Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus.

Congenital hyperinsulinism (CHI) is a condition characterised by severe and recurrent hypoglycaemia in infants and young children caused by inappropriate insulin over-secretion. CHI is of heterogeneous aetiology with a significant genetic component and is often unresponsive to standard medical therapy options. The treatment of CHI can be multifaceted and complex, requiring multidisciplinary input. It is important to manage hypoglycaemia in CHI promptly as the risk of long-term neurodisability arising from neuroglycopaenia is high. The UK CHI consensus on the practice and management of CHI was developed to optimise and harmonise clinical management of patients in centres specialising in CHI as well as in non-specialist centres engaged in collaborative, networked models of care. Using current best practice and a consensus approach, it provides guidance and practical advice in the domains of diagnosis, clinical assessment and treatment to mitigate hypoglycaemia risk and improve long term outcomes for health and well-being.

Neurodevelopmental impairments in children with septo-optic dysplasia spectrum conditions: a systematic review.

BACKGROUND: Septo-optic dysplasia (SOD) is a rare condition diagnosed in children with two or more of the following: hypopituitarism, midline brain abnormalities, and optic nerve hypoplasia. Children with SOD experience varied visual impairment and endocrine dysfunction. Autistic-like behaviours have been reported; however, their nature and prevalence remain to be fully understood. The present systematic review aimed to explore the type and prevalence of neurodevelopmental impairments in children with SOD spectrum conditions. METHODS: The search was conducted in PubMed, EMBASE, and PsycInfo. Hand-searching reference lists of included studies was conducted. All peer-reviewed, observational studies assessing behavioural and cognitive impairments or autism spectrum disorder (ASD) symptoms in children (< 18 years) with SOD, optic nerve hypoplasia, and SOD-plus were included. Studies were excluded if they did not report standardised measures of neurodevelopmental impairments or ASD outcomes. RESULTS: From 2132 screened articles, 20 articles reporting data from a total of 479 children were included in prevalence estimates. Of 14 studies assessing cognitive-developmental outcomes, 175 of 336 (52%) children presented with intellectual disability or developmental delay. A diagnosis of ASD or clinical level of symptoms was observed in 65 of 187 (35%) children across five studies. Only five studies assessed for dysfunction across behavioural, emotional, or social domains and reported impairments in 88 of 184 (48%) of children assessed. LIMITATIONS: Importantly, high heterogeneity among the samples in relation to their neuroanatomical, endocrine, and optic nerve involvement meant that it was not possible to statistically assess the relative contribution of these confounding factors to the specific neurodevelopmental phenotype. This was further limited by the variation in study designs and behavioural assessments used across the included studies, which may have increased the risk of information bias. CONCLUSIONS: This systematic review suggests that the prevalence of neurodevelopmental impairments in children within the SOD spectrum may be high. Clinicians should therefore consider including formal assessments of ASD symptoms and neurodevelopmental impairments alongside routine care. There is, additionally, a need for further research to define and validate a standardised battery of tools that accurately identify neurodevelopmental impairments in SOD spectrum conditions, and for research to identify the likely causal mechanisms.

An Epidemiology Model for Estimating the Numbers of US Patients With Multiple Myeloma by Line of Therapy and Treatment Exposure.

OBJECTIVES: Estimates on the distribution of patients with multiple myeloma (MM) by line of therapy (LOT) are scarce and get outdated quickly as new treatments become available. The objective of this study was to estimate the number of patients with MM by LOT and the number of patients who have received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies (mAbs). METHODS: A compartmental model was developed to calculate the number of patients by LOT. Two pathways were considered based on stem cell transplant eligibility, and at each pathway, treatments were stratified in 2 types: anti-CD38 mAbs or other. The model population was stratified into 4 subgroups based on age and cytogenetic risk. Model inputs were informed from real-world evidence. RESULTS: The model estimated that, in 2020, 126 869 patients were living with MM in the United States. Of these, 105 701 received treatment in any LOT, with 56 959, 27 252, 11 258, and 5217 in lines 1 to 4, respectively, and 5015 in line 5 or beyond. The model estimated that 3497 patients received at least 4 previous LOTs including proteasome inhibitors, immunomodulatory agents, and anti-CD38 mAbs. The model overall prevalence predictions aligned well with publicly available estimates. CONCLUSIONS: This study proposes a novel framework to estimate MM prevalence. It can assist clinicians to understand future trends in MM epidemiology, healthcare systems to plan for future resource use allocation, and payers to quantify the budget impact of new treatments.

