Persistent Hyperinsulinemic Hypoglycemia Research Articles

A case of persistent hyperinsulinemic hypoglycemia of infancy successfully managed with subcutaneous octreotide injection and nocturnal intravenous glucose supply.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is often resistant to medical therapy and is normally treated by subtotal pancreatectomy to avoid neurological complications. However, many problems after surgery, such as recurrence of hypoglycemia and diabetes mellitus, remain to be solved. This report concerns a case of PHHI that was resistant to octreotide or diazoxide alone but was successfully controlled with subcutaneous injection of octreotide in combination with nocturnal glucose infusion through central venous catheter. The patient exhibited natural remission of hyperinsulinism with age, and all treatment was ceased at the age of 4 yr. Growth and neurological development of the patient have been normal. This combined therapy can be a therapeutic option as a substitute for surgical solutions.

Long-term MRI findings of a case with persistent hyperinsulinemic hypoglycemia of infancy (nesidioblastosis)

Background and purpose To describe the sequential magnetic resonance imaging (MRI) findings in a neurologically handicapped newborn who had been suffered from neonatal hypoglycemia due to persistent hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) and to evaluate the following changes in the long-term radiological follow-up. Case A case of newborn with severe hypoglycemia due to nesidioblastosis is reported. The patient was presented with poor feeding, irritability, and seizures. Nesidioblastosis was diagnosed on the basis of high intravenous glucose requirement, high insulin to glucose ratio, negative urinary ketones. Normoglycemia was maintained by a combined treatment including glucose infusions and steroid, and then somatostatin analoques. The patient was assessed neurologically and radiologically by sequential cerebral MRI within 2 years follow-up. Results The most striking findings were cystic lesions on corona radiata, parietooccipital deep white matter and diffuse subcortical involvement of the brain at the initial MRI. The lesions were recovered radiologically at the 5 months of age. Diffuse hyperintensity of the periventricular white matter and optic radiation suggests abnormal and delayed myelination at 1 year of age, and periventricular leukomalacia and ventricular irregularity at 2 years of age. More delayed neurologic sequelae included mental retardation and spasticity. Conclusion Neonatal hyperinsulinemic hypoglycemia must be suddenly and appropriately diagnosed and treated to prevent any further neurological dysfunction and damage. MRI studies are crucial in nesidioblastosis to define the characteristics and severity of cerebral lesions after hypoglycemia. Long-term radiologic follow-up should be further investigated to predict the neurologic outcome, although the radiologic recovery period was seen in acute or subacute phase of the disease.

Persistent Hyperinsulinaemic Hypoglycaemia of Infancy in 43 Children: Long-term Clinical and Surgical Follow-up

To describe the clinical, surgical, biochemical, radiological and electrophysiological features of 43 Saudi children with persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) who have been followed since 1983. Data from 43 patients were retrospectively analysed. PHHI was diagnosed on the basis of high intravenous glucose requirement, high insulin to glucose ratio, negative urinary ketones and normal tandem mass spectrometry. The patients were assessed radiologically by brain magnetic resonance imaging and/or computed tomography and electrophysiologically by brain stem auditory evoked potential, visual evoked response and electroencephalogram. Patients who failed medical therapy received near total pancreatectomy. The patients were severely hypoglycaemic and intolerant to fast. Hypoglycaemic convulsion was the most commonly presenting complaint. Eighteen patients were developmentally delayed and 14 of them had brain atrophy. All patients, except nine, did not respond to medical treatment and underwent surgery. Four pancreatectomized patients developed diabetes and two had malabsorption. One baby had 180 cm resection of gangrenous bowel most likely secondary to octreotide. No common bile duct injury was encountered. One patient was treated medically during childhood and developed diabetes and gained weight during adolescence. PHHI is a relatively common and serious disease among Saudi children. Early intervention is necessary to avoid neurological damage in patients who are severely hypoglycaemic and unresponsive to medical therapy. Surgically and probably medically treated patients are at a high risk of developing diabetes, which could be the natural outcome of this disease. Care and spending time during surgery to visualize the common bile duct help in avoiding its injury.

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-dependent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody (2/3) genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus II has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be considered.

