Mitochondrial disease and endocrine dysfunction

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases

Management of a girl with delayed puberty and elevated gonadotropins

A girl presenting with delayed puberty and elevated gonadotropins may have a range of conditions such as Turner Syndrome (TS), Primary Ovarian Insufficiency (POI) and 46,XY DSD. An organized and measured approach to investigation can help reach a timely diagnosis. Management of young people often requires specialist multidisciplinary input to address the endocrine and non-endocrine features of these complex conditions, as well as the psychological challenges posed by their diagnosis. Next generation sequencing within the research setting has revealed several genetic causes of POI and 46,XY DSD which may further facilitate an individualized approach to care of these young people in the future. Pubertal induction is required in many and the timing of this may need to be balanced with other issues specific to the condition (e.g., allowing time for information-sharing in 46,XY DSD, optimizing growth in TS). Shared decision-making and sign-posting to relevant support groups from the outset can help empower young people and their families to manage these conditions. We describe three clinical vignettes of girls presenting with delayed puberty and hypergonadotropic amenorrhea and discuss their clinical management in the context of current literature and guidelines

New Technologies for the Identification of Novel Genetic Markers of Disorders of Sex Development (DSD)

Although the genetic basis of human sexual determination and differentiation has advanced considerably in recent years, the fact remains that in most subjects with disorders of sex development (DSD) the underlying genetic cause is unknown. Where pathogenic mutations have been identified, the phenotype can be highly variable, even within families, suggesting that other genetic variants are influencing the expression of the phenotype. This situation is likely to change, as more powerful and affordable tools become widely available for detailed genetic analyses. Here, we describe recent advances in comparative genomic hybridisation, sequencing by hybridisation and next generation sequencing, and we describe how these technologies will have an impact on our understanding of the genetic causes of DSD

Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations

BACKGROUND: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic–pituitary–gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown. SUBJECTS AND METHODS: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected. RESULTS: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro. CONCLUSION: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible

The Role of Operating Conditions in the Precipitation of Magnesium Hydroxide Hexagonal Platelets Using NaOH Solutions

Magnesium hydroxide, Mg(OH)2, is an inorganic compound extensively employed in several industrial sectors. Nowadays, it is mostly produced from magnesium-rich minerals. Nevertheless, magnesium-rich solutions, such as natural and industrial brines, could prove to be a great treasure. In this work, synthetic magnesium chloride and sodium hydroxide (NaOH) solutions were used to recover Mg(OH)2 by reactive crystallization. A detailed experimental campaign was conducted aiming at producing grown Mg(OH)2 hexagonal platelets. Experiments were carried out in a stirred tank crystallizer operated in single- and double-feed configurations. In the single-feed configuration, globular and nanoflakes primary particles were obtained, as always reported in the literature when NaOH is used as a precipitant. However, these products are not complying with flame-retardant applications that require large hexagonal Mg(OH)2 platelets. This work suggests an effective precipitation strategy to favor crystal growth while, at the same time, limiting the nucleation mechanism. The double-feed configuration allowed the synthesis of grown Mg(OH)2 hexagonal platelets. The influence of reactant flow rates, reactant concentrations, and reaction temperature was analyzed. Scanning electron microscopy (SEM) pictures were also taken to investigate the morphology of Mg(OH)2 crystals. The proposed precipitation strategy paves the road to satisfy flame-retardant market requirements

The growth hormone receptor gene deleted for exon three (GHRd3) polymorphism is associated with birth and placental weight.

Human growth hormone receptor (GHR) transcripts have two isoforms, full-length (GHRfl) or exon 3 deleted (GHRd3). An association of these isoforms has been found with small for gestational age (SGA) infants but does not influence adult height. The role of this polymorphism in the birth size spectrum in the general population is unclear

Implications of the Cosmic Background Imager Polarization Data

We present new measurements of the power spectra of the E-mode of CMB polarization, the temperature T, the cross-correlation of E and T, and upper limits on the B-mode from 2.5 years of dedicated Cosmic Background Imager (CBI) observations. Both raw maps and optimal signal images in the uv-plane and real space show strong detections of the E-mode (11.7 sigma for the EE power spectrum overall) and no detection of the B-mode. The power spectra are used to constrain parameters of the flat tilted adiabatic Lambda-CDM models: those determined from EE and TE bandpowers agree with those from TT, a powerful consistency check. There is little tolerance for shifting polarization peaks from the TT-forecast locations, as measured by the angular sound crossing scale theta = 100 ell_s = 1.03 +/- 0.02 from EE and TE cf. 1.044 +/- 0.005 with the TT data included. The scope for extra out-of-phase peaks from subdominant isocurvature modes is also curtailed. The EE and TE measurements of CBI, DASI and BOOMERANG are mutually consistent, and, taken together rather than singly, give enhanced leverage for these tests.Comment: 15 pages, 9 figures, submitted to ApJ -- Accepted version. The fine-bin spectrum, covariance matrix, and window functions are now available on the web (suitable for use in COSMOMC) at: http://www.astro.caltech.edu/~tjp/CBI/data2006/index.html The pipeline in the previous version inadvertently omitted one antenna, so the new spectrum contains ~15% more data. We emphasize that previous results were in no way biased, and that the (small) changes to the spectrum solely reflect the inclusion of the additional data. Numbers and figures in the paper have been updated correspondingly. All maps now have color bar

Birth after TESE–ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation

DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12–40) with low FSH and LH levels at 2.1 IU/l (N: 1–5 IU/l) and 0.1 IU/l (N: 1–4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur®:150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen–thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE–ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH