Small cell carcinoma of hypercalcemic type (SCCOHT) is a rare gynaecological neoplasm, originating mostly in the ovaries. Cervical origin of this very aggressive malignancy with unknown histogenesis is an extremely rare condition, without published management recommendations. Alterations in SMARCA4 gene are supposed to play the major role in SCCOHT oncogenesis and their identification is crucial for the diagnosis. Adequate genetic counselling of the patients and their families seems to be of great importance. Optimal management and treatment approaches are not known yet but may extremely influence the prognosis of young female patients that suffer from this very resistant disease. Nowadays, a translational research seems to be the key for the further diagnostic and treatment strategies of SCCOHT. The purpose of the case report is to provide practical information and useful recommendations on the diagnosis, management, and treatment of SMARCA4-deficient carcinoma of the uterine cervix resembling SCCOHT.
- MeSH
- DNA Helicases deficiency genetics MeSH
- Fatal Outcome MeSH
- Hypercalcemia diagnosis genetics metabolism therapy MeSH
- Nuclear Proteins deficiency genetics MeSH
- Humans MeSH
- Carcinoma, Small Cell diagnosis genetics metabolism therapy MeSH
- Adolescent MeSH
- Mutation MeSH
- Biomarkers, Tumor deficiency genetics MeSH
- Uterine Cervical Neoplasms diagnosis genetics metabolism therapy MeSH
- Transcription Factors deficiency genetics MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Renal Insufficiency, Chronic complications MeSH
- Hypercalcemia etiology genetics physiopathology MeSH
- Hyperparathyroidism diagnosis etiology therapy MeSH
- Hypoparathyroidism physiopathology therapy MeSH
- Bone Density Conservation Agents therapeutic use MeSH
- Humans MeSH
- Parathyroid Neoplasms complications therapy MeSH
- Nephrolithiasis etiology complications MeSH
- Parathyroid Diseases * diagnosis etiology therapy MeSH
- Osteitis Fibrosa Cystica etiology complications MeSH
- Parathyroid Hormone physiology MeSH
- Hyperparathyroidism, Primary diagnosis etiology therapy MeSH
- Hyperparathyroidism, Secondary diagnosis etiology therapy MeSH
- Vitamin D therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
The metabolic pathways that contribute to maintain serum calcium concentration in narrow physiological range include the bone remodeling process, intestinal absorption and renal tubule resorption. Dysbalance in these regulations may lead to hyper- or hypocalcemia. Hypercalcemia is a potentionally life-threatening and relatively common clinical problem, which is mostly associated with hyperparathyroidism and/or malignant diseases (90 %). Scarce causes of hypercalcemia involve renal failure, kidney transplantation, endocrinopathies, granulomatous diseases, and the long-term treatment with some pharmaceuticals (vitamin D, retinoic acid, lithium). Genetic causes of hypercalcemia involve familial hypocalciuric hypercalcemia associated with an inactivation mutation in the calcium sensing receptor gene and/or a mutation in the CYP24A1 gene. Furthermore, hypercalcemia accompanying primary hyperparathyroidism, which develops as part of multiple endocrine neoplasia (MEN1 and MEN2), is also genetically determined. In this review mechanisms of hypercalcemia are discussed. The objective of this article is a review of hypercalcemia obtained from a Medline bibliographic search.
- MeSH
- Hypercalcemia blood genetics physiopathology MeSH
- Hyperparathyroidism blood genetics physiopathology MeSH
- Humans MeSH
- Mutation genetics MeSH
- Calcium blood MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Idiopathic infantile hypercalcemia (IIH) is a rare disorder caused by CYP24A1 loss-of-function mutation, resulting in impaired degradation of 1,25-dihydroxyvitamin D3. Pamidronate, an intravenously administered bisphosphonate, which is a potent inhibitor of bone resorption, has been reported only once for treatment IIH. We present a case of a previously healthy 5-month-old boy with IIH, where calcemia peaked to 5 mmol/L. Treatment with methylprednisone and furosemide had only minor effects; therefore, 2 intravenous infusions of pamidronate (0.6 mg/kg per dose) corrected the serum calcium level to 2.95 mmol/L. Furthermore, CYP24A1 homozygous mutation p.R396W (c.1186c>t) was identified in this patient, confirming the clinical diagnosis of IIH. In conclusion, IIH has a favorable outcome once properly detected and appropriately treated. Pamidronate has a beneficial effect in those patients with IIH where glucocorticoids and furosemide fail to meet the expectations.
