Nutritional hypophosphatemic rickets secondary to Neocate® use.

Elemental formula is commonly used in children with feeding intolerance. We describe two, medically complex and feeding tube dependent, patients exclusively fed with Neocate® who subsequently developed hypophosphatemic rickets. Both patients had gross motor decline and pain with physical touch. They were found to have low serum phosphorus, normal calcium, and vitamin D studies, with elevated alkaline phosphatase suggestive of nutritional hypophosphatemia. Both courses were complicated by hypocalcemia following formula change and phosphorus supplementation, highlighting the need for careful management of phosphate repletion in affected individuals. Diligent serial electrolyte monitoring as well as attention to bone health is needed in conjunction with elemental nutrition. Formula change led to restoration of calcium and phosphorus homeostasis and radiographic improvement in these patients.

Evaluating RANKL and OPG levels in patients with Duchenne muscular dystrophy.

RANKL-OPG should be explored in DMD patients to potentially provide targeted therapy. We quantified RANKL and OPG levels in DMD patients compared with controls. RANKL, OPG, and RANKL:OPG significantly declined with age in DMD patients suggesting some bone turnover markers are difficult to assess or use as therapeutic indicators. INTRODUCTION: Osteoporosis in Duchenne muscular dystrophy (DMD) is multi-factorial in nature with high prevalence of fractures. RANKL-OPG should be explored to potentially provide targeted therapy for these patients. We quantified RANKL, OPG, and RANKL:OPG levels in DMD patients compared with controls and analyzed the influence of age, glucocorticoid use, ambulatory status, bone density, and fracture history. METHODS: DMD patients were enrolled at CHLA. Controls were recruited from general pediatric clinic and in collaboration with samples from a previously completed study. Free soluble RANKL and OPG levels were quantified using a sandwich ELISA. RESULTS: Fifty DMD patients and 50 controls were enrolled. DMD patients had a significant decline in RANKL, OPG, and RANKL:OPG with age (p = < 0.0001, p = 0.026, and p = 0.002, respectively) while healthy controls showed no significant change. RANKL trended lower in patients on glucocorticoids (p = 0.05), attributed to the significantly older age in the treatment group. RANKL and RANKL:OPG levels were significantly lower in the non-ambulatory group compared with the ambulatory group (p = 0.010 and 0.036 respectively), again likely due to their older age. There was no correlation of RANKL, OPG, or RANKL:OPG with DXA Z-score or presence of vertebral fractures. CONCLUSION: There was significant decline in RANKL, OPG, and RANKL:OPG with age in DMD patients compared with controls, potentially due to disease severity or worsening osteoblastic function. This suggests some bone turnover markers may be difficult to assess or use as therapeutic indicators in DMD patients. Larger studies are needed to evaluate the role of RANKL-OPG in DMD patients to provide better targeted therapy.

Bisphosphonate therapy in an infant with generalized arterial calcification with an ABCC6 mutation.

Generalized arterial calcification of infancy (GACI) is a rare genetic disorder with high infantile mortality, described to be due to ENPP1, and less commonly ABCC6 mutations. Bisphosphonate treatment has been described to improve survival in ENPP1-positive GACI patients, but few studies have described bisphosphonate treatment in ABCC6-positive patients. Without therapy, patients will die before 6 months of age. Our patient is now 3 years old, former recipient twin of twin-to-twin transfusion syndrome (TTTS). Initial fetal echocardiogram at 19 weeks showed calcifications of the ascending aorta and pulmonary artery (PA). She underwent utero laser therapy, and despite resolution of the TTTS, her follow-up scans showed progressive calcification of the aorta and PA. Postnatal echocardiogram showed calcification and supravalvar stenosis of the aorta and PA. CT on day of life 6 showed calcifications in the PAs, aortic arch, and descending aorta. Quantification of valvular calcification can be difficult; in our patient, increasing outflow tract gradient on echocardiogram was used to monitor disease progression. Molecular testing revealed an ABCC6 gene mutation. She was started on weekly IV pamidronate (0.1-0.3 mg/kg/week) on day 8 of life then transitioned to oral etidronate (15-20 mg/kg/day). Given progressive supravalvar aortic and pulmonary stenosis, she underwent surgical repair with patch augmentation of the PA and ascending aorta at 4 months old. She has done well post-operatively, continuing on enteral bisphosphonate therapy with no side effects to date. Her identical twin was confirmed to have the same mutation and remains asymptomatic with no calcifications. Aggressive bisphosphonate therapy should be started as soon as possible in patients with infantile arterial calcinosis due to ABCC6 or ENPP1 mutations. Echocardiographic evaluation can be used to monitor disease progression by arterial gradients. Molecular testing is also essential to evaluate for possible co-morbidities in these patients and pregnancy management for the future.

