Table 1.
Summary on syndromic diseases having suspected of proven association with CHI/HH.
| Disease category | Disease | Inheri-tance | Locus | Involved gene(s) | Key features | Prevalence of neonatal hypoglycemia | CHI/HH association | Treatment and response | Course and outcome |
|---|---|---|---|---|---|---|---|---|---|
| Overgrowth syndromes | Beckwith-Wiedemann syndrome | Sporadic, AD | 11p15.5 | Genes of the 11p15.5 DMR; KCNQ1 | Hemihyperplasia, macroglossia, omphalocele, visceromegaly | ~50% |
patUPD11p
: >30%; few cases with additional KATP mutation |
Often (70%) unresponsive to DXZ; almost half of reported cases received pancreatectomy | Most cases with persistent HI |
|
Epimutations
: <5% |
DXZ-reponsive in cases requiring treatment | Most cases with transient HI | |||||||
| Sotos syndrome | AD | 5q35.3 | NSD1 | Macrosomia, macrocephaly, DD/ID, dysmorphic features | <15% | Very rare, 25 cases reported | DXZ-reponsive; no case of pancreatectomy reported | Transient HI; mostly resolving within the first months of life | |
| Simpson-Golabi-Behmel syndrome | XL | Xq26.2 | GPC3 | Macrosomia, DD/ID, dysmorphic features | Increased, not specified | Not documented | NA | NA | |
| Weaver syndrome | AD | 2q27.1 | EZH2 | Macrosomia, DD/ID, dysmorphic features | Increased, not specified | Not documented | NA | NA | |
| Perlman syndrome | AR | 2q27.1 | DIS3L2 | Neonatal macrosomia, MCA, nephroblastomatosis, dysmorphic features | Several cases reported | Not documented | NA | NA | |
| PI3K-AKT pathway disorders | Sporadic, AD | 19q13.2, 3q26.3, 1q43-q44, 14q32.33, 12p13.32 | AKT2, PIK3CA, AKT3, AKT1, CCND2 | Regional overgrowth, vascular malformations, epidermal nevi | Increased frequency of hypoglycemia in infancy and thereafter, not specified | Hypoinsulinemic hypoglycemia (CHI phenocopy), predominantly with AKT2 | Unresponsive to DXZ and octreotide; may be managed with regular carbohydrate feeds; response to sirolimus reported | Variable course; spontaneous remission reported | |
| Monogenic develop-menttal disorders | Kabuki syndrome | AD | 12q13.12, Xp11.3 | KMT2D, KDM6A | DD/ID, dysmorphic features, CHD, MCA, postnatal growth defect | <7% | <2%, predominantly with KDM6A | Usually DXZ-responsive; few cases of pancreatectomy reported | Variable course; may require treatment for several years |
| Costello syndrome | AD | 11p15.5 | HRAS | Dysmorphic features, CHD, DD/ID, postnatal growth defect | ~44% | Rare | Usually DXZ-responsive; one case of pancreatectomy reported | Persistence up to 6 months reported | |
| Rubinstein-Taybi syndrome | AD | 16p13.3, 22q13.2 | CREBBP, EP300 | DD/ID, dysmorphic features, MCA, growth defect | Increased, not specified | Very rare | Limited data; more than half of patients responded to DXZ | Variable course; may require treatment for several years | |
| Coffin-Siris syndrome | AD | Multiple (12) | Multiple (12) | DD/ID, dysmorphic features, MCA | Anecdotal reports | Few cases reported | NA | NA | |
| CHARGE syndrome | AD | 8q12.2 | CHD7 | MCA, CHD, dysmorphic features, DD/ID | Anecdotal reports | Only 2 cases reported | NA | NA | |
| FOXA2-CHI | AD | 20p11.21 | FOXA2 | Hypopituitarism, MCA, DD/ID, dysmorphic features | Few cases reported | Few cases reported | Limited data; (partial) response to DXZ | Mostly transient; may be followed by impaired glucose tolerance and diabetes | |
| MEHMO syndrome | XL | Xp22.11 | EIF2S3 | DD/ID, hypopituitarism, epilepsy, obesity | Several cases reported | Few cases reported | Limited data; DXZ may improve glycemic response | Hyperinsulinemic hypoglycemia and postprandial hyperglycemia, diabetes may emerge | |
| Congenital central hypoventilation syndrome | AD | 4p13 | PHOX2B | Central hypoventilation, Hirschsprung disease | Episodic hypoglycemia reported in several cases | Several cases reported | Limited data; response to DXZ reported | Patients may exhibit postprandial hyperglycemia followed by (asymptomatic) hypoglycaemia | |
