Methicillin-resistant Staphylococcus aureus nasal colonization in a level III neonatal intensive care unit: Incidence and risk factors

Objective: To describe epidemiologic features and identify risk factors for methicillin-resistant Staphylococcus aureus (MRSA) acquisition in a level III neonatal intensive care unit (NICU). Setting: A prospective, cohort study in a university-affiliated NICU with an infection control program including weekly nasal cultures of all neonates. Methods: Demographic, clinical, and microbiologic data were prospectively collected between June 2009 and June 2013. Molecular characterization of MRSA isolates was done by multilocus variable number tandem repeat fingerprinting, staphylococcal cassette chromosome mec typing, and on representative isolates by multilocus sequence typing and s. pa typing. Results: Of 949 neonates, 217 (22.87%) had a culture growing MRSA, including 117 neonates testing positive at their first sampling. Of these latter infants, 96 (82.05%) were born with the infection and 59 (50.43%) had been transferred from the nursery. Length of stay and colonization pressure were strong independent predictors of MRSA acquisition. Among MRSA isolates, 7 sequence types were identified, with ST22-IVa, spa type t223, being the predominant strain. Conclusions: In an endemic area, early MRSA acquisition and high colonization pressure, likely related to an influx of colonized infants from a well-infant nursery, can support persistence of MRSA in NICUs. Surveillance, molecular tracking of strains, and reinforcement of infection control practices, involving well-infant nurseries in a comprehensive infection control program, could be helpful in containing MRSA transmission

46, XX DSD due to androgen excess in monogenic disorders of steroidogenesis: Genetic, biochemical, and clinical features

The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46, XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment

Congenital hypothyroidism (CH): the re-evaluation of diagnosis in CH patients with in situ gland identified by newborn screening

Background: Congenital Hypothyroidism (CH) is the most common endocrine disorder in childhood. Levothyroxine treatment within the first 2-3 weeks of life prevent neurological damage. Newborn screening (NS) by TSH dosage on dried blood spot allowed to early identification of risk for CH. In the last years the reduction of TSH recall threshold has led to an increased detection of mild forms with in situ gland at the first diagnosis. Therefore, the re-evaluation of diagnosis has become an important procedure to distingue transient forms from permanent ones.Aetiology: Transient CH may be caused by maternal factors (deficiency/excess of iodine, TSH receptor blockers, drugs) or neonatal factors (preterm and NICU infants; heterozygous mutations of the DUOX2 and DUOXA2 genes). Epidemiology: Before NS, the incidence of CH was 1:7000-10000 live births. After the introduction of NS it increased to 1:3000-4000. Currently, it is 1:1600-2800. This increase is correlated with the lowering TSH recall threshold, the increase in multiple pregnancies and preterm infants, and demographic changes. Re-evaluation of CH: it is performed after third year of life. According to the European guidelines, two different strategies can be adopted: the discontinuation of therapy over a period of 4-6 weeks or by decreasing the dose of Levothyroxine by 30% for 2–3 weeks followed by the dosing of serum levels of TSH and fT4. CH is permanent if an increase in TSH ≥ 10 mU/L is demonstrated. The etiology of CH can be identified using thyroid ultrasound (US), Iodine-123 scintigraphy, and in selected cases the perchlorate test. If the US shows a normal thyroid volume and scintigraphy shows low/absent tracer uptake, TSH resistance is presumable. If the US shows a normal or increased volume of thyroid, with a greedy absorption of the tracer to scintigraphy, dyshormonogenesis by the perchlorate test could be investigated. A radiolabel wash out of 10% of baseline uptake 2 hours after administration of perclorate is indicative of a defect in organification (partial with a wash out between 10-90%; total with a wash out >90%). The US findings of a normal or increased thyroid volume associated with high TSH and very low/unmeasurable thyroglobulin levels point to a deficiency of thyroglobulin synthesis. In our regional program of NS in the last ten years 491/454024 children were recalled for TSH and the diagnosis of CH was confirmed in 82.5%. The incidence of CH was 1:1121 births. 280 patients showed CH with in situ gland. After re-evaluation of diagnosis a permanent form of CH was detected in 55% of the cases (29% with hyperthyrotropinemia). A partial form of organification defect was detected in 34.5% of subjects submitted to perchlorate test and a TSH resistance due to a heterozygous mutation of the TSH-receptor gene was detected in 28.6%. Birth at term, the thyroid hypoplasia and a higher therapeutic dose of Levothyroxine (>2 mcg/Kg) at the re-evaluation were predictive factors of a permanent form. The frequent persistence of thyroid dysfunction in patients with borderline TSH values at the NS underlines the importance of reducing the recall threshold

