and Pratt in 1956, in a 24-year-old woman with nausea, abdominal pain and faintness after ingesting sugar and fructose and with no liking for sweet foods [21,49], and characterised as a hereditary inborn error by Froesch, Prader and colleagues in 1957 [50]. In 1963, Froesch and colleagues localised the defect to the hepatic aldolase that cleaves fructose-1-phosphate and described two adults aged 33 and 39 years with aversion to fructose-containing foods and absence of dental caries; in the same year, Levin and colleagues proposed the term "fructosaemia", by analogy with galactosaemia [21]. The first ALDOB variant, A149P (now p.Ala150Pro), was identified by Cross and colleagues in 1988 [21]. In 1970, Baker and Winegrad described fasting hypoglycaemia with metabolic acidosis associated with hepatic fructose-1,6-diphosphatase deficiency, in a 5-year-old girl whose older brother had died at 6 months with a similar illness [51,52]; in 1971 series of siblings from consanguineous couples followed (Baerlocher; Hulsmann and Fernandez), and the entity received the eponym Baker-Winegrad disease [9,24,44]. The first FBP1 variant, the 960insG insertion, was described by Kikawa and colleagues in 1995 in a Japanese patient [24].

The molecular era of hyperinsulinism began in 1995, when Thomas and colleagues linked the recessive familial form to 11p14–15.1 and identified splicing mutations in the sulfonylurea receptor gene (SUR, now ABCC8) that co-segregated with the disease in nine families [53]. KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, UCP2, HK1 and others followed, up to the current classification with more than forty genes and loci [2,10]. Otonkoski showed in 2003 that exercise-induced hyperinsulinaemic hypoglycaemia is a dominant trait characterised by pyruvate-induced insulin release [54] and, in 2007, that it results from failure to silence monocarboxylate transporter 1 (MCT1) in the beta cell [55]; in 2014, loss-of-function MCT1 deficiency was recognised as a ketolysis defect [56]. In 2011, Hussain and colleagues described the activating de novo AKT2 variant p.(Glu17Lys) in three children with fasting hypoglycaemia and undetectable insulin, the first cause of hypoglycaemia due to constitutive activation of insulin signalling [36]. Cytosolic PEPCK deficiency was demonstrated enzymatically by Vidnes and Søvik in 1976, in a boy with hypoglycaemic seizures on day 2 of life, treated unsuccessfully with subtotal pancreatectomy and diazoxide, who died at 2 years and 10 months; the first molecular confirmation in PCK1 was published by Adams and colleagues in 2014, in two sisters of Ashkenazi Jewish ancestry, followed by Santra (2016) and the Finnish patients of Vieira (2017) [27,57]. GeneGuidance dates the first molecularly confirmed patients to 2016, which OMIM contradicts [25,27]. Hypoinsulinaemic hypoglycaemia with hemihypertrophy was described by Hussain and colleagues in 2004 in a boy with left hemihypertrophy and hypoketotic, hypoinsulinaemic hypoglycaemia with a marked glycaemic response to IV glucagon, the same patient in whom the AKT2 variant was later identified [36,38].

1.4. Nomenclature, classification and scope

The term "congenital hyperinsulinism" replaced "nesidioblastosis", and the 2024 international consensus (De Leon and colleagues, under the International Consortium of Pediatric Endocrinology, ICPE) classifies hyperinsulinaemic disorders as acquired neonatal, acquired non-neonatal, isolated genetic (diffuse, focal and atypical or mosaic), syndromic genetic and hyperinsulinism mimics, that is, hypoketotic hypoinsulinaemic hypoglycaemias [1,10]. The term "fructosaemia" is obsolete for HFI [8]. This article organises the monogenic causes into eight pathophysiological classes: (1) hyperinsulinism, isolated or syndromic; (2) insulin signalling defects and insulin resistance; (3) counter-regulatory hormone deficiencies (cortisol, GH, hypopituitarism, GH insensitivity); (4) hepatic glycogen storage diseases; (5) gluconeogenesis defects (FBPase, PEPCK, pyruvate carboxylase, glycerol kinase); (6) fructose and galactose metabolism; (7) defects of fatty acid oxidation, ketogenesis and ketolysis; (8) other metabolic causes (organic acidurias, late-onset maple syrup urine disease (MSUD), tyrosinaemia, mitochondrial and liver diseases, congenital disorders of glycosylation, neurotransmitter defects).

HFI and gluconeogenesis defects receive diagnostic and therapeutic detail here; familial glucocorticoid deficiency is summarised; the remaining entities — congenital hyperinsulinism, glycogen storage diseases, defects of fatty acid oxidation, ketolysis and ketogenesis, hypopituitarism, septo-optic dysplasia, among others — are addressed by their position in the diagnostic algorithm and by the clues that distinguish them.

2. Molecular Genetics and Pathophysiology

2.1. Glucose homeostasis throughout fasting

Normoglycaemia requires four conditions: intact hepatic enzyme systems for glycogenolysis and gluconeogenesis (altered in glycogen storage diseases and gluconeogenesis defects); an adequate supply of gluconeogenic substrates (amino acids, glycerol and lactate); energy from beta-oxidation to produce glucose and ketone bodies (altered in fatty acid oxidation defects, FAO); and a normal endocrine system (altered in hyperinsulinism, in deficiencies of GH, adrenocorticotropic hormone [ACTH] and cortisol, and in Laron syndrome) [1]. In the child, the source of circulating glucose changes with the duration of fasting: food in the postprandial insulinaemic period (<2.5 h after a meal); hepatic glycogenolysis in short fasting (>2.5 to 8 h); declining glycogenolysis and increasing gluconeogenesis in short to moderate fasting (>8 to 12–15 h); hepatic gluconeogenesis in prolonged fasting (>15 h), with variation according to age and nutritional status [15]. This sequence is the basis of the "timing of hypoglycaemia" diagnostic criterion: a defect that manifests shortly after a meal points to hyperinsulinism; after 2.5–8 h, to glycogen storage diseases I, III and 0; after 8–24 h, to gluconeogenesis defects and "energy" defects (FAO, ketogenesis, respiratory chain) [15].

Glycogen can reach 8% of the wet weight of the liver after a meal (~2% in muscle), but only hepatic glycogen releases glucose into the circulation; in the post-absorptive state, the fall in the insulin/glucagon ratio activates the cyclic adenosine monophosphate (cAMP) cascade, phosphorylase kinase and glycogen phosphorylase, and adrenaline, cortisol and GH inhibit glycogenesis and stimulate glycogenolysis [58]. The neuroendocrine defence is hierarchical: the first response is suppression of insulin when PG falls below the post-absorptive mean (~85 mg/dL; 4.9 mmol/L); at 65–70 mg/dL (3.6–3.9 mmol/L) glucagon secretion and sympatho-adrenal activation follow; below 65 mg/dL (3.6 mmol/L) cortisol and GH rise, which are important in prolonged fasting [4]. During fasting, lipolysis releases glycerol and FFA, which the liver converts into BOHB and acetoacetate (AcAc); the BOHB concentration is the practical measure of ketogenesis [4].

The infant and young child use glucose at 4–6 mg/kg/min, two to three times more per kilogram than the adult, because the brain is proportionally larger; after 2–3 days of life adaptation to fasting is qualitatively the same as in the adult, but PG falls faster and hyperketonaemia appears earlier [4]. Children under 4 years may have PG <70 mg/dL and hyperketonaemia after an overnight fast [4]. Cerebral use of ketone bodies may fail if glucose falls before maximal induction of MCT1 at the blood-brain barrier, which explains seizures in ketotic hypoglycaemia [12]. In hypoketotic states — hyperinsulinism and FAO — neither ketones nor lactate replace glucose, and the risk of cerebral energy failure is greater [4]; in type I glycogen storage diseases, by contrast, lactate serves as an alternative cerebral substrate and partially protects the central nervous system [58].

2.2. Insulin secretion and signalling

In the beta cell, glucokinase (GCK), with a Michaelis constant close to blood glucose levels, acts as the sensor; glycolytic and mitochondrial metabolism increases the ATP/ADP ratio, closes the ATP-sensitive potassium channel (KATP, formed by the subunits SUR1, encoded by ABCC8, and Kir6.2, encoded by KCNJ11, both at 11p15.1), depolarises the membrane, opens voltage-dependent calcium channels and triggers exocytosis [1,3]. This pathway is modulated by the transcription factors HNF1A and HNF4A, by metabolic factors — leucine through glutamate dehydrogenase (GDH, GLUD1), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD, HADH), MCT1 (SLC16A1), uncoupling protein 2 (UCP2) — and by receptors for somatostatin, insulin, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [3]. Inappropriate insulin causes neuroglycopenia because it inhibits hepatic glycogenolysis and gluconeogenesis, increases muscle and adipose uptake and suppresses lipolysis and ketogenesis, depriving the brain, which is poorly sensitive to insulin, of glucose and ketones [3].

The genetic mechanisms of hyperinsulinism are grouped into KATP channelopathies (ABCC8, KCNJ11), metabolic defects (GCK, GLUD1, HADH, HK1; transporters SLC16A1 and UCP2) and transcription factors (HNF1A, HNF4A) [2,3]. In GCK hyperinsulinism, secretion is qualitatively normal but the glycaemic switch-off threshold is abnormally low [2]. Heterozygous non-coding variants that prevent silencing of HK1 in the beta cell are an important cause of isolated hyperinsulinism, and promoter or regulatory variants of SLC16A1 that prevent silencing of MCT1 (3- to 10-fold transcriptional stimulation) allow pyruvate generated during anaerobic exercise to stimulate insulin secretion [10,33,55].

Downstream of the insulin receptor, the phosphatidylinositol 3-kinase (PI3K)–AKT–mTOR pathway promotes translocation of the GLUT4 transporter [3]. Two groups of diseases in insulin-sensitive cells cause hypoglycaemia with the biochemistry of hyperinsulinism: insulin resistance syndromes due to receptor variants (INSR), in which insulin is very high during hypoglycaemia because of reduced clearance, and insulin signalling disorders (AKT2, PIK3CA, AKT3, PIK3R2, CCND2), in which the pathway is constitutively activated and insulin is suppressed [3,10]. In AKT2 p.(Glu17Lys) hypoglycaemia, the mutant protein is constitutively recruited to the membrane and activates signalling independently of insulin, with tonic nuclear exclusion of FoxO1 [36].

2.3. Mechanisms in the remaining classes

In cortisol and GH deficiencies, counter-regulation of prolonged fasting fails; hypoglycaemia is typically ketotic, except in infantile GH deficiency, which may be hypoketotic [15,59]. In familial glucocorticoid deficiency (FGD), ACTH resistance (MC2R, MRAP) or adrenal oxidative stress (NNT, TXNRD2) suppresses cortisol synthesis with the renin-aldosterone axis preserved [39,41]. In Laron syndrome, GH insensitivity due to GHR variants (5p13.1-p12) gives low insulin-like growth factor 1 (IGF-1) with normal or high GH, and hypoglycaemia is a recognised feature; the Oxford book attributes the syndrome to the growth hormone-releasing hormone receptor, which is incorrect [1,60].

In hepatic glycogen storage diseases, blocking glucose release from glycogen (GSD I, III, VI, IX) or its synthesis (GSD 0a, due to GYS2) shortens fasting tolerance; in GSD I, the glucose-6-phosphatase block also prevents the release of glucose produced by gluconeogenesis, so glucose and lactate move in opposite directions [58,59]. In FAO and ketogenesis defects, the lack of acetyl-CoA and ketone bodies prevents the liver from sustaining gluconeogenesis and the brain from using alternative fuels, hence hypoketotic hypoglycaemia [12,61]. In ketolysis defects (OXCT1, ACAT1, loss-of-function SLC16A1) ketogenesis is intact but tissues do not use ketone bodies, and the presentation is severe ketoacidosis, with inconsistent hypoglycaemia [12].

2.4. Hereditary fructose intolerance (ALDOB)

Aldolase B, expressed in the liver, renal cortex and small intestine, cleaves fructose-1-phosphate (F-1-P) and fructose-1,6-bisphosphate; in its absence, the highly active fructokinase accumulates F-1-P, which sequesters inorganic phosphate [13]. This results in inhibition of gluconeogenesis (through inhibition of aldolase A) and of glycogenolysis (through inhibition of glycogen phosphorylase a), with a rapid fall in glucose, and in ATP depletion, with increased uric acid, release of magnesium, impaired protein synthesis and liver and kidney injury; F-1-P also inhibits phosphomannose isomerase, causing a secondary glycosylation defect detectable on transferrin isoelectric focusing [8,13]. When fasting, without fructose, glycolysis and gluconeogenesis are intact and the patient tolerates long fasts; HFI is one of the few inborn errors in which hypoglycaemia occurs in the immediate postprandial period, and this hypoglycaemia is refractory to glucagon [8,13].

HFI is AR, with about 70 causal variants in ALDOB (9q31.1) [13]. Three missense variants — p.(Ala150Pro), p.(Ala175Asp) and p.(Asn335Lys) — are relatively common in patients of European origin and account for more than 90% of alleles in some European regions and for more than 50% in North America; p.(Ala150Pro) is the most frequent in all studies [8,13]. In 162 patients from 92 families, mostly French, A149P (historical numbering, = NM_000035.4:c.448G>C p.(Ala150Pro)) accounted for 64% of alleles, A174D (historical numbering, = NM_000035.4:c.524C>A p.(Ala175Asp)) 16% and N334K (historical numbering, = NM_000035.4:c.1005C>G p.(Asn335Lys)) 5%, and screening for these three variants confirmed the diagnosis in 75% of probands; haplotype analysis indicates that A149P and A174D each derive from a single founder and reached high frequency through genetic drift [21]. The historical nomenclature numbered codons without the initiator methionine, so it differs by one codon from the current one (A149P = p.Ala150Pro) [8,62]. The splicing variant c.324+1G>A is common in northern India, and multiplex ligation-dependent probe amplification (MLPA) detects copy number variants (CNV) in ~6% of alleles not identified by sequencing; in a small Italian cohort, a 6.5 kb intragenic deletion had an allele frequency of 11%, whereas no large deletion was found in 56 Spanish patients [8,13]. There is no clinically relevant genotype-phenotype correlation, and residual activity does not predict tolerance [8,13]. Carriers are asymptomatic, with a possible predisposition to gout and a postprandial rise in uric acid after fructose [8].

2.5. Gluconeogenesis defects

Fructose-1,6-bisphosphatase (FBP1). Hepatic FBPase is the rate-limiting enzyme of gluconeogenesis and blocks glucose synthesis from all precursors, including fructose; normoglycaemia then depends on ingested glucose and galactose and on hepatic glycogen, so hypoglycaemia appears when glycogen is limited (newborn) or exhausted (fasting) [13,22]. Lactate, pyruvate, alanine and glycerol accumulate, and the lactate/pyruvate (L/P) ratio rises owing to NADH accumulation [13]. Ketosis may be absent because pyruvate, converted into oxaloacetate, diverts acetyl-CoA to citrate and malonyl-CoA, which inhibits carnitine palmitoyltransferase 1 [13]. An IV fructose load induces hypoglycaemia through inhibition of phosphorylase a by F-1-P, but oral fructose up to 2 g/kg/day distributed throughout the day is tolerated [13]. The FBP1 gene (9q22.32) has one non-coding exon and seven coding exons [9]; more than 50 variants have been described, among them the exon 2 deletion (c.-24-26_170+5192del), common in Turkish and Armenian patients, the duplication c.959dup p.(Ser321IlefsTer13), present in 46% of alleles in Japan according to Saudubray's book and Nyhan's atlas (16 of 22 alleles in 13 Japanese patients in Kikawa's 1997 series cited by OMIM) and in 14% in Central Europe (historically described as the 960–961insG insertion), and c.841G>A p.(Glu281Lys), recurrent in Pakistani patients [13,24,44,62]. Some patients have no identified coding variant [13]. GeneReviews does not recognise a genotype-phenotype correlation [9]. Metformin inhibits FBPase and reproduces part of the biochemical phenotype (lower glucose production and lactic acidosis) [13].

