A Case Report of Compound Heterozygous CYP24A1 Mutations Leading to Nephrolithiasis Successfully Treated with Ketoconazole.

CYP24A1 is an enzyme that inactivates vitamin D. Loss-of-function mutations in this enzyme are rare but have been linked with idiopathic infantile hypercalcemia as well as adult-onset nephrocalcinosis and nephrolithiasis. Genetic testing for this mutation should be considered in the presence of calciuria, elevated serum calcium, elevated 1,25-dihydroxyvitamin D, and suppressed parathyroid hormone. We present a case with these lab findings as well as an elevated 25-hydroxyvitamin D/24,25-dihydroxyvitamin D ratio in whom compound heterozygous CYP24A1 mutations were found. His hypercalciuria resolved and 1,25-vitamin D level improved with ketoconazole treatment. We suggest that it is clinically important to identify patients with this phenotype as testing and treatment options are available which could reduce progression to chronic kidney disease in this population.

Paul Ehrlich's mastzellen: a historical perspective of relevant developments in mast cell biology.

Following the discovery of mast cells (or mastzellen) by the prolific physician researcher, Paul Ehrlich, many advances have improved our understanding of these cells and their fascinating biology. The discovery of immunoglobulin E and receptors for IgE and IgG on mast cells heralded further in vivo and in vitro studies, using molecular technologies and gene knockout models. Mast cells express an array of inflammatory mediators including tryptase, histamine, cytokines, chemokines, and growth factors. They play a role in many varying disease states, from atopic diseases, parasitic infections, hematological malignancies, and arthritis to osteoporosis. This review will attempt to summarize salient evolving areas in mast cell research over the last few centuries that have led to our current understanding of this pivotal multifunctional cell.

Intravenous immunoglobulin as a potential therapy for refractory urticaria - a review.

Urticaria can be a chronic and debilitating affliction and is a relatively common disorder affecting between 10- 20% of the population. Common causes include reactions to medication, food allergen, physical stimuli and venoms. Urticaria can be acute or chronic. Chronic urticaria lasts for more than 6 weeks and is commonly difficult to treat. The use of immunosuppressive agents for this disorder when antihistamines fail can result in significant morbidity. Recent advances in the pathogenesis, etiology, diagnosis and management of chronic urticaria have led to new paradigms in treatment of this disorder. Cyclosporine is often the most effective but has some unique adverse effects that may prevent it from being used in some patients. The use of intravenous immunoglobulin (IVIG) has proven effective in a variety of reports and we will review the mechanisms likely involved in the successful control of urticarial symptoms by immunomodulating therapy using IVIG. In this review, we will discuss mechanisms and pathogenesis of urticaria and the specific role of intravenous immunoglobulin (IVIG) in this disorder, especially in refractory or steroid-dependent cases.

Concomitant gene mutations of MBL and CYBB in chronic granulomatous disease: implications for host defense.

Chronic granulomatous disease (CGD) is associated with defective function of the NADPH-oxidase system in conjunction with phagocytic defects which leads to granuloma formation and serious infectious complications. This is often associated with significant morbidity and mortality. The association of defective phagocyte function with other coincidental immune defects is unknown. Defects in innate pathways seen with CGD, including complement systems, and toll-like and dectin receptor pathways, have not been described before. We present the case of a 2-year old male patient hospitalized with recurrent pneumonia, a non-healing skin ulcer, necrotizing lung granulomas, and epididymo-orchitis. Defective neutrophil chemiluminescence was detected by dihydrorhodamine (DHR) testing. Further evaluation demonstrated characteristic molecular mutations of CYBB consistent with CGD. Immune evaluation demonstrated polyclonal hyperglobulinemia, but a greatly reduced mannose binding lectin (MBL) level. Six biallelic polymorphisms in MBL gene and its promoter were analyzed using Light CyclerTM Real-time PCR assay. The LXPA/LYPB haplotype of MBL was detected in our patient; the latter is the defective haplotype associated with low MBL levels. Due to the implications for innate immunity and the protection against bacterial, viral, and fungal infections provided by MBL, a deficiency of this protein may have disastrous consequences on the long term outcomes of CGD. MBL deficiency can also complicate other disorders affecting the immune system, significantly increasing the risk of infection in such patients. Further studies looking at the frequency and implications of MBL deficiency in CGD are needed.