Periarticular Hyperphosphatemic Familial Tumoral Calcinosis in a Saudi Patient: A Case Report

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, autosomal recessive condition characterized by fibroblast growth factor 23 signaling pathway dysregulation, hyperphosphatemia and ectopic calcifications (which manifest as joint motion limitations), inflammatory bony pain, and disability. Given the rarity and multiorgan involvement of HFTC, a multidisciplinary approach including Dermatology, Ophthalmology, Dentistry, Nephrology, Endocrinology, Rheumatology, and Genetics is necessary for diagnosis and treatment. We present a multidisciplinary diagnostic and treatment approach for a patient with HFTC due to a GALNT3 gene mutation with unique imaging highlighting the extent of calcinosis seen in HFTC. In this case study, a 34-year-old female patient found to have HFTC was first evaluated at an outpatient academic dermatology center in October 2020 and studied for 1 year. Genetic testing revealing a homozygous c.1319C > A variant in GALNT3 predicted to result in a missense mutation p.Ala440Glu. HFTC should be considered for patients presenting with diffuse calcinosis cutis-like features, and a multidisciplinary evaluation should be pursued.

PurposeThe surgical success rate for primary hyperparathyroidism (PHPT) is currently 95%–98%. However, 3%–24% of patients show persistently elevated (Pe) parathyroid hormone (PTH) levels after parathyroidectomy (PTX). This single-center retrospective study aimed to compare the outcomes of patients with normal PTH and PePTH levels after successful PTX and to identify the factors associated with PePTH.MethodsThe normal group, defined as patients with normal serum calcium and PTH levels immediately after PTX, was compared with the PePTH group (patients with normal or low serum calcium and increased serum PTH levels up to 6 months postoperatively) to determine the causes of disease in the PePTH group.ResultsThere were no significant differences in age, sex, or preoperative estimated glomerular filtration rate between the normal PTH group (333 of 364, 91.5%) and the PePTH group (31 of 364, 8.5%). However, there were significant differences in preoperative 25-hydroxyvitamin D (17.9 and 11.8 ng/mL, respectively; P = 0.003) and PTH levels (125.5 and 212.4 pg/mL, respectively; P < 0.001) between the 2 groups. Among the 31 cases of the PePTH group, 18 were attributed to vitamin D deficiency.ConclusionPreoperative vitamin D deficiency is a predictive factor for PePTH. Therefore, preoperative administration of vitamin D supplements may reduce the probability of postoperative disease persistence. Patients with temporary laboratory abnormalities within 6 months after successful PTX should be monitored, and appropriate vitamin D and calcium supplementation may reduce the effort and cost of various examinations or reoperations.

Background. In this study, we endeavored to determine whether the incidence of cholelithiasis (CL) was increased in chronic renal failure (CRF) patients with secondary hyperparathyroidism on a peritoneal dialysis (PD) program. We also evaluated the factors that might have some influence on the development of CL. Methods. A total of 59 CRF patients undergoing PD were included in the study. We studied the following groups to determine whether parathyroid hormone (PTH) levels were increased in CRF-PD patients: twenty patients with secondary hyperparathyroidism (group 1) and 39 patients with normal PTH levels (group 2). PTH levels were maintained at three times the upper limit of normal. Biochemical parameters were obtained for each CRF-PD patient. All patients underwent abdominal ultrasonography to screen for the presence of cholelithiasis. For statistical analysis, χ2, t test, and logistic regression analysis were used; p < 0.05 was considered as significant. Results. We found an almost ten times higher incidence (25% vs. 2.6%) of CL in group 1 patients with statistical significance (p = 0.007). When the incidence of CL according to sex, creatinine, and PTH levels were considered, female gender, creatinine, and PTH levels were higher in group 1, which was also significant statistically. No significant relationship was detected between gallbladder stone formation and the other analyzed biochemical parameters. Conclusions. We found that the incidence of CL in CRF-PD patients with secondary hyperparathyroidism was higher than CRF-PD patients with normal PTH levels. It was also detected that female gender, high creatinine levels, and elevated PTH levels might influence the development of CL in CRF-PD patients.