Cytosolic (PCK1) and mitochondrial (PCK2) PEPCK. Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C, GTP-dependent) converts oxaloacetate into phosphoenolpyruvate; its absence blocks gluconeogenesis from lactate and amino acids and leads to accumulation of Krebs cycle intermediates, above all fumarate, in the urine [14,25]. PCK1 is located at 20q13.31; the variant c.925G>A p.(Gly309Arg) is a founder variant endemic in Finland, and a review of 32 patients from 25 families found no genotype-phenotype correlation, with environmental factors determining the phenotype [25,26]. OMIM retains mitochondrial PEPCK deficiency (PCK2, 261650) as a phenotype with unconfirmed molecular basis, and the reduced mitochondrial activity described in patients is, as a rule, a secondary phenomenon [7,29].

Pyruvate carboxylase (PC). Pyruvate carboxylase (PC) is anaplerotic for the Krebs cycle and the first step of gluconeogenesis from pyruvate; its deficiency (AR, ~1 in 250,000) presents mainly with severe neurological dysfunction and lactic acidosis, and hypoglycaemia is possible during crises but overnight blood glucose is usually normal [29]. The variant p.(Ala610Thr) is frequent in North American Amerindian populations with phenotype A [29,63]. Secondary PC deficiency occurs in biotin-responsive multiple carboxylase deficiency and in carbonic anhydrase VA deficiency [29].

Glycerol kinase (GK). Glycerol kinase deficiency (GKD) is XL, isolated (intragenic variants) or part of a contiguous gene deletion at Xp21.2–p21.3 that includes GK, NR0B1 (DAX1), DMD and sometimes IL1RAPL1, with congenital adrenal hypoplasia, Duchenne muscular dystrophy and intellectual disability [30,31]. Glycerol is not used for gluconeogenesis, accumulates in plasma and is read as triglyceride by the usual enzymatic methods (pseudohypertriglyceridaemia) [30,31]. An isolated finding of a GK variant on a panel does not exclude the contiguous deletion, which requires copy number analysis [31]. X-linked congenital adrenal hypoplasia (NR0B1) and the Xp21 contiguous deletion syndrome enter the differential.

2.6. Normalised reference variants

The following variants were normalised to Human Genome Variation Society (HGVS) nomenclature in VariantValidator (GRCh38, MANE Select transcript, Matched Annotation from NCBI and EMBL-EBI) and checked against ClinVar in October 2026. Two notations in the sources were corrected: the HMGCL nonsense variant frequent in the Iberian Peninsula is c.109G>T p.(Glu37Ter) and not "c.109G>A" (which encodes p.Glu37Lys), and the FBP1 duplication is written c.959dup, without the repeated base [12,13,62,63].

Table sources: [2,8,12–14,29,36,58,62–64]. Variants without a classification in the last column were not checked in ClinVar.

2.7. Inheritance, mosaicism and non-Mendelian mechanisms

Focal hyperinsulinism results from the combination of a paternal recessive ABCC8 or KCNJ11 variant with somatic loss of the maternal 11p15 allele (paternal isodisomy restricted to the lesion), a sporadic fetal event that also alters the balance of IGF2 and H19; all focal forms have this somatic loss [1,3]. Atypical or mosaic hyperinsulinism (LINE-HI) results from dominant somatic variants of ABCC8 or GCK, or from inappropriate expression of HK1 [10]. Paternal uniparental disomy of 11p in several tissues defines the Beckwith-Wiedemann spectrum (BWSp), with severe hyperinsulinism when a paternal ABCC8/KCNJ11 variant coexists [10]. In AKT2 hypoglycaemia, one of the three original patients had ~20% mosaicism in lymphocytes and buccal epithelium [36], and somatic activating variants of PIK3CA and AKT3 occur in the megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes [3]. In MCT1 deficiency, SLC16A1 heterozygotes (like OXCT1 heterozygotes) may have recurrent ketoacidosis under stress, and the same gene causes an opposite, dominant phenotype when regulatory variants prevent its silencing in the beta cell [12,33,65]. In GKD, there are rare symptomatic female carriers [30].

3. Clinical Spectrum and Manifestations by System

3.1. Symptoms and awareness of hypoglycaemia

Symptoms are divided into neurogenic — adrenergic (palpitations, tremor, anxiety, pallor, tachycardia) and cholinergic (sweating, hunger, paraesthesiae) — and neuroglycopenic (drowsiness, confusion, hallucinations, fainting, seizures, coma, cognitive impairment) [3,4]. In the newborn and young child, adrenergic signs are non-specific and hypoglycaemia manifests as seizures, hypotonia, poor feeding or apnoea [2,3]. Prior hypoglycaemia attenuates or abolishes neurogenic responses for more than 24 h after an episode (hypoglycaemia-associated autonomic failure, HAAF), and the same occurs during sleep and exercise; the neurogenic threshold shifts to values below 55 mg/dL, and this phenomenon has been described in infants aged 10–13 weeks [4]. With daily hypoglycaemia, adrenergic signs become attenuated, which explains direct presentation with seizures or coma [3].

3.2. Neonatal period

Hypoglycaemia immediately after birth reflects the immaturity of hepatic gluconeogenesis and ketogenesis [1]. In at-risk newborns, ketones are suppressed during hypoglycaemia, which increases cerebral vulnerability [4]. Perinatal stress-induced hyperinsulinism (PSHI) appears in the first 24 h in ~1/1,200–1/1,700 newborns, usually resolves within 10–14 days and corresponds to an exaggerated form of transitional hypoglycaemia due to hypoxic lowering of the insulin suppression threshold; the prolonged form, which persists for more than 2 weeks and may require diazoxide, occurs in ~1/12,000–1/13,600 [10]. Saudubray's book describes this transient neonatal hyperinsulinism in infants of diabetic mothers, small-for-gestational-age (SGA) newborns, fetal distress and asphyxia, with resolution within days or up to 4 months, a consistent response to diazoxide and normal genetics [3].

Congenital hyperinsulinism is the most frequent cause of persistent neonatal hypoglycaemia [2]. It presents in the first hours or days with seizures, hypotonia, poor feeding or apnoea; birth weight is above the 90th centile in at least 45% and most present in the first 72 h [1,2]. About half of patients present with hypoglycaemic seizures or coma, because they do not meet the criteria for neonatal glucose screening (mean birth weight 3.7 kg); in severe forms the mean glucose infusion rate required is 16 mg/kg/min and there may be transient hypertrophic cardiomyopathy and hypocortisolism [3]. The mean age at presentation varies with the gene: HNF4A 1 day; KATP 1 day to 1 year (mean 27.4 days); HADH 125 days; GLUD1 157 days [3].

Other metabolic causes present in the neonatal period with neurological deterioration dominated by hypoglycaemia (type V of the Saudubray classification): hyperinsulinism, FAO, GSD I and III, FBPase deficiency, HFI exposed to sucrose-containing formula, galactosaemia, tyrosinaemia type 1, transaldolase deficiency, neonatal haemochromatosis and mitochondrial DNA depletion syndromes; seizures, hypotonia and lethargy improve rapidly with normalisation of blood glucose, except in FAO defects [15]. About half of patients with FBPase deficiency present on days 1–4 with hyperventilation due to profound lactic acidosis and marked hypoglycaemia, and a sibship with a previous death from acidosis is often the warning sign [13,44]. In HMG-CoA lyase deficiency, about 50% present in the first 5 days with hypoglycaemia, metabolic acidosis, vomiting and reduced consciousness, with inappropriately low ketone bodies and very high lactate [12]. Among hormone deficiencies, X-linked congenital adrenal hypoplasia (NR0B1) manifests in ~60% of boys as acute infantile adrenal insufficiency (mean onset ~3 weeks), with vomiting, dehydration, hypotension, hyponatraemia, hyperkalaemia and hypoglycaemia [66]; lipoid adrenal hyperplasia (STAR) and P450scc deficiency (CYP11A1) cause neonatal salt-wasting adrenal insufficiency, hypoglycaemia and hyperpigmentation (in the Korean cohort of 31 patients with STAR, median diagnosis at 36.5 days, salt wasting in 58.6% and hyperpigmentation in 71%) [67,68]. Congenital hypopituitarism is associated with hypoglycaemia, micropenis, prolonged jaundice and midline malformations [1,4].

3.3. Infancy and childhood

AD hyperinsulinism (dominant ABCC8/KCNJ11, GCK, GLUD1) has normal birth weight and median onset at around 1 year (2 days to 30 years), frequently with an unprovoked seizure or hypoglycaemia during an intercurrent illness with reduced intake; intrafamilial variability ranges from severe to mild and from immediate to late onset [1,2]. In hyperinsulinism-hyperammonaemia syndrome (HIHA, GLUD1), hypoglycaemia occurs after protein-rich meals, with stable overnight blood glucose and ammonia 1.5–4 times the upper limit of normal unrelated to blood glucose; about half of patients have mild to moderate intellectual disability, epilepsy (atypical absences, myoclonic seizures), pyramidal syndrome or dystonia [2,3]. A 2026 retrospective review described the natural history of HIHA with patient-centred data [69].

Hepatic glycogen storage diseases present in the infant rather than the newborn, with hypoglycaemia 2–3 h after a meal in GSD I and III; hepatomegaly may be absent at birth and develops as glycogen accumulates [1,58]. In GSD I, fasting tolerance is often 2–3 h; in GSD III it is longer, with fasting ketosis, hyperlipidaemia and very high transaminases; GSD VI and GSD IX may present with ketotic hypoglycaemia and growth delay without evident hepatomegaly [58]. GSD 0a (GYS2) is not a storage disease: it causes fasting ketotic hypoglycaemia with morning irritability before breakfast after weaning, without hepatomegaly (the main reason for missed diagnosis), with postprandial hyperglycaemia and hyperlactataemia; the Oxford book attributes this picture to "GSD IV", which in fact corresponds to GSD 0a, since GSD IV presents with cirrhosis [1,58,70].

FAO defects have three presentations: acute hypoketotic hypoglycaemia with encephalopathy, hepatomegaly and liver dysfunction ("Reye-like" picture), precipitated by fasting or infection with vomiting and sometimes a cause of unexpected death during a mild illness; cardiomyopathy, arrhythmias or conduction defects; and myopathy with rhabdomyolysis [61]. Hypoglycaemia is a late event in decompensation [61]. HMG-CoA synthase 2 deficiency (HMGCS2D) usually begins in the first year after the neonatal period (10 days to 6 years), with lethargy progressing to coma, acidotic breathing, hepatomegaly and hypoketotic or non-ketotic hypoglycaemia; in the series of 75 patients (59 published and 16 unpublished), 91% had acute decompensation, 8% died, mostly in the first crisis, and 98% of survivors had normal development; there are asymptomatic biallelic individuals [64,71]. Normoglycaemic crises with encephalopathy and severe acidosis have been described, and about one third have hyperammonaemia [71].

Idiopathic ketotic hypoglycaemia (IKH) presents in late infancy or early childhood, triggered by infections with anorexia and vomiting or by an overnight fast of 12–14 h, with adrenergic symptoms followed by neuroglycopenic ones, ketotic breath and mild metabolic acidosis [12]. It is more frequent in children with low weight or relative macrocephaly and sometimes after intrauterine growth restriction (IUGR) and transient neonatal hyperinsulinism, and appears to represent the lower tail of the Gaussian distribution of fasting tolerance [12]. Sources differ on the age range: 6 months to 6 years for Saudubray's book, from 1–2 years for the Oxford book, and 7 months to 7 years as the range of "physiological" ketotic hypoglycaemia in a Slovak cohort [1,12,72]. In that cohort of 560 healthy children admitted for dehydration with vomiting or poor intake, 171 (30.5%) had PG ≤3.3 mmol/L; the independent factors were greater dehydration (odds ratio [OR] 2.505; 95% confidence interval [95% CI] 1.532–4.095), total absence of oral intake (OR 2.185; 95% CI 1.331–3.586), lower body mass index (BMI) (median 14.29 vs 15.46 kg/m²) and absence of diarrhoea (diarrhoea OR 0.178; 95% CI 0.068–0.468) [72]. GSD IXa, with a soft liver that may not be enlarged, is a relatively common and easily missed cause of ketotic hypoglycaemia and may explain the higher frequency of IKH reported in boys [12]; long-term outcomes are available for 89 UK patients with hepatic GSD IX [73].

In FGD, median presentation is at 2.0 years in FGD1 (MC2R; 0.02–16 years), with tall stature (mean standard deviation score +1.75), and at 0.08 years in FGD2 (MRAP; birth to 1.6 years), without tall stature, in a comparison of 40 FGD1 patients with 22 FGD2 patients; in FGD4 (NNT), the median is ~12 months (3 days to 39 months; 23 patients), with hypoglycaemia frequently ketotic and with seizures, hyperpigmentation often as the first sign, and diagnosis delayed by 8–18 months after a severe hypoglycaemic episode [40,41,74]. Treatment of FGD is summarised in section 7.7.

3.4. Hereditary fructose intolerance

Patients are healthy as long as they do not ingest fructose, sucrose or sorbitol, and there is no decompensation during breastfeeding [13]. The younger the child and the greater the load, the more severe the reaction: a newborn fed a formula containing fructose or sucrose risks severe liver and kidney failure and death, and the 24% sucrose solution used as analgesia for minor procedures can cause fatal hypoglycaemia [8,13]. Presentation now occurs earlier than at weaning, because fructose is added to formulas [8]. At weaning, the introduction of fruit and vegetables causes gastrointestinal discomfort, nausea, vomiting, agitation, pallor, sweating, tremor, lethargy, apathy, coma, myoclonus and seizures, with acute liver failure and generalised proximal tubular dysfunction [13]. Hypoglycaemia after fructose is brief and easily missed or masked by glucose ingested at the same time [13]. In the laboratory, after exposure, there is hypoglycaemia, lactic acidaemia, hypophosphataemia, hyperuricaemia, hypermagnesaemia and hyperalaninaemia [8].

Without recognition, the course becomes chronic and fluctuating, with faltering weight gain, hepatomegaly, jaundice, bleeding, oedema, ascites and proximal tubulopathy [13]. Aversion to sweet foods protects older children and is sometimes interpreted as neurotic behaviour; at school age, the diagnosis arises from hepatomegaly or growth delay; in adults, after severe reactions to infusions of fructose, sorbitol or invert sugar; about half of adults have no dental caries [13]. Even when treated from birth, some patients retain hepatomegaly with steatosis; hepatic adenoma and fibrosis, lenticular cataracts in untreated adolescents and adults, persistent proximal tubulopathy, higher glomerular filtration rate and systolic pressure than controls and one case of stage IV chronic kidney disease in a patient treated only at 5 years have been described [8]. Suspicion should also arise after a severe reaction (vomiting, hypoglycaemia, lethargy, liver or kidney failure) to sucrose-containing rotavirus vaccines [8].

