Results
Table 1 provides a summary of the demographic features of the patients, as well as the genotype, 18F-DOPA PET findings, details of the octreotide treatment and clinical outcomes. All identified mutations were point mutations, and no exonic deletions were found by MLPA. As reported previously, monoallelic paternal KATP-channel mutations are predominant in Japan and the molecular breakdown also reflected this trend. Three patients had biallelic mutations of the KATP-channel genes, and the remaining 12 had monoallelic paternal mutations suggestive of the possible focal form. 18F-DOPA PET scans were performed in 11 of the patients with monoallelic mutations. Four of them showed apparently diffuse uptake, and the remaining seven showed focal uptake: five in the head or the uncus and two in the body of the pancreas.
The octreotide treatment was effective, at least partially, in all the patients (Table 1). For the patients with biallelic mutations (patients 1–3), octreotide was less effective requiring a higher dosage than for the patients with monoallelic mutations (17–25 μg/kg/day); mean, 19·7 μg/kg/day; P = 0·02 by the Welch t-test), and two of them required additional treatment with hypertonic intravenous glucose infusion (patient 1) or enteral feeding (patient 2) to maintain normoglycaemia. As IV glucose could not be completely stopped, patient 1 underwent 90% pancreatectomy at the age of 4 months. After surgery, the patient continued to experience hypoglycaemia, which could be controlled with a lower octreotide dosage (12 μg/kg/day) without additional IV glucose. These patients with biallelic mutations were still being treated with octreotide at the time of the study at 2, 2 and 6 years of age, respectively. However, the required octreotide dosage was decreased to 6·5, 15 and 7·6 μg/kg/day, respectively.
Three patients with a focal 18F-DOPA uptake (patients 4, 6, 11) underwent partial pancreatectomy. Two of them (patient 4, 6) were cured, and octreotide treatment was discontinued at the time of the surgery. One (patient 11) remained hypoglycaemic after surgery due to incomplete resection of the focal lesion, and octreotide treatment was therefore continued at the same dosage.
Nine other patients with monoallelic mutations (four diffuse, four focal and one unknown uptake of 18F-DOPA) chose to continue the octreotide treatment without surgery. Three of them (patients 5, 7, 8) actually achieved remission at the age of 2·5, 3·3 and 5·9 years, respectively, requiring no additional treatment. These patients were subjected to continuous glucose monitoring for 3 days without any treatment, and no episodes of hypoglycaemia were reported. The remaining six patients with monoallelic mutations were still receiving octreotide. The dosage of octreotide, however, was gradually decreasing with age. In patient 9, after 4·6 years of treatment, the dosage could be decreased to 0·6 μg/kg/day as she was prepared for treatment discontinuation.
None of the 15 patients showed obvious psychomotor retardation. Patients 2, 3, 7, 8, 9, who underwent extended octreotide treatment, showed normal results in the formal assessment of the developmental quotients at 112, 82, 94, 102 and 107 (normal range >70), respectively (Table 1).
With regard to the route of administration, continuous infusion of octreotide seemed to be superior to multiple daily injections. Of the four patients who were converted to continuous subcutaneous infusion from multiple daily injections, two were able to tolerate a decrease in the required octreotide dosage from 18 to 9 μg/kg/day (patient 13) and from 8 to 6·4 μg/kg/day (patient 14). In the remaining two patients (patients 4 and 11), there were no changes in the octreotide dosage. However, in patient 4, continuous nocturnal nasogastric tube feeding could be discontinued after conversion to continuous infusion at the same dosage as that used for multiple injections.
Overall, except for the transient gastrointestinal symptoms (poor appetite, constipation, or change in stool colour) observed in three patients (patients 11, 13, 14), the treatment was well tolerated. Laboratory test results revealed no significant changes in the blood count, blood chemicals, serum electrolyte concentration and thyroid function during the course of the treatment, and gallstones did not develop in any of the patients. However, at the higher dosages (>17 μg/kg/day), growth deceleration was observed in two patients (patients 2 and 3) with biallelic mutations (Fig. 1). The deceleration appeared to be caused by the suppression of growth hormone secretion due to the octreotide treatment. In patient 3, serum IGF1 measurements were 16·3 nmol/l at 2·0 years of age, 16·5 nmol/l at 3·0 years and 11·4 nmol/l at 4·0 years. Growth hormone provocation tests performed at the age of 4·0 years showed reduced peak growth hormone values of 1·43 μg/l by the levodopa loading test and 3·33 μg/l by the clonidine loading tests (cut-off, 6 μg/l). Because the growth deceleration was more significant in patient 3, the octreotide dosage was gradually decreased from 17 μg/kg/day to 8 μg/kg/day during the age of 4 years, which resulted in the recovery of the growth rate accompanied by an increase in the serum IGF1 to 24·5 nmol/l at the age of 6 years, indicating that the suppression of growth and growth hormone secretion were dose dependent. Growth deceleration was negligible in the patients with monoallelic mutations who were treated with a lower octreotide dosage (Fig. 2).
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Figure 1.
Growth curve of patients with biallelic KATP-channel mutations treated by long-term, subcutaneous octreotide infusion (patients 1–3). A tendency towards growth deceleration was observed in patients 2 and 3 after 2 years of age, loss of approximately 1 and 2 SD of height, respectively. Growth deceleration was not observed in patient 1, who underwent 90% pancreatectomy and continued on octreotide at a lower dosage. The open arrow in the left panel shows when patient 1 underwent surgery, and the closed arrow in the right panel shows when the octreotide dosage was reduced from 17 to 8 μg/kg/day in patient 3, indicating the dose dependency of growth deceleration.
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Figure 2.
Growth curve of the patients with monoallelic KATP-channel mutations treated with long-term, subcutaneous octreotide infusion. No obvious growth deceleration was observed.