Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age.

Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.

Effect of breastfeeding on serum zinc levels and growth in healthy infants.

BACKGROUND: This study investigated the association among breastfeeding, serum zinc levels, and nutritional status of children. SUBJECTS AND METHODS: One hundred healthy infants were included in the study. Anthropometric measurements of the children were taken, and their plasma zinc levels were determined. The mothers were interviewed about the duration of breastfeeding and nutrition pattern of the children at the time of zinc measurement. RESULTS: Low zinc levels were associated with lower weight measurements (r=0.49, p<0.001), but the association between height and zinc level was not statistically significant (r=0.18, p>0.05). There was a negative correlation between breastfeeding duration and weight-for-age percentile (r=-0.2, p<0.05), height-for-age percentile (r=-0.3, p<0.05), and serum zinc level (r=-0.3, p=0.002). The pattern of nutrition correlated only with the weight of the infant (r=0.2, p<0.05) and not with either height or serum zinc levels (p>0.05). CONCLUSIONS: Exclusive breastfeeding beyond 6 months of age has negative effects on serum zinc levels and can be associated with low weight gain, which will be especially important in developing countries.

Critical points in the management of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA-1, MIM #264350) is caused by defective transepithelial sodium transport. Affected patients develop life-threatening neonatal-onset salt loss, hyperkalemia, acidosis, and elevated aldosterone levels due to end-organ resistance to aldosterone. In this report, we present a patient diagnosed as PHA-1 who had clinical and laboratory findings compatible with the diagnosis and had genetically proven autosomal recessive PHA-1. The patient received high doses of sodium supplementation and potassium-lowering therapies; however, several difficulties were encountered in the management of this case. The aim of this presentation was to point out the potential pitfalls in the treatment of such patients in the clinical practice and to recommend solutions.

Mutations in CYP24A1 and idiopathic infantile hypercalcemia.

BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children.

INTRODUCTION: In this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity. MATERIALS AND METHODS: Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups. RESULTS: Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5-2.1) and 2.1 (1.8-2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6-5.2), 1.5 (0.8-3.1), and 2.5 (1.8-3.5); FLI, 2.0 (0.8-3.5), 0.6 (0.3-1.2), and 1.5 (1-2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9-3.1), 2.8 (1.7-3.4), and 3.0 (2.2-3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05). CONCLUSION: Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.

Alendronate treatment in children with osteogenesis imperfecta.

BACKGROUND: Recent studies reported beneficial effect of cyclical intravenous administration of pamidronate in children and adolescents with osteogenesis imperfecta (OI). However, this treatment requires frequent hospital admissions and is relatively expensive. Alendronate is an oral bisphosphonate effectively used in adults with osteoporosis. Experience with alendronate treatment in children with OI is limited. AIMS: To report our experience with alendronate in children with OI. METHODS: 12 children with OI (7 with type I, 4 with type III and 1 with type IV; 7 boys, 5 girls) aged 1.8 to 15.4 years (7.9+/-; 4.4 yrs) were included in this retrospective study. The patients were treated with alendronate in a dose of 5-10 mg/day along with calcium (500 mg/day) and vitamin D (400-1000 IU/day) supplements for 19.8+/-11.3 months (range: 7-46 months). Serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), osteocalcin (OC), pyrilinks-D and urinary Ca/Cr ratio were studied 3 monthly and bone mineral density (BMD) by DXA on 6-12 monthly basis. RESULTS: Fracture rate of the patients significantly decreased after treatment (1.2+/-1.5 vs. 0.16+/-0.32 per year, P<0.05). Treatment improved bone density in each individual case. Z-scores of lumbar DXA (L2-L4) significantly increased during treatment (-4.60+/-1.30 vs - 2.47+/-1.52, P< 0.05). Urinary pyrilinks-D decreased with treatment (90.8+/-136.3 vs. 35.1+/-29.9, P< 0.05). Serum Ca, P, ALP, OC and urinary Ca/Cr did not change significantly during treatment. CONCLUSION: We conclude that alendronate is effective, safe and practical alternative to intravenous bisphosphonates in treatment of children with OI.