Normalization of cortical bone density in children and adolescents with hyperthyroidism treated with antithyroid medication.

UNLABELLED: We assessed bone size and bone density (BD) measurements using computed tomography (CT) in children and adolescents with hyperthyroidism treated with antithyroid medication. We found that cortical BD appeared to improve at 1 year and normalize at 2 years in all tested patients. INTRODUCTION: Our previous study demonstrated that cortical BD in children and adolescents with untreated hyperthyroidism was significantly decreased as compared to age-, sex- and ethnicity-matched healthy controls. The present report evaluated whether attainment of euthyroidism by medical antithyroid treatment was able to improve or normalize cortical BD in these patients. METHODS: Anthropometrics and three-dimensional CT bone measurements including cross-sectional area (CSA), cortical bone area (CBA) and cortical BD at midshaft of the femur (cortical bone), and CSA and BD of L(1) to L(3) vertebrae (cancellous bone) in 15 children and adolescents after 1- and 2-year treatments with antithyroid medication were reviewed and compared to their pretreatment results. RESULTS: All patients were euthyroid at 1 and 2 years after medical antithyroid treatment. After adjusting for age, height, weight and Tanner stage, a significant increase in cortical BD in all patients (15/15) was found after 1 year of treatment (P < 0.001). Normalization of cortical BD was demonstrated in all tested patients (10/15) after 2 years. There were no significant changes in the other cancellous or cortical bone parameters. CONCLUSION: Cortical BD was improved at 1 year and normalized at 2 years in hyperthyroid patients rendered euthyroid with antithyroid medication.

Bone size and density measurements in prepubertal children with Turner syndrome prior to growth hormone therapy.

UNLABELLED: Using computed tomography (CT), we found the decreases in bone size of vertebrae and femur, cortical bone area (CBA) of femur and bone density (BD) of vertebrae in prepubertal female with Turner syndrome (TS) compared to those of controls. INTRODUCTION: Bone mineral density results from previous studies utilizing single-photon absorptiometry (SPA) or dual-energy X-ray absorptiometry (DXA) in children with TS are controversial. The present study used CT to assess the differences in cancellous and cortical bone size and BD between prepubertal TS patients prior to growth hormone therapy and historical age and ethnicity-matched female controls. METHODS: Anthropometrics and CT bone measurements including cross-sectional area (CSA) and BD of lumbar vertebrae and femur and CBA of femur in prepubertal TS females were reviewed and compared with those in controls. RESULTS: Twenty-two prepubertal TS patients had delayed bone age, were shorter and lighter than controls (Ps < 0.001). After adjusting for weight, height and skeletal age, vertebral BD and CBA of the femur were lower in patients than in controls (P < 0.001 and P = 0.021, respectively). However, after additional adjusting for puberty, results were not different from controls. While a positive correlation between vertebral BD and age was noted in controls (r = 0.367, P = 0.092), a significant negative correlation was noted in patients (r = -0.615, P = 0.002). CONCLUSIONS: While the decrease in vertebrae and femur sizes of patients with TS appeared to be secondary to their small body size, the decreased BD of vertebrae and CBA of femur were likely secondary to estrogen deficiency.

Use of insulin pump therapy at nighttime only for children 7-10 years of age with type 1 diabetes.