Introduction

Improving diagnostic recognition of primary hyperparathyroidism with machine learning

Background/aimRadiofrequency ablation of solitary parathyroid adenoma has been used to treat primary hyperparathyroidism (pHPT) in high-risk patients for parathyroidectomy. This study aimed to evaluate the clinical efficacy of radiofrequency ablation for treating pHPT in patients with parathyroid adenomas.Materials and methodsThe sample for this retrospective study comprised all consecutive patients with solitary parathyroid adenoma treated with radiofrequency ablation between 2013 and 2021. Patients’ baseline serum calcium and parathyroid hormone (PTH) values were obtained. The patients were followed up with serial biochemical measurements after the intervention, then at the first-week, first-month, third-month, sixth-month, and twelfth-month follow-ups. The study’s primary outcome was a biochemical cure, defined as the reestablishment of normal serum calcium and PTH levels, persisting for at least 6 months after the ablation.ResultsThe changes in the serum calcium and PTH levels were significant (p < 0.05). The biochemical cure rate was 30.2% at 1 year. At the end of 1 year, the rate of patients with normal serum calcium levels was 86.6%, whereas the rate of patients with normal serum calcium and higher PTH levels was 55.8%.ConclusionRadiofrequency ablation of a solitary parathyroid adenoma may be considered an alternative treatment for pHPT, given that more than half of the cases investigated in this study had normocalcemic hyperparathyroidism at 1 year.

A 26-year-old man who had end-stage renal disease (ESRD) due to primary glomerulonephritis presented for a routine dental examination. He had peritoneal dialysis (PD) as renal replacement therapy for 2 years. He had smoking one to two packs of cigarettes a day for five years and did not drink alcohol. On clinical examination, the maxillary left canine tooth was absent. The left first molar tooth’s clinical crown was fully carious, but its roots were in the jaw. In the mandibular jaw, the right first molar tooth and the left first molar tooth were carious. A panoramic radiography (PR) was taken as a screening film after the examination. Radiographic imaging showed that the left canine tooth was impacted, and the left first molar tooth’s roots were in the maxillary jaw. In the mandibular jaw, the left third molar tooth was also impacted and the right first molar tooth was carious, but the roots were in the jaw. Bilateral styloid process elongations (SPEs) were also detected (right: 47 mm, left: 58 mm) in the PR of the patient (Figure 1). He had any complaints regarding SPE or Eagle’s syndrome. Figure 1. Bileteral styloid process elongation in an end-stage renal disease patient with peritoneal dialysis on a panoramic radiography. The styloid process (SP) is a cylindrical, long cartilaginous bone located on the temporal bone. There are many vessels such as carotid arteries and nerves adjacent to the SP.1,2 The normal length of the SP is approximately 20–30 mm.3–8 The length of SP and/or stylohyoid ligament, which are longer than 30 mm were considered to be SPE.3,5,7–10 SPE resulted in facial and neck pain is known as Eagle’s syndrome.5,6,10,11 More uncommonly, symptoms such as dysphagia, tinnitus, and otalgia may occur in patients with this syndrome. The symptoms and signs with this syndrome are due to the anatomic relationship between the SP and its surrounding structures.1,12 Therefore, it may also cause stroke due to the compression of carotid arteries.3,13 The exact cause of the elongated SP due to calcified and ossified bone and the ligament is not clear. It was suggested that local chronic irritations, surgical trauma, endocrine disorders in female at menopause, persistence of mesenchymal elements, growth of the osseous tissue and mechanical stress or trauma during development of SP could result in calcified hyperplasia of the SP.3,10,14,15 Extraskeletal (ectopic) calcification or ossification may have a role for the elongation of the SP. Ectopic calcification (EC) in nonosseous soft tissue may be due to three mechanisms: metastatic calcification due to disorders causing abnormal serum Ca and P levels, dystrophic calcification due to mineral deposition into metabolically impaired or dead tissue despite normal serum levels of Ca and P, and ectopic ossification. The patients with ESRD have risks for EC due to disorders (renal failure, dialysis, secondary hyperparathyroidism) causing metastatic calcification.16 In the present report, a detailed differential diagnosis was done for the disorders causing dystrophic calcification (scleroderma, dermatomyositis, systemic lupus erythematosis, trauma-induced etc.), ectopic ossification (post surgery, burns, neurologic injury, myositis ossificans etc.) and also, any diseases causing metastatic calcification. Except renal failure, disease causing metastatic calcification such as sarcoidosis, tumoral calcinosis, primary hyperparathyroidism, milk alkali syndrome etc. were investigated for this patient and any disease was detected.16 As a result, SPE found as incidental findings on PRs may be important clinically in not only patients with ESRD, but also normal population. Instead of many hypotheses and studies, the exact etiology of elongated SP and the role of ectopic calcification are unknown. Abnormality in Ca and P metabolism (EC) is very common in patients with ESRD. According to our knowledge, this is the first case study showing SPE associated with ESRD in a patient. In conclusion, this report suggests that EC or the abnormality in Ca and P metabolism may have a role in the elongation of SP. However, further studies and large samples are needed to clarify the etiology of this disorder, and the role of EC.

