A 6-month-old, neutered male, mixed-breed dog was examined for a 2-month persistent fever, nonhealing dermal metacarpal area wound, and leukocytosis (47.0-198.0 × 10(3)/μl). Serum chemistry findings included hypoalbuminemia, hyperglobulinemia, hyperphosphatemia, and hyperphosphatasemia. Complete blood cell count results revealed a moderate microcytic, hypochromic nonregenerative anemia with a profound leukocytosis (198.5 × 10(3)/μl), characterized by neutrophilia with toxicity and hypersegmentation, and significant band cells. Tick-borne disease titers (genera Anaplasma, Ehrlichia, and Borrelia) were negative, as were polymerase chain reaction for other infectious agents (genera Hepatozoon, Mycobacterium, Mycoplasma; and Canine distemper virus). No agents were identified in a deep dermal biopsy (conventional and special histochemical stains) of the chronic draining, metacarpal region lesion. Cytology of the draining tract revealed numerous mixed bacteria and a surprising lack of neutrophils. Chronic occult blood loss with iron deficiency was considered a possible cause of the anemia. Differentials for the leukon were chronic established inflammation (occult infectious agent), chronic neutrophilic leukemia, paraneoplastic leukocytosis (neoplastic source of granulocyte colony-stimulating factor [CSF] or granulocyte-macrophage CSF), and leukocyte adhesion deficiency (LAD). The possibility of a LAD disorder was further investigated because of the noted hypersegmented neutrophils, absence of neutrophils in the cytology sample, the animal's young age, and persistence of clinical and laboratory signs. Flow cytometry of blood neutrophils showed a 60% reduction in surface expression of the β2-integrin (CD18) subunit, whereas neutrophil function tests (oxidative burst and phagocytosis) were normal. Genetic testing revealed a homozygous missense mutation in the β2-integrin subunit gene, previously recognized only in purebred Irish Setters, leading to a diagnosis of LAD type 1 disorder in this mixed-breed dog.

To describe a case of hypocalcemia in a patient with a gain-of-function mutation in the calcium-sensing receptor that was undetected until adulthood and successfully treated with recombinant parathyroid hormone.The clinical findings, laboratory data, and a review of the pertinent literature are presented.A 55-year-old woman was hospitalized and seen by the endocrinology consult service for hypocalcemia that was refractory to repeated doses of intravenous calcium gluconate. She expressed concern about chronic leg muscle cramps and paresthesias of the lips and fingertips. In addition, she had no history of neck surgery, neck irradiation, or any autoimmune disease. She was a well-appearing female with no dysmorphic features or skin changes. Laboratory tests revealed hypocalcemia, hyperphosphatemia, hypomagnesemia, and hypovitaminosis D. Her parathyroid hormone concentration (PTH) was low at 14.2 pg/mL. Her PTH and calcium concentrations remained low despite repletion of magnesium and treatment with calcitriol and oral calcium replacement. A 24-hour collection for urinary calcium showed inappropriate hypercalciuria. Medical records showed her hypocalcemia to be chronic. Additionally, several family members had also complained of muscle cramps. A congenital cause of her hypoparathyroidism was considered, and genetic testing confirmed heterozygosity for a gain-of-function mutation in the calcium-sensing receptor gene associated with autosomal dominant familial isolated hypoparathyroidism (ADH). Treatment with subcutaneous recombinant human parathyroid hormone teriparatide (rhPTH [1-34]) 20 mcg twice daily for three days normalized her calcium and phosphorus concentrations.rhPTH (1-34) is an effective treatment for patients with hypoparathyroidism due to gain-of-function mutations in the calcium-sensing receptor. ADH can be insidious in presentation and the diagnosis can be missed unless there is a high index of suspicion.

Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare genetic disorder characterized by hypocalcemia and hyperphosphatemia due to imprinting defects in the maternally derived GNAS allele. Patients with PHP-Ib are usually identified by tetany, convulsions, and/or muscle cramps, whereas a substantial fraction of patients remain asymptomatic and are identified by familial studies. Although previous studies on patients with primary hypoparathyroidism have indicated that hypocalcemia can be associated with various neuromuscular abnormalities, such clinical features have been rarely described in patients with PHP-Ib. Here, we report a 12-year-old male patient with familial PHP-Ib and unique neuromuscular symptoms. The patient presented with general fatigue, steppage gait, and myalgia. Physical examinations revealed muscular weakness and atrophies in the lower legs, a shortening of the bilateral Achilles' tendons and absence of deep tendon reflexes. Laboratory tests showed hypocalcemia, hyperphosphatemia, elevated serum intact PTH level, and impaired responses of urinary phosphate and cyclic AMP in an Ellsworth-Howard test, in addition to an elevated serum creatine kinase level. Clinical features of the patient were significantly improved after 1 month of treatment with alfacalcidol and calcium. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and subsequent PCR analyses identified a methylation defect at exon A/B of GNAS and a microdeletion involving exons 4-6 of the GNAS neighboring gene STX16 in the patient and in his asymptomatic brother. The results suggest that various neuromuscular features probably associated with hypocalcemia can be the first symptoms of PHP-Ib, and that MS-MLPA serves as a powerful tool for screening of GNAS abnormalities in patients with atypical manifestations.

To analyze the clinical characteristics, diagnosis and treatment of pseudohypoparathyroidism (PHP).The clinical data of 15 patients with pseudohypoparathyrodism (including 9 male and 6 female patients) admitted in our hospital between January, 1990 and July, 2011 were reviewed.The disease course of the patients ranged from 3 days to 21 years, and such symptoms of tetany and fatigue were found in all the patients. Most of the patients had a history of seizures. Laboratory tests suggested commonly low serum calcium, hyperphosphatemia, and parathyroid hormone (PTH) elevation. Head CT indicated multiple intracranial calcifications in 9 cases, and abnormal thyroid function was found in 4 cases. No specific treatment was available for this disease, and life-long calcium and vitamin D supplementation was advised to prevent acute attacks and disease progression.PHP is a rare genetic disease with a high rate of misdiagnosis in initial diagnosis. For repeated tetany and epileptic attacks and children with congenital developmental defects, examinations of blood calcium, phosphorus, and PTH and brain CT should be ordered as soon as possible. Long-term calcium and vitamin D supplementation is suggested for the treatment, and the presence of concomitant thyroid dysfunction or hypogonadism necessitates corresponding treatments.

A 33-day-old female with an ulcerated infantile hemangioma (IH) undergoing oral therapy with propranolol 2 mg/kg per day developed hyperkalemia and hyperphosphatemia 24 h after starting medication. No electrocardiographic or clinical abnormalities secondary to the electrolyte changes were noticed. A laboratory tumor lysis syndrome (TLS) was diagnosed after excluding other causes of electrolyte imbalance in the diagnostic workup. No treatment was required to reverse the TLS condition, and the propranolol therapy was continued as the electrolyte alterations were only mild. One month later, the IH was remarkably reduced in size and no longer ulcerated. Maintenance of propranolol was extended for a total of 6 months. Parallel to the gradual involution of the IH, serum potassium and phosphorus levels returned within normal levels. We suggest that TLS may be a rare complication of ulcerated IH treated with propranolol. Clinicians must be aware and order appropriate screening tests for TLS in patients at risk.