OBJECTIVE: Because of age-related developmental and cognitive issues, children <10 years of age may not be able to wear an insulin pump safely when they are not under direct parental supervision. The purpose of this study was to determine if insulin pump therapy at nighttime only, when children are at home, could improve fasting and nighttime blood glucose levels without adverse effects. RESEARCH DESIGN AND METHODS: The study cohort consisted of 10 children aged 7-10 years. A randomized crossover design was used to compare nighttime-only pump usage from dinner and throughout the night, combined with a prebreakfast injection of intermediate-acting NPH and rapid-acting lispro insulin, with 3 insulin injections per day. Comparisons were made among mean blood glucose values and percentage of blood glucose levels within the target range (70-150 mg/dl) before meals, at bedtime, and at 3:00 A.M.; serum fructosamine levels; and scores on measures of adherence and fear of hypoglycemia. RESULTS: Compared with baseline levels, the use of the pump resulted in a significant decrease in the mean average (P < 0.001), breakfast (P < 0.0001), and 3:00 A.M. (P < 0.003) blood glucose levels. There was a decrease in the percentage of blood glucose values less than the target range (P < 0.01) and in fructosamine (P < 0.01) values and an increase in the percentage of blood glucose levels within the target range (P < 0.03). CONCLUSIONS: Nighttime-only insulin pump therapy may be a viable alternative that young children can use to improve glycemia when they are not capable of independently managing an insulin pump.

A pilot study of the continuous glucose monitoring system: clinical decisions and glycemic control after its use in pediatric type 1 diabetic subjects.

OBJECTIVE: To determine whether the continuous glucose monitoring system (CGMS) (MiniMed, Sylmar, CA) could be used to make clinical decisions and whether it has an impact on glycemia in pediatric type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Pediatric subjects were recruited if they had HbA(1c) >8.0% with management problems (n = 35) or episodes of severe or nocturnal hypoglycemia or hypoglycemia unawareness associated with HbA(1c) < or =8.0% (n = 12). A total of 47 patients with a mean HbA(1c) value of 8.6 +/- 1.6% (mean age 11.8 +/- 4.6 years, youngest 2.7 years, and diabetes duration 5.5 +/- 3.5 years) on three to four insulin injections/day (n = 24) or insulin pump therapy (n = 23) were followed with the CGMS for a mean of 69.5 +/- 28 h. Comparisons were made between the number of high (>150 mg/dl) and low (<70 mg/dl) glucose patterns discerned with the sensor or the logbook, and HbA(1c) levels were evaluated. RESULTS: In patients on injection therapy, 30 high or low glucose patterns were discerned with the logbook records and 120 patterns with the CGMS. Specific alterations of the diabetes regimen were made. An overall significant change in HbA(1c), from 3 months before wearing the sensor to 6 months after (analysis of variance 0.04), was found in the subjects. Post hoc analysis showed a significant change in HbA(1c) from 8.6 +/- 1.5% at baseline to 8.4 +/- 1.3% at 3 months (paired Student's t test 0.03). CONCLUSIONS: The CGMS can be used by pediatric patients to detect abnormal patterns of glycemia. The information that was obtained could be used to alter the diabetes regimen and impact glycemic outcome.

Increased body weight and decreased radial cross-sectional dimensions in girls with forearm fractures.

A large number of children sustain fractures after relatively minor trauma and several investigators have associated these fractures to a deficient accumulation of bone during growth. This study was conducted to better characterize the skeletal phenotype associated with low-energy impact fractures of the forearm in girls. The densities of cancellous, cortical, and integral bone and the cross-sectional area were measured in the radius of 100 healthy white girls (aged 4-15 years) using computed tomography (CT); 50 girls had never fractured and 50 girls had sustained a forearm fracture within the previous month. Fractured and nonfractured groups were matched for age, height, weight, and Tanner stage of sexual development. Compared with controls, girls with fractures had, on average, 8% smaller cross-sectional area at the distal radius (1.82 +/- 0.50 cm2 vs. 1.97 +/- 0.42 cm2; p < 0.0001) but similar cancellous, integral, and cortical bone densities. Neither radial length nor the amount of fat or muscle at the midshaft of the radius differed between girls with and without fractures. Both study subjects and matched controls were overweight. Although mean height was at the 50th percentile, mean weight was at the 90th percentile for age-adjusted normal values. Girls who sustain forearm fractures after minor trauma have small cross-sectional dimensions of the radius and tend to be overweight. The smaller cross-sectional area confers a biomechanical disadvantage that, coupled with the greater body weight, increases the vulnerability to fracture after a fall.

Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development.