Selective pancreatic ATP-sensitive-potassium channel openers for the treatment of glucose homeostasis disorder

Disorders of glucose homeostasis may be associated with severe pathologies such as type 1 and type 2 diabetes, insulinoma, persistent hyperinsulinemic hypoglycemia of infancy (PHHI), polycystic ovary syndrome (PCOS) and/or obesity. Specific activation of the Kir6.2/SUR1 K ATP channel subtype has been shown to be beneficial for the treatment of these pathologies. Starting from diazoxide, a nonselective Kir6.2/SUR1 K ATP channel activator, many research groups have conducted searches in an attempt to discover more potent and selective drugs. Several 3-alkylaminoarylthiadiazine 1,1-dioxides (BPDZ-44, BPDZ-73, BPDZ-415, NNC-55-0118, NN-414) have been described as potent Kir6.2/SUR1 K ATP channel openers and are reported to inhibit insulin release without a pronounced effect on smooth muscle mechanical activity NN-414 was the most extensively studied drug and had entered clinical trials, although its development was discontinued due to liver toxicity. Other chemical series have also been developed, but none has led to compounds as potent and/or as selective as the lead arylthiadiazine drugs. Based on the therapeutic interest of Kir6.2/SUR1 K ATP channel activators, the discovery of new series with improved pharmacodynamic and/or pharmacokinetic properties remains a priority.

Management of Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) - a Challenge for the Pediatrician

We present a 6 months male infant with persistent hyperinsulinemic hypoglycemia of infancy (PHHI)- the former nesidioblastosis. The main presenting symptoms were recurrent episodes of hypoglycemic seizures (persistent hypoglycemic status of 30 mg/dL serum glucose) high requirements of i.v. glucose for maintaining euglycemic status. The main diagnostic markers were: high insulin to glucose ratio,negative urinary ketones, normal growth hormone level, normal cortisol level during hypoglycemia, no visible pathological masses on abdominal and cranial MRI . As a medical treatment we used Octreotid and we needed several adjustments of the dose to maintain euglycemic status, between 4 µg/kg/day s.c. and 10 µg/kg/day s.c. Our goal were to prevent the neurological damage and the minimum compromise in the fragile equilibrium of advantages and disadvantages of the treatment in order to maintain the best outcome we could get. Our patient is in his second year of treatment with no severe hypoglycemia during the last 12 months and with good neurological and physical development. The long term outcome is difficult to be predicted.

Costello syndrome and hyperinsulinemic hypoglycemia

Costello syndrome is characterized by mental retardation, loose skin, coarse facies, skeletal abnormalities, cardiovascular abnormalities (congenital heart defects, cardiomyopathy, rhythm disturbances), and predisposition to neoplasia. Endocrine abnormalities including growth hormone deficiency, adrenal insufficiency, glucose intolerance, parathyroid adenoma with hyperprolactinemia and hypoglycemia have been described. Hypoglycemia has been documented due to growth hormone and cortisol deficiency. We report on two patients with Costello syndrome and persistent hyperinsulinemic hypoglycemia and review the endocrine manifestations of Costello syndrome. Both patients required diazoxide therapy to stop the unregulated insulin secretion and maintain normoglycemia. The mechanism of persistent hyperinsulinism in patients with Costello syndrome is unclear.

Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters

Genetic variations in drug metabolizing enzymes and targets are established determinants of adverse drug reactions and interactions, but less is known about the role of genetic polymorphisms in membrane transport proteins. MRP1 (ABCC1) is one of 13 polytopic membrane proteins that comprise the 'C' subfamily of the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 and related ABCC family members, including MRP2, 3, 4 and 5 (ABCC2, 3, 4 and 5), each have a distinctive pattern of tissue expression and substrate specificity. Together, these five transporters play important roles in the disposition and elimination of drugs and other organic anions, and in maintenance of blood-tissue barriers, as confirmed by enhanced chemosensitivity of respective knockout mice. Moreover, Mrp2 (Abcc2) deficient animals display mild conjugated hyperbilirubinemia, corresponding to a human condition known as Dubin-Johnson syndrome (DJS). Naturally occurring mutations in MRP/ABCC-related drug transporters have been reported, some of which are non-synonymous single nucleotide polymorphisms. The consequences of the resulting amino acid changes can sometimes be predicted from in vitro site-directed mutagenesis studies or from knowledge of mutations of analogous (conserved) residues in ABCC proteins that cause DJS, Pseudoxanthoma elasticum (ABCC6), cystic fibrosis (CFTR/ABCC7) or persistent hyperinsulinemic hypoglycemia of infancy (SUR1/ABCC8). Continual updating of databases of sequence variants and haplotype analysis, together with in vitro biochemical validation assays and pharmacological studies in knockout animals, should make it possible to determine how genetic variation in the MRP-related transporters contributes to the range of responses to drugs and chemicals observed in different human populations.