3.5. Fructose-1,6-bisphosphatase deficiency

The picture is one of episodic crises of lactic acidosis and hypoglycaemia — respiratory distress or hyperventilation, apnoeas, irritability, drowsiness, seizures, lethargy or coma, tachycardia, hypotonia and moderate hepatomegaly — above all in early childhood [9,13]. Almost half have neonatal hypoglycaemia, mostly in the first 4 days, because of insufficient glycogen stores; most present before 6 months, and one exception has been described at 4 years; in a series of 13 Japanese patients from 11 families, onset ranged from day 1 to 4 years [9,24,44]. Triggers are fever with food refusal and vomiting, fasting, infections and ingestion of large amounts of fructose (~1 g/kg in one dose), especially after fasting; one infant developed hyperventilation with a lactate of 20 mmol/L on starting baby foods at 6 months [13,44]. Patients generally have 4–5 episodes before diagnosis [9]. Between crises they are asymptomatic, sometimes with mild intermittent acidosis; crisis frequency decreases with age and most survivors have normal growth and development, although some have brain injury from early, prolonged hypoglycaemia and others obesity from carbohydrate overtreatment [9,13]. Without treatment, the course may worsen with multiorgan failure (liver, brain, then heart), and sepsis, blindness and a Reye-like picture have been described [9].

Unlike HFI, there are no gastrointestinal symptoms with chronic fructose ingestion, no aversion to sweet foods and no faltering weight gain, and liver function is rarely abnormal outside crises [13]. The French and Belgian series of 18 patients showed, however, that liver involvement is the rule: at follow-up, hepatomegaly in 8/18, raised transaminases in 6/15 and hyperechogenic liver in 7/11; during crises, hepatomegaly in 10/17, raised transaminases in 13/16, acute liver failure in 6/14 and hyperechogenicity in 4/14, with steatosis in adulthood [75]. Crises in adults are rare and associated with illness with fasting (including Ramadan fasting), pregnancy, alcohol, weight loss and intense training [9,52]. Ketonuria is frequently positive during crises, even though the disease is classified among the hypoketotic causes [44].

3.6. Cytosolic PEPCK, pyruvate carboxylase and glycerol kinase deficiencies

In PEPCK-C deficiency, the review of 32 patients from 25 families describes hypoglycaemia during catabolism with onset usually in infancy (neonatal to adult), raised urinary Krebs cycle intermediates, mildly raised transaminases and raised lactate [26]. In the Finnish national series (24 patients: 21 children and 3 adults, diagnosed in 2016–2019), episodes were mainly in the morning and triggered by infection, fasting or poor intake, intense exercise, alcohol and breastfeeding (in an affected mother); the first episode frequently appeared at 1–2 years, and could appear or recur at school age or in adulthood; 5 had neonatal hypoglycaemia and 12/24 hypoglycaemic seizures [14]. In the two Ashkenazi sisters of the first molecular description, the elder presented at 20 months with fasting hypoglycaemia during fever, with lethargy and ketonuria, appropriately raised GH and cortisol, undetectable insulin and normal C-peptide, and had at least 12 similar episodes over 5 years, sometimes with significant lactic acidaemia; liver biopsy at 4 years showed mild portal inflammation and fibrosis and macrovesicular steatosis [27]. Transient acute liver failure after gastroenteritis has been described, with hyperammonaemia and encephalopathy mimicking a urea cycle or mitochondrial defect, as well as the death of a 3-year-old boy with a "febrile seizure" during a respiratory infection, hypoglycaemia and cerebral oedema, diagnosed by post mortem trio exome [25,29,57].

Pyruvate carboxylase deficiency has three phenotypes: B (French, neonatal and usually fatal, with hypothermia, hypotonia, rigidity, tremor, severe lactic acidosis, tubulopathy and liver failure), A (North American, 2–5 months, progressive hypotonia, crises of lactic acidosis with stress, severe intellectual disability and seizures) and C (benign, with crises of lactic acidosis and ketoacidosis and near-normal development) [29]. GKD has infantile (severe delay), juvenile (episodic vomiting, metabolic acidosis, stupor, coma, with a risk of hypoglycaemia and hyperketonaemia) and adult (asymptomatic, detected through pseudohypertriglyceridaemia) forms; in the complex form, adrenal hypoplasia dominates and may be rapidly fatal (sodium loss, hypoglycaemia, hyperkalaemia), with raised creatine kinase (CK) due to Duchenne dystrophy [30,31].

3.7. Insulin signalling defects and insulin resistance

In hypoinsulinaemic hypoglycaemia with hemihypertrophy (AKT2), there is macrosomia at birth, asymmetric overgrowth (typically left hemihypertrophy) and severe fasting hypoglycaemia from ~6 months, with seizures after ~3 h without feeding; the biochemistry mimics hyperinsulinism (suppressed ketones and FFA) but insulin and C-peptide are low or undetectable [35,36]. Follow-up of two patients up to 17 years showed neither dyslipidaemia nor steatosis, and spontaneous remission is possible [76]. A second independent case confirmed the phenotype of hypoketotic hypoinsulinaemic hypoglycaemia [77].

Severe insulin resistance syndromes due to INSR form a continuum: in Donohue syndrome (leprechaunism), there is universal hyperinsulinism with fasting hypoglycaemia and postprandial hyperglycaemia from birth, IUGR and postnatal growth restriction, hypotonia, intellectual disability, characteristic facies (proptosis, infraorbital folds, large ears, gingival hypertrophy), hypertrichosis, acanthosis nigricans, genital enlargement and organomegaly, with death usually in the first year; in Rabson-Mendenhall syndrome, which is milder, insulin falls after the first year and hyperglycaemia and ketoacidosis replace hypoglycaemia [78]. The heterozygous INSR variant causes type A insulin resistance and also an AD form of familial hyperinsulinaemic hypoglycaemia (HHF5) with postprandial hypoglycaemia aggravated by exercise and a raised insulin:C-peptide ratio (24 people from 9 families) [2,78].

3.8. Exercise-induced hyperinsulinism and Mahvash disease

In exercise-induced hyperinsulinism (SLC16A1, AD), described in Saudubray's book as a rare condition with non-ketotic hypoglycaemia characteristic of hyperinsulinism [79], there is inappropriate insulin release after brief anaerobic exercise or a pyruvate load, with hypoglycaemia within ~30 min, loss of consciousness and seizures, in childhood or later [2,33]; in a Finnish series, 3 of 153 patients with hyperinsulinism had this cause [2]. Mahvash disease (GCGR, AR) is a rare cause of occasional hypoglycaemia, mainly in adults, with marked hyperglucagonaemia without glucagonoma syndrome, diffuse alpha-cell hyperplasia and glucagon-positive pancreatic neuroendocrine tumours; fewer than 20 cases had been described by 2026, and in a 7-year-old girl raised arginine was detected on newborn screening [80].

3.9. Adolescent and adult

In the adult without diabetes, the most frequent causes of hypoglycaemia are drugs, critical illness, hormone deficiencies, non-islet cell tumours, accidental, surreptitious or malicious hypoglycaemia and endogenous hyperinsulinism (insulinoma, post-bariatric hypoglycaemia, non-insulinoma pancreatogenous hypoglycaemia syndrome) [10,45]. Monogenic causes that may manifest for the first time at this age include HFI exposed to infusions of fructose, sorbitol or invert sugar, PEPCK-C deficiency (adults with alcohol, intense exercise or breastfeeding), the rare crises of FBPase deficiency during prolonged fasting, AD hyperinsulinism with onset up to 30 years, the asymptomatic adult form of GKD with pseudohypertriglyceridaemia, Mahvash disease and insulinoma in multiple endocrine neoplasia type 1 (MEN1) [2,9,10,13,14,31,80]. In HMG-CoA lyase deficiency there are rare cases of adult onset and pregnancies are high risk [12].

4. Clinical Recognition and Warning Signs

4.1. Newborns requiring glucose screening and exclusion of a persistent disorder

The PES distinguishes two groups of newborns: those at risk of hypoglycaemia who require glucose screening, and those in whom a persistent disorder must be excluded before discharge [4]. Saudubray's book adds that, even with broad screening, about half of congenital hyperinsulinisms present with seizures or coma, because most do not meet the screening criteria [3].

In newborns at known risk of a genetic form (sibling with congenital hyperinsulinism, glucose-6-phosphatase deficiency or FAO), the PES recommends consulting the specialist before discharge, performing the tests that can exclude the disorder within weeks (genetics, acylcarnitines) and carrying out a "safety" fasting test to ensure PG >70 mg/dL if a meal is missed (minimum 6–8 h); in at-risk newborns without suspicion of a persistent disorder, the 6–8 h safety fast checks PG >60 mg/dL [4]. Newborn siblings of patients with FBPase deficiency should avoid fasting, be fed regularly, be monitored for hypoglycaemia and acidosis (lethargy, poor intake, vomiting, hypothermia, tachypnoea) and have a low threshold for 5–10% IV glucose, especially if they have low birth weight, are preterm or are infants of a diabetic mother [9]. In hyperinsulinism, molecular testing or careful glucose monitoring from birth is the rule for at-risk newborns [2].

The 2011 American Academy of Pediatrics (AAP) clinical report on glucose homeostasis in late-preterm (34 0/7–36 6/7 weeks) and term newborns starts from the consensus of a National Institutes of Health panel (2008) that there is no plasma glucose value or range proven to be associated with brain injury, and that the <47 mg/dL threshold used as a definition has no rigorous scientific justification; it therefore proposes a pragmatic approach, with a safety margin above the values associated with clinical signs [46]. For practical purposes, it regards as at risk only late-preterm infants, small-for-gestational-age (SGA) infants, large-for-gestational-age infants and infants of diabetic mothers, and does not recommend routine screening in the healthy term newborn after a normal pregnancy and delivery; any newborn with compatible signs has blood glucose measured within minutes [46]. Infants of diabetic mothers may have asymptomatic hypoglycaemia from the 1st hour and generally up to 12 h, and SGA or large-for-gestational-age infants from 3 h and up to 10 days of life; at-risk newborns are fed within the 1st hour of life and screened 30 minutes later, late-preterm and SGA infants are fed every 2 or 3 hours and screened before each feed for at least 24 h (extended if glucose remains below 45 mg/dL), and infants of diabetic mothers and large-for-gestational-age infants up to 12 h if they maintain values above 40 mg/dL [46]. In the asymptomatic at-risk newborn, the AAP accepts IV glucose only below 25 mg/dL between birth and 4 h or below 35 mg/dL between 4 and 24 h, with a pre-prandial target above 45 mg/dL; in the symptomatic newborn, the treatment threshold is 40 mg/dL, with laboratory sampling immediately before an IV mini-bolus of 200 mg/kg of glucose (2 mL/kg of 10% dextrose) and/or a continuous infusion of 10% dextrose at 80–100 mL/kg/day, keeping glucose between 40 and 50 mg/dL [46]. Test-strip blood glucose varies by 10–20 mg/dL from the true value, more so in the low range, and no bedside method is adequate on its own for screening; plasma glucose is 10–18% higher than whole-blood glucose, and transport in a fluoride tube avoids falsely low values due to glycolysis [46]. Signs of hypoglycaemia are non-specific (jitteriness, cyanosis, seizures, apnoea, tachypnoea, weak or high-pitched cry, hypotonia or lethargy, poor sucking, eye-rolling), and the AAP suggests Whipple's triad to attribute them to hypoglycaemia; before discharge, the newborn should maintain normal blood glucose on the usual diet for at least 3 feed-fast cycles, which allows recognition of persistent hyperinsulinism and fatty acid oxidation defects [46]. These thresholds for the first 24 h are lower than those of the PES, which targets >50 mg/dL in the first 48 h and >60 mg/dL thereafter, because the two documents address different problems: the AAP the normal transition in the first hours, the PES the identification of persistent disorders [4,46].

4.2. Clues from the history

The history includes a three-generation pedigree with consanguinity, unexplained neonatal or infant deaths and Reye syndrome-like episodes, gestational diabetes, birth weight, Apgar score and resuscitation, the sequence "normal baby who fed well and then deteriorated" (more suggestive of an inborn error), the age at detection of hypoglycaemia, the relationship with fasting and metabolic stress, and seizures [1]. The PES adds the time of the episode and its relationship with feeding and gestational age [4]. Specific clues include postprandial hypoglycaemia after protein-rich meals with stable overnight blood glucose (HIHA), severe hypoglycaemia after anaerobic exercise (SLC16A1), a family history of neonatal diabetes, MODY (ABCC8, KCNJ11, HNF1A, HNF4A, GCK) or intellectual disability and epilepsy (GLUD1), and ethnic origin (founder ABCC8 variants in Ashkenazi Jews and Finns) [2,3]. A detailed nutritional history of weaning, aversion to sweet foods and absence of dental caries point to HFI; symptoms after the introduction of fruit juices, after fasting with fever or with the rotavirus vaccine point to HFI or FBPase deficiency [8,13,44]. The history of medicines and toxins (insulin, sulfonylureas, alcohol, beta-blockers, salicylates), fundoplication (postprandial hypoglycaemia in 25–30%) and bariatric surgery should always be explored [4].

4.3. Clues from physical examination

The examination includes weight, length and head circumference, posture, tone and abnormal movements, dysmorphic features and macrosomia [1]. Hepatomegaly is moderate in hyperinsulinism and FAO defects and severe in GSD I and III, and may be absent in the newborn with GSD I/III [1]. Cardiomyopathy and arrhythmias suggest FAO; micropenis and midline malformations (cleft palate) suggest GH and ACTH deficiency; hyperpigmentation, recurrent abdominal pain, anorexia and weight loss suggest adrenal insufficiency; omphalocele, hemihypertrophy and macroglossia suggest Beckwith-Wiedemann [1,4]. Hemihypertrophy with hypoglycaemia and undetectable insulin suggests AKT2; megalencephaly, PIK3CA or AKT3; Kabuki dysmorphic features (mainly KDM6A), overgrowth with macrocephaly in Sotos, syndactyly with arrhythmia in Timothy, cystic kidneys with hyperinsulinaemic hypoglycaemia (PMM2 promoter) and fat pads and cardiac or vertebral malformations point to syndromic hyperinsulinism [1–3,15]. Tall stature with hyperpigmentation suggests FGD1 [39]. Elfin facies, scant subcutaneous fat and muscle mass, hypertrichosis and acanthosis nigricans suggest Donohue [3,78]. A doll-like appearance and short stature accompany GSD I and Fanconi-Bickel syndrome [15].

4.4. Warning and emergency signs

Emergency signs are hypoglycaemia with altered consciousness or seizures, severe metabolic acidosis with hyperventilation (gluconeogenesis defects, HMG-CoA lyase, organic acidurias), hypotension with hyponatraemia and hyperkalaemia (adrenal insufficiency, including X-linked adrenal hypoplasia and undiagnosed X-linked adrenoleukodystrophy), acute liver failure (HFI, FBPase deficiency, PEPCK-C, tyrosinaemia, FAO), arrhythmia or cardiomyopathy (FAO) and a glucose requirement >8 mg/kg/min in the newborn [10,15,66]. In any child with a seizure, altered consciousness or an apparent febrile seizure, glucose should be measured, a lesson drawn from the fatal case of PEPCK-C deficiency [25]. A simplistic diagnosis of fasting ketoacidosis or idiopathic ketotic hypoglycaemia should be questioned when there is concomitant severe metabolic acidosis [15]. In sudden infant deaths with suspected hypoglycaemia, a genetic condition with a recurrence risk of up to 25% should be considered and the post mortem sampling described in section 5.10 carried out [1,59].

