WHAT'S KNOWN ON THIS SUBJECT:Being an androgen antagonist and a possible estrogen agonist, several endocrinologic effects of DEHP have been demonstrated mostly in vitro and in animals. A limited number of studies have linked the endocrinologic effects of DEHP and its metabolite, MEHP, in humans. WHAT THIS STUDY ADDS:To our knowledge, this is the first study to define a possible effect of DEHP and MEHP in pubertal gynecomastia. The etiology of pubertal gynecomastia is attributed either to excessive estrogen, deficient androgen, increased aromatase enzyme activity, or a combination. abstract OBJECTIVE: Several untoward health effects of phthalates, which are a group of industrial chemicals with many commercial uses including personal-care products and plastic materials, have been defined. The most commonly used, di-(2-ethylhexyl)-phthalate (DEHP), is known to have antiandrogenic or estrogenic effects or both. Mono-(2-ethylhexyl)-phthalate (MEHP) is the main metabolite of DEHP. In this study, we aimed to determine the plasma DEHP and MEHP levels in pubertal gynecomastia cases. PATIENTS AND METHODS:The study group comprised 40 newly diagnosed pubertal gynecomastia cases who were admitted to Hacettepe University Ihsan Dog ramacı Children's Hospital. The control group comprised 21 age-matched children without gynecomastia or other endocrinologic disorder. Plasma DEHP and MEHP levels were measured by using high-performance liquid chromatography. Serum hormone levels were determined in some pubertal gynecomastia cases according to the physician's evaluation. RESULTS:Plasma DEHP and MEHP levels were found to be statistically significantly higher in the pubertal gynecomastia group compared with the control group (P Ͻ .001) (DEHP, 4.66 Ϯ 1.58 and 3.09 Ϯ 0.90 g/mL, respectively [odds ratio: 2.77 (95% confidence interval: 1.48 -5.21)]; MEHP, 3.19 Ϯ 1.41 and 1.37 Ϯ 0.36 g/mL [odds ratio: 24.76 (95% confidence interval: 3.5-172.6)]). There was a statistically significant correlation between plasma DEHP and MEHP levels (r: 0.58; P Ͻ .001). In the pubertal gynecomastia group, no correlation could be determined between plasma DEHP and MEHP levels and any of the hormone levels.CONCLUSIONS: DEHP, which has antiandrogenic or estrogenic effects, may be an etiologic factor in pubertal gynecomastia. These results may pioneer larger-scale studies on the etiologic role of DEHP in pubertal gynecomastia. Pediatrics 2010;125:e122-e129

There is a good genotype-phenotype correlation in VDDR-IA. However, some patients may recover from the loss of CYP27B1 function, probably due to 1α-hydroxylase activity exerted by a non-CYP27B1 enzyme.

Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r2 = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r2 = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.

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The CYP27B1 gene encodes 25-hydroxyvitamin D-1α-hydroxylase. Mutations of this gene cause vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700), which is a rare autosomal recessive disorder. To investigate CYP27B1 mutations, we studied 8 patients from 7 unrelated families. All coding exons and intron-exon boundaries of CYP27B1 gene were amplified by PCR from peripheral leukocyte DNA and subsequently sequenced. Homozygous mutations in the CYP27B1 gene were found in all the patients and heterozygous mutations were present in their normal parents. One novel single nucleotide variation (SNV, c.1215 T>C, p.R379R in the last nucleotide of exon 7) and three novel mutations were identified:, a splice donor site mutation (c.1215+2T>A) in intron 7, a 16-bp deletion in exon 6 (c.1022-1037del16), and a 2-bp deletion in exon 5 (c.934_935delAC). Both c.1215 T>C and c.1215+2T>A were present together in homozygous form in two unrelated patients, and caused exon 7 skipping. However, c.1215 T>C alone has no effect on pre-mRNA splicing. The skipping of exon 7 resulted in a shift of downstream reading frame and a premature stop codon 57 amino acids from L380 (p.L380Afs*57). The intra-exon deletions of c.1022-1037del16 and c.934_935delAC also resulted in a frameshift and the creation of premature stop codons at p.T341Rfs*5, and p.T312Rfs*19, respectively, leading to the functional inactivation of the CYP27B1 gene. Clinically, all the patients required continued calcitriol treatment and the clinical presentations were consistent with the complete loss of vitamin D1α-hydroxylase activity. In conclusion, three novel mutations have been identified. All of them caused frameshift and truncated proteins. The silent c.1215 T>C SNV has no effect on pre-mRNA splicing and it is likely a novel SNP. The current study further expands the CYP27B1 mutation spectrum.