Low temperature completely rescues the function of two misfolded K ATP channel disease-mutants

The pancreatic ATP-sensitive potassium channels comprise two subunits: SUR1 and Kir6.2. Two SUR1 mutations, A116P and V187D, reduce channel activity causing persistent hyperinsulinemic hypoglycemia of infancy. We investigated whether these mutations cause temperature sensitive misfolding. We show that the processing defect of these mutants is temperature sensitive and these two mutations disrupt the association between SUR1 and Kir6.2 by causing misfolding in SUR1 at 37 °C but can be rescued at 18 °C. Extensive electrophysiological characterization of these mutants indicated that low temperature largely, if not completely, corrects the folding defect of these two SUR1 mutants observed at 37 °C.

Uso de octreotide na Hipoglicemia Hiperinsulinêmica Persistente Infantil

This paper presents a clinical case of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and a literature review on this subject. We report on a newborn who presented with hypoglycemic episodes in her first 24 hs of life and was treated successfully with octreotide until the moment. PHHI is the most common cause of persistent hyperinsulinism in infancy and can be hazardous for the development of the central nervous system. There are few current options for clinical treatment, with variable efficacy, and octreotide seems to be the best option before surgical treatment, the only way to control the disease. Preoperative evaluation allows one to adequately distinguish between focal or diffuse processes and suggests the extension of pancreatic resection, improving surgical results and reducing the incidence of postoperative sequelae. Partial pancreatectomy is the procedure of choice in focal disease.

Glucokinase: old enzyme, new target

Glucokinase (GK) plays a key role as a glucose sensor in pancreatic β-cells and in the regulation of glucose utilisation in hepatocytes. Defects in the GK gene have been linked to maturity-onset diabetes of the young (non-insulin-dependent [MODY-2]), permanent neonatal diabetes (PNDM) and persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI). Expression of GK is regulated by the upstream pancreatic promoter or the downstream hepatocyte promoter by a scenario involving several transcription factors and signalling pathways that are not yet understood in full. Thus, the development of specific drugs that enhance either GK activity or GK expression could be useful for treatment of the diabetic syndromes. Due to a recent breakthrough leading to the identification of a novel class of small molecules termed glucokinase activators, the old enzyme became a new target in diabetes therapy.

Congenital Disorder of Glycosylation Id Presenting with Hyperinsulinemic Hypoglycemia and Islet Cell Hyperplasia

Inborn errors in protein glycosylation, such as the congenital disorders of glycosylation (CDGs), generate multifaceted syndromes that impair many organ systems. We here report the diagnosis of the third known patient with CDG-Id. The patient's phenotype was extremely severe, and she succumbed at 19 d of age. Leading features included hyperinsulinemic hypoglycemia, and autopsy revealed islet cell hyperplasia with increased beta-cell mass. Other features were a Dandy-Walker malformation, facial dysmorphisms, and profound hypotonia. The patient carried a novel homozygous point mutation (512G>A) in the hALG3 gene, which encodes a mannosyltransferase. Lentiviral complementation with wild-type hALG3 corrects the biochemical defect in the patient's fibroblasts. Our findings underscore the importance of proper glycosylation in several major organ systems and emphasize that CDG should be ruled out in patients with persistent hyperinsulinemic hypoglycemia of unknown etiology.

Hyperinsulinemic Hypoglycemia in Beckwith-Wiedemann Syndrome due to Defects in the Function of Pancreatic β-Cell Adenosine Triphosphate-Sensitive Potassium Channels

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.

Persistent Hyperinsulinemic Hypoglycemia in 15 Adults With Diffuse Nesidioblastosis

Persistent hyperinsulinemic hypoglycemia (PHH) in adults that is not caused by an insulinoma is a rare and not well-characterized disease that has been named nesidioblastosis. In this study, we defined and scrutinized criteria for its histologic diagnosis, assessed its relative incidence, and discussed its pathogenesis. In pancreatic specimens from 15 adult patients with PHH in whom no insulinoma was detected and in 18 adult control patients, the endocrine tissue was screened for islet and beta-cell changes. The diagnostic reliability of the findings was checked by an interobserver analysis. The relative frequency of the disease was assessed in a series of 232 patients with PHH. Finally, genetic analysis of the menin gene was performed. Among the various indicators of islet changes, beta-cell hypertrophy characterized by enlarged and hyperchromatic beta-cell nuclei was the most significant and diagnostic finding in patients with PHH. The interobserver analysis revealed 100% specificity and 87.7% sensitivity. The hyperfunctional state of the beta-cells was not associated with changes in the subcellular distribution of insulin and proinsulin, proliferative activity, or mutations of the menin gene. Our results indicate that diffuse nesidioblastosis in adult patients with PHH resembles that seen in neonates suffering from PHH. The most important criterion for the diagnosis is the beta-cell hypertrophy. As approximately 4% of adult patients with PHH are affected by diffuse nesidioblastosis, this disease is not as rare as it has been thought to be. Pathogenetically, the defective insulin secretion could be based on a molecular defect.

