Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure

Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46, XY patient with a homozygous disruption of CYP11A1.The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation.Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned

The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency

OBJECTIVE. Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias. DESIGN AND METHODS. Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network. RESULTS. Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients. CONCLUSIONS. SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common

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

Characteristics and outcome of 16 periprosthetic shoulder joint infections

Purpose: Shoulder arthroplasties are increasingly performed, but data on periprosthetic joint infections (PJI) in this anatomical position are limited. We retrospectively investigated the characteristics and outcome of shoulder PJI after primary arthroplasty from 1998 to 2010 in a single centre. Methods: Periprosthetic joint infection was defined as periprosthetic purulence, presence of sinus tract or microbial growth. A Kaplan-Meier survival method was used to estimate relapse-free survival of prosthesis. Results: From 1,571 primary shoulder prostheses, we evaluated 16 patients with a PJI at different stages, i.e, early (n=4), delayed (n=6) and late (n=6) infections. The median patient age was 67 (range 53-86) years, and 69% were females. The most commonly isolated microorganism was Propionibacterium acnes in 38% of patients (monobacterial in four and polymicrobial in two patients). In 14 of the 16 patients, surgical interventions consisting of debridement and implant retention (6 patients), exchange (7) and explantation (1) were performed. Four patients had a relapse of infection with P. acnes (n=3) or Bacteroides fragilis (n=1). The relapse-free survival of the prosthesis was 75% (95% confidence interval 46-90%) after 1 and 2years, 100% in six patients following the treatment algorithm for hip and knee PJI and 60% in 10 patients not followed up. All but one of the relapses were previously treated without exchange of the prosthesis. Conclusions: As recommended for hip and knee PJI, we suggest treating shoulder PJI with a low-grade infection by microorganisms such as P. acnes with an exchange of the prosthesis. Cohort studies are needed to verify our result

Genetic disorders of nuclear receptors.

Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis

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

Perioperative Antibiotikaprophylaxe bei elektiver Gelenkprothesenimplantation

Eine Gelenkprotheseninfektion ist eine schwerwiegende Komplikation, die nach einer Gelenkprothesenimplantation auftreten kann. Zu den Präventionsmassnahmen einer Infektion gehört eine Palette von Massnahmen wie zum Beispiel prä- und postoperative Checklisten, sorgfältige Operationspräparation, Haarentfernung und Hautdesinfektion, strikte Hygienemassnahmen, eine gute chirurgische Technik mit ­kurzer Operationsdauer, postoperativ Entfernen von Urinkatheter und eine korrekte Wundpflege nach Operation. Eine systemische präoperative Antibiotikaprophylaxe (AMP) ist ein Faktor, der zu diesen zahlreichen Präventionsmassnahmen gehört. SWISSNOSO veröffentlichte Richtlinien zu Verantwortlichkeiten und Ablauf der Verabreichung der AMP in den Jahren 2015 [1] und 2018 [2]. Deren Empfehlungen für den Fachbereich Orthopädie und Traumatologie des Bewegungsapparates sind in den Tabellen 1a und 1b wiedergegeben

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