Maximum contaminant levels are used to control potential health hazards posed by chemicals in drinking water, but no primary national or international limits for aluminum (Al) have been adopted. Given the differences in toxicological profiles, the present evaluation derives total allowable concentrations for certain water-soluble inorganic Al compounds (including chloride, hydroxide, oxide, phosphate and sulfate) and for the hydrated Al silicates (including attapulgite, bentonite/montmorillonite, illite, kaolinite) in drinking water. The chemistry, toxicology and clinical experience with Al materials are extensive and depend upon the particular physical and chemical form. In general, the water solubility of the monomeric Al materials depends on pH and their water solubility and gastrointestinal bioavailability are much greater than that of the hydrated Al silicates. Other than Al-containing antacids and buffered aspirin, food is the primary source of Al exposure for most healthy people. Systemic uptake of Al after ingestion of the monomeric salts is somewhat greater from drinking water (0.28%) than from food (0.1%). Once absorbed, Al accumulates in bone, brain, liver and kidney, with bone as the major site for Al deposition in humans. Oral Al hydroxide is used routinely to bind phosphate salts in the gut to control hyperphosphatemia in people with compromised renal function. Signs of chronic Al toxicity in the musculoskeletal system include a vitamin D-resistant osteomalacia (deranged membranous bone formation characterized by accumulation of the osteoid matrix and reduced mineralization, reduced numbers of osteoblasts and osteoclasts, decreased lamellar and osteoid bands with elevated Al concentrations) presenting as bone pain and proximal myopathy. Aluminum-induced bone disease can progress to stress fractures of the ribs, femur, vertebrae, humerus and metatarsals. Serum Al ≥100 µg/L has a 75-88% positive predictive value for Al bone disease. Chronic Al toxicity is also manifest in the hematopoietic system as an erythropoietin-resistant microcytic hypochromic anemia. Signs of Al toxicity in the central nervous system (speech difficulty to total mutism to facial grimacing to multifacial seizures and dyspraxia) are related to Al accumulation in the brain and these symptoms can progress to frank encephalopathy. There are four groups of people at elevated risk of systemic Al intoxication after repeated ingestion of monomeric Al salts: the preterm infant, the infant with congenital uremia and children and adults with kidney disease. There is a dose-dependent increase in serum and urinary Al in people with compromised renal function, and restoration of renal function permits normal handling of systemically absorbed Al and resolution of Al bone disease. Clinical experience with 960 mg/day of Al(OH)(3) (~5 mg Al/kg-day) given by mouth over 3 months to men and women with compromised renal function found subclinical reductions in hemoglobin, hematocrit and serum ferritin. Following adult males and females with reduced kidney function found that ingestion of Al(OH)(3) at 2.85 g/day (~40 mg/kg-day Al) over 7 years increased bone Al, but failed to elicit significant bone toxicity. There was one report of DNA damage in cultured lymphocytes after high AlCl(3) exposure, but there is no evidence that ingestion of common inorganic Al compounds presents an increased carcinogenic risk or increases the risk for adverse reproductive or developmental outcomes. A number of studies of Al exposure in relation to memory in rodents have been published, but the results are inconsistent. At present, there is no evidence to substantiate the hypothesis that the pathogenesis of Alzheimer's Disease is caused by Al found in food and drinking water at the levels consumed by people living in North America and Western Europe. Attapulgite (palygorskite) has been used for decades at oral doses (recommended not to exceed two consecutive days) of 2,100 mg/day in children of 3-6 years, 4,200 mg/day in children of 6-12 years, and 9,000 mg/day in adults. Chronic ingestion of insoluble hydrated Al silicates (in kg) can result in disturbances in iron and potassium status, primarily as a result of clay binding to intestinal contents and enhanced fecal iron and zinc elimination. Sufficiently high doses of ingested Al silicates (≥50 g/day) over prolonged periods of time can elicit a deficiency anemia that can be corrected with oral Fe supplements. There is essentially no systemic Al uptake after ingestion of the hydrated Al silicates. Rats fed up to 20,000 ppm Ca montmorillonite (equivalent to 1,860 ppm total Al as the hydrated Al silicate) for 28 weeks failed to develop any adverse signs. The results of dietary Phase I and II clinical trials conducted in healthy adult volunteers over 14 days and 90 days with montmorillonite found no adverse effects after feeding up to 40 mg/kg-day as Al. Since the Al associated with ingestion of hydrated Al silicates is not absorbed into the systemic circulation, the hydrated Al silicates seldom cause medical problems unless the daily doses consumed are substantially greater than those used clinically or as dietary supplements. A no-observable-adverse-effect-level (NOAEL) of 13 mg/kg-day as total Al can be identified based on histologic osteomalacia seen in adult hemodialysis patients given Al hydroxide for up to 7 years as a phosphate binder. Following U.S. EPA methods for calculation of an oral reference dose (RfD), an intraspecies uncertainty factor of 10x was applied to that value results in a chronic oral reference dose (RfD) of 1.3 mg Al/kg-day; assuming a 70-kg adult consumes 2 L of drinking water per day and adjusting for a default 20% relative source contribution that value corresponds to a drinking water maximum concentration of 9 mg/L measured as total Al. A chronic NOAEL for montmorillonite as representative of the hydrated Al silicates was identified from the highest dietary concentration (20,000 ppm) fed in a 28-week bioassay with male and female Sprague-Dawley rats. Since young rats consume standard laboratory chow at ~23 g/day, this concentration corresponds to 56 mg Al/kg-day. Application of 3x interspecies uncertainty factor and a 3x factor to account for study duration results in a chronic oral RfD of 6 mg Al/kg-day. Of note, this RfD is 5-10 fold less than oral doses of Al silicates consumed by people who practice clay geophagy and it corresponds to a maximum drinking water concentration of 40 mg Al/L. To utilize the values derived here, the risk manager must recognize the particular product (e.g., alum) or source (e.g., groundwater, river water, clay or cement pipe) of the Al found in tap water, apply the appropriate analytical methods (atomic absorption, energy dispersive X-ray diffraction, infrared spectral analysis and/or scanning transmission electron microscopy) and compare the results to the most relevant standard. The drinking water concentrations derived here are greater than the U.S. EPA secondary maximum contaminant level (MCL) for total Al of 0.05-0.2 mg/L [40 CFR 143.3]. As such, domestic use of water with these concentrations is likely self-limiting given that its cloudy appearance will be greater than the maximum permitted (0.5-5.0 nephalometric turbidity units; 40 CFR Parts 141 and 142). Therefore, the organoleptic properties of Al materials in water determine public acceptance of potable water as contrast to any potential health hazard at the concentrations ordinarily present in municipal drinking water.