Targeted local activation of Fas in pancreatic beta cells for treatment of insulinomas and disorders of pathological autonomic insulin secretion

The prognosis of patients with insulinomas is poor when multiple or malignant tumors are present. Also, pancreatectomy is frequently necessary as life-saving procedure to rescue patients from hypoglycaemic episodes associated with persistent hyperinsulinemic hypoglycaemia of infancy (PHHI, nesidioblastosis). Therapeutic compounds that selectively destroy autonomically insulin producing cells may cure both multifocal or malignant insulinomas and nesidioblastosis. The aim of this study is to target the apoptosis-inducing actions of Fas-ligand (FasL) specifically to autonomic pancreatic beta cells. We demonstrate that artificial immobilisation of the extracellular inactive domain of FasL on the cell surface by fusion to an appropriate immobilisation domain is sufficient to convert these fusion proteins to bioactive compounds mimicking the apoptosis inducing actions of membrane-bound forms of FasL. To target this principle to pancreatic beta cells, fusion proteins of FasL with a peptide domain of the glucagon-like peptide 1 (GLP-1) analog exendin 4 (FasL-Ex4) were generated. Receptors for the incretin hormone GLP-1 (GLP-1R) are specifically expressed on the surface of insulin producing cells and exendin 4 (Ex4) binds to GLP-1R with high affinity. Expression of GLP-1R was verified by RT-PCR, fluorescence immunocytochemistry and FACS phenotyping in pancreatic beta cell lines INS-1, betaTC3 and BHK cells stably overexpressing rat GLP-1R and in primary human pancreatic beta cells. GLP-1R negative BHK and Cos-7 cells served as controls. Surface immobilisation of FasL-Ex4 fusion proteins specifically in GLP-1R positive cells was demonstrated by fluorescence immunocytochemistry and FACS. FasL dependent induction of apoptosis and activation of apoptotic signal transduction pathways are currently examined. These results demonstrate that FasL-Ex4 fusion proteins hold the potential as therapeutic compounds to target FasL apoptotic activity specifically to GLP-1R expressing insulin producing cells for non surgical treatment of insulinomas and nesidioblastosis in vivo.

Genotypes of the pancreatic β‐cell K‐ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a disorder of glucose metabolism that is characterized by dysregulated secretion of insulin from pancreatic beta-cells. This disease has been reported to be associated with mutations of the sulfonylurea receptor SUR1 (ABCC8) or the inward-rectifying potassium channel Kir6.2 (KCNJ11), which are two subunits of the pancreatic beta-cell ATP-sensitive potassium channel. In 14 Japanese PHHI patients, all exons of SUR1 and Kir6.2 genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Four patients responded to diazoxide, and nine patients underwent a subtotal pancreatectomy. Histologically, seven patients were diagnosed to have a focal form and two a diffuse form of the disease. We found nine novel mutations in the SUR1 gene and two in the Kir6.2 gene. In the SUR1 gene mutations, three were nonsense mutations (Y512X, Y1354X and G1469X), one was a one-base deletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). The other three mutations occurred in introns 14, 29 and 36, which might cause aberrant splicing of RNA. Two siblings in one family were heterozygotes for a missense mutation, K1385Q, which was maternally inherited. In Kir6.2 gene screening, one patient was found to be a compound heterozygote of a missense mutation (R34H) and a one-base deletion (C344fs/ter). The novel mutations reported here could be pathological candidates for PHHI in Japan. They also reveal that SUR1 and Kir6.2 mutations in the Japanese population exhibit heterogeneity and that they occurred at a frequency similar to other genetic populations.

Multidisciplinary Management of Surgical Disorders of the Pancreas in Childhood

To describe the frequency and range of pancreatic disorders in children requiring surgical intervention and to highlight the importance of multidisciplinary management. An audit of all children under 17 years of age referred with surgical disorders of the pancreas or pancreatitis to a regional pediatric gastroenterology unit in the United Kingdom during a 10-year period. A retrospective chart review of clinical features, pathology and outcome was undertaken. Surgical intervention was required for the following pancreatic disorders: persistent hyperinsulinemic hypoglycemia of infancy (n = 4), pancreatic tumors (n = 5), pancreaticobiliary malunion (n = 12), pancreatic trauma (n = 6) and pancreatitis (n = 10). The indications for surgery in acute pancreatitis were a persistent pseudocyst (n = 1) and treatment of an underlying cause of pancreatitis (n = 4); in chronic pancreatitis, surgery was used to treat symptomatic pancreatic duct strictures (n = 4). One child died of a progressive lymphoma but all others who underwent surgery are alive and well. All 33 children with acute pancreatitis, including four with pancreatic necrosis, survived. Surgery for pancreatic disorders in children is rarely required but may be necessary a) for definitive management of primary pancreatic pathology, b) to treat sequelae of acute or chronic pancreatitis and c) to treat an underlying cause of pancreatitis. There is a broad spectrum of potential pathologies. These patients are best managed by a multidisciplinary team approach.