- MeSH
- Biomarkers metabolism MeSH
- Diphosphonates therapeutic use MeSH
- Diagnosis, Differential MeSH
- Hypercalcemia diagnosis drug therapy genetics MeSH
- Bone Density Conservation Agents therapeutic use MeSH
- Infant MeSH
- Humans MeSH
- Mutation MeSH
- Child, Preschool MeSH
- Steroid Hydroxylases genetics MeSH
- Calcium metabolism MeSH
- Treatment Outcome MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
UNLABELLED: We report on a male infant presenting at 4 months of age with failure to thrive, dehydration, hypotonia, lethargy, and vomiting. Laboratory and imaging tests revealed severe hypercalcemia (5.8 mmol/l), suppressed parathyroid hormone (0.41 pmol/l), hypercalciuria (8.0 mmol/mmol creatinine), elevated 25-hydroxyvitamin D3 (over 600 nmol/l), and nephrocalcinosis. These symptoms are characteristic of idiopathic infantile hypercalcemia (IIH, MIM 143880). Conservative therapy (parenteral rehydration, diuretics, corticosteroids, bisphosphonates, and vitamin D prophylaxis withdrawal) was not able to improve the symptoms and laboratory values, and acute hemodiafiltration was necessary to normalize hypercalcemia. Clinical symptoms resolved rapidly after normalization of serum calcium levels. Molecular genetic testing revealed a homozygous mutation (R396W) in the CYP24A1 gene (MIM 126065) encoding 25-hydroxyvitamin D3 24-hydroxylase, which is the key enzyme responsible for 1,25-dihydroxyvitamin D3 degradation. The CYP24A1 gene mutation leads to the increased sensitivity of the patients to even prophylactic doses of vitamin D and to the development of severe symptomatic hypercalcemia in patients with IIH. CONCLUSION: Our patient is only the thirteenth patient with IIH caused by mutation in the CYP24A1 gene and the first one needing acute hemodiafiltration for severe symptomatic hypercalcemic crisis. In all patients with suspected IIH the DNA analysis for CYP24A1 gene mutations should be performed regardless of the type of vitamin D supplementation and serum levels of vitamin D.
- MeSH
- Child MeSH
- Phosphates deficiency MeSH
- Hypercalcemia etiology genetics classification MeSH
- Hypocalcemia diagnosis etiology genetics classification MeSH
- Hypoparathyroidism drug therapy MeSH
- Calcitonin secretion MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Vitamin D Deficiency MeSH
- Infant, Newborn MeSH
- Parathyroid Hormone secretion MeSH
- Calcium Metabolism Disorders diagnosis classification MeSH
- Osteoporosis, Postmenopausal diagnosis classification MeSH
- Signs and Symptoms MeSH
- Rickets diagnosis classification metabolism MeSH
- Calcium deficiency MeSH
- Vitamin D MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Infant, Newborn MeSH
Hyperkalcemie a hypofosfatemie jsou projevy poměrně vzácných familiárních onemocnění, která však mají mimořádný diferenciálně diagnostický význam. Mutace v receptoru pro kalcium (CaSR) se klinicky manifestuje jako familiární hypokalciurická hyperkalcemie (FHH) nebo jako vysoce závažná novorozenecká hyperparatyreóza. Extrémně vzácná je hyperkalciurická hypokalcemie. Prognóza nejčastější formy mutace v CaSR - FHH je sice považována za onemocnění benigní, nicméně je-li přehlédnuta, může vést k mylné diagnóze primární hyperparatyreózy. Prognóza a léčebné postupy jsou však u obou onemocnění zásadně odlišné. Familiární hypofosfatemie se vyskytuje v rámci hereditární křivice, která je důsledkem nedostatečné produkce aktivního metabolitu vitaminu D nebo poruchy funkce receptoru pro vitamin D (VDR). Nejčastěji se manifestuje jako dominantní hypofosfatemická křivice vázaná na X receptor (receptor pro retinoid) nebo autozomálně dominantní hypofosfatemická křivice. Velmi vzácná je forma autozomálně recesivní. Vždy je třeba vyloučit hypofosfatemii onkogenní. V práci jsou diskutovány otázky patogeneze, diferenciální diagnostiky a léčby familiární hypokalciurické hyperkalcemie a hereditární hypofosfatemické křivice.
