Jorma Komulainen

Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1

ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant K(ATP) channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predisposes to later insulin deficiency.

Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia

Purpose Osteoporosis and pathologic fractures are occasionally found in patients with childhood acute lymphoblastic leukemia (ALL). This study was performed to determine the degree of possible osteopenia in long-term survivors of childhood ALL. Patients and Methods Lumbar spine (L2-L4) and femoral neck bone mineral densities (BMDs) (g/cm2) were measured in 29 survivors (aged 12 to 30 years, median 17) of childhood ALL 2 to 20 (median 8) years after discontinuation of chemotherapy. These results were compared with those from 273 healthy controls and expressed as a percentage of the age- and sex-matched control values (mean ± standard deviation). Results Lumbar and femoral BMDs were significantly reduced in survivors of childhood ALL. Particularly, male gender (lumbar: 91.7 ± 10.4%, p = 0.008; femoral: 91.9 ± 11.3%, p = 0.005) and a history of cranial irradiation (lumbar: 93.0 ± 8.9%, p = 0.005; femoral: 94.4 ± 13.3%, p = 0.03) were associated with low lumbar and femoral BMDs. Conclusions The detected deficit in bone density in survivors of childhood ALL may predispose these patients to osteoporotic fractures later in adulthood. A follow-up of BMD in survivors of childhood ALL should facilitate the identification of patients who would require specific therapeutic interventions to prevent further decrease of their skeletal mass and preserve their BMD.

Ketoacidosis at the diagnosis of type 1 (insulin dependent) diabetes mellitus is related to poor residual beta cell function. Childhood Diabetes in Finland Study Group.

The determinants of the degree of metabolic decompensation at the diagnosis of type 1 (insulin dependent) diabetes mellitus (IDDM) and the possible role of diabetic ketoacidosis in the preservation and recovery of residual beta cell function were examined in 745 Finnish children and adolescents. Children younger than 2 years or older than 10 years of age were found to be more susceptible to diabetic ketoacidosis than children between 2 and 10 years of age (< 2 years: 53.3%; 2-10 years: 16.9%; > 10 years: 33.3%). Children from families with poor parental educational level had ketoacidosis more often than those from families with high parental educational level (24.4% v 16.9%). A serum C peptide concentration of 0.10 nmol/l or more was associated with a favourable metabolic situation. Low serum C peptide concentrations, high requirement of exogenous insulin, low prevalence of remission, and high glycated haemoglobin concentrations were observed during the follow up in the group of probands having diabetic ketoacidosis at the diagnosis of IDDM. Thus diabetic ketoacidosis at diagnosis is related to a decreased capacity for beta cell recovery after the clinical manifestation of IDDM in children.

Reduced bone density at completion of chemotherapy for a malignancy

OBJECTIVES Osteoporosis and pathological fractures occur occasionally in children with malignancies. This study was performed to determine the degree of osteopenia in children with a malignancy at completion of chemotherapy. METHODS Lumbar spine (L2–L4) bone mineral density (BMD; g/cm2) and femoral neck BMD were measured by dual energyx ray absorptiometry in 22 children with acute lymphoblastic leukaemia (ALL), and in 26 children with other malignancies. Apparent volumetric density was calculated to minimise the effect of bone size on BMD. Results were compared with those of 113 healthy controls and expressed as age and sex standardised mean Z scores. RESULTS Patients with ALL had significantly reduced lumbar volumetric (−0.77) and femoral areal and volumetric BMDs (−1.02 and −0.98, respectively). In patients with other malignancies, femoral areal and apparent volumetric BMDs were significantly decreased (−0.70 and −0.78, respectively). CONCLUSIONS The results demonstrate that children with a malignancy are at risk of developing osteopenia. A follow up of BMD after the completion of chemotherapy should facilitate the identification of patients who might be left with impaired development of peak bone mass, and who require specific interventions to prevent any further decrease in their skeletal mass and to preserve their BMD.

Impaired Development of Bone Mineral Density During Chemotherapy: A Prospective Analysis of 46 Children Newly Diagnosed with Cancer

Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2–L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual‐energy X‐ray absorptiometry in 46 children (age 2.9–16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy‐terminal propeptide (PICP), and type I collagen carboxy‐terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6‐month follow‐up. A significant decrease in lumbar BMDvol (–2.1%, p < 0.05), and in femoral BMDareal (–9.9%, p = 0.0001) and BMDvol (–8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow‐up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.