Dietary phosphorus restriction up-regulates intestinal vitamin D receptor (VDR), but the tissue specificity of the up-regulation and the mechanism of receptor accumulation remain unknown. Therefore, the effects of low phosphorus diet (LPD) on VDR content in intestine, kidney, and splenic monocytes/macrophages were examined. Male Sprague-Dawley rats weighing 50-100 g were fed a normal diet (NPD; 0.6% Ca, 0.65% P) as controls followed by an LPD (0.6% Ca, 0.1% P) for 1-10 days (D1-D10). LPD rapidly decreased serum P levels by D1 from 11.11 +/- 0.19 mg/dl (mean +/- SE) to 4.98 +/- 0.37 mg/dl (n = 9). LPD increased total serum Ca from 10.54 +/- 0.09 mg/dl to 11.63 +/- 0.15, 12.17 +/- 0.15, and 12.39 +/- 0.18 mg/dl by D1, D2, and D3, respectively, and then remained stable. Serum 1,25-(OH)2D3 rapidly increased from 123 +/- 5.4 pg/ml to 304 +/- 35 pg/ml by D1, reached a plateau through D5, and then gradually increased to 464.9 +/- 27.7 pg/ml by D10. Intestinal VDR quantitated by ligand binding assay increased 3.5-fold from 169.6 +/- 13.7 fmol/mg of cytosol protein in rats fed NPD (n = 12) to a peak of 588.3 +/- 141.88 fmol/mg of protein by D3 (n = 6; p < 0.001) and then decreased to a plateau level of 2.5-fold greater than NPD (p < 0.05) during D5 to D10. In contrast, LPD did not up-regulate kidney or splenic monocyte/macrophage VDR. Northern blot analysis showed that intestinal VDR mRNA increased 2-fold by D2 (n = 3) of LPD and then gradually decreased to control levels after D5. In contrast, kidney VDR mRNA levels did not change during the first 5 days of P restriction and then subsequently decreased to 50% of NPD controls. The results of these studies indicate that VDR up-regulation during dietary phosphorus restriction is tissue-specific and that the mechanism of the up-regulation is time-dependent. Acutely (D1-D5), phosphorus restriction up-regulates intestinal VDR through increased VDR gene expression, whereas chronic (D5-D10) phosphorus restriction appears to alter VDR metabolism through nongenomic mechanisms that are consistent with prolongation of the half-life of the receptor. The nature of the tissue-specific regulation of VDR during phosphorus restriction remains to be determined.

