Severe adrenal insufficiency in six neonates with normal newborn screening for CAH.

BACKGROUND: Newborn screening (NBS) reduces the risk of mortality in congenital adrenal hyperplasia (CAH), mainly due to the salt-wasting form of 21-hydroxylase deficiency. There is limited knowledge regarding the results of NBS in non-CAH primary adrenal insufficiency (non-CAH PAI). PATIENTS AND METHODS: Clinical and NBS for CAH data of neonates who were diagnosed with non-CAH PAI between January and December 2022 were examined. RESULTS: Patients (n = 6, 4 females) were presented with severe hyperpigmentation (n = 6), hypoglycemia (n = 4), hyponatremia (n = 3), hyperkalemia (n = 1), respiratory distress syndrome (n = 1) between 3rd hour to 2 months of life. All had normal NBS results. The median first-tier 17-hydroxyprogesterone (17OHP) concentration in NBS for CAH was 0.14 ng/mL (range; 0.05-0.85). Molecular studies revealed biallelic mutations in the MC2R (n = 4; 3 homozygous, 1 compound heterozygous), MRAP (n = 1) and STAR (n = 1) genes. Glucocorticoid with or without mineralocorticoid replacement was initiated once the diagnosis of non-CAH PAI was established. CONCLUSION: Neonates with non-CAH PAI have always normal NBS due to persistently low 17OHP, even when these newborn infants are severely symptomatic for adrenal insufficiency. Clinicians should be alert for signs of adrenal insufficiency in neonates, even if the patient has a 'normal' screening for CAH, so as not to delay diagnosis and treatment. This fact should be kept in mind particularly in countries where these conditions are more common than elsewhere.

Clinical, biochemical and genetic features with nonclassical 21-hydroxylase deficiency and final height.

BACKGROUND: The clinical, laboratory, genetic properties and final height of a large cohort of patients with nonclassical 21-hydroxylase deficiency (NC21OHD) in Turkey were analyzed. METHODS: This multicenter, nationwide web-based study collected data. RESULTS: The mean age was 9.79±4.35 years (229 girls, 29 boys). The most common symptoms were premature pubarche (54.6%) and hirsutism (28.6%). The peak cortisol was found below 18 µg/dL in three (15.45%) patients. A mutation was detected in the CYP21A2 gene of 182 (87.5%) patients. The most common mutation was V281L. Final height in female patients who were diagnosed and treated before attaining final height or near final height was found to be shorter than the final height in female patients who were diagnosed after attaining final height or near final height. CONCLUSIONS: The final height of the patients who were treated during childhood was found to be shorter than the final height of patients during the adolescent period.

Low 25-hydroxyvitamin D level is not an independent risk factor for hepatosteatosis in obese children.

BACKGROUND: Obesity is an important risk factor for non-alcoholic fatty liver disease. Few studies have evaluated the association between vitamin D and non-alcoholic fatty liver disease in obese children. Therefore, we conducted a study to examine the relationship of vitamin D levels and hepatosteatosis in obese children. METHODS: One hundred and eleven children with obesity participated in this study. Hepatosteatosis was diagnosed and graded using ultrasonography in all patients. Study participants were divided based on the presence of hepatosteatosis into two subgroups (hepatosteatosis and non-hepatosteatosis). Serum levels of 25-hydroxyvitamin D, calcium, phosphate, alkaline phosphatase, parathormone, and lipids were measured and compared. RESULTS: Hepatosteatosis existed in 52% of obese children without chronic diseases. There was no statistically significant difference in the vitamin D level between the hepatosteatosis and non-hepatosteatosis groups. Alanine aminotransferase levels and the triglycerides-to-high density lipoprotein ratio were significantly higher, and the high density lipoprotein levels were significantly lower in the hepatosteatosis group compared to the non-hepatosteatosis group. CONCLUSIONS: Vitamin D deficiency is not directly related with hepatosteatosis. A high ALT level and a high triglycerides-to-HDL ratio and low HDL levels are more significant in hepatic steatosis in obese children.

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.

Hypophosphatemic rickets caused by a novel splice donor site mutation and activation of two cryptic splice donor sites in the PHEX gene.

X-linked hypophosphatemic rickets (XLH) is the most common inherited form of rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in a sporadic Turkish girl with hypophosphatemic rickets. The patient was 2 years of age with a complaint of inability to walk. She had bowing of legs and growth retardation. Laboratory data showed normal calcium, low phosphate with markedly elevated ALP, and low phosphate renal tubular reabsorption. She was treated with Calcitriol 0.5 mg/kg/day and oral phosphate supplement with good response. The entire coding region of PHEX gene was sequenced from patient's peripheral leukocyte DNA and a novel 13 bp deletion at the donor splice site of exon5 was found (c.663+12del). Instead of using the donor splice site of intron 4 to splice out exon 5 and intron 5, the spliceosome utilized two nearby cryptic donor splice sites (5' splice site) to splice out intron 4, resulting in two smaller transcripts. Both of them could not translate into functional proteins due to frameshift. Her parents did not carry the mutation, indicating that this is a de novo PHEX mutation likely resulting from mutagenesis of X chromosome in paternal germ cells. We conclude that c.663+12del is a novel mutation that can activate nearby cryptic 5' splice sites. The selection of cryptic 5' splice sites adds the complexity of cell's splicing mechanisms. The current study extends the database of PHEX mutation and cryptic 5' splice sites.

Central corneal thickness in children with diabetes.

PURPOSE: To evaluate the central corneal thickness in children with diabetes and to determine the association between diabetes mellitus-related variables and central corneal thickness. METHODS: Fifty-nine patients (mean age: 13.2 years) with diabetes mellitus and 38 controls (mean age: 10.3 years) were compared in terms of central corneal thickness assessed by ultrasound pachymetry. The effects of age, gender, the duration of diabetes mellitus, the mean and current hemoglobin A1C (HbA1C) level, and fasting blood sugar level on central corneal thickness were investigated. Analysis of covariance and multivariate regression analysis were used for statistical analysis. RESULTS: The analysis of covariance with age as the covariant indicated that the diabetes mellitus group had significantly increased central corneal thickness (mean: 576.9+/-41.8 microm) compared with the control group (mean: 521+/-16.6 microm) (P<.0001). A multivariate regression model evaluating the effects of age, gender, duration of diabetes mellitus, fasting blood glucose, and the mean and current HbA1C levels on central corneal thickness was statistically significant (F(4,54)=3.33, P=.016). The results indicated that the current HbA1c value was the only significant predictor for central corneal thickness (B=0.29, t=2.13, P=.038) (B=9.7 microm per 1% HbA1C and B=13.3 microm per 1% HbA1C for right and left eyes, respectively). CONCLUSIONS: Diabetic patients have a significantly increased (approximately 55 microm) central corneal thickness compared with healthy controls. Current HbA1C value, which is the marker of metabolic control of the disease, is the only disease-related variable that predicts a higher central corneal thickness.