| Gene / etiology | Molecular defect and inheritance | Distinguishing phenotype / biomarker | Focal / diffuse / syndromic status | Management implication |
|---|---|---|---|---|
| **ABCC8 / KCNJ11** | Loss-of-function variants in beta-cell KATP channel genes; diffuse HI from recessive bi-allelic or dominant mono-allelic variants; focal HI from a **paternally inherited recessive** variant plus paternal isodisomy of **11p15** confined to the lesion (pqac-00000027, pqac-00000020) | Severe neonatal hypoketotic hypoglycemia; diazoxide-unresponsive cases strongly enriched for KATP defects; paternally inherited single variant predicts focal lesion with high PPV/sensitivity; persistent CHI commonly due to these genes (pqac-00000027, pqac-00000020, pqac-00000021) | **Diffuse or focal**; atypical/mosaic forms also reported with somatic variants (pqac-00000027, pqac-00000023) | Rapid **ABCC8/KCNJ11** testing guides care; if diazoxide-unresponsive and focal likely, perform **18F-DOPA PET** and limited resection; focal lesions are usually surgically curable, whereas diffuse disease may require 90–98% pancreatectomy and long-term diabetes surveillance (pqac-00000027, pqac-00000028, pqac-00000023) |
| **GLUD1** | Activating/regulatory variants affecting glutamate dehydrogenase; inheritance not specified in retrieved evidence (pqac-00000027) | **Moderately elevated plasma ammonia**; protein/leucine-induced hypoglycemia; neurodevelopmental and seizure burden may be high (pqac-00000027, pqac-00000024) | Non-syndromic genetic HI (pqac-00000027) | Gene-specific dietary management may include **protein restriction**; usually considered outside KATP/focal surgical pathway (pqac-00000011, pqac-00000027) |
| **HADH (SCHAD)** | Enzyme defect; inheritance not specified in retrieved evidence (pqac-00000027) | May show **elevated plasma C4-OH acylcarnitine** and **urine 3-OH-glutarate**; protein-induced hypoglycemia reported (pqac-00000027) | Non-syndromic genetic HI (pqac-00000027) | Dietary modification may help; review cited **high-carbohydrate/low-fat diet** as gene-specific support, but evidence level in retrieved material is limited (pqac-00000011) |
| **GCK** | Activating variants; somatic **GCK** variants also linked to LINE/mosaic pathology; one 2024 case report suggests **GCK duplication** as a novel cause of nesidioblastosis (mechanism/new association still uncertain) (pqac-00000027, pqac-00000016) | May develop **ketotic hypoglycemia with prolonged fasting**, unlike typical hypoketotic HI (pqac-00000027) | Can be **diffuse/non-focal**; **localized islet nuclear enlargement (LINE)/mosaic** with somatic variants; adult nesidioblastosis reported in a case with chromosome 7 duplication containing **GCK** (pqac-00000027, pqac-00000016) | Often **diazoxide-unresponsive** per guideline discussion; if localized somatic disease suspected, pathology/imaging interpretation is important; mechanistic significance of copy-number gain remains provisional (pqac-00000022, pqac-00000027, pqac-00000016) |
| **HK1** | Heterozygous **non-coding variants** preventing beta-cell silencing of **HK1**; inappropriate pancreatic HK1 expression also reported in atypical tissue (pqac-00000027, pqac-00000023) | Isolated HI; mechanism is aberrant beta-cell expression of hexokinase 1 rather than classic KATP dysfunction (pqac-00000027) | Usually **isolated**; may contribute to **atypical / mosaic** pancreatic disease (pqac-00000023, pqac-00000027) | Include **non-coding regions** in testing because exome/panels can miss deep intronic/non-coding causes; no gene-specific approved therapy identified in retrieved evidence (pqac-00000027) |
| **SLC16A1** | Activating promoter-region variants affecting monocarboxylate transporter 1 (MCT1) (pqac-00000027) | **Anaerobic exercise-induced hypoglycemia** (pqac-00000027) | Non-syndromic genetic HI (pqac-00000027) | History of exercise-triggered episodes helps diagnosis; management implication is trigger recognition/avoidance plus standard HI therapy as needed (pqac-00000027) |
| **HNF1A / HNF4A** | MODY-related transcription factor variants; transient neonatal hyperinsulinism may occur with family history suggestive of MODY (pqac-00000025) | Family history of MODY; some cases improve over time (pqac-00000025, pqac-00000024) | Non-syndromic genetic HI; not focal KATP-type disease in retrieved evidence (pqac-00000025) | Consider targeted testing when MODY pedigree is present; severity may decrease over time, allowing medication reduction; requires later diabetes surveillance (pqac-00000024, pqac-00000025) |
| **KMT2D / KDM6A (Kabuki syndrome)** | Chromatin-regulating genes; **KMT2D** usually de novo AD, **KDM6A** X-linked dominant in Kabuki syndrome; mechanism for HH is **not fully clarified** and likely epigenetic/beta-cell developmental (pqac-00000029, pqac-00000020) | Syndromic features of Kabuki syndrome; HH prevalence reported as **0.3–4%** in KS and association is stronger for **KDM6A**-KS than **KMT2D**-KS (pqac-00000029) | **Syndromic HI** (pqac-00000029, pqac-00000020) | Evaluate for multisystem syndrome and provide genetic counseling; mechanism remains uncertain, so management is mostly standard HI treatment plus syndrome-specific care (pqac-00000025, pqac-00000029) |
| **11p15 / Beckwith-Wiedemann spectrum (BWS/BWSp)** | Imprinting defect / paternal UPD11p; in focal lesions there is loss of maternal heterozygosity at **11p15** with loss of nuclear **p57** staining; severe HI in BWSp can occur with **11pUPD** plus a paternally inherited **ABCC8/KCNJ11** variant (pqac-00000027, pqac-00000023, pqac-00000021) | Syndromic overgrowth context; pathology may show expanded endocrine tissue over large pancreatic areas; requires methylation testing when clinically suspected (pqac-00000027, pqac-00000023) | **Syndromic**, may mimic/extensively involve pancreas; focal-type molecular mechanism overlaps with 11p15 loss in lesion tissue (pqac-00000023, pqac-00000027) | Perform **11p methylation testing** if BWSp suspected; surgery can be more complex than classic focal HI because endocrine overgrowth may be extensive (pqac-00000027, pqac-00000023) |
| **Acquired perinatal-stress HI (PSHI)** | Acquired, not established genetic etiology in current evidence; linked to maternal diabetes, perinatal stress, birth asphyxia, IUGR, maternal drug exposure, or high maternal glucose infusion during delivery (pqac-00000025) | Presents in first 24 h of life; affects about **1 in 1,200–1,700** newborns; often resolves within **10–14 days**; severe persistent form beyond 2 weeks occurs in about **1 in 12,000–13,600** newborns (pqac-00000025) | **Acquired**, not focal genetic CHI (pqac-00000025) | Genetic testing is **not usually recommended** initially; treat supportively, including diazoxide if prolonged/severe; retest after 72 h if still hypoglycemic during transitional period (pqac-00000025) |


*Table: This table summarizes the main genetic and acquired etiologies of hyperinsulinemic hypoglycemia/congenital hyperinsulinism, highlighting distinguishing biomarkers, histologic patterns, inheritance, and immediate management implications. It is designed as a concise knowledge-base artifact for genotype-phenotype-treatment mapping.*