Lanthanum carbonate (FOSRENOL®) is an effective, well-tolerated phosphate binder. The ability of lanthanum to reduce serum phosphorus levels to ≤5.5 mg/dL in patients with end-stage renal disease (ESRD) was assessed in a clinical practice setting.A 16-week, phase IV study enrolled 2763 patients at 223 US sites to evaluate the efficacy of lanthanum carbonate in controlling serum phosphorus in patients with ESRD, and patient and physician satisfaction with, and preference for, lanthanum carbonate after conversion from other phosphate-binder medications. Patients received lanthanum carbonate prescriptions from physicians. These prescriptions were filled at local pharmacies rather than obtaining medication at the clinical trial site. Changes from serum phosphorus baseline values were analyzed using paired t tests. Patient and physician preferences for lanthanum carbonate versus previous medications were assessed using binomial proportion tests. Satisfaction was analyzed using the McNemar test. Daily dose, tablet burden, and laboratory values including albumin-adjusted serum calcium, calcium × phosphorus product, and parathyroid hormone levels were secondary endpoints.Serum phosphorus control (≤5.5 mg/dL) was effectively maintained in patients converting to lanthanum carbonate monotherapy; 41.6% of patients had controlled serum phosphate levels at 16 weeks. Patients and physicians expressed markedly higher satisfaction with lanthanum carbonate, and preferred lanthanum carbonate over previous medication. There were significant reductions in daily dose and daily tablet burden after conversion to lanthanum carbonate.Serum phosphorus levels were effectively maintained in patients converted from other phosphate-binder medications to lanthanum carbonate, with increased satisfaction and reduced tablet burden.ClinicalTrials.gov: NCT0016012.

Calcific uremic arteriolopathy is defined as a syndrome consisting of ischemic skin ulceration due to calcification of the wall of the arterioles of the subcutaneous tissue as a result of hyperparathyroidism in uremic patients.A 55-year old female patient, hypertense, with heart failure and kidney failure treated with hemodialysis, who presented lower limb pain and hypercalcemia. On physical examination, skin lesions with symmetrical peripheral pulses present in the limbs. Laboratory tests revealed hypercalcemia, hyperphosphatemia, and very high parathyroid hormone levels. Parathyroidectomy was performed and biopsy of skin lesions, the patient having a torpid course causing exitus. Autopsy was performed, with histologic features characteristic of calcific uremic arteriolopathy.Calcific calcium uremic arteriolopathy or calciphylaxis is a complex and variable disease that is difficult to diagnose and whose treatment is complicated. Despite the efforts of the investigators, there are still many questions regarding its pathogenesis. This acts as an incentive for further research to establish the most appropriate actions to take to maintain an adequate quality of life for the patients and avoid complications that trigger death in some cases.