Independently of plasma 25-hydroxyvitamin D (P-25(OH)D) levels, elevated parathyroid hormone (PTH) levels may exert an adverse effect on muscle health, postural stability, well-being, and quality of life. Using a cross-sectional design, we investigated 104 healthy postmenopausal women with low P-25(OH)D (< 50nmol/l) levels, who had either secondary hyperparathyroidism (SHPT) with elevated PTH levels (> 6.9pmol/l, n = 52) or normal PTH levels (n = 52). The average PTH value in women with SHPT was 8.5 (interquartile range 7.5-9.7) pmol/l and 5.3 (4.4-6.3) pmol/l in women with normal PTH (p < 0.001). Plasma phosphate was significantly lower in women with SHPT than in women with normal PTH (1.01 ± 0.14 vs. 1.09 ± 0.13mmol/l; p < 0.01). In the total cohort, average level of 25(OH)D were 38 (31-45) nmol/l, with no differences between groups. SHPT was associated with impaired muscle strength as assessed by both maximum muscle strength and maximum force production at knee flexion with the knee fixed at 60° and 90° (pall < 0.05). Postural stability was impaired during semi tandem standing (p = 0.001). However, the two groups did not differ in terms of self-reported physical activity, muscle-related symptoms, quality of life, or lean muscle mass as assessed by dual-energy X-ray absorptiometry. Independently of 25(OH)D levels, mild to moderately elevated PTH levels are associated with adverse effects on muscle strength and postural stability. Why some individuals respond to vitamin D insufficiency with an elevated PTH and others do not need further elucidation, but elevated PTH itself seems to affect muscle function and postural stability.

Recently, normocalcemic (NC) and normohormonal (NH) variants of primary hyperparathyroidism (pHPT) have been described, with distinct biochemical profiles from the typical high serum calcium and parathyroid hormone (PTH) levels. Here, we investigate whether biochemical profile affects cure rate, as well as the kinetics of intraoperative PTH (IOPTH). This is a single-center, retrospective study of pHPT patients undergoing parathyroidectomy. Patients were grouped based on preoperative calcium and PTH levels into typical, NC (normal calcium, elevated PTH, no evidence of secondary hyperparathyroidism), and NH (elevated calcium, unsuppressed PTH) biochemical profiles. All patients had IOPTH monitoring and ≥6-month post-op serum studies to confirm surgical cure. Patient variables were analyzed with Kruskal-Wallis test and Chi-square analysis. IOPTH kinetic curves were analyzed using a linear mixed model. From June 2006 to October 2014, 646 patients met inclusion criteria. Biochemical profile was typical in 460 patients (71%), NC in 101 (16%), and NH in 85 (13%). IOPTH levels were higher at all time points in typical patients, p < 0.001. Surgical cure rates were significantly lower for NC patients (90.1%) than for typical (98.5%) or NH patients (97.7%), p < 0.001, although a stricter criteria for cure was used in this group(normal calcium AND normal PTH). In a multivariable linear mixed model, NC patients had a significantly slower rate of IOPTH decline (p < 0.001 at 10min). Here, we better characterize the atypical variants of pHPT. Using a stricter definition of cure in the NC variant, these patients have a lower surgical cure rate than typical or NH variants in pHPT. The IOPTH curve is affected by biochemical profile, with both NC and NH patients having lower absolute values and NC patients having a slower decline.