Normative Basal Values of Hormones and Proteins of Gonadal and Adrenal Functions from Birth to Adulthood

In clinical practice, it is fundamental to compare the results of hormonal examinations obtained in the laboratory with reliable reference values. This is particularly difficult when faced with rare conditions, such as disorders of sex development, where not routinely assayed peptide hormones as well as intermediate steroid metabolites are often needed and local reliable reference values are not available. There are considerable differences among techniques and assays used in clinical and research laboratories. In fact, laboratory hormonology is undergoing a critical transition between techniques for quantitative determination: established immunoassays and mass spectrometry. Harmonizing results from different laboratories is a major challenge along the path leading to the establishment of consensus reference intervals for steroid hormones. Most of the efforts are being concentrated on testosterone, with very encouraging results being provided by the harmonization of liquid chromatography-tandem mass spectrometry results. However, this goal is still far from being achieved for the other steroid and small-molecule hormones, and a much more challenging perspective is foreseeable for protein hormones. In addition to technical issues, the importance of the definition and of the characterization of the reference population as well as sampling and processing methodology should not be underestimated, as these aspects may impact on hormonal axis and compound stability. The aim of the present review is to provide a comprehensive overview of the circulating reference values in basal condition of the hormones and proteins involved in sex development reported to date in the peer-reviewed literature. We present a series of tables where we have collected the reference intervals for each specific hormone and protein

A Case of Acrodermatitis Dysmetabolica in a Child Affected by Citrullinemia Type I: When Early Diagnosis and Timely Treatment Are Not Enough

An infant with a prenatal diagnosis of citrullinemia, who started standard treatment at birth (L-arginine; sodium benzoate and a personalized diet characterized by a low protein intake and supplementation of essential nutrients and amino acids), presented at 4 months of age with extended, progressive, and severe skin lesions consistent with acrodermatitis dysmetabolica. Guidelines for the diagnosis and management of urea cycle disorders underline that a low-protein diet places patients at risk of essential fatty acids, trace elements, and vitamin deficiency. At hospital admission, our patient had normal levels of zinc and alkaline phosphatases. The plasmatic amino acid profile revealed a severe and generalized deficiency. In particular, the serum levels of arginine, valine, and isoleucine were very low and the dermatitis did not improve until the blood levels of these amino acids increased. In our patient, skin lesions happened despite an early diagnosis of citrullinemia and timely treatment due to compliance issues as a consequence of linguistic barriers

Mutational and functional studies on NR5A1 gene in 46,XY disorders of sex development: identification of six novel loss of function mutations

Objective: To study the functional properties of six novel missense mutations of the NR5A1 gene encoding the steroidogenic factor 1 (SF-1) identified in six patients with 46,XY disorders of sex development (DSD) and to describe their relative phenotype–genotype relationship. Design: Genetic and functional studies. Setting: University department. Patient(s): Six 46,XY DSD patients. Intervention(s): None. Main Outcome Measure(s): Sanger sequencing and multiplex ligation-dependent probe amplification analysis to identify the mutations or deletions/duplications of the NR5A1 gene. Functional studies by transactivation assays to predict the impact of mutations on molecular function. Result(s): NR5A1 exons sequencing identified in six 46,XY DSD patients six novel mutations: p.T40R, p.T47C, p.G328W, p.A351E, p.R427W, and p.Q460R. Five missense variants were heterozygous, and one was homozygous (p.R427W). Functional analysis revealed a significant loss of DNA-binding and transactivation ability for all variants, except for p.Q460R, which showed a modest reduced activity compared with that of the wild-type protein. Phenotypes associated with these mutations varied from males with spontaneous puberty, substantial T production, and possible fertility, to females with and without müllerian structures and primary amenorrhea. Conclusion(s): We describe six novel mutations in NR5A1 gene and showed that they might affect protein structure, therefore compromising seriously the SF-1 role in regulating gonadal development. Clinically, we suggest that NR5A1 analysis should be performed whenever atypical sex organs are evidenced or there is an abnormal sexual development, to have proper diagnosis and better management of patients