4.5. Newborn screening

Newborn screening by mass spectrometry detects some of the causes of hypoglycaemia: HMG-CoA lyase deficiency is included in the screening of several countries, including the USA, through 3-hydroxyisovalerylcarnitine (C5-OH), which has to be differentiated from other causes of raised C5-OH [12]; FAO and carnitine cycle defects (including MCAD deficiency), galactosaemia and tyrosinaemia type 1 have their own approach. Raised glutamine in dried blood spots has been proposed as a screening marker for PEPCK-C deficiency, still as a hypothesis [25,26], and in Mahvash disease raised arginine was detected on the screening of one child [80]. Hyperinsulinism, HFI and FBPase deficiency are not detected by the newborn screening programmes described in the sources consulted, so recognition depends on the clinical picture and targeted glucose screening.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Confirming hypoglycaemia

Diagnosis requires PG measured by a laboratory method: whole-blood glucose is ~15% lower than plasma glucose, erythrocyte glycolysis reduces glucose by up to 6 mg/dL/h (0.3 mmol/L/h) if processing is delayed, and bedside glucose meters have an accuracy of ~±10–15 mg/dL (0.6–0.8 mmol/L) in the hypoglycaemic range [4]. The meter value triggers sampling and treatment, but the diagnosis is confirmed in the laboratory, without delaying correction [4,47]. The PES recommends investigating the underlying mechanism of all persistent hypoglycaemia disorders to allow specific treatment (recommendation 2.1, strong, high-quality evidence) [4].

5.2. Critical sample

The critical sample is collected at spontaneous presentation, before treatment, because IV glucose alters BOHB, FFA and insulin within minutes, and because metabolites normalise rapidly [4,81]. The PES regards PG, bicarbonate, BOHB and lactate as available and useful for separating the major categories, and instructs that plasma be stored for insulin, FFA and C-peptide (suspected hyperinsulinism) and for total and free carnitine and the acylcarnitine profile (suspected FAO); laboratory reference ranges for insulin and BOHB may be inadequate for interpreting values during childhood hypoglycaemia [4]. The British Inherited Metabolic Disease Group (BIMDG) defines the most important samples as glucose and insulin, followed by cortisol and lactate, and insists that correction should not be delayed if blood is difficult to obtain [16].

The Oxford book lists as basic screening glucose, calcium, sodium, pH, base excess and bicarbonate, liver function, ammonia, uric acid, full blood count (neutropenia in GSD Ib) and urine dipstick for pH, ketones and reducing substances, alongside investigation of non-genetic causes [1]. When there is no critical sample, a provocative fasting test is the most informative method, because tests with normal glucose are rarely informative [4].

5.3. Interpretation: the critical sample algorithm

The figure in the PES article ("Metabolic Clues to Hypoglycemia Diagnosis"), consulted in the official PubMed Central version, organises interpretation on the basis of bicarbonate, BOHB, lactate and FFA measured during hypoglycaemia (figure 1 of Thornton 2015) [4].

Saudubray's book structures the approach around four clinical criteria: liver size, the characteristic timing of hypoglycaemia, the association with lactic acidosis (gluconeogenesis) and the association with hyperketosis or hypoketosis (the latter suggests FAO, ketogenesis, hyperinsulinism and defects of the INSR/PI3K/AKT pathway) [15]. Timing is a guide: unpredictable and postprandial hypoglycaemia (<2.5 h) suggests hyperinsulinism or fabricated or induced illness (Munchausen by proxy); after a short fast (>2.5–8 h), GSD I, III or 0; after a moderate to long fast (>8–24 h), "enzymatic" gluconeogenesis defects (FBPase, PEPCK-C) or "energy" defects (FAO, ketogenesis, respiratory chain) [15]. With permanent hepatomegaly, the cause is usually an inborn error: dominant hepatomegaly without liver failure points to GSD I and III; FBPase deficiency and FAO defects may have moderate to marked hepatomegaly during crises; fibrosis or cirrhosis (tyrosinaemia type 1), S-adenosylhomocysteine hydrolase deficiency, respiratory chain defects (complex III, UQCRB, which mimics FBPase) and CDG (PMM2-CDG and MPI-CDG, with hepatic fibrosis and protein-losing enteropathy) also cause hypoglycaemia with an abnormal liver [15]. Without hepatomegaly, most hypoglycaemias due to inborn errors appear after ≥8 h of fasting; severe fasting hypoglycaemia without ketosis suggests FAO (without severe acidosis), HMG-CoA lyase or synthase deficiency (with acidosis) and PEPCK-C; ketoacidosis with hypoglycaemia suggests ketolysis defects, organic acidurias, late-onset MSUD and GKD; and adrenal insufficiencies, including X-linked adrenoleukodystrophy, always remain in the differential [15].

Ketonuria is always abnormal in the newborn, but physiological in catabolism in late infancy, childhood and adolescence; total ketone bodies >6 mmol/L with bicarbonate <18 mmol/L are not physiological, and ketosis without acidosis, hyperlactataemia or hypoglycaemia is probably physiological [15]. Absence of ketonuria during hypoglycaemia, fasting or catabolism suggests FAO, a ketogenesis defect, a hyperinsulinaemic state (any age), GH deficiency in the infant or citrin deficiency; SCHAD, short-chain acyl-CoA dehydrogenase (SCAD) and MCAD deficiencies may nevertheless present with recurrent ketotic hypoglycaemia [15]. Significant fasting ketonuria without acidosis occurs in GSD III (marked hepatomegaly) and GSD 0 (normal liver), in IKH and in adrenal insufficiency [15]. In severe hypoketotic hypoglycaemia, hyperammonaemia (generally <250 μmol/L) suggests HIHA or FAO with cardiac involvement, and in HIHA ammonia is usually 80–180 μmol/L [3,15]. The Oxford book notes that lactate is not raised in HIHA, unlike FAO defects, organic acidaemias and mitochondrial diseases [1].

5.4. Practical algorithm by age

5.5. Diagnostic criteria for hyperinsulinism and the glucagon stimulation test

The 2024 consensus recommends that the diagnosis of hyperinsulinism be based on measurements, during hypoglycaemia, of fuels (BOHB, FFA) and hormones (insulin, GH, cortisol) and on the glycaemic response to a pharmacological dose of glucagon (recommendation 1.1, strong, moderate-quality evidence), with insulin measured by a high-sensitivity assay [10]. Suppression of BOHB and a preserved glycaemic response to glucagon are the most sensitive markers; without multiple pituitary hormone deficiency, an excessive response to glucagon in the newborn may be considered diagnostic even with low insulin, and in the event of discrepancy (raised insulin with high ketones and no response to glucagon) markers of insulin action are given priority [10]. Newborns tested before 72 h should be retested after 72 h if hypoglycaemia persists, and stimulation tests with glucose, leucine or protein are not used for diagnosis, but help to define the subtype [10].

Sources: [2–4,10,59]. The Oxford book regards an infusion rate >8 mg/kg/min as "virtually diagnostic" of hyperinsulinism [1]; the normal rate is 4–6 mg/kg/min in the newborn according to the consensus (5–8 mg/kg/min according to GeneReviews) and 3–5 mg/kg/min in the infant and child [2,10]. The units in Saudubray's chapter for ketone bodies and FFA are printed in μmol/L, which is not compatible with physiological values, and were read as mmol/L [3]. Insulin secretion is pulsatile and a single sample may miss hyperinsulinaemia [3].

The glucagon stimulation test is performed only after the critical sample has been collected: with glucose <50 mg/dL, glucagon 30 μg/kg or 0.5–1 mg is given IM or as an IV bolus, glucose is measured every 10 min for 40 min, the test is stopped if glucose remains <50 mg/dL at 30 min, and at 40 min the patient is fed and treatment resumed to achieve PG >70 mg/dL [10]. An exaggerated response (>30 mg/dL) is "almost pathognomonic" of hyperinsulinism and excludes a primary hepatic or metabolic defect [2,4]. The response is dramatic in hyperinsulinism, absent in glycogen storage diseases, variable in FAO defects and endocrine deficiencies, and absent in fructose-induced hypoglycaemia in HFI and during crises of FBPase deficiency [1,8,13]. Saudubray's book has abandoned the glucagon test in the investigation of fasting hypoglycaemia because it is dangerous (it may precipitate catabolic decompensation once glycogen is depleted) and reserves it for spontaneous postprandial hypoglycaemia with suspected hyperinsulinism [12,59].

5.6. Functional tests

Metabolic profile throughout the day. This is indicated at initial or recurrent presentation with hypoglycaemia, hyperlactataemia, hyperketosis or hypoketosis and is always performed before any provocative test: with a venous catheter, glucose (measured immediately), acid-base balance, lactate and pyruvate (immediate deproteinisation with perchloric acid), FFA, ketone bodies, ammonia and hormones (insulin, cortisol, GH) are collected before and 1 h after breakfast, lunch and dinner and at 04:00, with amino acids, carnitine and acylcarnitines once and a fractionated 24 h urine collection [59]. In GSD I and gluconeogenesis defects, glucose and lactate move in opposite directions and hypoglycaemia and hyperlactataemia are maximal when fasting; in GSD III, VI and IX they move in parallel, with a moderate postprandial rise in both; in GSD 0 there is fasting hypoglycaemia with ketosis and postprandial hyperlactataemia and hyperglycaemia; in hyperinsulinism, insulin >3 μU/mL with glucose <2.8 mmol/L is abnormal [59]. Continuous glucose monitoring for 2–3 days during normal activity is useful for symptoms at home and in known glycogen storage diseases [59].

Diagnostic fasting test. Saudubray's book restricts it, because it is dangerous, to unexplained hypoglycaemia after baseline investigation (organic acids, acylcarnitines, enzymatic or molecular studies) has excluded FAO and adrenal insufficiency, or to the assessment of fasting tolerance under treatment, always in a specialised metabolic unit, after 3 days of adequate feeding and without infection in the preceding week [59]. Duration is 12 h below 6 months, 20 h from 6 to 12 months and 24 h from 1 year, ending during the day; the safety monitors are glucose and bicarbonate, measured every 30 min when glucose falls below 3.2 mmol/L, and the test is stopped immediately with glucose <2.6 mmol/L, bicarbonate <15 mmol/L or neurological symptoms, at which point the full sample is collected [59]. Suspected ACTH deficiency contraindicates the test [59]. The 2024 consensus describes the protocol for hyperinsulinism:

Source: [10]. The PES regards a PG of 50 mg/dL (2.8 mmol/L) as sufficient to trigger the necessary metabolic and neuroendocrine responses and recommends stopping earlier if there is distress or BOHB >2.5 mmol/L [4]. Normal values at the end of fasting or during hypoglycaemia, at any age, are insulin <3 mU/L with glucose <2.8 mmol/L, ACTH <80 pg/mL and GH >10 ng/mL; the cortisol value printed in the source table (">120 ng/mL") is inconsistent with the interpretation threshold in the same chapter (cortisol <250 nmol/L with glucose <2.8 mmol/L indicates adrenocortical insufficiency), which is the one used here [59].

Source: [59]; the column order follows that of the text extracted from the original table.

Oral glucose load test. This is indicated in moderate or intermittent hypoglycaemia or hyperlactataemia of unknown origin: after 3–8 h of fasting, 2 g/kg of glucose (maximum 50 g) as a 10% solution, with glucose, lactate, pyruvate, BOHB and AcAc every 30 min for 3–4 h [59]. A marked fall in lactate from a high fasting value suggests a gluconeogenesis defect or GSD I; an exaggerated rise from a normal lactate suggests the other glycogen storage diseases, including GSD 0; a brief rise followed by an abrupt fall in glucose occurs in some hyperinsulinisms; a paradoxical rise in ketones occurs in PC deficiency (with low 3OHB/AcAc) and in respiratory chain defects (with high 3OHB/AcAc); the test is stopped with glucose <2.6 mmol/L and may precipitate lactic acidosis in PDH deficiency [59].

Tests for exercise-induced hyperinsulinism. Diagnosis is made with a supervised anaerobic exercise test or an IV pyruvate load, with paired glucose and insulin [33,54]. The exercise test in Saudubray's procedures chapter is intended for metabolic myopathies and is different [59].

Fructose tolerance tests and other loading tests. The sources differ. Saudubray's book accepts, in an experienced centre and when the history is suggestive without identified variants, the IV fructose test (200 mg/kg as a 20% solution over 2 min, with glucose and phosphate at 0, 5, 10, 15, 30, 45, 60 and 90 min; in HFI, glucose and phosphate fall within 10–20 min, phosphate first) and advises against the oral test [13]; Nyhan's atlas describes it as preferable when used and reports a patient in coma after 500 mg/kg [44]. The HFI GeneReviews considers that the test may be fatal and should not be used, and the FBPase deficiency GeneReviews classifies it as dangerous [8,9]. Galactose, fructose, fat and phenylpropionate loads and the glucagon test to differentiate glycogen storage diseases have fallen into disuse [59]. In FBPase deficiency and GKD, loading tests (fructose, glycerol, alanine, ketogenic diet, exercise) and the fasting test should not form part of the initial investigation [13,30].

5.7. Derived biochemical indices

The lactic acidosis table in Saudubray's book characterises gluconeogenesis defects (glucose-6-phosphatase, FBPase, PEPCK-C) by maximal hyperlactataemia when fasting and during hypoglycaemia, L/P <15, raised fasting or normal ketone bodies (low in PEPCK-C), raised fasting alanine and, in urinary organic acids, lactate with fumarate and succinate in PEPCK-C; PC deficiency and malate-aspartate shuttle (MAS) defects by permanent hyperlactataemia, L/P >30, postprandial ketones, very low 3OHB/AcAc, raised ammonia, proline and citrulline and low glutamine [59]. Many patients with respiratory chain defects do not have hyperlactataemia [59].

In urine, raised plasma alanine with urinary lactate, fumarate and succinate suggests hyperlactataemia, mitochondrial disease, PEPCK-C or FBPase; very high 3-hydroxybutyrate with AcAc suggests ketosis or a ketolysis defect; low 3-hydroxybutyrate with dicarboxylic and 3-hydroxydicarboxylic acids suggests FAO; glycerol suggests GKD or Xp21 deletion; 3-hydroxy-3-methylglutaric acid with 3-hydroxyisovaleric and 3-methylglutaconic acids suggests HMG-CoA lyase; 2-methyl-3-hydroxybutyric acid with tiglylglycine suggests beta-ketothiolase; hexanoylglycine and suberylglycine suggest MCAD [59].

5.8. Entity-specific diagnosis

Hereditary fructose intolerance. There are no consensus criteria [8]. When it is suspected, fructose is eliminated immediately; improvement within days — fall in transaminases and bilirubin, correction of coagulation and of the tubulopathy (proteinuria, glycosuria, hyperaminoaciduria, hyperphosphaturia, hypophosphataemia, hyperuricosuria, metabolic acidosis) — is the first clue [13]. The diagnosis is established by a suggestive clinical picture after exposure and biallelic pathogenic or likely pathogenic variants in ALDOB, or, rarely, by deficient hepatic aldolase B activity; biallelic variants of uncertain significance (VUS) or one pathogenic variant with one VUS neither establish nor exclude the diagnosis [8]. Molecular testing in leucocytes is non-invasive and avoids the secondarily low aldolase B activity of the injured liver [13]. Sequencing detects 75–100% of variants and deletion/duplication analysis 0–25%, depending on the population [8].