Bone mass and biochemical markers of bone turnover increase significantly during puberty. We studied the possible relationships between markers of bone formation and bone resorption and increases in skeletal size, bone volume, and bone density in healthy children at different stages of sexual development. Serum concentrations of bone specific alkaline phosphatase (BALP) and osteocalcin (bone Gla protein, BGP), urinary levels of pyridinoline (Pyr) and deoxypyridinoline (Dpyr) and computed tomography (CT) measurements of the cross-sectional areas of the vertebrae and the femurs, the apparent density of cancellous bone in the vertebrae, and the volume and the material density of cortical bone in the femurs were determined in 126 boys and 143 girls, ages 7-18 years. Serum levels of BALP and BGP and urinary concentrations of Pyr and Dpyr peaked in early puberty and were lowest in the later stages of puberty. CT measurements for the cross-sectional areas of the vertebrae and the femurs, the femoral cortical bone areas, and the apparent density of cancellous bone increased in all children during puberty, while values for material bone density did not change significantly with the stage of sexual development. BALP and BGP showed significant inverse correlations with the material density of bone (r = -0.23 and -0.24, respectively), but no association with bone volume in the appendicular or axial skeleton. In contrast, Pyr and Dpyr correlated with femoral cross-sectional area (r = -0.24 and -0.33, respectively) and cortical bone area (r = -0.29 and -0.33, respectively), and with the apparent density of vertebral cancellous bone (r = -0.26 and -0.19, respectively), but not with the material density of bone. We conclude that, during puberty, there is a differential association between the two components of bone mass and the markers of bone formation and bone resorption; while markers of bone formation are related to the material density of bone, markers of bone resorption are related to the volume of bone.

Serum levels of insulin-like growth factor I and the density, volume, and cross-sectional area of cortical bone in children.

Insulin-like growth factor I (IGF-I) is a major regulator of bone growth during childhood. However, beyond knowledge that IGF-I influences longitudinal growth, its associations to changes in the cross-sectional dimensions, the volume, or the material density of bone during growth are unknown. We assessed the relationships between serum IGF-I and measurements of cross-sectional area, cortical bone area, and cortical bone density at the midshaft of the femur in 197 normal healthy white children and adolescents (103 boys and 94 girls; aged 7.8-18.2 yr). Bone determinations were obtained using computed tomography, and levels of IGF-I were measured by RIA after an extraction procedure. IGF-I correlated significantly with both cross-sectional area (r = 0.49; P < 0.0001) and cortical bone area (r = 0.50; P < 0.0001), but did not correlate with the material density of cortical bone (r = -0.08). Multiple regression analyses showed that circulating levels of IGF-I were associated with cross-sectional area (P = 0.03) and cortical bone area (P = 0.04) values, even after correcting for the confounding effects of age, gender, weight, and femoral length. We conclude that IGF-I is a major determinant of the cross-sectional properties of bone, but does not influence the material density of bone, in the appendicular skeleton.

Diagnosis of hidden central hypothyroidism in survivors of childhood cancer.

To determine how often central hypothyroidism remains undetected by routine out-patient tests of thyroid hormone, we studied 208 pediatric cancer survivors referred for evaluation because of signs of subtle hypothyroidism or hypopituitarism. Of the 208 (68 females and 140 males), 110 had brain tumors, 14 had other head/neck tumors, 11 had solid tumors remote from head and neck, and 73 had leukemia. Patients were evaluated 1-16 yr (mean, 6.1+/-4.1 yr) after tumor diagnosis. The nocturnal TSH surge and response to TRH were measured. Of 160 patients with free T4 in lowest third of normal, 34% had central hypothyroidism (blunted TSH surge or low/delayed TSH peak or delayed TSH decline after TRH); 9% had central hypothyroidism with mild TSH elevation (mixed hypothyroidism). Another 16% had mild primary hypothyroidism (TSH, 5-15 mU/L). Of 48 with free T4 in the upper two thirds of normal, 14% had central hypothyroidism; 17% had mild primary hypothyroidism. Incidence of central, mixed, and mild primary hypothyroidism 10 yr after tumor diagnosis was significantly related to total cranial radiation dose (P < 0.0001). Of 62 patients with central hypothyroidism, 34% had not developed GH deficiency. TSH surge identified 71%, and response to TRH identified 60% of those with central hypothyroidism. More than half of the slowly growing patients who have received cranial or craniospinal radiation for childhood cancer develop subtle hypothyroidism. In our study group, 92% of patients with central hypothyroidism and 27% with mixed hypothyroidism would have remained undiagnosed using baseline thyroid function tests alone. Both TSH surge and response to TRH must be evaluated to identify all of these patients.

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: report of five new cases and review.

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

Antiobesity effect of diazoxide in obese Zucker rats.

