Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma-a case report and review.

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC-MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC-MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.

Primary hyperparathyroidism: clinical manifestations, diagnosis and evaluation according to the Fifth International Workshop guidelines.

Primary hyperparathyroidism (PHPT) is a frequent endocrine disease which mainly affects the skeletal system and kidney. Some of its signs and symptoms are similar to those seen in rheumatic diseases such as rheumatoid arthritis, Sjögren's disease, fibromyalgia, polymyalgia rheumatica, gout or systemic lupus erythematosus. Coexistence of primary hyperparathyroidism with those pathologies potentiate their effects on muscles, bones and joints, increasing the risk of complications such as osteoporosis and fractures. Therefore, rheumatologists should be familiar with symptoms and diagnostic criteria of PHPT and consider it in the differential diagnosis of rheumatic diseases. In 2022 the Fifth International Workshop guidelines on the PHPT evaluation and management were published. They are based on a profound analysis of advances in research concerning multiple fields, that include genetics, outcomes and new imaging modalities of PHPT. They have led to revision of previous renal indications for parathyroidectomy in PHPT. There is also more evidence for the other recommendations regarding evaluation of the disease. This article summarizes the most relevant elements of these recommendations and refers them to Polish realities. I focus on the symptoms of primary hyperparathyroidism and its diagnosis as I consider these areas to be the most important for non-endocrinologists.

Osteitis fibrosa cystica-a forgotten radiological feature of primary hyperparathyroidism.

Although bone disease and stone disease are the universally accepted classical manifestations of primary hyperparathyroidism, clinical parathyroid bone disease is rarely seen today in the United States (<5% of patients) and Western Europe. Nevertheless, in a given patient, classical skeletal involvement can be the first sign of primary hyperparathyroidism, but not recognized because it is not usually included, anymore, in the differential diagnosis of this manifestation of skeletal disease. We describe four cases of primary hyperparathyroidism in which the first clinical manifestation of the disease was a pathological fracture that masqueraded as a malignancy. The presence of large osteolytic lesions gave rise to the initial diagnosis of a primary or metastatic cancer. In none of the reported cases was primary hyperparathyroidism with osteitis fibrosa considered as the diagnosis. It would seem to us that this course is best explained by the fact that in many countries such manifestations of primary hyperparathyroidism have become a rarity. In fact, the incidence of osteitis fibrosa among patients with primary hyperparathyroidism in the US is estimated as so rare, that in majority of medical centers routine x-ray examinations of the bones in these patients is not recommended. The X-ray or computed tomography scan findings of osteitis fibrosa cystica include lytic or multilobular cystic changes. Multiple bony lesions representing brown tumors may be misdiagnosed on computed tomography scan as metastatic carcinoma, bone cysts, osteosarcoma, and especially giant-cell tumor. Distinguishing between primary hyperparathyroidism and malignancy is made readily by the concomitant measurement of parathyroid hormone which in primary hyperparathyroidism, again, will be markedly elevated. In the hypercalcemias of malignancy, such elevations of parathyroid hormone are virtually never seen. CONCLUSION: When radiographic evidence of a lytic lesion and hypercalcemia are present, primary hyperparathyroidism should always be considered in the differential diagnosis.

Iodine supplementation during pregnancy of hypothyroid women treated with L-thyroxine neither influences neonatal TSH nor prevents decrease in maternal free thyroid hormone concentrations in second and third trimesters.

INTRODUCTION: Pregnant women require about 250 µg of iodine daily. Hypothyroid women treated with L-thyroxine do not utilise iodine, and metabolism of L-thyroxine tablets is an additional source of iodine for their foetuses. The aim of the study was to evaluate the influence of iodine supplementation in hypothyroid pregnant women treated with L-thyroxine on neonate TSH concentration and maternal thyroid parameters. MATERIAL AND METHODS: Ninety-two pregnant women with primary hypothyroidism on adequate thyroid hormone replacement were voluntarily divided into two groups: "thyroxine" (n = 38) treated with L-thyroxine only, and "thyroxine + iodine" (n = 54) treated additionally with 150 µg/day of iodine since 10th gestational week. Primary outcomes were the maternal thyroid function tests (TSH, fT4, fT3) and neonatal TSH concentrations at the 3-4th day of life. Urinary iodine concentration was measured at first and third trimester to compare iodine status in both groups. RESULTS: Iodine supplementation significantly increased median urinary ioduria in the third trimester (from 95.15 µg/L to 151.50 µg/L), but did not prevent the decrease of maternal fT4 and fT3 concentrations in the second and third trimester. Median neonate TSH concentration in both groups was within normal range, but was 33% higher in the "thyroxine + iodine" than in the "thyroxine" group (1.91 mU/L vs. 1.34 mU/L). Moreover, 8.77% of newborns in the "thyroxine + iodine" group had TSH > 5 mIU/L. CONCLUSIONS: We did not find evidence for a positive influence of iodine supplementation on thyroid function of either hypothyroid pregnant women sufficiently treated with L-thyroxine or their neonates. (Endokrynol Pol 2016; 67 (4): 367-374).

Gestational diabetes insipidus. Case Report.