Source: [8]. Associated findings are proximal tubulopathy, abnormal transferrin isoelectric focusing and elevation of multiple plasma lysosomal enzymes, above all aspartylglucosaminidase [8]. Raised carbohydrate-deficient transferrin normalises with diet and has been proposed as a useful biochemical test, but the pattern is not characteristic and it should not be used in isolation [8,82,83]. Without identified variants and with a strong history, hepatic enzyme activity is used (mean activity towards F-1-P of 5% [0–15%, up to 30% described] and towards F-1,6-P2 of 17% [5–30%]; Vmax ratio F-1,6-P2/F-1-P from 2 to ∞, against ~1 in controls) [13]. Aldolase is normal in blood cells, muscle and fibroblasts (aldolase A), and intestinal mucosa is not recommended [13].

FBPase deficiency. Suggestive findings are hypoglycaemia (<40 mg/dL in the newborn; <60 mg/dL thereafter), high anion gap metabolic acidosis, lactate >4 mmol/L, pH <7.35, bicarbonate <20 mmol/L, possibly raised L/P, hyperalaninaemia, normal or low ketosis in some patients, hyperuricaemia, increased FFA and, in urinary organic acids during crises, glycerol-3-phosphate and glycerol, which normalise afterwards [9]. During crises, lactate may reach 15–25 mmol/L with L/P up to 40 and glucagon-resistant hypoglycaemia; raised glycerol causes pseudohypertriglyceridaemia, and methods with glycerol subtraction (glycerol blanking) avoid the error [9,13]. Glycerol and glycerol-3-phosphate are better detected with urease pretreatment without extraction, hydrophilic interaction chromatography or ion-pairing reversed-phase chromatography [13]. The diagnosis is established by biallelic variants in FBP1 and/or deficient activity in liver or mononuclear leucocytes; genetics is preferred, with sequencing detecting ~90% of variants and deletion/duplication analysis ~10% [9]. Hepatic activity is residual (0–30%) and obligate heterozygotes have intermediate values; mixed leucocytes are unsuitable, whereas isolated and stimulated monocytes (or cultured with calcitriol) appear reliable; fibroblasts, amniocytes and chorionic villi do not express FBPase [13,44]. A severe phenotype with normal leucocyte activity has been described [84]. The sample for the enzyme assay is stable for 24 h at +4 °C [9].

PEPCK-C deficiency. The pattern is fasting hypoglycaemia with hyperlactataemia, inadequate ketones and raised urinary excretion of fumarate and other Krebs cycle intermediates, a reproducible but non-specific pattern; glucose during the episode is essential because the abnormalities are episodic, and plasma glutamine is raised in some patients [14,25,26]. In liver failure, the amino acid profile with hyperammonaemia may mimic a proximal urea cycle defect [25]. Diagnosis is molecular (panel or exome), and the enzyme assay, available in specialised laboratories, confirmed a homozygous 12 bp deletion [25].

PC deficiency. In type B, high L/P with low 3OHB/AcAc (<2; normal 2.5–3) is almost pathognomonic, with hyperammonaemia 100–600 μmol/L, citrulline 100–400 μmol/L, raised lysine and proline and low glutamine, and cystic periventricular leucomalacia at birth is suggestive [29].

Glycerol kinase deficiency. Raised urinary glycerol (gas chromatography-mass spectrometry of organic acids) and falsely raised triglycerides in non-lipaemic serum, which do not fall with treatment, are the clues; confirmation is by a GK variant (which identifies female carriers and asymptomatic men) or activity in fibroblasts (<1–5% in the complete form) [30,31]. Glycerol-blanked triglycerides, serum free glycerol and the nuclear magnetic resonance lipid profile correct the error (in one family, triglycerides 5.28 vs 0.81 mmol/L by resonance, and low-density lipoprotein (LDL) cholesterol underestimated, 0.93 vs 2.18 mmol/L); a review of 39 patients proposed a clinical diagnostic score [31,85]. In every boy with GKD it is mandatory to establish whether there is a contiguous deletion, with copy number analysis and measurement of ACTH, cortisol, electrolytes, glucose and CK [31].

Hormone deficiencies. In the fasting test, glucose <2.8 mmol/L with simultaneous cortisol <250 nmol/L suggests adrenocortical insufficiency, and with GH <10 ng/mL suggests GH deficiency, although the test is usually of little use for the latter [59]. Suspected primary adrenal insufficiency requires simultaneous ACTH and cortisol; an ACTH stimulation test may be needed for secondary or tertiary insufficiency [4]. The Endocrine Society recommends a low diagnostic threshold in acutely ill patients and defines the short corticotropin test (250 μg) as the standard, with morning ACTH and cortisol if it is not possible [86]. In FGD, cortisol is low with markedly raised ACTH and a preserved renin-aldosterone axis, which distinguishes it from the other primary adrenal insufficiencies [39]. Without an acute sample, clinical examination, the Synacthen test and metabolic and genetic investigation exclude most causes without inducing hypoglycaemia [12].

Insulin signalling and insulin resistance. In hypoketotic hypoglycaemia with suppressed FFA and undetectable insulin and C-peptide, activation of the insulin signalling pathway (AKT2, PIK3CA, AKT3, PIK3R2, CCND2) should be considered and confirmed molecularly before starting drugs for hyperinsulinism or considering pancreatic surgery [10,35]. High insulin with low C-peptide during hypoglycaemia suggests exogenous insulin [4]. Very high insulin with fasting hypoglycaemia and postprandial hyperglycaemia suggests INSR insulin resistance; type B insulin resistance syndrome (anti-receptor antibodies) is the acquired equivalent [10,78].

Idiopathic ketotic hypoglycaemia. There is no specific test; it is a diagnosis of exclusion that requires ruling out drugs (beta-blockers, alcohol), liver disease (including mitochondrial), adrenal insufficiency, hypopituitarism or isolated GH deficiency, glycogen storage diseases (including GSD 0 and IXa), Fanconi-Bickel, gluconeogenesis defects, defects of ketone body utilisation or transport, organic acidaemias, MSUD and FAO [12]. During hypoglycaemia, lactate and alanine are frequently low with raised branched-chain amino acids [12]. The PES recommends reassessing GSD 0, VI and IX (especially in boys) and MCT1 deficiency in recurrent ketotic hypoglycaemia [4]. A controlled fasting test is useful to define how long the child can fast safely [12].

5.9. Genetic testing: strategy, limitations and reporting

The 2024 consensus recommends genetic testing in all children with hyperinsulinism, except those with a probable acquired form (recommendation 1.2, strong), evaluation for multisystem syndromes (recommendation 1.3) and insulinoma screening in all children whose hyperinsulinism appears after 2 years (recommendation 1.4) [10]. Rapid ABCC8 and KCNJ11 testing has priority in diazoxide non-responders, because a single paternal recessive variant predicts a focal lesion with a sensitivity of 97% and a positive predictive value of up to 94%; without a variant or with hyperinsulinism persisting beyond 3 months, a next-generation sequencing (NGS) panel, exome or genome covering all known genes is indicated [10]. In non-responders without genetic evidence of diffuse disease, 18F-DOPA positron emission tomography (18F-DOPA PET) localises the focal lesion with a sensitivity of 75–100% and a specificity of 88–100% in 286 cases with histology; a negative PET does not exclude a small focal lesion (recommendation 1.5) [10]. 68Ga-NODAGA-exendin-4 PET is under evaluation, and intraoperative ultrasound after PET has a sensitivity of 80% and a specificity of 100% [2,10].

No test detects all abnormalities. Sanger sequencing does not detect large CNV; exome and panels do not detect deep intronic variants (ABCC8, HADH, HK1) nor, if they are coding-only, promoter or regulatory variants of SLC16A1 and PMM2 (c.-167G>T, hyperinsulinism with polycystic kidney disease); suspected BWSp requires separate 11p15 methylation testing; low-grade mosaicism (LINE-HI, AKT2) may escape blood testing and require tissue [10,33,36]. In GKD, copy number analysis is needed for the Xp21 deletion [31]; in HFI, MLPA identifies CNV in ~6% of alleles not detected by sequencing [13]. The proportion of probands with hyperinsulinism without an identified molecular cause is 21–55%, depending on the method used [2]; Saudubray's book estimates a genetic cause in ~50% of diazoxide-responsive and 80–90% of diazoxide-resistant cases [3]. The proportion of variants detectable by a method is not equivalent to the clinical sensitivity of the test for the disease. Some centres use NGS as first line and others perform metabolic investigation before panels; NGS does not replace biochemistry, requires functional tools to validate variants, and genes with both dominant and recessive inheritance (ABCC8, KCNJ11, SLC16A1, INSR) complicate interpretation [59]. The probability of diagnosis by exome increases with consanguinity, affected siblings or trio analysis [59].

The report should state the gene, the transcript with version (for example, NM_000035.4 for ALDOB, NM_000507.4 for FBP1, NM_002591.4 for PCK1, NM_000352.6 for ABCC8), the HGVS c. and p. nomenclature, zygosity, parental origin when known (decisive in focal hyperinsulinism) and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [10,62]. ABCC8 and KCNJ11 missense variants are difficult to classify with regard to dominance; a single paternal variant suggests a focal form but may be dominant, and electrophysiology and immunostaining help [3]. A VUS requires segregation studies and, when possible, functional or biochemical testing; in HFI and FBPase deficiency, apparent homozygosity suggests an undetected deletion or uniparental isodisomy [2,8,9]. ClinVar for PCK1 listed 17 pathogenic variants, 7 likely pathogenic and 165 VUS — numbers that measure submissions and not frequencies [25].

Enzyme activity retains a place when genetics is inconclusive: hepatic aldolase B in HFI, hepatic FBPase or FBPase in stimulated monocytes in FBPase deficiency, glycerol kinase in fibroblasts in GKD [13,30]. Biochemical prenatal testing for FBPase deficiency is not reliable, because placental activity is low [22].

5.10. Investigation after unexplained death

A full autopsy (including the skull, with consent) is important in undiagnosed patients: liver, spleen, muscle, heart, kidney and brain are frozen, and material is fixed for histology in 4% buffered formaldehyde and for electron microscopy; if autopsy is refused, photographs, radiographs, blood, urine, cerebrospinal fluid, a skin biopsy (fibroblasts) and needle biopsies of liver and muscle are collected, preferably with a pre-prepared kit [59]. FBPase is rapidly inactivated after death, which limits post mortem enzyme studies [44]. Post mortem trio exome sequencing identified PEPCK-C deficiency in a 3-year-old boy who died with hypoglycaemia and cerebral oedema [25].

5.11. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing (PGT) are possible when the familial variants have been identified: in diffuse hyperinsulinism they allow treatment from birth, but in the focal form prenatal testing is not informative because it does not predict the somatic event [2]. In HFI and FBPase deficiency, carrier detection, prenatal diagnosis and PGT depend on the identified variants [8,9]; biochemical prenatal diagnosis of FBPase deficiency is not reliable [22].

6. Differential Diagnosis

6.1. Monogenic causes of hypoglycaemia by class

Table sources: [2,3,7,10,12,13,15,29,30,35,39,58,60,61,66,70,78–80,87–91]. IKH, a diagnosis of exclusion, has its list of exclusions in section 5.8.

6.2. Syndromic hyperinsulinism

Syndromic hyperinsulinism accounts for up to 10% of all congenital hyperinsulinisms, is usually diazoxide-responsive and resolves in the neonatal period (Sotos), in the first year (Beckwith-Wiedemann) or within a few years (CDG, Kabuki, Turner); Beckwith-Wiedemann, Kabuki and Turner are the most frequent [3]. In Kabuki syndrome, patients with KDM6A are more prone to hypoglycaemia, and hyperinsulinism is usually associated with mosaicism [1,10]. Dysmorphic features may not be evident at birth [3].

Source: [2,3,10]. Hyperinsulinism has also been described in Moebius, Cowden, Nager and Usher type C syndromes and in other chromosomal abnormalities [3].

6.3. Acquired causes and mimics

Acquired neonatal hyperinsulinism includes maternal diabetes (including gestational; large-for-gestational-age newborn), PSHI (SGA, maternal hypertension, pre-eclampsia, eclampsia) and maternal drugs (ritodrine, sulfonylureas, high glucose infusion rate during labour) [10]. After the neonatal period, acquired hyperinsulinism includes insulinoma (sporadic or in MEN1), post-surgical forms (gastric bypass, fundoplication; non-insulinoma pancreatogenous hypoglycaemia syndrome, NIPHS, ORPHA:276608), drugs (insulin, sulfonylureas) and autoimmune forms [92] — Hirata disease (insulin autoimmune syndrome) after drugs with a sulfhydryl group (methimazole, carbimazole, alpha-lipoic acid) or after measles, mumps, rubella, varicella-zoster, coxsackie B and hepatitis C [10]. Mimics with suppressed insulin include type B insulin resistance syndrome (anti-receptor antibodies after HIV, HTLV1, hepatitis C, lymphoproliferative disease or lupus) and non-islet cell tumour hypoglycaemia due to pro-IGF2 secretion (Doege-Potter syndrome) [10]. Fabricated or induced illness (Munchausen by proxy) enters the differential of unpredictable hyperinsulinaemic hypoglycaemia at any age, and high insulin with low C-peptide suggests exogenous insulin; not all assays detect analogues [4,15]. Metformin, alcohol, beta-blockers and salicylates complete the pharmacological list [4,12,13].

6.4. Biochemical differential of hypoglycaemias with lactic acidosis

Source: table 2b of the FBP1 deficiency GeneReviews [9], with the FAO row adjusted according to Saudubray's book [59]. The GeneReviews table attributes ketonuria and normal to very high ketosis to GSD I, which diverges from the description of low ketosis in GSD I in Saudubray's book [9,15]. FBPase deficiency is distinguished from GSD I by the absence of hepatonephromegaly and of permanent hyperlipidaemia and hyperuricaemia, and by the presence of glycerol in organic acids [9,13]; from PC deficiency, by the neurological context of the latter [13]; from FAO defects, by their hypoketosis with hyperammonaemia, myopathy, cardiomyopathy and acylcarnitines [9]; from PGM1-CDG, by its short stature, cleft palate, bifid uvula, dilated cardiomyopathy, rhabdomyolysis and abnormal transferrin isoforms [9]. Hepatic forms of respiratory chain disease with fasting hypoketotic hypoglycaemia and hyperlactataemia are the most difficult differential [13].