Hyperinsulinism and insulin resistance are characteristic findings in obese subjects. Obesity in both humans and experimental animals is associated with a reduced number of insulin receptors and a decreased insulin-mediated glucose disposal, whereas sensitivity to insulin's antilipolytic action is unaltered. To evaluate the antiobesity effect of diazoxide (DZ), an inhibitor of glucose-stimulated insulin release, 7-week-old Zucker obese and lean rats were studied. Obese and lean rats were grouped into DZ-treated (150 mg/kg/d) and control (C) groups. DZ-treated obese rats consumed similar amounts of calories per kilogram body weight (BW) compared with C obese animals, but gained less weight (P<.01). Postabsorptive plasma free fatty acids (FFA), cholesterol, and triglycerides were significantly higher in obese versus lean animals (P<.01). DZ treatment reduced plasma triglyceride levels in obese animals (P<.001), but had no significant effect on FFA or cholesterol concentrations. Plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests (GTTs) were significantly lower in DZ obese versus C obese rats (P<.01) despite a decrease in plasma insulin concentrations in DZ-treated animals (P<.01). In contrast, DZ lean rats developed glucose intolerance (P<.05). Sensitivity and responsiveness to the antilipolytic effect of insulin in isolated adipocytes were significantly decreased in DZ obese as compared with C obese rats (P<.01). Moreover, adipocyte specific insulin receptor binding was increased in both DZ lean and DZ obese animals (P<.01). This was accompanied by increased basal and insulin-stimulated glucose transport in both genotypes (P<.01). In conclusion, DZ increased insulin receptor binding and glucose transport while decreasing hyperinsulinemia and insulin sensitivity to the antilipolytic action of insulin. This combined effect resulted in improved glucose tolerance and a decrease in weight gain in obese rats, implying that pharmacologic modification of the disturbed insulin metabolism of obesity may be therapeutically beneficial.

Does glycemic control affect growth velocity in children with insulin-dependent diabetes mellitus.

To determine the effect of glycemic control on linear growth in children with insulin-dependent diabetes mellitus type 1, we studied 82 patients (40 male, 42 female) over a 6-year period. The mean +/-SD for age of onset and duration of IDDM were 7.3 +/- 3.9 years and 4.8 +/- 3.5 years, respectively. At each clinic visit, glycemic control was assessed by measuring glycosylated hemoglobin (GHb). For a total of 751 clinic visits, the mean +/- SD for chronologic age and GHb were 11.5 +/- 3.8 years and 10.2% +/- 2.3%, respectively. Good glycemic control was correlated with more frequent clinic visits (r= 0.219, P < 0.05). Growth was assessed by determining both weight and height, which were normalized for age and sex by calculating Z scores for weight and height and GHb. Moreover, regression analysis revealed no significant correlation between GHb levels and delta Z for either weight or height. While a significant correlation was observed between delta Z for weight and height (r = 0.30, P < 0.01), the relationship was not affected by glycemic control. Therefore, these data demonstrate that weight gain and growth rate do not seem to be significantly affected by glycemic control. This study also confirms that linear growth velocity is dependent on weight gain and suggests that in type 1 children, weight gain and level of growth-producing hormones such as insulin-like growth factor-1 (IGF-1) are more important regulators of linear growth than glycemic control.

Caloric restriction for 24 hours increases mean night growth hormone.

UNLABELLED: In obesity, serum growth hormone (GH) is usually low, confounding GH assessment of short obese children. We evaluated whether 24-h caloric restriction would permit better discrimination between normal GH secretion and GH deficiency (GHD) by elevating night GH levels. DESIGN AND PATIENTS: Serum was obtained every 20 minutes 2000-0800 h before and 2200-0400 h after 24 hours of caloric restriction (8% of usual calories) in 24 normal height children [14 normal (weight for height 10-90th percentile); 10 obese (weight for height > 95th percentile)] and in 31 short children (height shorter than -2.0 SD below mean for age). All samples from both nights per child were assayed for GH simultaneously to eliminate interassay variability. RESULTS: Mean GH increased significantly in all groups after caloric restriction (P < 0.01). Obese children had lower baseline mean GH and GH amplitude compared to normal (P < 0.01); GH increased into normal range after restriction. Basal GH studies in short children were not significantly below normal. Surprisingly, some with low stimulated GH increased their night GH into the normal range after caloric restriction. CONCLUSIONS: Caloric restriction for 24 h enhances night GH similarly in short and in normal children, and thus does not increase the diagnostic utility of night GH studies in non-obese short children. Caloric restriction reverses suppressed GH secretory state of obese children, perhaps by decreasing diet-dependent somatostatin inhibition of GH secretion.

