Table 1.
Published CHI Cases Managed With mTOR Inhibitors
| Reference | No. of Cases; Age mTOR Started | HI Genetics, PET, Histology | Prior Unresponsiveness to Other CHI Medications, Doses (Response to Medication Specified) | Max Dose mTOR Inhibitor, mg/m2/d | mTOR Plasma Level, ng/mL | Feeds, IV Fluids, Other Medication During mTOR Trial | mTOR Follow-Up Duration | Complications While on mTOR Inhibitor | Glycemic Control; Mono or Combination | Fasting Length on mTOR Inhibitor | mTOR Stopped, Reason |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Senniappan [7] | N = 4, 8–16 wk | 2: maternal het ABCC8 1: no mutations 1: Hom ABCC8. PET: 3 diffuse | Diaz (20 mg/kg/d) + oct (35 μg/kg/d) + gcg (5 μg/kg/h) + IV | NS, 1.5–2.5 mg/m2/d | NS, aimed 5–15 | IV gcg, oct stopped in 3 pt; 1 pt remained on oct | 36–45 wk | 2 pt: mild lipid elevation. | Yes | 6–8 h | No (stopped for 3 d in 1 case, reason NS) |
| 1 pt: transient elevation AST | 3 pt: mono and 3 hourly on-demand feeds | ||||||||||
| 1 pt: none | 1 pt: with oct | ||||||||||
| Shah [22] | N = 1, 9 wk | Comp het ABCC8 | Diaz (15 mg/kg/d) + oct (30 μg/kg/d) + gcg (5 μg/kg/hr) + IV | 1.6 | 2.5–12.8 | IV, gcg discontinued; oct decreased | 7 wk | None | Yes; combined with oct (20 μg/kg/d) | 4 h | No, ongoing at age 16 wk |
| Amato LA, [24] | N = 1, 7 mo | De novo het ABCC8 | Diaz (20 mg/kg/d) + oct (27 μg/kg/d) + frequent feeds | 6 | NS, aimed 5–15 | Decreased hypercaloric feeds | 3 mo | Growth failure | Yes; combined with oct (36 μg/kg/d) | NS | No, ongoing at age 12 mo |
| Abraham [25] | N = 1, 3 mo | Hom ABCC8 | Diaz (20 mg/kg/d) + oct (60 μg/kg/d) + gcg (5 μg/kg/h) + IV + lanr 10 mg/m + pancreatectomy | 5 | NS, aimed 5–15 | IV, medications discontinued except for lanr maintained until 7 mo of age | 10 mo | C. jejuni gastroenteritis | Yes; during first 4 mo with lanr. Following 6 mo mono | 6 h | Yes, age 13 mo as CHI resolved |
| PET: diffuse | |||||||||||
| Histology: diffuse | |||||||||||
| Méder [8] | N = 1, 8 wk | Comp het ABCC8 | Diaz (20 mg/kg/d) + oct (35 μg/kg/d) + nif + IV | NS | 9.62 | IV, medications discontinued | 10 mo | NEC, persistent mild elevation of LFTs and lipidsa | Yes | 6 h | No, ongoing at age 1 y |
| PET: diffuse | Mono | ||||||||||
| Minute [26] | N = 1, 8 YOL | Biallelic het ABCC8 | Diaz (10 mg/kg/d) + 3 hourly feeds + IM gcg inj | 7mg/m2/d | 12.1 | Diaz reduced to 4 mg/kg/d. No need for gcg | 6 m | Oral aphthosis, mild acne. Transient hematemesis | Yes; combined with diaz | NS | No, ongoing at age 8 y, 6 mo |
| PET: diffuse | |||||||||||
| Kara [27] | N = 2 Pt 1: 15 DOL; pt 2: 5 YOL | Pt 1: hom KCNJ11 | Max doses of diaz + oct + gcg + IV; pt 2 had previous 80% pancreatectomy | Pt 1: 2 | Pt 1: 27.9 | Pt 1: IV, medications discontinued | NS | Mild elevation liver enzymes (pt 2); renal and hepatic failure (pt 1); sepsis (pt 1) | Yes; mono in pt 1; combined with oct (6.6 μg/kg/d) in pt 2 | 10 h in pt 2; NS in pt 1 | Yes, in pt 1 from side effects; ongoing in pt 2 |
| Pt 2: hom ABCC8 | Pt 2: 1 | Pt 2: NS | Pt 2: Oct decreased | ||||||||
| Güemes [23] | N = 1, 3 mo | UPD 11p15 (BWS) | Diaz (15 mg/kg/d) + oct (30 μg/kg/d) + gcg (5 μg/kg/hr) + iv | 11 | Max 24.7 | IV, gcg discontinued; oct decreased | 19 mo | None | Yes; combined with oct (27 μg/kg/d) | 4 h | No, ongoing at age 22 mo |
