| Domain | Key findings | Supporting citation IDs |
|---|---|---|
| Definition | Congenital isolated hyperinsulinism (CHI) is inappropriate insulin secretion despite hypoglycemia and is the most common cause of persistent hypoglycemia in infancy/childhood. Presentation is usually neonatal or early infancy and may be life-threatening because of recurrent neuroglycopenia. | (pqac-00000001, pqac-00000003, pqac-00000010) |
| Histologic/clinical subtypes | **Diffuse CHI:** whole-pancreas β-cell involvement, often due to recessive or dominant KATP-channel defects; often medically difficult and may require near-total pancreatectomy. **Focal CHI:** localized lesion, classically from a paternally inherited ABCC8/KCNJ11 variant plus somatic loss of maternal 11p15; potentially curable by limited resection. **Atypical CHI:** less common mixed/nonclassic histology. | (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000006) |
| Major causal genes | Most common genes are **ABCC8** and **KCNJ11** (KATP channel; SUR1/Kir6.2). Other reported genes include **GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, UCP2, CACNA1D**, and less commonly syndromic/non-isolated causes in broader HI cohorts. KATP defects account for ~40–50% of persistent CHI in recent national data. | (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000006) |
| Gene-specific phenotype notes | **ABCC8/KCNJ11:** often diazoxide-unresponsive when inactivating; diffuse with biallelic/dominant forms, focal with single paternal recessive variant. **GLUD1:** hyperinsulinism-hyperammonemia, usually diazoxide responsive. **GCK:** activating variants can cause CHI. **HADH, HNF4A, HNF1A:** often diazoxide responsive in many cases. **SLC16A1:** exercise/protein-sensitive phenotypes reported in HI literature. | (pqac-00000000, pqac-00000004, pqac-00000005) |
| Typical inheritance | Autosomal recessive and autosomal dominant forms both occur; focal disease typically reflects paternal inheritance plus somatic maternal allele loss in the lesion. Consanguinity increases incidence in some populations. | (pqac-00000000, pqac-00000001, pqac-00000010) |
| Critical sample hallmarks | During hypoglycemia, typical findings are detectable/inappropriately unsuppressed insulin and C-peptide, suppressed ketones and free fatty acids, and high glucose infusion requirement often >8–10 mg/kg/min. Example review data include insulin 14.4 µIU/mL, C-peptide 1 ng/mL, ketones 0.5 mmol/L in a CHI case. | (pqac-00000000, pqac-00000001, pqac-00000015, pqac-00000016) |
| Dynamic testing | A positive glycemic response to glucagon during hypoglycemia supports excess insulin action and depleted hepatic glycogen stores in CHI. | (pqac-00000000, pqac-00000001) |
| Imaging/pathology | **18F-DOPA PET/CT** is central for distinguishing focal from diffuse disease and localizing focal lesions preoperatively; reported performance in one cohort/review: sensitivity 88%, specificity 94%, accuracy 88–100%. | (pqac-00000005, pqac-00000006) |
| First-line treatment | **Diazoxide** is the only approved first-line chronic drug; it opens SUR1-containing KATP channels. Effectiveness exceeds 70% overall in one 2024 single-center summary, but response strongly depends on genotype. | (pqac-00000001, pqac-00000004, pqac-00000007) |
| Second-line/adjunct treatment | **Octreotide** is the common second-line therapy for diazoxide-unresponsive CHI; long-acting somatostatin analogs such as **lanreotide** are used in practice. Home **CGM** is increasingly used for management and feeding/treatment adjustment. | (pqac-00000004, pqac-00000005, pqac-00000007) |
| Surgery | **Focal lesionectomy/partial pancreatectomy** can be curative. **Near-total pancreatectomy** is reserved for refractory diffuse CHI because of later diabetes/exocrine insufficiency risk. In the Ukrainian national cohort, complete recovery occurred in all 14 focal cases after surgery. | (pqac-00000001, pqac-00000003, pqac-00000006, pqac-00000007) |
| Emerging/refractory therapies | **Sirolimus** and **nifedipine** are described as refractory/off-label options in reviews. **GLP-1 receptor antagonist exendin(9-39)** has been tested in pilot trials; NCT00571324 was an open-label randomized crossover phase 1/2 study (n=9), and NCT00835328 studied infants with diazoxide-refractory CHI. | (pqac-00000007, pqac-00000011, pqac-00000014) |
| Epidemiology | Reported incidence is ~1:28,000–1:50,000 in Western populations, rising to ~1:2,500 where consanguinity is higher. Japanese estimates cited in a 2024 series were 1 in 13,600 for transient CHI and 1 in 31,600 for persistent CHI. | (pqac-00000010, pqac-00000004) |
| Genetic diagnosis rates | In the 2024 Ukrainian national study, a molecular diagnosis was made in **67.5% (27/40)** overall, including **86.3% (19/22)** of persistent CHI and **44.4% (8/18)** of early-remission CHI. | (pqac-00000003) |
| Histology proportions | In 19 surgically characterized Ukrainian persistent CHI cases, histology was **focal 73.7% (14/19)**, **diffuse 10.5% (2/19)**, **atypical 15.8% (3/19)**. | (pqac-00000003) |
| Clinical presentation stats | Hypoglycemia presents in the **first week in 60–70%** of cases; **~50%** present with seizures; **20–30%** are diagnosed in the first year and **~10%** after age 1 year. | (pqac-00000010) |
| Neurodevelopment/QoL burden | Abnormal neurodevelopmental outcomes have been reported in **26–44%** of children in the QoL review. HI Global Registry/family survey data showed **70% (36/51)** of parents of children <5 years felt life was “ruled by HI,” **48% (59/123)** reported physical health impact, and **67% (82/123)** mental health impact. | (pqac-00000013, pqac-00000009) |
| Economic burden | A UK cost-of-illness study estimated total annual CHI cost to the NHS at **£3,408,398.59**, average **£2,124.95 per patient**; **5.9%** of patients (95 infants in first year of life) accounted for **61.8%** of total costs. | (pqac-00000009, pqac-00000012) |


*Table: This table condenses the main disease-definition, genetics, diagnostic, treatment, and burden-of-disease findings for congenital isolated hyperinsulinism. It is useful as a quick-reference evidence map with directly traceable context-ID citations.*