Hypercalcemia and hypophosphatemia are symptoms of two relatively rare hereditary diseases and are extraordinarily important from the standpoint of the differential diagnosis. Mutation in calcium sensing receptor gene (CaSR) clinically manifests as familial hypocalciuric hypercalcemia (FHH) or as the much more serious neonatal hyperparathyreosis. Hypercalciuric hypocalcemia is extremely rare. Prognosis for the most frequent mutations in the CaSR gene FHH is considered benign; nevertheless, if overlooked it can lead to an incorrect diagnosis of primary hyperparathyreosis, which has a fundamentally different prognosis and treatment. Familial hypophosphatemia sometimes occurs as hereditary rickets, which is a consequence of insufficient production of vitamin D‑ hormone or abnormal function of vitamin D receptors (VDR). The disease manifests as X‑linked dominant hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets. Autosomal recessive form is very rare. Oncogenic hypophosphatemia should be excluded in differential diagnosis. In this review the issues of pathogenesis, differential diagnosis and treatment of FHH and hypophosphatemic rickets are discussed.
- MeSH
- Diagnosis, Differential MeSH
- Hypophosphatemia, Familial diagnosis MeSH
- Calcium Phosphates metabolism MeSH
- Hypercalcemia diagnosis genetics MeSH
- Hyperparathyroidism diagnosis genetics MeSH
- Humans MeSH
- Mutation MeSH
- Receptors, Calcium-Sensing genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
We present a male patient with neonatal severe primary hyperparathyroidism, whose manifestation was exceptionally serious for the heterozygous inactivating mutation he carried in the CASR gene. The patient presented soon after birth with respiratory distress requiring long-term mechanical ventilation, bone and chest deformities, feeding problems, and hypotonia. He had hypercalcaemia, hypophosphataemia, and hyperparathyroidism. There was no known history of calcium metabolism disorders in the family. As the impact on calcaemia of a rescue therapy with bisphosphonates was only transient, a subtotal and subsequently total parathyroidectomy were performed in the fourth month of life. Afterwards his clinical status improved and the fractures healed, but his neuropsychological development is delayed due to cerebral atrophy. Genetic analysis revealed a heterozygous missense CASR mutation R185Q, and an approximately equal expression of the mutated and wild-type RNA in the parathyroid tissue. The mother of the child was homozygous for the wild-type allele; the father is unknown. In conclusion, this patient demonstrates how serious neonatal hyperparathyroidism can be when caused by a heterozygous mutation. This may be attributable to a combination of dominant-negative action of the mutant allele with an intrauterine foetal hyperparathyroidism developed in the mother's normocalcaemic environment, further aggravated by a putative maternal vitamin D deficiency during pregnancy.
- MeSH
- Point Mutation genetics MeSH
- Adult MeSH
- Phenotype MeSH
- Heterozygote MeSH
- Hypercalcemia genetics complications MeSH
- Hyperparathyroidism genetics surgery complications MeSH
- Humans MeSH
- Vitamin D Deficiency diagnosis epidemiology MeSH
- Infant, Newborn MeSH
- Parathyroidectomy MeSH
- Prenatal Diagnosis MeSH
- Receptors, Calcium-Sensing genetics MeSH
- Severity of Illness Index MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Diagnosis, Differential MeSH
- Child MeSH
- Hypercalcemia drug therapy genetics urine MeSH
- Hypocalcemia diagnosis drug therapy genetics MeSH
- Drug Therapy, Combination MeSH
- Humans MeSH
- Membrane Proteins genetics MeSH
- Magnesium Deficiency MeSH
- Nephrocalcinosis drug therapy genetics ultrasonography MeSH
- Renal Insufficiency etiology prevention & control MeSH
- Calcium metabolism adverse effects MeSH
- Metabolism, Inborn Errors drug therapy genetics classification MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