Hypoparathyroidism refers to a group of disorders in which extracellular calcium levels cannot be maintained within the normal range due to relative or absolute deficiency of parathyroid hormone (PTH). The clinical features of hypoparathyroidism are consistent with hypocalcaemia and, predominantly, neuromuscular dysfunction. Although hypocalcaemia-induced seizures are well documented hypoparathyroidism-induced epilepsy is often misdiagnosed as idiopathic epilepsy.We reported a 57-year-old woman with new-onset seizure due to hypoparathyroidism. At first, diagnosis of epilepsy was established and the antiepileptic therapy was initiated with gradual increase of the dose. Computerized tomography scan of the head revealed bilateral basal ganglia and cerebellar calcification and many punctiform calcifications between cortical and subcortical parts. During hospitalization, laboratory tests showed hypocalcemia, hyperphosphatemia and low PTH level. Once the diagnosis of hypoparathyroidism was established, a proper treatment with calcium and vitamin D was started, and the patient was discharged from hospital with full seizure control.Standard evaluation of serum calcium levels in patients with new-onset epileptic seizures should be obligatory part of a diagnostic algoritam to avoid misdiagnosis of idiopathic epilepsy.

INTRODUCTION:

Paget's disease is a chronic metabolic condition characterized by a local imbalance between the resorbing activity of osteoclasts and the osteogenic activity of osteoblasts which leads to the remodeling of bone tissue with richly vascularised foci of loose and compact bone. The disease usually affects the elderly and males predominate. Lesions generally occur in pelvic bones, bodies of lumbar vertebrae, femoral bones, skull, and tibiae. Symptoms depend on the extent of lesions and include pain caused by microfractures or secondary degenerative-productive lesions, warmth in the affected area, bone deformations, fractures, neurological symptoms in the form of compressive or ischemic radiculopathy or compression of cranial nerves, and external carotid steal syndrome with increased flow through the affected bone. The natural course of the disease can be divided into the following stages: hot (prevalence of increased bone resorption); mixed (bone destruction is accompanied by formation of new bone); cold (predominance of osteoblast activity, diffuse enhancement of bone density, bone enlargement and expansion). Laboratory tests reveal higher levels of markers of bone formation (alkaline phosphatase, N-telopeptide alkaline phosphatase, osteocalcin) and markers of bone resorption (telopeptide of type 1 collagen, hydroxyproline in urine). Radiology of long bones shows the coexistence of foci of compact and loose bone tissue. The spine reveals picture-frame vertebral bodies with increased anteroposterior dimension and sclerotic remodeling, Thickening of the skull cap is noted. Paget's disease should be differentiated with fibrous dysplasia of bone, hyperparathyroidism, 'juvenile Paget's disease' (familial idiopathic hyperphosphatemia), lymphoma, and metastatic cancer. Salmon calcitonin represented a breakthrough in therapy. Today, bisphosphonates are recommended to treat Paget's disease.

CASE REPORT:

We present the case of a 50-year-old female who underwent physical examination in January 2011 and was diagnosed with a bone tumor of the skull cap in the right forehead area. X-ray showed osteosclerosis of the skull suggesting Paget's disease. The patient was admitted in March 2011 to the Department of Hematology where multiple myeloma was excluded. Diagnosis was reattempted in January of 2012 at the Clinical Unit of Rheumatology and Connective Tissue Diseases, Second University Hospital in Bydgoszcz. During her stay at the hospital, several laboratory tests (alkaline phosphatase, calcium, parathyroid hormone, osteocalcin, telopeptide of type 1 collagen), together with radiographs of the skull, forearm, pelvis, and lower leg provided ground for the diagnosis of Paget's disease. The patient was qualified for treatment with ibandronic acid.