From: An expanded clinical spectrum of hypoinsulinaemic hypoketotic hypoglycaemia
Individual 1 | Individual 2 | Individual 3 | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Gestational age (w); birth weight (g), head circumference (cm) | 37+0; 3430 (+ 0.74 SD), 37.5 (+ 2.07 SD) | 37+2; 2215 (-2.14 SD), 33.5 (-0.71 SD) | 34+4; 3470 (+ 2.25SD), 36.5 (+ 2.3 SD) | ||||||||||
Sex | male | male | male | ||||||||||
Typical PI3K-associated features | haemangioma on third digit of left hand | none | macrocephaly, hydrocephalus with low-lying cerebellar tonsils requiring VP-shunt, cutis marmorata, telangiectasia (face/neck), mild secondary hypothyroidism | ||||||||||
Other clinical features | left-sided neonatal stroke with secondary haemorrhage (associated with a lipoprotein (Lp)a glycoprotein variant), small VSD and ASD, infantile esotropia, hyperopia, astigmatism | umbilical hernia, transient neonatal cholestasis: max. direct bilirubin 4.72 mg/dl (ref < 1 mg/dl), gGT max. 455 U/l (ref < 200 U/l), AP max. 892 U/l (ref < 469 U/l) | glandular hypospadia, undescended testes, transient total hyperbilirubinaemia, marginally low cortisol response to CRH stimulation | ||||||||||
Developmental delay | yes, mild (presumably associated with neonatal stroke) | no | yes, mild | ||||||||||
Age at genetic diagnosis (y) | 12 | N/A | 1.25 | ||||||||||
Age at diagnosis of hypoglycaemia | day 1 of life | day 1 of life | 2 months | ||||||||||
Metabolic profile during hypoglycaemia | Day of life/age | 11 | 17 | 35 | 38 | 39 | 6 | 21 | 39 | 45 | 2 month old | ||
Glucose (mmol/L) | 2.3 | 1.9 | 2.3 | 1.7 | 0.8 | 2.4 | 2.3 | 2.3 | 3 | 2.9 | |||
Insulin (mU/L) | 3.9 | 0.6 | < 0.1 | 0.8 | 0.5 | 0.8 | 0.6 | 0.7 | 0.02 | 1.3 | |||
C-peptide (ng/ml) | 1.66 | 0.1 | n.d. | n.d. | 0.3 | 0.31 | n.d. | 0.67 | 0.07 | 1.38 | |||
FFA (mmol/L) | 0.34 | 0.34 | 0.01 | 0.15 | 0.15 | 0.37 | < 0.1 | n.d | n.d | 0.22 | |||
BHB (mmol/L) | 0.51 | 0.01 | 0.23 | 0.01 | 0.01 | n.d | < 0.1 | n.d | 0.4 | 0.2 | |||
Pathogenic mutation | de novo germline mutation in PIK3CA (c.323G>A p.(Arg108His)) | none detected | de novo mosaic mutation in PIK3CA (c.2740G>A p.(Gly914Arg)) | ||||||||||
Additional investigations related to hypoglycaemia | 18F-DOPA PET/CT: diffuse tracer uptake; biochemically no indication of free fatty acid oxidation disorders; organic acid disorders; urea cycle disorders; congenital disorders of glycosylation; no mutation in known CHI genes† | no mutation in known CHI genes† | no mutation in known CHI genes† | ||||||||||
Carbohydrate amounts initially required for therapeutic management (without formal titration) | 16 mg/kg/min at day 12 of life (i.v. and oral) | 6.4 mg/kg/min at day 3 of life (i.v. and oral) | 10 mg/kg/min at 2 months of age | ||||||||||
Formal testing of minimum glucose requirement (titrated continuous i.v. glucose infusion) | not performed | 4 mg/kg/min at 6 weeks of life | not performed | ||||||||||
Medication for hypoglycaemia (initial dosage) | unresponsive to DZX (15 mg/kg/d), improvement on somatostatin infusions (15 µg/kg/d) in parallel with nutritional change | unresponsive to DZX (15 mg/kg/d) | unresponsive to hydrocortisone (20 mg/m2) | ||||||||||
HH medication-related side effects | DZX: oedema, hypertrichosis; somatostatin: gall bladder sludge | none | none | ||||||||||
PEG feeding | no | no | no | ||||||||||
Feeding regime at discharge (after diagnosis of hypoglycaemia) | at 2 months of age: starch-enriched meals every 6 h | at 2 months of age: starch-enriched meals every 3–4 h | at 2 months of age: starch-enriched meals every 4 h | ||||||||||
Age at patient’s last clinic visit | 12 years | 4 months | 1 year | ||||||||||
Current management of hypoglycaemia | at 12 years of age: none; normal fasting tolerance, at least 15 h (not formally assessed) | at 3 years of age: none; fasting tolerance not formally assessed | at 12 months of age: none; fasting tolerance 12 h | ||||||||||
Individual 4 | Individual 5 | Individual 6 | |||||||||||
Gestational age (w); birth weight (g); head circumference (cm) | 41; 3120 (-1.07 SD); 34 (+ 0.1 SD) | 35; 3050 (+ 1.22 SD); 35 (+ 1.10 SD) | 36+1; 3150 (+ 0.57 SD) | ||||||||||
Sex | female | female | male | ||||||||||
Typical PI3K-associated features | none | left sided hemi-hypertrophy | right sided hemi-hypertrophy | ||||||||||
Other clinical features | hypoxic ischaemic encephalopathy, meconium aspiration syndrome with neonatal sepsis, atrial septal defect | low set eyes, small mouth, small facial bones in comparison to the cranium, round and small labia majora, bilateral cystic nephropathy, high grade adrenal tumour | multiple jejunal atresia | ||||||||||
Developmental delay | yes, severe | none | none | ||||||||||
Age at genetic diagnosis (y) | N/A | N/A | N/A | ||||||||||
Age at diagnosis of hypoglycaemia | 10 months | day 2 of life | day 1 of life | ||||||||||
Metabolic profile during hypoglycaemia | Day of life/age | 13 months | 2 months | 18 months | 24 months | 6 weeks | |||||||
Glucose (mmol/L) | 2.4 | 1.3 | 1.1 | 1.7 | 2 | ||||||||
Insulin (mU/L) | < 5 | < 1.5 | < 1.5 | < 1.5 | < 0.3 | ||||||||
C-peptide (ng/ml) | < 0.3 | ND | ND | ND | ND | ||||||||
FFA (mmol/L) | 0.35 | 0.37 | ND | ND | 0.6 | ||||||||
BHB (mmol/L) | 0.05 | 0 | ND | 0 | < 0.1 | ||||||||
Pathogenic mutation | none detected | none detected | not proven | ||||||||||
Additional investigations related to hypoglycaemia | mosaicism for AKT2 c.49G>A excluded by RFLP; no basal AKT or GSK3 hyperphosphorylation in dermal fibroblasts; no mutations identified on high depth sequencing of overgrowth-associated genes | liver biopsy: normal; mosaicism for AKT2 c.49G>A excluded by RFLP; no basal AKT or GSK3 hyperphosphorylation in dermal fibroblasts; no mutations identified on high depth sequencing of overgrowth-associated genes; no epigenetic or copy number abnormalities at chromosome 11p15 detected by methylation-sensitive MLPA | mosaicism for AKT2 c.49G>A excluded by RFLP; no epigenetic or copy number abnormalities at chromosome 11p15 detected by methylation-sensitive MLPA | ||||||||||
Initial glucose requirement | 6 mg/kg/min | 10–19 mg/kg/min in neonatal period | ND | ||||||||||
Formal testing of minimum glucose requirement (continuous i.v. glc infusion) | 6 mg/kg/min (13 months) | not performed | not performed | ||||||||||
Medication for hypoglycaemia (initial dosage) | no response to DZX or sirolimus; prednisolone at 1 mg/kg | unresponsive to DZX | none | ||||||||||
HH medication-related side effects | rapid weight gain in response to steroids | none | N/A | ||||||||||
PEG feedings | yes | yes | no | ||||||||||
Feeding regime at discharge (after diagnosis of hypoglycaemia) | regular bolus feeds during the day, overnight continuous PEG feed | four-hourly bolus feeds | initially parenteral nutrition due to short gut, then regular bolus feeds. | ||||||||||
Age at patient’s last clinic visit | N/A – patient deceased | 14 years | 8 months | ||||||||||
Current management of hypoglycaemia | N/A | frequent daytime meals and waking once at night to consume fruit juice enriched with starch and glucose. | fasting tolerance > 8 h |