Winged-helix transcription factors and pancreatic development

The forkhead gene family, named after the founding gene member in Drosophila, is characterized by a unique DNA-binding domain. This so-called forkhead box encodes a winged-helix DNA-binding motif, the name of which describes the structure of the domain when bound to DNA. The three Fox (forkhead box) group A genes, Foxa1, Foxa2 and Foxa3, are expressed in embryonic endoderm, the germ layer that gives rise to the digestive system, and contribute to the specification of the pancreas and the regulation of glucose homoeostasis. Deletion of the Foxa2 gene in pancreatic beta-cells in mice results in a phenotype resembling PHHI (persistent hyperinsulinaemic hypoglycaemia of infancy). Molecular analyses have demonstrated that Foxa2 is an important regulator of the genes encoding Sur1, Kir6.2 and Schad (short chain L-3-hydroxyacyl-CoA dehydrogenase), mutation of which causes PHHI in humans. Foxa1 was shown to be an essential activator of glucagon gene expression in vivo. An additional winged-helix protein, Foxo1, contributes to pancreatic beta-cell function by regulating the Pdx1 gene, which is required for pancreatic development in cooperation with Foxa2.

A Case of Hyperinsulinemia of Undetermined Origin, Successfully Treated with Long-acting Octreotide

Major causes of fasting hypoglycemia in adults are insulinoma, factitious hypoglycemia and nesidioblastosis. The primary treatment for insulinoma is surgical removal of the tumor, but there are cases with hyperinsulinemia that cannot undergo surgery. Somatostatin analogue is one of the treatments used in such cases of insulinoma or persistent hyperinsulinemic hypoglycemia. We report here a patient who had undetermined hyperinsulinemia and was successfully treated with a long-acting somatostatin analogue, which had recently become available. The patient, a 72-year-old female, who had previously been diagnosed as insulinoma and undergone partial pancreatectomy, was admitted complaining of the recurrence of hypoglycemic attacks after an interval of ten years. On admission, hypoglycemia (42 mg/dl), hyperinsulinemia (IRI: 79.3 microU/m) and low HbA1c (3.6%) were present. In 75 g-OGTT at 30 min after load, IRI reached 6623 microU/ml, while plasma glucose level was 88 mg/dl. The anti-insulin antibody was not present. Since attempts at tumor localization by imaging techniques failed and the patient refused further examinations or surgical treatment, we recommended her to take a medication with a somatostatin analogue. Insulin suppression test using 50 microg of octreotide improved plasma glucose and IRI levels, suggesting the usefulness of the treatment, and a monthly administration of 20 mg of long-acting octreotide has successfully controlled her symptoms of hypoglycemia for 10 months. Our case demonstrated the utility of the long-acting somatostatin analogue for long-term treatment of undetermined hyperinsulinemia. A preliminary loading test using short-acting octreotide may be useful to determine appropriate medication, especially in cases who cannot receive surgical treatment.

Persistent Hyperinsulinaemic Hypoglycaemia of Infancy: 15 Years' Experience at the Royal Children's Hospital (RCH), Melbourne

To review the clinical outcome and report our experience of patients with persistent hyperinsulinemic hypoglycaemia of infancy (PHHI). Retrospective case series of 14 patients diagnosed with PHHI at the Royal Children's Hospital in Melbourne in the period between 1988 and 2004. Diagnoses of insulinoma, Beckwith syndrome and transient hyperinsulinism were excluded. Six patients (43%) presented on day 1, with a median presenting age of 2.75 months; ten (71.4%) presented with seizures. All were initially treated with diazoxide, of whom six (43%) recovered and are off medication, while four patients (28.5%) required surgery (twice in one patient). One developed permanent diabetes mellitus. Developmental delay occurred in nine (64%), and was severe in two (14.5%) patients, possibly associated with delayed treatment. PHHI is a rare but severe condition. The aim of management of PHHI should be on the one hand to prevent mental retardation and developmental delay due to severe and persistent hypoglycaemia, and on the other hand to avoid the induction of diabetes mellitus following surgery. Satisfactory outcome depends on early effective medical treatment and judicious use of surgery by an experienced operator.