6.5. Differential of hereditary fructose intolerance

HFI is confused with pyloric stenosis, reflux, galactosaemia, tyrosinaemia, non-IgE-mediated food hypersensitivity, congenital infection, glycogen storage diseases and ornithine transcarbamylase deficiency and, later, with Wilson disease, leukaemia and growth delay [13]. Secondary fructosuria occurs in liver injury (tyrosinaemia) [13]. Fructose malabsorption causes abdominal pain and diarrhoea, with fructose in the stools (in HFI fructose appears in the urine), and the hydrogen breath test requires an oral load that is dangerous if HFI is present, so HFI should be excluded first [8,13]. In sucrase-isomaltase deficiency, sucrose causes distension and osmotic diarrhoea but free fructose is tolerated [13]. Food protein-induced enterocolitis syndrome (FPIES) with fructose sensitivity and co-occurrence with phenylketonuria, coeliac disease and Duchenne dystrophy that delayed diagnosis have been described [8]. In liver failure, unexplained jaundice, hypoglycaemia or a Reye-like picture in the infant, the list of hereditary diseases includes FAO defects, hepatic glycogen storage diseases, CDG, urea cycle disorders, Wilson disease, MSUD, mitochondrial DNA depletion, tyrosinaemia 1, propionic and methylmalonic acidaemias, FBPase deficiency, galactosaemia, alpha-1 antitrypsin deficiency and transaldolase deficiency, alongside acquired causes (infectious hepatitis, sepsis, disseminated intravascular coagulation, autoimmune hepatitis, alloimmune neonatal haemochromatosis, toxins, haemophagocytic lymphohistiocytosis) [8]. In late-onset HFI, isolated fructose-induced postprandial hypoglycaemic crises are rare or absent [15].

7. Treatments and Risk Management Strategies

7.1. Principles and glycaemic targets

Treatment has three stages: collecting the critical sample, correcting the hypoglycaemia immediately and preventing recurrence according to the aetiological class [2,4]. The PES recommends maintaining PG >70 mg/dL (3.9 mmol/L) in newborns with a suspected congenital disorder and in infants and children with a confirmed disorder (recommendation 3.1, strong, low-quality evidence), and PG >50 mg/dL (>2.8 mmol/L) before 48 h and >60 mg/dL (>3.3 mmol/L) after 48 h in high-risk newborns without a suspected congenital disorder (recommendation 3.2, weak, very low-quality evidence); the approach is individualised (good practice statement 3.3) [4]. The target lies within the normal range of 70–100 mg/dL (3.9–5.6 mmol/L) to avoid neuroendocrine activation and HAAF; in glycogen storage diseases and gluconeogenesis defects, maintaining normal PG also prevents metabolic acidosis and growth delay [4]. The 2024 consensus adopts the 70–100 mg/dL target in hyperinsulinism (recommendation 2.1), accepts on an individual basis a lower threshold of 63 mg/dL (3.5 mmol/L) because in severe hyperinsulinism 15–20% of measurements fall below 70 mg/dL, and recommends capillary blood glucose before meals and at bedtime, considering the evidence insufficient to recommend routine continuous glucose monitoring [10]. GeneReviews, citing the same consensus, recommends continuous monitoring in children with very unstable blood glucose in the first years, whatever the cause [2]. Non-specific glucocorticoids in newborns with hypoglycaemia are discouraged [4].

7.2. Acute treatment

The reference doses of IV glucose in children are those of the guidelines, described below; the US label, cited for comparison, gives no paediatric dose in mg/kg and indicates, for insulin-induced hypoglycaemia in adults, 10–25 g IV (20–50 mL of 50% glucose), with blood drawn beforehand for glucose without waiting for the result, and a maximum rate without glycosuria of 0.5 g/kg/h (~8.3 mg/kg/min); this is the dose used in adults, without a guideline dose of its own [93]. In severe symptomatic hypoglycaemia, the PES and the 2024 consensus indicate a glucose bolus of 200 mg/kg (2 mL/kg of 10% glucose) followed by a continuous infusion of 10% glucose at the maintenance rate for age or, in hyperinsulinism, at a rate sufficient to maintain PG >70 mg/dL, typically ≥8 mg/kg/min (recommendation 2.2, strong) [4,10]. After a 200 mg/kg bolus followed by 8 mg/kg/min, steady state is reached within 10 min; in hyperinsulinism, requirements may reach 20–30 mg/kg/min (above the label's maximum rate, for information), the rate is increased in increments of ≥4 mg/kg/min while avoiding fluid overload, and high concentrations require a central venous catheter [10]. In undiagnosed hypoglycaemia, the BIMDG indicates 10% glucose, 2 mL/kg (200 mg/kg), followed by an infusion of 4–6 mg/kg/min [16]. Saudubray's emergencies chapter gives a bolus of 0.2–0.5 g/kg followed by an infusion of 10% glucose with electrolytes (~10 mg/kg/min) via a peripheral line, and notes that a rate equal to hepatic glucose production (8 mg/kg/min in the newborn) is usually sufficient in GSD I and gluconeogenesis defects, whereas hyperinsulinism requires 10–20 mg/kg/min and responds promptly to parenteral glucagon [81]. In FAO defects, lipolysis is suppressed with 10–12 mg/kg/min (120–150 mL/kg/day of 12–15% glucose), preferably with insulin, and during intercurrent illness with vomiting IV glucose is given at least at the rate of physiological hepatic production (3–12 mg/kg/min according to age), without waiting for hypoglycaemia, which is a late event [61,81]. Once blood glucose has normalised in GSD I or neonatal FBPase deficiency, the infusion may be replaced by continuous enteral feeding with a lactose-free formula and maltodextrin, with 50–60% of energy as carbohydrate, equivalent to 10–12 mg/kg/min of glucose [81].

Without IV access and with known hyperinsulinism, the reference glucagon dose is that of the consensus: 0.5–1 mg or 20–30 μg/kg IM or SC, with an effect lasting 40–60 min [10]. The labels, cited for comparison, have as their indication severe hypoglycaemia in insulin-treated diabetes: the Portuguese SmPC for GlucaGen® indicates 1 mg SC or IM in adults and children >25 kg or >6–8 years and 0.5 mg in children <25 kg or <6–8 years, and the US label an equivalent dose, repeatable after 15 min; the fixed dose coincides with the consensus, and the weight-based dose appears in no label [94,95]. The PES considers 0.5–1.0 mg effective regardless of weight, by the IV, IM or SC route, and notes that smaller doses (0.03 mg/kg) cause less nausea and vomiting but may be ineffective if not given IV [4]. Saudubray's hyperinsulinism chapter prints "0.3 mg/kg (max. 1 mg)"; the 0.03 mg/kg (30 μg/kg) dose in GeneReviews, the PES and the consensus shows that the book's value is a decimal-place error, and it should not be used [2–4,10]. Glucagon acts only if there is hepatic glycogen: the US label warns that in prolonged fasting, adrenal insufficiency and chronic hypoglycaemia glycogen may be insufficient and the patient should receive glucose, and the response is absent in glycogen storage diseases, in HFI exposed to fructose and during crises of FBPase deficiency [1,8,13,95]. The label contraindicates glucagon in phaeochromocytoma and insulinoma; in congenital hyperinsulinism its use is off-label and supported by the guidelines [10,95]. When glucose requirements are extreme or there is a risk of fluid overload, the consensus recommends glucagon as a continuous IV infusion (2.5–20 μg/kg/h; recommendation 2.3) or 1–2 mg/24 h; by comparison, the Portuguese SmPC for GlucaGen® does not permit IV infusion, because of solution instability, so it requires dedicated hospital preparation and protocol; according to the guidelines, the infusion stabilises blood glucose and reduces glucose intake by ~40% [2,3,10]. Adverse effects of the infusion include vomiting (13%), rash (2%) and respiratory distress (19%), and necrolytic migratory erythema is rare; prolonged SC infusion is unreliable owing to the formation of fibrils and crystals [10].

During crises of FBPase deficiency, GeneReviews indicates a bolus of 2 mL/kg of 10% glucose followed by a high-rate infusion; if pH is <7.1 or acidosis worsens, sodium bicarbonate at half the calculated dose over 30 min, although acidosis generally corrects with glucose alone [9]. Saudubray's book indicates, as a practical rule, 1 mL/kg of 20% glucose followed by 10–12 mg/kg/min in the newborn and bicarbonate; recovery from acidosis with glucose is in itself a diagnostic indicator [13]. In acute HFI intoxication, all fructose is withdrawn, IV glucose is given and liver support is provided in intensive care (fresh frozen plasma or exchange transfusion) with correction of acidosis [8,13]. In ketolysis defects, bicarbonate is used if pH <7.1, with a risk of hypernatraemia [12]; in HMG-CoA lyase deficiency, IV bicarbonate corrects severe acidosis [12]. In HMGCS2D, high-rate IV glucose, correction of acidosis and intensive care (ventilation; sodium benzoate and renal replacement therapy in severe hyperammonaemia) are the mainstays [71]. In primary carnitine deficiency, L-carnitine is life-saving [1,81].

7.3. Drugs: dosage, mechanism and adverse effects

The Portuguese doses come from the INFARMED SmPCs (GlucaGen® and Hidrocortisona Generis®), the European doses from the European Medicines Agency (EMA) SmPCs and the remainder from the FDA labels and the guidelines [94,105]. Diazoxide has no centralised marketing authorisation in the European Union and no authorised medicinal product in Portugal (Proglicem® is not authorised), and is not available on the Portuguese market; in Brazil, the open database of the Brazilian Health Regulatory Agency (ANVISA) lists one active diazoxide registration (Tensuril®, Cristália), without indication of the pharmaceutical form in the extract, and the electronic package insert database was unavailable (HTTP 502), so the Brazilian package inserts were not read [96,108,109]. The 2024 consensus recommends continuous IV glucagon infusion in hyperinsulinism; by comparison, the Portuguese SmPC for GlucaGen® states that the reconstituted solution is unstable and cannot be administered as an IV infusion, so this use, outside the label conditions, requires dedicated hospital preparation and protocol [10,94].

Diazoxide is the first-line drug for hyperinsulinism (recommendation 2.4, strong), approved by the FDA in 1976 and designated an essential medicine by the World Health Organization, but approved in only 16% of Latin American countries and unavailable in many regions [10]. The paediatric half-life is 15 ± 5.3 h, which justifies 2–3 daily doses [10]; the label reports a half-life of 9.5–24 h in four children on long-term use and of ~30 h in adults, with monitoring for up to 7 days in hyperglycaemic complications [101]. Response is defined by a fasting test with hyperketonaemia (BOHB >1.8 mmol/L) before PG falls below 50–60 mg/dL; non-response suggests KATP channel disease, and also GCK or HK1 hyperinsulinism [10]. The reference dose is that of the consensus, 5–15 mg/kg/day in infants and children [10]. Saudubray's book proposes 10–15 mg/kg/day in 3 doses and a 5-day response test (absence of hypoglycaemia on a normal diet and during a fast of 6 h in the newborn and 12 h in the child), and GeneReviews accepts doses of up to 20 mg/kg/day [2,3]. The label, cited for comparison, indicates up to 15 mg/kg/day in infants, which coincides with the consensus, and up to 8 mg/kg/day in children and adults, which the consensus exceeds in older children; the Saudubray and GeneReviews doses lie above the label maximum [10,101]. Adverse effects in the consensus include hypertrichosis (84.1%), coarse features (24%), neutropenia (15.6%), thrombocytopenia (4.7%), hyperuricaemia (5.0%), pulmonary hypertension (2.4%) and serious events leading to discontinuation (9.7%), more frequent in PSHI and in preterm infants [10]. In a four-centre UK cohort, 13/177 (7%) patients treated with diazoxide developed pulmonary hypertension, 8 of them within the first 2 weeks, with a median maximum dose of 7 mg/kg/day; risk factors were congenital heart disease (p=0.008) and a fluid volume >130 mL/kg/day in the preceding 24 h (p=0.019), and resolution required complete discontinuation (median 41 days; persistence >12 months in 3) [110]. The authors recommend echocardiography and fluid restriction to 130 mL/kg/day before initiation [110]; the consensus recommends a full blood count beforehand, echocardiography 1 week after initiation and full blood count with differential and uric acid every 6 months [10]. On 6 October 2026, the FDA approved labelling supplement S-025, which adds a warning of necrotising enterocolitis in newborns and infants, including fatal cases, mainly preterm and low birth weight infants: new feeding intolerance, vomiting, abdominal distension, blood in the stools or lethargy require discontinuation of the drug [101]. Extended-release diazoxide choline (Vykat® XR) is approved only for hyperphagia in Prader-Willi syndrome and cannot replace the oral suspension [111].

Somatostatin analogues are second line (recommendation 2.5, weak) and are off-label in hyperinsulinism; octreotide acts about 3 h after the SC bolus, also inhibits glucagon and GH, and causes tachyphylaxis [2,10]. The consensus recommends monitoring, at least every 6 months, growth, gallbladder ultrasound, liver enzymes, growth factors and thyroid function [10]. Nifedipine and sirolimus should not be used outside a research protocol (recommendation 2.6): nifedipine may be useful in CACNA1D hyperinsulinism, and sirolimus has been associated with serious infections, hepatitis, diabetes and pancreatic insufficiency; glucocorticoids are ineffective in hyperinsulinism [10]. Carbohydrate supplementation (recommendation 2.7, weak) includes continuous intragastric infusion via nasogastric tube or gastrostomy with glucose or maltodextrin up to 20%, formula with 15% carbohydrate and uncooked cornstarch above 9 months [10]. Surgical treatment of hyperinsulinism consists of resection of the focal lesion (cure >95%) and 90–98% pancreatectomy in uncontrolled diffuse disease, with recurrence of hypoglycaemia in 50–60% and diabetes in up to 91% at 14 years [3,10].

7.4. Hereditary fructose intolerance

There are no published clinical guidelines for HFI and no licensed drug; treatment is immediate and complete elimination of all sources of fructose, sucrose and sorbitol, natural and added, replaced by glucose, maltose and starch [8,13,19]. The list of foods and additives to avoid includes fructose, high-fructose corn syrup, honey, agave syrup, invert sugar, maple syrup, molasses, palm and coconut sugar, sorghum, sucrose, sorbitol, sucralose and polysorbate; labels with "sugar", "natural flavourings" or "sugar-free" raise suspicion, and diets for fructose malabsorption, which are less restrictive, are not suitable [8]. The table adapted from Boston University allows sugar-free dairy products, unprocessed meat, fish and poultry, unsweetened cereals, asparagus, cabbage, cauliflower, celery, green beans, green pepper, lettuce, nuts, onion, potato and spinach, as well as glucose, dextrose, dextrin, maltose and non-caloric sweeteners, and prohibits all fruits and juices, the remaining vegetables (including sweet potato), sugary desserts, ketchup, jams, soft drinks and sorbitol-containing lozenges [8]. No fructose limits have been defined for any age; symptom thresholds range from 40 to 250 mg/kg/day, against an average Western intake of 1–2 g/kg/day, and insufficient restriction may manifest only as growth delay, so intake should be kept as low as possible and not guided by subjective tolerance [8,13]. A daily sugar-free multivitamin, with ascorbic acid and folate, and follow-up by a dietitian are recommended [8,13].

Medicines are a frequent source of exposure: syrups, immunoglobulin solutions, irrigation fluids, enemas, amiodarone infusion with polysorbate 80, infant formulas (the European Union allows up to 20% of carbohydrate as sucrose) and paediatric nutritional drinks [8,13]. A search of the British medicines compendium for "fructose, sorbitol, sucrose or sucralose" returned 1574 results in 2020, including trastuzumab, filgrastim, some IV immunoglobulins, vaccines, iron and enemas [8]. During hospitalisation, the team should be informed, the patient should have a wristband and an alert in the record, the pharmacist validates parenteral products case by case, and the 24% sucrose solution is not given to newborns with HFI; infusions of fructose, sorbitol or invert sugar are potentially fatal and the patient should carry an emergency card [8,13]. Vaccines are safe with fructose up to 2.4 mg/kg per dose: M-M-RVAXPRO and ProQuad® only above 6.5 kg (~16.5 mg of sucrose); Rotarix® powder and solvent (Europe only; 22.5 mg of sucrose/sorbitol) only above 9.3 kg; Rotarix® prefilled oral suspension and RotaTeq® (>1000 mg of sucrose per dose) are avoided at any weight [8,112]. Hepatomegaly may persist for months to years, with increased intrahepatic triglycerides on magnetic resonance spectroscopy [13].