| Ünal S, [28] | N = 1, 35 DOL | Hom KCNJ11 | Diaz (25 mg/kg/d) + oct (40 μg/kg/d) + gcg (10 μg/kg/h) + nif (1 mg/kg/d) | 0.5 | NS | Diaz, nif, gcg stopped; oct decreased to 5 μg/kg/d | 4 mo | None | Yes; combined with oct (5 μg/kg/d) | NS | No, ongoing at age 5 mo |
| Loke K-Y, [29] | N = 1, 15 mo | Paternal het ABCC8 | Partially responsive to diaz (12.6 mg/kg/d) | 4.4 | 25–30 | Diaz stopped | 15 mo | Oral ulcers, elevation of ALT and CK | Yes; mono | NS | Yes, age 3 y, 3 mo as CHI resolved |
| PET: diffuse | |||||||||||
| Szymanowski [17] | N = 10 (6 French, 4 British), 1–57 mo | 3: Hom ABCC8 | 5: Diaz (6–11 mg/kg/d) + SST analogs (23–66 μg/kg/d) | 9 received sirolimus (max 5.9) and 1 everolimus (9.8) | Sirolimus, 6.6–14.1; everolimus, 9.9 | 5 pt showed whole or partial glycemic response | 1–16 mo | Triglyceride elevation (5), anemia (1), stomatitis (4), sepsis (2), varicella zoster (1), exocrine pancreatic insufficiency (2) | Yes; 3 pt (30%) | b | Yes, in 7 from ineffectiveness in glycemic control; 3 pt still on mTOR, after 4, 15, and 16 mo |
| 1: No mutation identified | 1: SST analog (20 μg/kg/d) + gcg (7.5 μg/kg/h) + IV | 5 pt did not respond to mTOR inhibitors | |||||||||
| 1: Comp het KCNJ11 | 3: SST analog (11–20 μg/kg/d) + IV | ||||||||||
| 2: Comp het ABCC8 | 1: SST analog (18 μg/kg/d) | ||||||||||
| 2: Maternal ABCC8 | |||||||||||
| 1: De novoABCC8 | |||||||||||
| PET in 3 cases, not focal | |||||||||||
| Haliloglu [30] | N = 2, 17 and 21 DOLc | 2: Hom ABCC8 | Pt 1: diaz (15 mg/kg/d) + oct (40 μg/kg/d) + gcg (10 μg/kg/h) + IV | Pt 1: 3.1 | Pt 1: 1.4; pt 2: 9.9 | Pt 1: IV, gcg stopped; oct decreased to 6 μg/kg/d | Pt 1: 9 mo | 2 pt: elevation of AST and ALT | Yes; combined with oct (6 μg/kg/d in pt 1 and 23 μg/kg/d in pt 2) | NS | Yes, in both because of hepatitis |
| Pt 2: diaz (20 mg/kg/d) + oct (40 μg/kg/d) + IV | Pt 2: 0.5 | Pt 2: IV, diaz stopped; oct reduced (23 μg/kg/d) | Pt 2: 1 mo | ||||||||
| Al-Balwi [31] | N = 3; 2, 4, 5 mo | 2: Hom KCNJ11 | Diaz (20 mg/kg/d) + oct (40 μg/kg/d). 1 pt had a previous pancreatectomy | 9–3 | 9–14 | No modification of other meds | 47–60 d | Mild increase LDL (2)_ mild leucosis (2) | No | NS | Yes, in the 3 pt as no response |
| 1: Hom ABCC8 | |||||||||||
| Histology: diffuse | |||||||||||
| Dastamani [20] | N = 1, 16.6 YOL | Autosomal dominant ABCC8 | Responsive to diaz (15.9 mg/kg/d) | 4.25 | NS, aimed 5–15 | Diaz dose reduced | 1 mo | Facial cellulitis, abscess, and DM | NS | NS | Yes, at 17.6 years because of DM |
| Korula [32] | N = 1, 29 DOL | Hom KCNJ11 | Diaz (20 mg/kg/d) + oct (28 μg/kg/d) + nif + IV | 4 | NS, aimed 5–15 | IV fluids, diaz, nif, and oct discontinued | 13 mo | None | Yes; combined with cornstarch | 5 h | No, ongoing at 14 m of age |
| PET: diffuse |
Abbreviations: comp, compound; diaz, diazoxide; DOL, days of life; gcg, glucagon; het, heterozygous; HI, hyperinsulinaemic hypoglycaemia; hom, homozygous; inj, injection; lanr, lanreotide; LFT, liver function test; max, maximum; mono, monotherapy; NEC, necrotizing enterocolitis; nif, nifedipine; NS, not specified; oct, octreotide; pt, patient; SST, somatostatin; UPD, paternal uniparental disomy; YOL, y of life.
a
NEC was attributed to octreotide as patient responded well to its discontinuation rather than a sirolimus effect.
b
5 pt: whole or partial response, fast increased to 3 to 10 h; 5 patients: no response.
c
Both patients were also detected to have congenital hypothyroidism with normally positioned gland in the neonatal period.