Heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A1) can cause transient adrenal insufficiency and life-threatening failure to thrive.

The first and rate-limited step of steroidogenesis in all steroidogenic tissues is the conversion of cholesterol to pregnenolone, catalysed by P450scc side-chain cleavage enzyme (CYP11A1 gene-SCC). SCC deficiency has been characterised as an autosomal recessive disorder, although it may also be inherited as an autosomal dominant trait in humans. Here, we describe a family of three members carrying the same novel heterozygous CYP11A1 mutation, a c.235G > A missense variant in exon 1: pVal79Ile. A 46 XY boy (P1) was presented at the age of 3 months with early onset adrenal insufficiency and life-threatening failure to thrive, with low adrenal androgens but normal external genitalia. Five years later, the parents had twin girls, one of whom (P2) presented acute adrenal crisis a few hours after birth. The father (P3), born at term, was reported as having suffered from failure to thrive during the neonatal period, though not his only male sibling. This report of severe early adrenal insufficiency caused by a heterozygous mutation of the CYP11A1 gene clearly demonstrates that SCC deficiency may be inherited as an autosomal dominant trait in humans.

The role of biphosphonates in the management of thalassemia-induced osteoporosis: a systematic review and meta-analysis.

Thalassemia Major (TM) is a clinical entity with a high prevalence of low bone mass. The aim of the present study was to perform a meta-analysis of all available data on the role of bisphosphonates (BPs) in the therapy of thalassemia major-induced osteoporosis. The PRISMA recommendations for reporting systematic reviews and meta-analyses were used to guide the present study. We searched PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) through March 31, 2017 for articles related to thalassemia and BPs. To meta-analytically synthesize the primary endpoint, we used the standardized mean difference (SMD) after Hedges's g transformation under the scenario of a random effects model. Heterogeneity across studies was examined using the I2 statistic. Nine randomized controlled trials (RCTs) containing original data were included in this review. Three studies were performed in Italy, one in Australia, three in Greece, one in Cyprus, and one in China. The BPs investigated included zoledronate, alendronate, pamidronate, clodronate, and neridronate. Zoledronate and alendronate showed a tendency to perform best as compared to neridronate and the placebo effect with respect to femoral neck, lumbar spine, total hip, and total body in terms of bone mass density (g/cm2). BPs and in particular, zolendronate, were quite effective in the treatment of osteoporosis. These findings suggested that bisphosphonates are still a front-line treatment of osteoporosis in TM. However, to draw more meaningful and significant conclusions for the use and efficacy of BP in TM, larger and more complete RCTs should be conducted.

Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene.

CONTEXT: Central precocious puberty (CPP), defined as the development of secondary sex characteristics prior to age 8 years in girls and 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal axis. Mutations in the imprinted gene MKRN3 have been recently implicated in familial cases of CPP. OBJECTIVE: The objective of the study was to uncover the genetic cause of CPP in a family with two affected siblings. DESIGN AND PARTICIPANTS: The entire coding region of the paternally expressed MKRN3 gene was sequenced in two siblings, a girl with CPP and her brother with early puberty, their parents, and their grandparents. RESULTS: A novel heterozygous missense variant in the MKRN3 gene (p.C340G) was detected in the two affected siblings, their unaffected father, and the paternal grandmother. As expected, the mutated allele followed an imprinted mode of inheritance within the affected family. In silico analysis predicts the mutation as possibly damaging in all five software packages used. Furthermore, structural alignment of the ab initio native and mutant MKRN3 models predicts that the p.C340G mutation leads to significant structural perturbations in the 3-dimensional structure of the C3HC4 really interesting new gene motif of the protein, further emphasizing the functional implications of the novel MKRN3 alteration. CONCLUSIONS: We report a novel MKRN3 mutation (p.C340G) in a girl with CPP and her brother with early puberty. MKRN3 alterations should be suspected in all cases with familial CPP or early puberty, especially if male patients are also involved or the precocious puberty trend does not follow the usually observed mother-to-daughter inheritance.

Influence of developmental and hormonal factors on bone health in adolescent females: a cross-sectional study and review of the literature.

OBJECTIVE: To study bone density in healthy Greek girls going through puberty and determine the influence of developmental and hormonal factors. DESIGN: Sixty healthy female adolescents (average age of 13.88±2.53 years) were included. Bone mineral density (BMD) was measured at the hip by DXA (dual energy X-ray absorptiometry). Pubertal stage was determined by Tanner's criteria. Creatinine, calcium, phosphorus, parathyroid hormone, calcitonin and 25-OH-vitamin D levels were measured in blood samples. The European physical fitness test battery (EUROFIT) was used to assess the parameters of physical fitness that are related to strength. RESULTS: Adolescent girls had a mean (±SD) BMD value of 0.947±0.144 g/cm2 at the total hip (total hip BMD). Tanner's stage for pubic hair and body mass index (BMI) constituted significant, positive and independent predicting factors for bone density of total hip. Deficiency of 25OH-vitamin D was a negative predicting factor of bone density. Blood levels of calcium and phosphorus, the hours that adolescents devoted to sports, and handgrip strength, were independent predicting factors of bone density at the hip. CONCLUSIONS: Bone density and consequently bone health is determined by factors that can be modified in order to achieve optimal bone growth and reduce the risk of fractures and osteoporosis in later life.

Relationship of highly sensitive C-reactive protein and lipid levels in adolescents with type 1 diabetes mellitus.

BACKGROUND: Atherosclerosis appears to begin in youth with type 1 diabetes mellitus (T1DM). Highly sensitive C-reactive protein (hsCRP) is an independent marker of cardiovascular disease (CVD) risk in adults, but its relation to dyslipidemia and other CVD risk factors in adolescents with T1DM is unknown. OBJECTIVE: To study the association between lipids and hsCRP in youth with T1DM. DESIGN: Cross-sectional cohort. METHODS: hsCRP and fasting lipids were measured in 74 patients with T1DM, mean age 16.2 +/- 2.62 yr, mean duration of diabetes 7.3 +/- 4.0 yr, and mean hemoglobin A1c (HbA1c) 8.5 +/- 1.3%. According to the American Heart Association/Centers for Disease Control recommendations, hsCRP values were divided into three groups: group 1: <1.0 mg/L, low CVD risk; group 2: 1.0-3.0 mg/L, average CVD risk; and group 3: >3 mg/L, high CVD risk. Univariate linear regression between hsCRP and lipid and clinical parameters was used, with adjustment for age. RESULTS: hsCRP was significantly associated with triglycerides (Tg), apoB, systolic blood pressure (SBP), and diastolic blood pressure (DBP). Subjects in the high CVD risk group had no further worsening of lipids or BP, except for a higher Tg level. ApoB, SBP, and DBP were elevated in females with hsCRP > or =1 compared with the low-risk group, and high-density lipoprotein was decreased. In males, this difference was only significant for SBP. CONCLUSIONS: Elevation of hsCRP to a level > or =1.0 mg/L appears to be associated with elevated lipid levels in adolescents with T1DM, particularly in females. hsCRP is a marker in youth that clusters with dyslipidemia and may indicate an increased CVD risk in youth with T1DM.