7.5. Fructose-1,6-bisphosphatase deficiency

There are no published guidelines; the GeneReviews recommendations are based on the authors' experience and an international survey [9]. The Society for the Study of Inborn Errors of Metabolism (SSIEM) survey, covering 36 centres in 15 countries and 126 patients, showed highly variable practices: 75% of centres restrict sucrose or fructose (7 only sucrose-rich foods, 4 fruit and sugars, 13 fruit, vegetables and sugars) and 25% (9 centres, 35 patients) do not restrict when the patient is well; restrictions are more frequent above 16 years (85%) than from 1 to 10 years (67%) and from 11 to 16 years (63%) [52]. The distribution by region was uneven: in Northern Europe, 28 of 41 patients had no restriction, whereas outside Europe 24 of 32 restricted sugars and fruit [52]. Twenty centres (56%) routinely prescribed uncooked cornstarch before the overnight fast to 47/126 patients (37%), with a mean dose of 1.1 g/kg/dose (median 1 g/kg, whatever the fasting tolerance), and two centres used slow-release starch (Glycosade®), whose efficacy has been described only in GSD Ia/Ib; there are no efficacy data for starch in FBPase deficiency [52]. The authors conclude that restrictions are probably unnecessary in older patients [52].

GeneReviews recommends, in the outpatient setting, meals every 2–3 h in infants, 1–2 g/kg of uncooked cornstarch in milk or water at bedtime from 6–12 months if there is nocturnal hypoglycaemia, IV glucose for surgery with several hours of fasting, written protocols for parents, the attending physician and the school, an emergency letter, contact with the destination centre before travel, carbohydrate and hydration during prolonged exercise, restriction of fructose, sucrose, glycerol and sorbitol (small amounts tolerated, avoided during acute illness), routine vaccination including annual influenza vaccination with carbohydrate-rich meals after the vaccine, perioperative planning with the metabolic centre, a medical alert bracelet and transition to adult care [9]. Small amounts of fructose (≤2 g/kg/day) are well tolerated, but a single intake >1 g/kg is harmful, especially in young children [9]. During mild illness (fever, cough, loose stools, still eating, no lethargy), the frequency of carbohydrate intake is increased with glucose polymers and intervention is early, while glucose is still normal, because hypoglycaemia is a late event in decompensation; ketonuria is an early indicator, and antipyretics should be free of fructose, sucrose, glycerol and sorbitol [9]. Saudubray's book restricts fructose, sucrose and sorbitol in young children and limits fat to 20–25% and protein to 10% of energy [13]. Glycerol infusion (with or without fructose), practised in Japan for cerebral oedema with hypoglycaemia, is dangerous unless FBPase deficiency has been excluded, and repeated sorbitol infusions for cerebral oedema were lethal in an undiagnosed child [13,44]. Fasting tolerance improves with age; one patient developed gout at 32 years and was treated with allopurinol [44]. In obesity due to overfeeding, a fructose-free hypocaloric diet (800–900 kcal/m²/day) allowed weight loss without acidosis or hypoglycaemia, a personal observation of the authors of the Saudubray chapter [13].

7.6. PEPCK-C deficiency, pyruvate carboxylase deficiency and glycerol kinase deficiency

In PEPCK-C deficiency there is no drug, guideline or GeneReviews chapter: IV dextrose is started as soon as the condition is suspected in a child with unexplained hypoglycaemia or liver failure, and in the long term fasting is avoided with a written emergency regimen of glucose polymers during intercurrent illness, sufficient to prevent recurrence of liver failure in one series [25,57]. Counselling covers the triggers (infection, missed meals, intense exercise, alcohol, breastfeeding in an affected mother), and the risk persists into adulthood [14,25]. In PC deficiency, the measures for hypoglycaemia are those for fasting and intercurrent illness; the underlying disease includes secondary biotin-responsive deficiency (biotinidase and holocarboxylase synthetase deficiencies) and the differential with pyruvate dehydrogenase complex deficiency [29].

In isolated GKD, pseudohypertriglyceridaemia should be recognised and lipid-lowering drugs stopped: one patient was treated for 13 years without effect, and discontinuation in three paediatric cases had no adverse effects [31,113,114]. Prevention relies on fluids, calories and glucose during intercurrent illness; during crises, IV glucose sufficient to block lipolysis, avoiding lipids and glycerol-containing solutions (including some anaesthetics); frequent meals with complex carbohydrates, extra before intense exercise and during infections, a low-fat diet, alcohol avoidance and home ketonuria testing as an early sign [30]. After puberty, most do not need a diet, but there is an increased risk of glucose intolerance [30]. In the complex form, hydrocortisone, fludrocortisone and oral salt are started promptly, with stress doses and an emergency plan, and adrenal insufficiency should be actively excluded in any boy with GKD [31,115].

7.7. Hormone deficiencies

The treatment of adrenal insufficiency is hydrocortisone replacement: the Endocrine Society recommends ~8 mg/m²/day in children and 15–25 mg/day in 2–3 doses in adults (or cortisone acetate 20–35 mg/day), with fludrocortisone (median 0.1 mg/day) in primary insufficiency with mineralocorticoid deficiency, education on stress doses, a steroid card and emergency parenteral glucocorticoid [86]. The European SmPC for Alkindi® indicates 8–10 mg/m²/day in isolated adrenal insufficiency and 10–15 mg/m²/day in congenital adrenal hyperplasia, in 3–4 doses, with doubling or tripling of the dose in less severe situations (mild infection, moderate fever, minor surgery) and replacement with parenteral hydrocortisone in a facility with resuscitation equipment in severe ones (gastroenteritis with vomiting or diarrhoea, high fever, major accident, surgery under general anaesthesia) [103]; the US label indicates 8–10 mg/m²/day as the starting dose, rounded to 0.5 or 1 mg [104]. The paediatric stress dose in mg/m² does not appear in the Solu-Cortef® label; its dosage follows the guidelines for congenital adrenal hyperplasia and familial glucocorticoid deficiency [106].

In FGD, hydrocortisone is lifelong, with the paediatric practice of 7–12 mg/m²/day in 3 doses and requirements of 13–18 mg/m²/day in patients with NNT; the Alkindi® SmPC, by comparison, indicates 8–10 mg/m²/day, and the requirements of patients with NNT lie above that range; fludrocortisone is justified only with documented mineralocorticoid deficiency, which is usually absent; ACTH is not a treatment and cosyntropin serves only for diagnosis [39,41]. In X-linked adrenal hypoplasia, lipoid hyperplasia and P450scc deficiency, hydrocortisone and fludrocortisone are lifelong, with salt in the infant; without treatment, these diseases are fatal [66–68]. In Laron syndrome, somatropin is ineffective and mecasermin is approved (USA, 2005; EU, 2007, under exceptional circumstances, 2–18 years); in the long-term trial of recombinant IGF-1, 49% of children had hypoglycaemia before and during treatment [60,107].

7.8. Glycogen storage disease 0a, idiopathic ketotic hypoglycaemia and defects of fatty acid oxidation, ketogenesis and ketolysis

In GSD 0a, the diet is high in protein with low glycaemic index complex carbohydrates, snacks every 2–4 h, uncooked cornstarch 1–1.5 g/kg at bedtime and every 6 h during intercurrent illness, and a dose of starch in the morning or 1 h before intense activity; Saudubray's book indicates 1.5–2 g/kg at bedtime and during infections [58,70]. Short stature and osteopenia improve with prevention, and the prognosis is good [58,116]. The ACMG guidelines cover GSD I and GSD III, but not GSD 0 [70,117,118].

In IKH, most episodes are prevented with maltodextrin drinks every 3 h, day and night, during illness, or with IV glucose if the child vomits; hypoglycaemia before breakfast in health is treated by shortening the overnight fast or with uncooked cornstarch in the evening, and home blood glucose monitoring is useful [12]. In IKH and most inborn errors, prevention relies on limiting fasting and maintaining a high glucose intake during intercurrent illness [43].

In FAO defects, glucose drinks are started at the first sign of illness, every 2–3 h, with reintroduction of feeding within 24–48 h and admission for IV glucose if there is vomiting or deterioration; the initial diet is fat-free and medium-chain triglycerides (2–3 g/kg/day) help in long-chain defects only once the site of the defect is known; carnitine is controversial, except in transporter deficiency [61,81]. In ketogenesis defects, fasting is avoided, high carbohydrate is given during stress, IV glucose if the child refuses food or vomits, moderate protein and leucine restriction in lyase deficiency, and carnitine is frequently given without proven value [12]. In HMGCS2D, in a Vietnamese cohort of 19 patients, fasting avoidance, L-carnitine, maltodextrin and glucose-containing fluids during illness after the genetic diagnosis reduced crises from 11 to 2, all were alive and 18/19 had normal development [119]. In ketolysis defects, meals are frequent in the first year and thereafter fasting for more than 12 h is avoided; ketogenic diets are dangerous, and a child with MCT1 deficiency treated with a ketogenic diet for absence epilepsy developed severe acidosis [12,33,120].

7.9. Insulin signalling, insulin resistance and exercise-induced hyperinsulinism

In AKT2 hypoglycaemia, there is no targeted therapy; the three original patients needed surgically placed enteral tubes for overnight carbohydrate feeding, and drugs for hyperinsulinism and pancreatic surgery should be avoided without molecular confirmation [35,36]. In Donohue syndrome, hypoglycaemia is prevented with frequent feeding, nasogastric tube and/or IV glucose and more protein in the evening meals; insulin and metformin are ineffective, and mecasermin is used off-label (table 7.3) [78]. In exercise-induced hyperinsulinism, anaerobic exercise is avoided or modified, and diazoxide has only a partial response; the Proglycem® label covers hypoglycaemia due to hyperinsulinism without distinguishing genetic subtypes [33,101].

7.10. Comparative regulatory status

NDA (New Drug Application) and BLA (Biologics License Application) designate the FDA authorisation procedures; the dates are those of the original approval and of the supplements cited.

Sources: [10,60,95,97–104,106–108,111,121–125].

The EMA has granted orphan designations for congenital hyperinsulinism to glucagon (EU/3/12/960, of 2012-03-05, and EU/3/14/1342), to a recombinant human monoclonal antibody against the insulin receptor (EU/3/16/1702, 2016-07-14), to a synthetic glucagon analogue with seven substitutions (EU/3/17/1887, 2017-06-20), to a glucagon analogue linked to an immunoglobulin Fc (EU/3/18/2022, 2018-05-25) and to exendin (9-39) (EU/3/19/2223, 2019-11-13); the designation of an oral somatostatin receptor type 5 antagonist (EU/3/20/2376) was withdrawn [124]. For NIPHS, exendin (9-39), glucagon and pasireotide have been designated [124]. An orphan designation is not equivalent to a marketing authorisation.

7.11. Clinical trials

The trials do not allow indirect comparisons: the populations (age, severity, IV glucose dependence, genetic cause), durations and endpoints (IV glucose infusion rate, events by capillary blood glucose, time in hypoglycaemia by continuous monitoring) differ. The dasiglucagon trial in infants had 12 patients and a 48 h endpoint; sunRIZE was negative on the primary and key secondary endpoints, and the reductions described by the sponsor in pre-specified and post hoc analyses ("nominally significant", without p values) do not replace that result [129,130]. The ~40% placebo effect in sunRIZE shows the influence of behavioural factors and of capillary blood glucose measurement, acknowledged by the FDA itself [134]. LUCIDITY studied post-bariatric hypoglycaemia, not congenital hyperinsulinism, and the results come from a market announcement, not peer-reviewed [132]. The ketohexokinase inhibitor trial in HFI had no placebo arm in patients, for ethical reasons [133].

7.12. Developments in the last 12 months and level of evidence

Other agents under evaluation in hyperinsulinism include mTOR inhibitors, soluble glucagon and other somatostatin agonists [2,3]. The absence, in a targeted search, of any announcement after October 2024 on the resubmission of dasiglucagon for congenital hyperinsulinism does not demonstrate that the process has ended [121,123].

7.13. Agents and situations to avoid

7.14. Divergences between guidelines and sources

Where doses diverge, the reference is the guideline or consensus dose; the label (FDA, EMA or national SmPC/package insert) is given for comparison.

7.15. Pregnancy, lactation, perioperative care and transition

In hyperinsulinism, after near-total or subtotal pancreatectomy, insulin-dependent diabetes is managed as pre-existing diabetes; after conservative treatment or focal resection, hypo- and hyperglycaemia are monitored, and hyperglycaemia is treated as gestational diabetes; in a fetus at risk, growth is monitored, because macrosomia in the 3rd trimester increases obstetric complications and caesarean section [2]. In maternal HFI with strict fructose avoidance, the disease does not appear to harm either mother or child; in a family with a mother and three affected children, the children's complications resulted from their own poorly controlled HFI [8]. In FBPase deficiency, successful pregnancies have been described; preconception planning with frequent meals and self-monitoring, follow-up at a high-risk obstetric centre with a metabolic physician, frequent home monitoring, overnight uncooked starch as needed, increased intake in the 3rd trimester and continuous glucose infusion during delivery are recommended [9]. In HMG-CoA lyase deficiency, pregnancies are high risk (in 8 pregnancies there was one termination, one intrauterine death and one maternal death at 9 weeks), with IV glucose during delivery and during illnesses with vomiting [12]. In PEPCK-C deficiency, breastfeeding triggered hypoglycaemia in an affected mother [14]. The sources consulted do not describe the passage of diazoxide into breast milk.

In the perioperative period, any fasting is covered with IV glucose (FBPase deficiency, glycogen storage diseases, FAO, ketogenesis, GKD), avoiding solutions with fructose, sorbitol or glycerol and lipids in patients in whom they are contraindicated, and with stress doses of hydrocortisone in cortisol deficiencies [8,9,30,103]. The 2024 consensus recommends, before discharge, a fasting tolerance test in all patients with hyperinsulinism, gastrostomy if hypoglycaemia persists, plans for disconnection of the overnight infusion (continuous monitor, enuresis alarm), emergency glucagon and an emergency plan in the language of the family and the country, psychological support and contact with patient associations; more than 65.2% needed to adjust the regimen in the 3 months after discharge (patient report) [10]. Transition programmes to adult care should address treatment, neurocognitive and memory deficits, hypoglycaemia unawareness, the risk of diabetes and the implications of the genetic diagnosis (recommendation 5.3) [10]; in FBPase deficiency, transition is part of the GeneReviews plan [9].

8. Reproductive Options and Family Counselling

8.1. Principles

The recurrence risk depends on the aetiological diagnosis; therefore, in a family with a child with hypoglycaemia without an established cause, the proband's DNA should be stored [1,2]. In sudden infant deaths with suspected hypoglycaemia, a genetic condition with a recurrence risk of up to 25% should be considered [1]. Carrier detection is possible when the causal variant is known and, in some diseases, through biochemical abnormalities; prenatal diagnosis requires molecular or biochemical confirmation in the proband [1].