Growth response in Turner syndrome with recombinant human growth hormone therapy.

Ten Turner syndrome girls whose mean age was 10.9 +/- 2.7 years were treated with recombinant human growth hormone (rhGH), dose 0.6 U/kg/week. Five of them had classical 45, XO karyotype. The mean height velocity increased from 2.8 +/- 1.3 cm/year before treatment to 6.1 +/- 2.06 cm/year after treatment for a period of 1.4 years. The response of treatment correlated well with pretreatment height velocity (<3 cm/year) but not with karyotype. However, the response has been decreasing and an increased dose after the first year of treatment is recommended.

A novel mutation of anti-Mullerian hormone gene in Persistent Mullerian Duct Syndrome presented with bilateral cryptorchidism: a case report.

BACKGROUND: We report a novel mutation in a case of Persistent Mullerian Duct Syndrome (PMDS). PMDS is characterized by the persistence of female reproductive organs derivatives in a 46,XY subject due to the failure of the Mullerian duct to regress in utero. To date, 53 different mutations of the anti-Mullerian hormone (AMH) gene, including the present one, have been identified. CLINICAL CASE: A 2-week-old male presented with bilateral cryptorchidism and normal male external genitalia. His karyotype was 46,XY. hCG stimulation test was normal. At age 1 year and 4 months, he underwent laparoscopic surgery which revealed a uterus and fallopian tubes. The anti-Mullerian hormone (AMH) level was undetectable (<0.01 ng/mL). Diagnosis of Persistent Mullerian Duct Syndrome, probably due to an AMH mutation, was made. GENETIC STUDIES: A unique homozygous T to G base substitution was found at position 2219, near the middle of the exon 5, changing codon CTG to CGG in anti-Mullerian hormone (AMH) gene. This mutation causes leucine to be converted to arginine at position 426 belonging to a (L)RA(L)LLLKALQ highly conserved sequence in the AMH gene. Both parents are heterozygous for the mutation. CONCLUSION: Persistent Mullerian Duct Syndrome (PMDS) is a rare cause of bilateral cryptorchidism, when in doubt the existence of Mullerian derivatives should be explored by laparoscopy. Assay of serum AMH helps to distinguish between mutations of AMH and AMH receptor. If serum AMH is very low or undetectable, sequencing of the AMH gene usually confirms the presence of a mutation.

Insulin pump therapy in type 1 pediatric patients: now and into the year 2000.

There are a number of medical conditions such as growth failure in children, pregnancy, lipid abnormalities, and early complications that are improved by the meticulous glycemic control that can be achieved with insulin pump therapy (CSII). By using an insulin pump, many patients with severe hypoglycemia, the dawn phenomenon, extremes of glycemic excursion, recurrent diabetic ketoacidosis (DKA) and hypoglycemia unawareness have amelioration of these problems. However, pump therapy involves problems such as weight gain, recurrent ketosis due to pump failure, infections, and risk of hypoglycemia. Owing to many developmental issues, young children may not be able to wear the pump without parental supervision. We have used the pump at night time only in these patients. This has allowed children of 7-10 years of age to benefit from improved nocturnal glycemia without the risk of pump therapy when they are without an adult to help. We have also used the pump in subjects with recurrent DKA and in our general patient population (mean age 13.6+/-3.9 years). In our pump cohort, CSII led to improvement in quality of life, knowledge, adherence, and responsibility. A reduction in hypoglycemia, DKA rate and mean HbA(1c) was associated with pump usage. For this to occur, however, pump education must be geared to the pediatric subject and his/her family. Education materials and tools help in learning how to use the pump and how to deal with the intricacies of basal and bolus dosing, and the effect of exercise, food and illness on diabetes management. The pump has improved since it was first introduced and these modifications have made it easier, more painless and less hazardous. With the development of continuous glucose sensors and implantable pumps, the next century will see pump therapy lead to the artificial pancreas.

Diagnosis of ACTH deficiency. Comparison of overnight metyrapone test to either low-dose or high-dose ACTH test.

Test sensitivity and accuracy of 250 microg/m(2) ACTH test, 1 microg/m(2) ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.