Continuous subcutaneous insulin infusion in the treatment of children and adolescents with type 1 diabetes mellitus

Continuous subcutaneous insulin infusion (CSII) with a portable insulin pump has been used for several years in the treatment of adult patients with diabetes mellitus (DM). This treatment, however, has rarely been utilised in children and adolescents. We studied the use of CSII in 16 children and adolescents with type 1 DM at Tampere and Kuopio University Hospitals between 1992 and 1997. The longest treatment periods are more than 4 years. The reasons for switching to CSII treatment and the goals achieved were evaluated. Glycaemic control before and during CSII treatment and the occurrence of hypoglycaemia and ketoacidosis were analysed. Compared with conventional insulin treatment, improved glycaemic control and a reduced frequency of hypoglycaemic events were achieved with CSII in those with particularly poor initial metabolic control (HbA1c >10.0%). The overall satisfaction with pump therapy was high in both patients and their families. According to our experience, CSII may be of benefit, especially in young infants with type 1 DM, but also in affected adolescents with unacceptable glycaemic control.

Disturbance in bone turnover in children with a malignancy at completion of chemotherapy

BACKGROUND Osteoporosis and pathological fractures have been observed in children with a malignancy. The mechanisms of osteopenia in childhood malignancies have not been well established. The purpose of the present study was to evaluate changes in bone turnover and in bone hormonal metabolism in children with a malignancy at completion of their chemotherapy. PROCEDURE Serum levels of human intact osteocalcin, type I collagen carboxyterminal propeptide (PICP), type I collagen carboxyterminal telopeptide (ICTP), 25-hydroxyvitamin D [25-(OH)-D], 1,25-dihydroxyvitamin D [1, 25-(OH)(2)-D], intact parathyroid hormone, insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), alkaline phosphatase, calcium, and phosphate were analyzed in 22 children with acute lymphoblastic leukemia and in 26 children with other malignancies. Results were expressed as Z-scores [mean (95% confidence intervals)] relative to healthy Caucasian-children. RESULTS The marker of collagen degradation (ICTP) was significantly increased [1.43 (1.10-1.76), P < 0.0001] compared to reference values, whereas the markers of bone formation (PICP, osteocalcin) were not changed [0.07 (-0.55 to 0.49), 0.35 (-0.05 to 0.74), respectively, NS]. Serum 25-(OH)-D, 1,25-(OH)(2)-D, and calcium were significantly reduced [-0.65 (-0.87 to -0.42), -0.68 (-0.92 to -0. 42), -1.42 (-1.80 to -1.04), P < 0.0001, respectively]. CONCLUSIONS Disturbance in bone turnover with low serum 25-(OH)-D, 1, 25-(OH)(2)-D, and calcium was observed in children with a malignancy at completion of their chemotherapy. A controlled study determining the possible benefits of vitamin D and calcium supplementation on bone turnover could be considered in these patients.

Breastfeeding stimulates total and cow’s milk‐specific salivary IgA in infants

Breastfeeding may increase the rate of mucosal maturation and IgA production. We sought to determine the effect of breastfeeding vs. formula‐feeding on the maturation of oral mucosa by measuring the salivary total antibodies and cow’s milk protein‐specific IgA. Fifty‐eight saliva samples were collected from 39 healthy, full term infants. At the age of 3 months (n = 25) eight infants received only breast milk and seventeen formula (cow’s milk based n = 10, hydrolysed n = 7) and breast milk; and at the age of 6 months (n = 33) eleven received breast milk, seventeen formula and breast milk and five were not breastfed any more (cow’s milk based n = 14, hydrolysed n = 8). Total IgA, IgG, IgM and protein, and β‐lactoglobulin specific IgA were measured from saliva with enzyme‐linked immunoassay (ELISA). The antibody results were proportioned to total protein. No differences in antibody levels between the feeding groups were found at 3 months of age. At 6 months, total IgA, total IgM and β‐lactoglobulin‐specific IgA were higher among the breastfed infants compared to those receiving formula as supplement to breast milk or not breastfed any more (breast milk vs. any formula p = 0.029, p = 0.015, p = 0.058; breast milk vs. cow’s milk formula p = 0.025, p = 0.044, p = 0.038). To conclude, breastfeeding stimulated the mucosal immune system to produce IgA to saliva, which is a marker for immunological maturation and likely provides protection against environmental antigens.

Prepubertal girls with insulin-dependent diabetes mellitus have higher exogenous insulin requirement than boys

Abstract In a population based study, the prescribed insulin dose of 348 prepubertal children with insulin-dependent diabetes mellitus (IDDM) was analysed 2 years after the diagnosis of diabetes. Girls had an insulin dose 13.6% higher than that in boys. When children younger than 5 years of age at diagnosis were analysed separately, the difference in insulin dose between boys and girls remained. The increased insulin dose in girls was not explained by possible differences in endogenous insulin secretion, body mass index, metabolic control or the number of daily insulin injections. Our observations indicate that prepubertal girls with IDDM have a poorer insulin sensitivity than boys.