BACKGROUND AND AIMS It is well established that patients on chronic hemodialysis (HD) have an increased risk of hepatitis B virus (HBV) infection and reduced response to HBV vaccines compared with the general population.1 While advances in immunology and vaccinology have evolved several HBV vaccine modifications to enhance immunogenicity2; there is need to identify modifiable clinical factors that may help enhance response to HBV vaccines in the chronic HD population. This multi-center study aims to document the response to HBV vaccine among chronic HD patients across DaVita centers in Saudi Arabia and to identify the factors that independently affect the response of HD patients to the HBV vaccine. METHOD Patients eligible for HBV vaccination among our patient cohort who had received a full course of HBV vaccination (Engerix-B®, GlaxoSmithKline, United Kingdom) in all DaVita Clinics in Saudi Arabia were included in the analysis. We excluded patients who did not complete the vaccine protocol or had missing data and who were treated by immunosuppressive drugs. Levels of the antibody to the surface antigen (anti-HBs) were measured about 2 months after the last dose of the vaccine using enzyme-linked immunoassay methods. The age (in years), dialysis vintage, hepatitis C infection, diabetic status, mean albumin, parathyroid hormone (PTH), ferritin and hemoglobin levels 2 months prior to and during the 6 months of completing the vaccination protocol were recorded. Response to HBV vaccine was recorded as ‘no response’ if anti-HBs was &amp;lt; 10 mIU/L; ‘weak response’ if the anti-HBs level is between 10–99.9 mIU/L, and ‘good response’ when ≥ 100 mIU/L. Univariate and multivariate ordinal logistic regression models were used to identify the factors independently associated with response to HBV vaccine. RESULTS We had 509 patients with a mean age of 54.1 ± 15.1 years, 252 (49.5%) being female. Diabetes mellitus was the etiology of kidney failure in 60.5% of the patients. Most (91.1%) had concomitant hypertension and 4.3% were positive for hepatitis C virus infection. BMI was at least 30 kg/m2 in 26.1% of the study population. Immune response occurred in 374 {73.5%, [95% confidence interval (95% CI) 69.4–77.3%]}. Good response occurred in only 53.1% (95% CI 48.6%–57.4%). The factors independently associated with response to HBV vaccination were age, mean albumin, PTH, ferritin levels and BMI (Table 1). Diabetic status and Kt/v did not predict vaccine response. CONCLUSION A complex interaction of inflammatory markers, nutritional status, bone mineral disease parameters affects the response to HBV vaccines. Improving chronic dialysis patients’ albumin and PTH levels may increase the likelihood of achieving a good response to HBV vaccines.

Background and Aims Ectopic soft tissue calcifications, especially cardiovascular calcifications, are frequently observed in patients with chronic kidney disease (CKD) and are associated with increased morbidity and mortality. Sclerostin, a well-known inhibitor of bone formation, shows significantly increased serum levels in CKD patients. Since the process of ectopic calcification shares many similarities with physiological bone formation, we investigated a possible role for sclerostin in ectopic calcification development. Method CKD was induced in wild type (WT) (n=21) and sclerostin knockout (Sost ko) mice (n = 21), both on a C57Bl6/J background, by the alternate administration of a 0.30% and 0.15% adenine supplemented diet, containing 1% phosphate. A normal renal function control group receiving standard mouse chow (WT C57Bl6/J n = 8) was also included in the study. Serum creatinine and phosphate levels were measured at the start and end of the study to assess CKD development. At sacrifice, the calcium content of the kidneys, heart and aorta was determined by flame atomic absorption spectrometry. Results The adenine-supplemented diet led to a clear induction of CKD in both the Sost ko and wild type mice, as reflected by increased serum creatinine (0.38 ± 0.09 mg/dL in control mice vs 0.65 ± 0.18 mg/dL in adenine-exposed mice, p&amp;lt;0.0001) and phosphate levels (9.12 ± 1.16 mg/dL in control mice vs 19.03 ± 3.11 mg/dL in adenine-exposed mice, p&amp;lt;0.0001). The Sost ko and WT mice receiving the adenine diet, developed the same degree of renal failure, since there were no differences in serum levels of creatinine (p=0.0507) and phosphate (p=0.4890). Significantly higher amounts of calcium were measured in the kidney (0.05 ± 0.01 mg/g wet tissue vs 3.70 ± 2.00 mg/g wet tissue, p&amp;lt;0.0001) and the heart (0.03 ± 0.01 mg/g wet tissue vs 0.07 ± 0.04 mg/g wet tissue, p&amp;lt;0.0001) of adenine-exposed mice, compared to mice receiving the control diet. Furthermore, Sost ko mice had a significantly higher calcium content in the heart compared to the WT mice with renal failure (0.05 ± 0.03 mg/g wet tissue in WT mice vs 0.08 ± 0.05 mg/g wet tissue in Sost ko mice, p = 0.0029). No differences were observed in aortic calcium content between control mice and mice with renal failure. Conclusion In this study we managed to develop a mouse model of CKD-induced soft tissue calcification in the heart and kidneys of the animals, however no calcifications developed in the aorta. The higher calcium content that was observed in the heart of Sost ko mice compared to WT mice, might be an indication of a protective function of sclerostin during ectopic cardiac calcification