Gestational diabetes insipidus is a very rare complication. However, undiagnosed and untreated may lead to serious complications in both mother and fetus. In this study, a case of 34-year-old female patient with diabetes insipidus associated with pregnancy was reported. We discussed process of diagnosis and treatment with particular emphasis on the monitoring of water-electrolyte imbalance during labor.

Real-time ultrasound elastography - a new tool for diagnosing thyroid nodules.

INTRODUCTION: Real-time elastography (RTE) is a non-invasive ultrasound method of estimation of tissue stiffness by measuring the degree of local tissue displacements after a small compression. Recent data has shown its ability to differentiate benign from malignant tumours. The aim of this study was to evaluate the accuracy of RTE in the diagnosis of malignant and benign thyroid nodules. MATERIAL AND METHODS: 71 thyroid nodules in 52 patients: 42 females and 10 males aged 28-77 were examined using conventional ultrasonography (US), fine-flow CD imaging and RTE. All nodules previously underwent fine-needle aspiration biopsy (FNAB), and patients with malignant and suspicious cytological results were referred for surgery. The final diagnosis was based on FNAB results in patients with benign cytology and on the histopathology reading in those who underwent surgery. An elasticity score (ES) from 1 to 5 was determined for each nodule according to the Ueno classification. RESULTS: An elasticity score (ES) of 4 or 5 was found in 19 out of 22 (86.5%) thyroid cancers and in only 1 out of 31 (3%) benign nodules. This was strongly indicative for malignancy (p 〈 0.0001) with sensitivity 86%, specificity 97%, positive predictive value (PPV) 95% and negative predictive value (NPV) 91%. CONCLUSIONS: RTE is a highly sensitive and specific method of diagnosing thyroid nodules. This technique can be employed in selecting thyroid nodules for fine-needle aspiration biopsy.

Bilateral, incidentally found adrenal tumours - results of observation of 1790 patients registered at a single endocrinological centre.

INTRODUCTION: During the last 22 years we registered 1790 patients with incidentally found adrenal tumours (AI, adrenal incidentalomas). In 351 of them, bilateral tumours were detected. The aim of our study was to analyze the character of bilateral tumours and summarize the methods of their management. MATERIAL AND METHODS: In the whole group of 1790 patients, there were 1311 women and 479 men, aged 11-87 years. The group of patients with bilateral adrenal tumours included 258 women and 93 men, 25-83 years old. Hormonal investigations and imaging examinations were performed to search for subclinical adrenal hyperfunction and to define the malignant potential of the tumours. RESULTS: Sixty-nine patients were treated by surgery for oncological or endocrinological purposes (mainly pre-Cushing's syndrome). Histological findings included malignant tumours: metastases - 9, adrenal cancer - 7, and lymphomas - 5; and non-malignant tumours: adenomas - 24, nodular hyperplasia - 14, myelolipomas - 4, and pheochromocytomas - 4. Subclinical Cushing's syndrome was relatively more frequent in nodular hyperplasia (40%) than in adenomas (30%). CONCLUSIONS: Indications for surgery were recommended in 20% of patients with bilateral AI, most frequently for adenomas, nodular hyperplasia, and oncological pathologies, with a good prognosis in the non-malignant group. (Pol J Endocrinol 2010; 61 (1): 69-73).

In acromegaly, increased bone mineral density (BMD) is determined by GH-excess, gonadal function and gender.

OBJECTIVES: The aim of our study was to evaluate bone metabolism and bone mineral density (BMD), and to indicate the main determinants of these parameters in a large group of patients with active acromegaly. METHODS: A group of 121 active acromegalics, aged 23-80 years, from a single endocrinological center was studied. Serum GH, IGF-I, LH, FSH, PRL, estradiol/testosterone, osteocalcin (OC), type I collagen carboxyterminal telopeptide (ICTP) as well as BMD by DXA at spine L2-L4, femoral neck, Ward's triangle and trochanter were measured. RESULTS: Serum OC and ICTP concentrations were elevated (mean+/-SEM: 31.7+/-2.2 microg/L, p<0.001; 7.3+/-0.5 microg/L, p<0.001, respectively), and positively correlated with each other, as well as with IGF-I. BMD (Z-scores) was increased at L2-L4, femoral neck and trochanter (0.35+/-0.15, p=0.016; 0.60+/-0.11, p<0.001 and 0.59+/-0.13, p<0.001; respectively). The main determinants of Z-scores and ICTP were gonadal status and gender, while of OC was IGF-I. Eugonadal acromegalics had higher than normal serum OC and ICTP, as well as Z-scores at all measured sites. Hypogonadal patients (2/3 of the population) had significantly higher serum ICTP concentrations and lower BMD at all sites, when compared to eugonadal acromegalics. Thirty five percent of hypogonadal subjects had T-score<-1. Men had significantly higher serum ICTP and lower Z-scores than women. CONCLUSIONS: (i) In active acromegaly, enhanced IGF-I-dependent bone turnover and increased BMD is observed. (ii) In hypogonadal acromegalics, high bone resorption decreases BMD and may lead to osteoporosis. (iii) There is a smaller increase in bone resorption and greater increase in BMD in women with acromegaly than in men.