Variable presentation and outcomes of primary hyperparathyroidism in children and adolescents.

OBJECTIVES: Primary hyperparathyroidism (PHPT) in paediatric and adolescent age group presents with some unique challenges for clinicians. While the disease in the adult counterparts presents with symptoms which are described quite extensively in literature, children/adolescents have manifestations which are quite different and severe compared to the former. The present case series aimed to highlight the peculiarities of presentation of PHPT in children and adolescents. CASE PRESENTATION: In this case series, we present experience of 5 cases of PHPT in children and adolescents from our centre. We compared our data with the data already available in literature. We have also described salient presenting features of PHPT in individuals less than 19 years old previously reported in literature and pointed out the specificities of this disease at this age group. CONCLUSIONS: PHPT in children and adolescents should be considered as a separate entity compared to that in adults, given its unique features, such as rachitic features, and severity of different presenting phenotypes. Persistence of rachitic features despite vitamin D correction, pancreatitis, bilateral nephrolithiasis and otherwise unexplained psychiatric abnormalities of insidious onset require greater clinical vigilance and serum/urine calcium testing to rule out this uncommon yet possible entity.

Rickets in proximal renal tubular acidosis: a case series of six distinct etiologies.

OBJECTIVES: Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. CASE PRESENTATION: We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. CONCLUSIONS: Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA.

A Rare Differences of Sex Development: Male Sex Reversal Syndrome (NonSyndromic 46, XX with Negative Sex-Determining Region of Y Chromosome Gene).

46, XX testicular differences of sex development (DSD) is a rare cause of DSD presenting as a phenotypical male with chromosomal sex of 46, XX. Sex-determining region of the Y chromosome (SRY)-positive 46, XX DSDs have a well-characterized pathogenetic mechanism, whereas in SRY-negative 46, XX DSDs, the pathogenesis is not clearly delineated. Herein, we present a case of a 3½-year-old child who presented with ambiguous genitalia and bilateral palpable gonads. On the basis of a karyotype and fluorescent in situ hybridization, we arrived at a diagnosis of SRY-negative 46, XX testicular DSD. Basal serum estradiol and human menopausal gonadotrophin stimulated estradiol levels and inhibin A blood levels were against the presence of any ovarian tissue. Imaging of the gonads showed bilateral normal-looking testis. A clinical exome sequencing revealed a heterozygous missense variant NR5A1:c275G>A (p. Arg92gln) located at exon 4 in the affected child. Protein structure analysis was further performed, and the variant was found to be highly conserved. Sanger's sequencing showed that the mother was heterozygous for the variant detected in the child. This case highlights the rarity of SRY-negative 46, XX testicular DSD with a unique variant. Largely under characterized, this group of DSDs needs to be reported and analyzed to add to the spectrum of presentation and genetic characteristics. Our case is expected to add to the database, knowledge, and approach to cases of 46, XX testicular DSD.

Glial Cell Missing Homolog 2 Mutation Causing Severe Hypoparathyroidism: Report of Two Cases With Novel Mutations.

Hypoparathyroidism is a common encounter in endocrinology practice. A thorough search for the etiology is generally futile, and most cases are labeled as idiopathic. Familial idiopathic hypoparathyroidism is a large chunk of these idiopathic cases. Here we present 2 cases who presented with features of hypocalcemia and were eventually diagnosed with hypoparathyroidism. Our first case is that of a middle-age woman who presented with spontaneous tetany and perioral numbness. She had very low serum calcium values, low serum magnesium, hypokalemia, hypercalciuria, and undetectable parathormone levels. She was initially managed with parenteral calcium, magnesium, and oral potassium chloride, which was shifted to oral replacements once stabilized. Focused exome sequencing for causes of hypoparathyroidism and hypocalcemia revealed a frameshift mutation in glial cell missing homolog 2 (GCM2) (NM_004752.4) on chromosome 6, c737dupA variant (p. Asp246Glufs*25) located at exon 5. The second case presented is that of a 1-month-old infant presenting with hypocalcemic seizures, severe hypocalcemia, hyperphosphatemia, and low parathormone levels. The infant was stabilized with parenteral calcium and trial of subcutaneous teriparatide for further improvement. Oral calcium and calcitriol were instituted once stabilized, and teriparatide was tapered off. Focused exome sequencing revealed a homozygous mutation involving GCM2 (ENST0000379491.5) on chromosome 6, variant CM2 chr6:10876558_10877139insT located on exon1-2. Both of these mutations are novel and underscore the profound effect of GCM2 on parathyroid gland development in infants and maintenance in adults.

Renal Tubular Acidosis Presenting as Nephrogenic Diabetes Insipidus.

BACKGROUND: Nephrogenic diabetes insipidus (DI) can be primary or secondary to various causes. CASE CHARACTERISTICS: One child with Fanconi syndrome with proximal renal tubular acidosis (RTA) due to nephropathic cystinosis, and other with Distal RTA with hearing loss. OBSERVATION: Both cases showed features of nephrogenic DI, which resolved after treating the primary pathology. MESSAGE: Renal Tubular acidosis may cause nephrogenic DI.

Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function.

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 µM versus 6.4 ± 1.2 µM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.

Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: safety summary.

