Table 1 Clinical characteristics, metabolic profile and treatment of individuals studied

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