| CHI with renal tubular and hepatic dysfunction | AD | 20q13.12 | HNF4A (p.R76W) | Renal Fanconi syndrome, hepatic dysfunction | Probably >50% | Several cases reported | Limited data; mostly responsive to DXZ | Mostly transient; may be followed by impaired glucose tolerance and diabetes | |
| Schaaf-Yang syndrome | AD | 15q11.2 | MAGEL2 | DD/ID, contractures, dysmorphic features | Unknown | Two unrelated observations | Limited data; variable response to DXZ | Few data; DZX treatment up to age 6 reported | |
| Chromoso-mal (contiguous gene) syndromes | 9p deletion syndrome | Sporadic, AD | 9p24.1-24.2 | SMARCA2, RFX3 (?) | DD/ID, dysmorphic features, MCA | Unknown | Several cases reported | DZX-responsive | Variable course; may require treatment for several years |
| Turner syndrome | Sporadic | Xp | KDM6A (?) | Growth defect, hypogonadism, dysmorphic features | Increased, not specified | Several cases reported | Variable response to DXZ; 4 cases with pancreatectomy | Variable course; may require treatment for several years | |
| Usher-CHI syndrome | AR | 11p15.1 | ABCC8 | Sensorineural deafness, retinitis pigmentosa | 100% | 100% | DXZ-resistant; most cases received pancreatectomy | Persistent HI | |
| Trisomy 13 | Sporadic | 13 | Unknown | MCA, dysmorphic features, severe DD/ID | Unknown | Few cases reported | Variable response to DZX | Outcome dictated by underlying disease | |
| 16p11.2 microdeletion | AD | 16p11.2 | Unknown | Non-specific DD/ID | Unknown | Very rare; few cases reported | Limited data; may respond to DZX | Limited data | |
| Trisomy 21 | Sporadic | 21 | Unknown | Dysmorphic features, MCA, DD/ID | Unknown | Increased frequency in cohorts tested for CHI | Limited data; mostly DZX-responsive; 1 case of pancreatectomy | Mostly transient; remission within the first year | |
| Channelo-pathies | Timothy syndrome | AD | 12p13.33 | CACNA1C | CHD, long-QT syndrome, syndactyly, DD/ID, dysmorphic features | Intermittent hypoglycemia in ~40% | Not documented | Limited data; may respond to DZX | Recurrent episodes of hypoglycemia |
| PASNA | AD | 3p21.1 | CACNA1D | Aldosteronism, epilepsy, hypotonia, DD/ID | Increased, not specified | Two cases reported | Limited data; may respond to DZX or Ca2+ channel blockers | Limited data; DZX treatment up to age 4 reported | |
| Long-QT syndrome | AD | 11p15.5, 7q36.1 | KCNQ1, KCNH2 | QTc prolongation, cardiac arrhythmia | Intermittent hypoglycemia reported | Hyperinsulinemia after glucose challenge | Limited data; usually no medical treatment required | Postprandial hyperinsulinemia and reactive hypoglycemia | |
| Metabolic disorders | CDG syndrome | AR | 16p13.2, 15q24.2, 3q27.1, 1p31.3 | PMM2, MPI, ALG3, PGM1 | DD/ID, brain and ocular anomalies, hepatopathy, enteropathy, coagulopathy, cystic kidneys | <10-89%, depending on CDG type; PMM2-HI: separate clinical and genetic subtype | Several cases reported | Usually DZX-responsive; may also improve with oral mannose; 1 case of pancreatectomy; | Variable course; may require prolonged DZX treatment |
| Tyrosinemia | AR | 15q25.1 | FAH | Hepatic dysfunction, renal tubular dysfunction, DD/ID | Occasional | Few cases reported | DZX-responsive; specific treatment with NTBC | Mostly transient; dependent on metabolic control | |
| Adenosine kinase deficiency | AR | 10q22.2 | ADK | DD/ID, epilepsy, hypermethioninemia, dysmorphic features, CHD | Increased, not specified | Few cases reported | DZX-responsive; specific treatment with methionine restriction | Mostly transient; dependent on metabolic control |
CHD, congenital heart defect; CHI, congenital hyperinsulinism; DD/ID, developmental delay/intellectual disability; DMR, differentially methylated region; DZX, diazoxide; HH, hyperinsulinemic hypoglycemia; HI, hyperinsulinism; MCA, multiple congenital anomalies; NA, no data available.