8.2. Risks by mode of inheritance and scenario

8.3. Cascade testing and newborns at risk

Asymptomatic siblings of patients with HFI should be tested, because early diagnosis allows fructose restriction and avoidance of sucrose-containing rotavirus vaccines; carriers are asymptomatic and not at risk of HFI, and intrafamilial variability has been described [8]. In HFI, the Clinical Genome Resource (ClinGen) classified actionability as strong in the paediatric context and limited in adults, a difference that reflects the natural history: identifying the infant before major exposure prevents encephalopathy and liver and kidney failure [19]. In FBPase deficiency, asymptomatic siblings are also tested, and the newborn at risk is fed regularly and monitored as described in section 4.1 [9]. In HMGCS2D there are asymptomatic biallelic individuals, which justifies testing siblings [64]. In hyperinsulinism, newborns at risk undergo molecular testing or glucose monitoring from birth, and carrier testing of the partner is recommended, especially if of the same ancestry; the carrier frequency of ABCC8/KCNJ11 variants in the population is ~1% or less, but c.3989-9G>A has a carrier frequency of 1:83 in Ashkenazi Jews [2]. In GKD, molecular confirmation identifies female carriers and asymptomatic men [30].

8.4. Prenatal diagnosis, PGT and counselling of minors

Prenatal diagnosis and PGT are possible in the forms with identified variants (HFI, FBPase deficiency, diffuse hyperinsulinism) and, in diffuse hyperinsulinism, allow treatment from birth; in the focal form prenatal testing is not informative [2,8,9]. Biochemical prenatal diagnosis of FBPase deficiency is not reliable, because fibroblasts, amniocytes and chorionic villi do not express the enzyme [13,22]. Testing of asymptomatic minor siblings is recommended in diseases in which the diagnosis changes management in childhood — HFI, FBPase deficiency, HMGCS2D and hyperinsulinism [2,8,9,64]; the clinical sources consulted do not address carrier detection in minors without direct clinical benefit. The 2024 consensus includes genetic counselling in the discharge plan of all patients with hyperinsulinism [10].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency by entity and region

9.2. Founder populations and diversity

Founder variants with diagnostic implications are those of ABCC8 in Ashkenazi Jews (c.3989-9G>A, with a carrier frequency of 1:83, and p.(Phe1387del)) and in Finns (p.(Val187Asp), recessive, and p.(Glu1506Lys), dominant), those of ALDOB in Europeans (p.(Ala150Pro), p.(Ala175Asp), p.(Asn335Lys)) and c.324+1G>A in northern India, those of FBP1 in Japan and Central Europe (c.959dup), in Turkey and Armenia (exon 2 deletion) and in Pakistan (c.841G>A), that of PCK1 in Finland (c.925G>A), those of HMGCL in the Iberian Peninsula (c.109G>T) and in Saudi Arabia (c.122G>A), that of GYS2 in patients of Italian origin (p.(Arg246Ter)) and that of PC in North American Amerindians (p.(Ala610Thr)) [2,8,12–14,29,44,58]. HMG-CoA lyase deficiency is the most frequent organic acidaemia in the Iberian Peninsula and Saudi Arabia [12]. In populations with high consanguinity, the incidence of congenital hyperinsulinism and of recessive diseases such as FBPase deficiency increases [3,9]. The PCK1 variant c.925G>A is endemic in Finland and should not be generalised to other populations; families from the Arabian Gulf have also been described [25].

9.3. Portugal and Brazil

The sources consulted include few Portuguese and Brazilian data: in the international survey on FBPase deficiency there were 2 patients in Brazil, both diagnosed in adulthood [52], and the HMGCL nonsense variant c.109G>T is described as frequent in the Iberian Peninsula, without a separate Portuguese estimate [12]. The sources consulted do not provide Portuguese or Brazilian incidence of congenital hyperinsulinism, HFI or FBPase deficiency, which does not demonstrate that such data are absent from the literature.

9.4. European networks and patient associations

Endo-ERN (European Reference Network on rare endocrine conditions) covers hyperinsulinism, hypopituitarism and adrenal insufficiency, and MetabERN (inherited metabolic diseases) covers glycogen storage diseases, HFI and defects of gluconeogenesis, FAO and ketogenesis [17,18]. Congenital Hyperinsulinism International, represented on the 2024 consensus committee, maintains a list of national associations and the HI Global Registry, a patient-driven registry [10,139,140]. In the United Kingdom there are the Children's Hyperinsulinism Charity, Metabolic Support UK and Climb (Children Living with Inherited Metabolic Diseases), and the BIMDG publishes emergency protocols for undiagnosed hypoglycaemia, ketolysis defects and HMG-CoA lyase deficiency [1,16,141,142]. The Boston University HFI laboratory and Genetic Metabolic Dietitians International (GMDI) provide dietary resources for HFI [8]. In Portugal, APOFEN brings together families with inherited metabolic diseases, although its website does not specifically list the hypoglycaemias [143].

10. Illustrative Clinical Case

10.1. Hypoinsulinaemic hypoglycaemia with asymmetric growth due to AKT2 p.(Glu17Lys)

Hussain and colleagues described in 2011 three unrelated children, born to unaffected, non-consanguineous European parents, with severe recurrent fasting hypoglycaemia and asymmetric growth [36]. Patient 1, already described by the authors, had severe hypoglycaemia from infancy with undetectable plasma insulin, despite a classic biochemical profile of hyperinsulinism — low ketone bodies and branched-chain amino acids, without a rise in FFA —, increased birth weight and overgrowth of the left side of the body [36]. Patients 2 and 3 had a similar metabolic profile and left facial overgrowth [36]. From ~6 months, all three had severe symptomatic hypoglycaemia, with reduced consciousness and seizures, whenever fasting exceeded ~3 h, which led to surgical placement of enteral tubes for overnight carbohydrate feeding [36].

Sequencing of preproinsulin, IGF1, IGF2 and their receptors was normal, and there was no basal hyperphosphorylation of the insulin receptor in fibroblasts [36]. Exome sequencing of the index case revealed 326 rare variants, including the heterozygous AKT2 variant NM_001626.6:c.49G>A p.(Glu17Lys), in the pleckstrin homology (PH) domain; Sanger sequencing confirmed it in lymphocytes and in dermal fibroblasts from the left and right sides and showed it to be absent in the parents (germline de novo) [36,62]. The same variant was found in the other two probands — one heterozygous and the other with ~20% mosaicism in lymphocytes and buccal epithelium — and was absent from 1,130 control genomes and exomes (470 European) [36]. Functionally, mutant AKT2 was constitutively recruited to the membrane of serum-starved HeLa cells and maintained tonic nuclear exclusion of FoxO1 in 3T3-L1 adipocytes [36]. Figure 1 of the article shows patient 1 with enlargement of the left leg and the left truncal adipose tissue and the surgical feeding tube, the heterozygous and mosaic electropherograms, the pedigrees with de novo occurrence, the AKT2 domains and the membrane localisation of the mutant protein (figure 1 of Hussain 2011) [36].

The case teaches that hypoketotic hypoglycaemia with suppressed FFA and undetectable insulin and C-peptide does not exclude an "insulin-like" mechanism: it points to activation of the signalling pathway downstream of the receptor, one of the hyperinsulinism mimics in the 2024 classification [10]. Molecular confirmation should precede drugs for hyperinsulinism and any pancreatic surgery, which have no target in this disease [35]. Feeding through a surgically placed enteral tube was the solution for these three patients and does not constitute standardised treatment; the guidelines have no recommendation specific to this entity, and follow-up of two patients up to 17 years showed absence of steatosis and dyslipidaemia and the possibility of spontaneous remission [35,76].

10.2. Decompensation of FBPase deficiency in adulthood

A 29-year-old woman with FBPase deficiency confirmed molecularly in childhood (variants not stated in the report), with a written emergency plan (oral glucose polymer; IV glucose if the oral route was impossible), had about 20 h of almost no intake because of epigastric pain and vomiting and developed acute confusion [144]. In the pre-hospital setting she had a Glasgow coma scale score of 8/15 and capillary blood glucose of 0.4 g/L (2.2 mmol/L); in the emergency department, Glasgow 10, respiratory rate 26/min, heart rate 120/min and blood pressure 140/80 mmHg; blood gases showed pH 7.185, bicarbonate 6.3 mmol/L, pCO2 16.6 mmHg (adequate respiratory compensation by Winter's formula, 17.5 ± 2), base excess −22 and lactate 6.49 mmol/L; ketone bodies were not measured [144]. She received 30% IV glucose via a peripheral line, a continuous glucose infusion and fluids, with blood glucose rising to 1.1 g/L (6.1 mmol/L); thoraco-abdomino-pelvic computed tomography was normal, and after 48 h in intensive care she made a complete neurological recovery, without ventilation [144]. The report includes no imaging figures. The case shows that, in an adult with known disease, prolonged fasting due to vomiting is the typical trigger and that hypoglycaemia with lactic acidosis and hyperventilation may be confused with more common causes. GeneReviews recommends starting the emergency regimen at the first signs of illness, while glucose is still normal, because hypoglycaemia is a late event in decompensation [9].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by class

Hyperinsulinism. Outside syndromic hyperinsulinism and HIHA, developmental delay affects up to 50% of patients, unrelated to the genetic defect; severe brain injury results from profound and prolonged hypoglycaemia with coma or neonatal status epilepticus and typically shows bilateral cavitated occipital lesions on magnetic resonance imaging, and the medical or surgical strategy has little influence on the neurological outcome [3]. The consensus reports neurodevelopmental deficits in 26–44% even in transient hyperinsulinism, a particularly high risk in GLUD1 and feeding problems in 68.6% [10]. In the HI Global Registry (193 participants from 34 countries, mean age at follow-up 12.52 years), 66% of all participants and 72% of those aged ≥5 years (n=145) reported an adverse neurodevelopmental outcome; among those aged ≥5 years, 50% had a diagnosed neurological, neurodevelopmental or sensory disorder, 57% developmental delay and 18% a mental health problem — data reported by patients or families and subject to registry selection bias [140]. Most medically treated patients enter remission after months or years; some develop glucose intolerance and, rarely, ketotic hypoglycaemia later, and severity may decrease over time in the ABCC8, KCNJ11, HNF1A and HNF4A forms [2,10]. Resection of the focal lesion cures >95% of patients; after 95–98% pancreatectomy in the diffuse form, hypoglycaemia recurs in 50–60% and diabetes reaches up to 91% at 14 years [3,10]. Glycaemic surveillance is lifelong in those who are cured, because HNF1A, HNF4A, GCK, ABCC8 and KCNJ11 also cause monogenic diabetes [3].

Hereditary fructose intolerance. With early diet and adherence, the prognosis is excellent, with normal growth, intelligence and life expectancy; without adherence, it progresses to chronic liver and/or kidney disease, and hepatic steatosis may persist even in patients treated from birth [8,13].

FBPase deficiency. With diagnosis and management, the course is benign, with normal growth and development in most, fasting tolerance that improves with age and uncomplicated pregnancies; obesity due to overfeeding is frequent and liver disease (steatosis) requires lifelong follow-up [9,13,75]. The "normal" fasting tolerance reported by centres (without biochemical confirmation) was 30% of patients aged 1 to 10 years, 36% of those aged 11 to 16 and 58% above 16 years [52].

Other entities. In IKH, neurological sequelae are rare even with seizures, most stop having hypoglycaemic episodes by 7 years and episodes after puberty are extremely rare [12]. In HMGCS2D, 98% of survivors have normal development, but 8% died, mostly in the first crisis [64]; the neurological prognosis is worse in neonatal HMG-CoA lyase deficiency [12]. In isolated GKD, the prognosis is very good with appropriate management and decompensations decrease after puberty [30]. In GSD 0, the adults described did well [70]. In PEPCK-C deficiency, neurological development is usually normal, but the risk of hypoglycaemia persists into adulthood and one death in childhood has been described [25,29]. In Donohue syndrome, death usually occurs in the first year [78].

11.2. Surveillance table

The surveillance intervals for HFI and FBPase deficiency come from recommendations without formal guidelines, based on the opinion of the GeneReviews authors [8,9].

12. Summary and Final Considerations

Persistent or recurrent hypoglycaemia in the newborn beyond 48–72 h, in the infant and in the child requires an aetiological diagnosis, because the monogenic causes are numerous, treatment differs between classes and delay has a neurological cost. The centrepiece is the critical sample collected during hypoglycaemia, before glucose: laboratory PG, bicarbonate, BOHB, lactate, FFA and insulin, with C-peptide, cortisol, GH, ammonia, acylcarnitines and urinary organic acids. Without acidaemia, low BOHB and FFA indicate hyperinsulinism, confirmed by a glucagon response ≥30 mg/dL and by a glucose infusion rate >8 mg/kg/min in the newborn; low BOHB with high FFA indicates a fatty acid oxidation or ketogenesis defect; with acidaemia, high lactate indicates a gluconeogenesis defect or GSD I, and high BOHB indicates ketotic hypoglycaemia, glycogen storage disease or GH or cortisol deficiency. The timing of hypoglycaemia in relation to meals, liver size, hyperammonaemia, hemihypertrophy, micropenis and hyperpigmentation complete the orientation, and undetectable insulin and C-peptide with the biochemistry of hyperinsulinism point to activation of insulin signalling.

HFI is distinguished by immediate postprandial hypoglycaemia after fructose, sucrose or sorbitol, with liver failure, tubulopathy, aversion to sweet foods and absence of dental caries; the diagnosis is molecular in ALDOB, with copy number analysis, and treatment is lifelong avoidance of these sugars, including medicines and sucrose-containing rotavirus vaccines. FBPase deficiency presents with fasting hypoglycaemia, lactic acidosis and hyperventilation, frequently in the first days of life, with urinary glycerol-3-phosphate and pseudohypertriglyceridaemia, and is treated with fasting avoidance, an early emergency regimen and avoidance of IV fructose, glycerol and sorbitol. PEPCK-C deficiency causes hypoketotic morning hypoglycaemia with urinary fumarate and transient liver failure, with a founder variant in Finland; GKD requires a search for the Xp21 deletion with adrenal insufficiency.

Functional tests — fasting, glucagon, loading tests — are dangerous and are performed only in a specialised centre and after fatty acid oxidation defects and adrenal insufficiency have been excluded; the fructose tolerance test divides the sources and GeneReviews advises against it. Genetic testing is recommended in all children with non-acquired hyperinsulinism and confirms the remaining entities, but no method detects all variants: CNV, deep intronic and regulatory variants, 11p15 methylation abnormalities and mosaicism require targeted techniques. In acute treatment, 200 mg/kg of IV glucose followed by an infusion keeps PG >70 mg/dL; glucagon (0.5–1 mg or 20–30 μg/kg) acts only if there is glycogen. Diazoxide is first line in hyperinsulinism, with a thiazide, echocardiography and, since October 2026, a necrotising enterocolitis warning in the US label; somatostatin analogues and glucagon are off-label; dasiglucagon and ersodetug are not approved for congenital hyperinsulinism, and the phase 3 trial of ersodetug was negative. Follow-up includes home glucose surveillance, a written emergency plan, neurodevelopmental assessment, liver and kidney surveillance in HFI and liver surveillance in FBPase deficiency, and transition to adult care, within a European framework provided by the Endo-ERN and MetabERN networks.

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