PTH dependant hypercalcemia or rare forms of primary hyperparathyroidism
ICD code: E21
Hyperparathyroidism is due to the excessive secretion of PTH by one or more parathyroid glands. It leads to hypercalcemia and increased excretion of calcium in the urine. Rare forms of primary hyperparathyroidism are 1-hyperparathyroidism diagnosed in children or young adults and 2-hyperparathyroidism associated with germline mutations in susceptibility genes. The symptoms are mainly related to the level of serum calcium and/or to the kidney/urinary tract complications. In addition, the features associated with the genetic defects may also lead to the diagnosis.
PTH non-dependant hypercalcemia
Hypercalcemia with low PTH is due to an excess in vitamin D action/concentration or to an increased flux of calcium from the bone (hypophosphatasia, bone resoprtion due to PTHrP or cytokines production). The symptoms are mainly related to the level of serum calcium and/or to the kidney/urinary tract complications. Hypercalcemia due to anomalies in vitamin D metabolism is mainly diagnosed in neonates and young children with severe hypercalcemia and nephrocalcinosis. Hypophosphatasia may be diagnosed because of hypercalcelmia, hyperphosphatemia, low PTH and severely impaired bone mineralization.
Parathyroid cancer usually manifests as severe hypercalcemia, i.e. anorexia, polyuria, fatigue, dehydration, bone pain, subcortical bone resorption, pathological fractures and renal complications of hypercalciuria. A mass may be palpable in the neck.
Familial Hypocalciuric Hypercalcemia (FHH)
Familial hypocalciuric hypercalcemia (FHH) is a generally asymptomatic genetic disorder of phosphocalcic metabolism characterised by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma parathyroid hormone (PTH) concentration.FHH is biologically characterised by moderate but significant hypercalcemia associated with levels of PTH and urinary calcium excretion that appear inappropriate in the presence of the hypercalcemia: serum levels of PTH are, in general, normal or slightly increased and calciuria is low. FHH is usually asymptomatic but rarely symptoms of fatigue, weakness, excessive thirst and concentration problems are experienced.
Neonatal Severe Primary Hyperparathyroidism (NSHPT)
Neonatal Severe Primary Hyperparathyroidism (NSHPT) is a severe and sometimes lethal disease if it is left untreated. its is characterised by severe hypercalcemia, very high levels of PTH, and bone resorption. As consequences, the neonates may present with fractures and renal insufficiency. In most cases, the parathyroidectomy of 4 glands is necessary to control the disease.
Hypoparathyroidism is due to the lack of production/secretion of PTH. It is characterised by low calcium, high phosphate and low PTH. Symptoms are mainly related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms); in severe cases, hypocalcemia leads to cardiac complications. Long-term complications are frequent such as tissues calcifications, nephrocalcinosis, cognitive and neuropsychiatric difficulties. In children, hypoparathyroidism is mainly due to the impaired development of parathyroid glands; in adolescents and adults, hypoparathyroidism may be due to autimmune diseases, drug side-effects and neck surgery.
Autosomal Dominant Hypocalcemia
Autosomal dominant hypocalcemia (AD hypocalcemia) is a disorder of calcium homeostasis characterised by variable degrees of hypocalcemia with abnormally low levels of parathyroid hormone (PTH) and persistant normal or elevated calciuria. Clinical expression and age of onset are extremely variable (depending on the degree of hypocalcemia), ranging from completely asymptomatic patients to patients with limited symptoms (cramps, asthenia, paresthesias) and patients with severe symptoms (i.e. recurrent seizures) similar to that of hypoparathyroidism.
Pseudohypoparathyroidism (PHP) and related disorders
Pseudohypoparathyroidism (PHP) has been recently reclassified as Inactivated PTH/PTHrP Signalling Disorder (iPPSD).PHP (iPPSD) is characterised by the end-organ resistance to PTH. Patients present with hypocalcemia, hyperphosphatemia and elevated PTH in absence of vitamin D deficiency. Symptoms related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms). PTH resistance develops usually during infancy, yet may be diagnosed in adults patients. In some subtypes of PTH (iPPSD), patients present with resistances to other hormones (TSH, GHRH, Calcitonin), early-onset obesity, variable degree of cognitive impairment, ectopic ossifications in cutaneous and adipose tissues and Albright Osteodystrophy (brachydactyly, stocky build and adult short stature).
Vitamin D Dependent Rickets (VDDR) type 1 and 2
Hypocalcemic vitamin D-dependent rickets (VDDR-I) is an early-onset hereditary vitamin D metabolism disorder characterised by severe hypocalcemia and hypophosphatemia leading to osteomalacia and severe rickets. The disease manifests within the first year of life with hypotonia, tetany, seizures, muscle weakness, poor growth, fractures, impaired motor development, teeth defects including enamel hypoplasia and, in some VDDR2, alopecia. The rickets is resistant to 25OHvitamin D treatment and requires an expert care.
Inherited and rare forms of hypophosphatemia and phosphate wasting
Phosphate wasting leads to hypophosphatemia hence osteomalacia, rickets, mineralization defects, bone deformities, bone pain, poor growth, anomalies of teeth mineralization and muscle function impairment. Additional features may include nephrocalcinosis, craniosynostosis, Chiari 1, hearing impairment, entesopathies and hyperparathyroidism. Hypophosphatemia associated with phosphate wasting is usually diagnosed in young children, yet the features are so variable that diagnosis may be reached only in adults or parents of affected patients. Hypophosphatemia associated with phosphate wasting is caused by genetic conditions leading to an increased production/action of the hormone FGF23. In rare cases, the low phosphate level is due to anomalies in the renal phosphate transport (genetic or aquired).
Acquired oncogenic hypophosphatemia or Tumor Induced Osteomalacia (TIO)
Oncogenic hypophosphatemia or Tumor Induced Osteomalacia (TIO) leads to severe hypophosphatemia and phosphate wasting due to a tumoral secretion of FGF23 by mesenchymal tumors; the calcium level is also usually low. Patients (usually adults) present with severe muscular defects, fractures, pseudofractures, bone and muscular pain. It is crucial to localize the source of FGF23 secretion through the best available imaging techniques.
Hyperphosphatemia and tumoral calcinosis
Hyperphosphatemia may be due to the impaired excretion of urinary phosphate. Most cases are of genetic origin and are characterised by a lack of FGF23 secretion. Patients may present with joints and bone pain, diaphysitis and often severe ectopic calcifications.