Pituitary apoplexy in an adolescent male with macroprolactinoma presenting as middle cerebral artery territory infarction.

Pituitary apoplexy typically presents with acute headache, vomiting, visual disturbance, and confusion. Herein, we report a rare presentation of ischemic stroke due to pituitary apoplexy. A 16.5-year-old male presented with reduced Glasgow Coma Scale (GCS) score, slurred speech, right-sided hemiparesis, and bitemporal hemianopia. Magnetic resonance imaging of the brain showed a large hemorrhagic sellar/suprasellar mass and an area of cortical T2/FLAIR hyperintensity with corresponding diffusion restriction in the middle cerebral artery territory. Computed tomography (CT) intracranial angiogram showed luminal occlusion of the clinoid and ophthalmic segments of both internal carotid arteries (ICAs, left>right) due to mass pressure effect. Biochemical investigations confirmed hyperprolactinemia and multiple pituitary hormone deficiencies. Stress-dose hydrocortisone was commenced with cabergoline, followed by urgent endoscopic transsphenoidal debulking of the tumor (subsequent histology showing prolactinoma). Postoperative CT angiogram showed improved caliber of ICAs. Intensive neurorehabilitation was implemented and resulted in complete recovery of motor and cognitive deficits. At the last assessment (18.8 years), the patient remained on complete anterior pituitary hormone replacement without cabergoline. Pituitary apoplexy is a medical emergency requiring prompt recognition and treatment and should be suspected in patients presenting with sudden, severe headache; nausea; or visual disturbance and meningism. Ischemic stroke is a rare manifestation of pituitary apoplexy in the pediatric population.

Central Diabetes Insipidus in Children and Adolescents: Twenty-Six Year Experience from a Single Centre.

Introduction: Paediatric cohorts of central diabetes insipidus (CDI) have shown varying prevalence for different causes of CDI. The objective of this study was to determine the causes of CDI and long-term outcome in children and adolescents from a Tertiary Paediatric Endocrinology unit. Methods: The clinic database was searched to identify patients with CDI managed between 1993 and 2019. Relevant clinical information was collected from patient records. Results: A total of 138 CDI patients, median age 6 years (range <1-18) at presentation, were identified. Principal CDI aetiologies were craniopharyngioma (n = 44), acute central nervous system (CNS) insult (n = 33), germinoma (n = 15), postneurosurgery (indication other than craniopharyngioma and germinoma, n = 20), midline CNS malformation (n = 14), Langerhans cell histiocytosis (n = 5), and familial (n = 2). Idiopathic CDI in this cohort was infrequent (n = 5). Patients with CNS malformations/infections presented with CDI at a younger age compared to patients with CNS tumours (p < 0.0001). Five patients, initially presenting as idiopathic CDI, were subsequently diagnosed with germinoma after a median interval of 3.3 years. All patients with CDI related to craniopharyngioma and nearly all (87%) patients with CDI related to germinoma had concomitant GH, ACTH, and TSH deficiency. The majority of patients who manifested CDI due to acute CNS insult either deceased (30%) or had transient CDI (33.3%). Conclusion: Surgery for craniopharyngioma was the most common underlying aetiology of CDI with ubiquitous occurrence of panhypopituitarism in these patients. Manifestation of CDI in patients with acute CNS insult carries poor prognosis. We affirm that neuroimaging assessment in idiopathic CDI should be continued beyond 3 years from diagnosis as a significant number of patients exhibited progression of infundibular thickening 3 years post-CDI diagnosis.

IgG4-related hypophysitis in adolescence.

OBJECTIVES: IgG4-related hypophysitis is a novel clinical disease entity, which is typically seen in the sixth decade of life and is typically complicated by hypopituitarism. We describe an adolescent female with IgG4-related hypophysitis with normal pituitary function and summarize the relevant literature. CASE PRESENTATION: A 11.8-year-old girl presented with headache and left VI cranial nerve palsy. MRI brain identified an enlarged pituitary gland. Endocrine investigations revealed normal pituitary function. She underwent a transsphenoidal biopsy of the pituitary gland, and histological examination confirmed the diagnosis of IgG4-related hypophysitis. Serum IgG4 concentrations were normal and no evidence of other organ involvement was found. Although the patient tested strongly positive for TB on an interferon gamma release assay, pituitary biopsy was negative for granuloma formation and acid-fast bacilli (Ziehl-Neelson staining). IgG4-related hypophysitis was treated with oral prednisolone and mycophenolate-mofetil with a good response. CONCLUSIONS: We describe to the best of our knowledge, the youngest patient in the published literature with IgG4-related hypophysitis presenting without pituitary insufficiency. A literature review identified only five cases of IgG4-related hypophysitis in adolescence. Serum IgG4 concentrations were normal in all, except one of the adolescent patients reported so far, and appear unhelpful in diagnosis in this age group.

Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population.

OBJECTIVE: An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. DESIGN: We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. RESULTS: We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). CONCLUSION: We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov (Registration number: NCT04329299).

Prolactinoma in childhood and adolescence-Tumour size at presentation predicts management strategy: Single centre series and a systematic review and meta-analysis.

OBJECTIVE: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis. PATIENTS AND DESIGN: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%). CONCLUSIONS: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.

Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings.

INTRODUCTION: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate limb shortening. It results from loss-of-function NPR2 mutations affecting the C-type natriuretic peptide receptor. Resistance to growth hormone (GH) action has previously been suggested. We describe outcomes of 2 siblings with AMDM after prolonged high-dose GH treatment. PATIENTS/METHODS: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological features of AMDM. Subsequent genetic testing identified a novel homozygous NPR2 mutation. GH provocation testing showed relatively high GH levels. Serum insulin-like growth factor 1 (IGF-1) was ∼2 SD below age/sex-specific mean. High-dose GH (0.075 mg/kg/day) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF-1 towards +3 SDS for age/sex. Annualized height velocities for first 3 years on GH were 7.0, 5.4, and 4.7 cm/year for patient A and 9.4, 8.0, and 5.9 cm/year for patient B. Height gain during puberty was 10.6 (Pt-A) and 5.9 (Pt-B) cm. Final heights after 8.5 years of GH treatment were 130.5 cm (-6.57 SDS, Pt-A) and 134 cm (-4.58 SDS, Pt-B). CONCLUSIONS: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. The final height of our patients was significantly higher than average reported final height (120 cm) of AMDM patients.

Evaluating the Use of microRNA Blood Tests for Gastric Cancer Screening in a Stratified Population-Level Screening Program: An Early Model-Based Cost-Effectiveness Analysis.

OBJECTIVES: To evaluate cost-effectiveness of a novel screening strategy using a microRNA (miRNA) blood test as a screen, followed by endoscopy for diagnosis confirmation in a 3-yearly population screening program for gastric cancer. METHODS: A Markov cohort model has been developed in Microsoft Excel 2016 for the population identified to be at intermediate risk (Singaporean men, aged 50-75 years with Chinese ethnicity). The interventions compared were (1) initial screening using miRNA test followed by endoscopy for test-positive individuals and a 3-yearly follow-up screening for test-negative individuals (proposed strategy), and (2) no screening with gastric cancer being diagnosed clinically (current practice). The model was evaluated for 25 years with a healthcare perspective and accounted for test characteristics, compliance, disease progression, cancer recurrence, costs, utilities, and mortality. The outcomes measured included incremental cost-effectiveness ratios, cancer stage at diagnosis, and thresholds for significant variables. RESULTS: The miRNA-based screening was found to be cost-effective with an incremental cost-effectiveness ratio of $40 971/quality-adjusted life-year. Key drivers included test costs, test accuracy, cancer incidence, and recurrence risk. Threshold analysis highlights the need for high accuracy of miRNA tests (threshold sensitivity: 68%; threshold specificity: 77%). A perfect compliance to screening would double the cancer diagnosis in early stages compared to the current practice. Probabilistic sensitivity analysis reported the miRNA-based screening to be cost-effective in >95% of iterations for a willingness to pay of $70 000/quality-adjusted life-year (approximately equivalent to 1 gross domestic product/capita) CONCLUSIONS: The miRNA-based screening intervention was found to be cost-effective and is expected to contribute immensely in early diagnosis of cancer by improving screening compliance.

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management.

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

Using referral rates for genetic testing to determine the incidence of a rare disease: The minimal incidence of congenital hyperinsulinism in the UK is 1 in 28,389.

Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.

Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.