The novel oxazolidinone tedizolid phosphate is in late-stage clinical development. In an effort to improve efficacy and safety, the adverse event profile and safety aspects of tedizolid phosphate have been evaluated in several preclinical animal models and through ongoing clinical trials. Early dose-ranging studies demonstrated a favorable overall adverse event profile and low thrombocytopenia rates, which have been consistently confirmed in phase 2 and 3 clinical trials. Pharmacokinetic modeling suggests a lower potential for monoamine oxidase interaction, and animal and human subject testing has confirmed these predictions. Studies in special patient populations showed a consistent and predictable pharmacokinetic profile across age groups and comorbid conditions, without evidence of increased incidence of adverse effects over matched controls. The favorable safety profile makes tedizolid phosphate an important new option for the management of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus.

Activity of ceftaroline against extracellular (broth) and intracellular (THP-1 monocytes) forms of methicillin-resistant Staphylococcus aureus: comparison with vancomycin, linezolid and daptomycin.

BACKGROUND: Ceftaroline fosamil is approved for treatment of acute bacterial skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We examined the activity of its active metabolite (ceftaroline) against intracellular forms of S. aureus in comparison with vancomycin, daptomycin and linezolid. METHODS: Two methicillin-susceptible S. aureus (MSSA) and 11 MRSA strains with ceftaroline MICs from 0.125 to 2 mg/L [two strains vancomycin- and one strain linezolid-resistant (EUCAST interpretative criteria); VISA and cfr+] were investigated. The activity was measured in broth and after phagocytosis by THP-1 monocytes in concentration-dependent experiments (24 h of incubation) to determine: (i) relative potencies (EC(50)) and static concentrations (C(s)) (mg/L and × MIC); and (ii) relative activities at human C(max) (E(C)(max)) and maximal relative efficacies (E(max)) (change in log(10) cfu compared with initial inoculum). Ceftaroline stability and cellular accumulation (at 24 h) were measured by mass spectrometry. RESULTS: Ceftaroline showed similar activities in broth and in monocytes compared with vancomycin, daptomycin and linezolid, with no impact of resistance mechanisms to vancomycin or linezolid. For all four antibiotics, intracellular E(C)(max) and E(max) were considerably lower than in broth (∼0.5 log(10) versus 4-5 log(10) cfu decrease), but the EC(50) and C(s) showed comparatively little change (all values between ∼0.3 and ∼6× MIC). The mean cellular to extracellular ceftaroline concentration ratios (20 mg/L; 24 h) were 0.66 ± 0.05 and 0.90 ± 0.36 in uninfected and infected cells, respectively. CONCLUSION: In vitro, ceftaroline controls the growth of intracellular MRSA to an extent similar to that of vancomycin, linezolid and daptomycin for strains with a ceftaroline MIC ≤ 2 mg/L.

Contribution of Catalase and Superoxide Dismutase to the Intracellular Survival of Clinical Isolates of Staphylococcus aureus in Murine Macrophages.

The present study was performed in order to carefully investigate the interaction of Staphylococcus aureus with murine macrophages and the contribution of catalase and superoxide dismutase in intracellular persistence of Staphylococcus aureus within murine macrophages during in vitro infection. We have reported that Staphylococcus aureus internalized by murine macrophages did not appear to be rapidly killed. Data indicating the contribution of a single catalase and superoxide dismutase in intracellular survival of Staphylococcus aureus were provided using established biochemical assays. The results of the present experiment suggest that the survival of Staphylococcus aureus within phagocytic cells is facilitated by its ability to resist oxidative products. Organisms in the log phase of growth clearly demonstrate a resistance to oxidative products.

Staphylococcal catalase protects intracellularly survived bacteria by destroying H2O2 produced by the murine peritoneal macrophages.

To determine the interrelationship between the hydrogen peroxide (H(2)O(2)) mediated killing and the potential role of bacterial catalase and SOD in the evasion of host defense, we examined three clinical isolates of Staphylococcus aureus and evaluated their intracellular survival mechanism within murine peritoneal macrophages. Fluorescent microscopy and bacterial colony-forming unit (cfu) count revealed that phagocytic capacity of murine peritoneal macrophages was highest after 2h of in vitro infection with S. aureus. To understand whether catalase and SOD contributing in the intracellular survival, were of bacterial origin or not, 3 amino 1,2,4 triazole (ATZ) and Diethyldithiocarbamic acid (DDC) were used to inhibit specifically macrophage derived catalase and SOD respectively. Catalase activity from the whole staphylococcal cell in presence of ATZ suggested that the released catalase were of extracellular origin. Scanning electron microscopy revealed the degraded host cell membrane integrity during prolonged infection. Purified bacterial catalase from the intracellularly survived S. aureus recovered after 5h of infection and its inhibition by ATZ in the zymography strengthened the scope of involvement of these anti-oxidants in the intracellular survival of S. aureus.

Staphylococcal catalase regulates its virulence and induces arthritis in catalase deficient mice.

To figure out whether in vivo expression of Staphylococcal catalase could correlate with the virulence and pathogenicity of the bacteria in the catalase deficient Swiss albino mice. 3 Amino 1, 2, 4 triazole (ATZ) (2 mg/g body wt) treated catalase deficient mice were infected with virulent S. aureus and bacterial burden, antioxidant enzyme levels were estimated after 3, 5 and 10 days of infection. Arthritic scores and levels of serum uric acid in mice were also determined. ATZ treatment was found to have slowed down the clearance of bacteria from blood and their rapid elimination from spleen. Increased tissue catalase activities in the spleen and liver of ATZ pre-treated mice even after 5 days of infection suggested its bacterial origin. It was further verified by zymographic analysis. Increased swelling of joints was observed after 5 days of infection. Uric acid level was found lesser in ATZ treated mice. ATZ treatment slowed the bacterial passage from blood with a lower tissue anti-oxidant enzymes leading to induction of joint inflammation.