Dyslipidemia, hypertension, diabetes mellitus and also primary hyperparathyroidism (pHPT) are associated with an increased risk of cardiovascular diseases. Metabolic abnormalities in mild pHPT have been reported, but never in cases with normal calcium and high parathyroid hormone (PTH) levels, i.e. suffering from 'normocalcemic pHPT'. Our aim was to explore the occurrence of these metabolic abnormalities in individuals with normocalcemic pHPT identified in a population-based screening, and the effects of parathyroidectomy vs conservative treatment on metabolic variables. A population-based screening of 5202 post-menopausal women identified 30 patients with normal calcium, inappropriately high PTH and normal creatinine. A 5-year follow-up included 15 parathyroidectomized (PTx) and nine conservatively followed cases, in a non-randomized setting, together with age-matched controls. Biochemical variables and body mass index (BMI) were investigated. At study entry, cases had higher calcium, PTH, glucose, low-density lipoprotein (LDL)/high-density lipoprotein (HDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, total triglycerides, and BMI compared to controls (P = < 0.0001-0.035). The cases had a lower HDL-cholesterol value (P = 0.013) and one third of the cases had hypertriglyceridemia. During follow-up, the PTx cases decreased in calcium, PTH, LDL/HDL-cholesterol, total and LDL-cholesterol (P = 0.0076-0.022). Investigated biochemical variables remained adverse in conservatively followed cases during follow-up except a decreased LDL-cholesterol value. All surgically treated patients had parathyroid adenoma. Cases with normocalcemic pHPT have increased proatherogenic lipoprotein levels, BMI and glucose levels compared to age-matched controls. Parathyroidectomy has positive effects on some of these variables and reverses them to the same level as the controls, while conservative treatment fails to normalize the investigated metabolic variables.

Objective The clinical relevance of altered lymphocyte function and its possible relation with uremic toxins such as parathyroid hormone (PTH) is not well understood. We studied the changes in cellular immunity in patients on continuous ambulatory peritoneal dialysis therapy and examined the relationship between T-lymphocyte function and plasma levels of PTH. Patients and Methods Thirty-seven patients (16 male, 21 female) were enrolled in the study. The patients were divided into 2 groups: 22 patients with increased levels of PTH and 15 patients with normal levels of PTH. Lymphocyte subsets (CD2+, CD3+, CD3+/4+, CD3+/8+, CD19+, CD3−/16+56+, CD4/CD8 ratio) were quantitated in both groups using monoclonal antibodies and flow cytometric analysis. Analysis of variance testing was performed to analyze differences between the groups. Results A significant increase in CD3 was observed in patients with increased levels of PTH (71.6±7.9 vs. 57.5±28.1, p<.05). CD3/8 population was also increased in patients with elevated PTH (26.96±8.01 vs. 20.8±13.78, p=NS). CD4/CD8 ratios were lower in patients with elevated PTH than in those who had normal PTH (1.67±0.78 vs. 3.03±2.54, p<.05). No specific differences were observed between these 2 patient groups in CD19 and natural killer cells. Conclusions Elevated PTH seems to affect lymphocyte function and is associated with changes in cellular immunity in a peritoneal dialysis population. Our study is continuing in order to enlarge the study population and collect more data, which will lead to more solid conclusions.

Ectopic calcification in soft tissue is associated with several disorders including pseudohypoparathyroidism (PHP), which is characterized by resistance or nonresponse to parathyroid hormone (PTH) function. Association between PHP and 22q11DS, also known as DiGeorge syndrome, is rare, especially in children. We describe a newborn girl diagnosed with 22q11DS, presenting ectopic calcifications in soft tissue and suspicion of PHP. PTH function showed values close to the upper limit of the reference value. Radiology showed bone callus in the right wrist. PHP can be a new clinical finding associated with 22q11DS. Parathyroid function investigation in individuals with 22q11DS, presenting bone dysmorphisms and/or calcium metabolism alterations, should be considered.