BACKGROUND: Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects. We describe the largest case series to date of 5 unrelated patients with SOX3 duplication with a variable clinical phenotype, including the smallest reported SOX3 duplication. CASE REPORTS: Five male patients who presented with congenital hypopituitarism (CH) were identified to have Xq27.1 duplication encompassing SOX3. The size of the duplication ranged from 323.8 kb to 11 Mb. The duplication was maternally inherited or de novo in 2 patients each (and of unknown inheritance in 1 patient). The age at presentation was variable. Three patients had multiple pituitary hormone deficiencies, whereas 2 patients had isolated growth hormone deficiency. All patients had micropenis and/or small undescended testes. Structural pituitary and/or other midline cranial abnormalities (callosal hypogenesis/absence of the septum pellucidum) were present in all patients. Two patients had a neural tube defect in addition to CH. CONCLUSIONS: This is the largest series reported to date of unrelated patients with CH in association with Xq27.1 duplication encompassing SOX3. The clinical phenotype is variable, which may be due to genetic redundancy or other unknown aetiological factors. We have expanded the phenotypic spectrum through description of the smallest Xq27.1 duplication (323.8 kb) with CH reported to date, as well as a second family with CH and a neural tube defect.

Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLOGY: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). RESULTS: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). CONCLUSIONS: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

The heterogeneity of focal forms of congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic ß-cells. Histologically, there are two major subgroups, focal and diffuse. Focal CHI is typically unresponsive to diazoxide and can be cured with surgical removal of the focal lesion. AIMS: We report on three patients with focal CHI to illustrate the marked clinical, genetic, radiological, and histological heterogeneity. METHODS AND RESULTS: The first two patients had focal CHI due to a paternal (c.3992-9G→A) ABCC8 mutation. One of these patients was fully responsive to a small dose (5 mg/kg · d) of diazoxide, whereas the other patient was medically unresponsive. In both patients, the focal lesions were accurately localized preoperatively by [(18)F]dihydroxyphenylalanine (DOPA) positron emission tomography (PET) and surgically resected. The third patient had a paternally inherited ABCC8 (A1493T) mutation, and the initial [(18)F]DOPA PET scan indicated extensive uptake of DOPA in the body and tail of the pancreas. However, despite surgical resection of the body and tail, this patient continued to have severe CHI. A subsequent [(18)F]DOPA PET scan now showed markedly increased DOPA uptake in the remaining body and head of the pancreas. This focal lesion occupied virtually the whole of the pancreas. conclusions: These three cases illustrate that focal lesions even with the same genotype (c.3992-9G→A) may have a different clinical presentation and that [(18)F]DOPA PET scans in very large focal lesions may be difficult to interpret.

Genetics of congenital hyperinsulinemic hypoglycemia.

A genetic diagnosis is now possible for approximately 45%-55% of patients with hyperinsulinemic hypoglycemia. Understanding the genetic etiology of the disease in these patients is clinically important because a genetic diagnosis will provide information on prognosis, recurrence risk, and importantly may also guide clinical management. The aim of this review is to provide an outline of the 7 different molecular mechanisms underlying this heterogeneous disease and to demonstrate that the clinical phenotype can act as a useful guide when prioritizing the order of genetic testing.

The clinical problem of hyperinsulinemic hypoglycemia and resultant infantile spasms.

Hyperinsulinemic hypoglycemia (HH) is a cause of severe hypoglycemia in the newborn and infancy period and is associated with a high risk of neurologic handicap and epilepsy. Infantile spasms after exposure to HH is rare and has been described in only 1 previous report. We report the clinical, biochemical, and neurodevelopmental characteristics of 5 patients with neonatal-onset HH who subsequently developed infantile spasms. All 5 patients had neonatal-onset HH of varying severity and duration. These patients presented with the characteristic ictal pattern of spasms in clusters at a mean age of 6.6 months. Characteristic hypsarrhythmia was noted in only 3 of 5 patients. Structural abnormality was found in only 1 of 4 patients who underwent MRI of the brain. Infantile spasms responded to medical treatment in 3 patients, spasms in 1 patient were refractory to antiepileptic drugs, and treatment duration was insufficient for us to comment on the response in 1 patient. Developmental delay was evident in all of them. In conclusion neonatal HH of varying severity is associated with later (after a latent period) development of infantile spasms. The latent period before the onset of the spasms can be variable; hence, long-term neurodevelopmental follow-up (until 1 year of age) is necessary.