Hyperphosphataemic Familial Tumoural Calcinosis

Hyperphosphataemic familial tumoural calcinosis is a rare autosomal recessive disorder of phosphate retention. It causes hyperphosphataemia and painful calcium phosphate deposits around large joints, with normal calcium.

Causes are loss of function variants in GALNT3, FGF23 and KL, which reduce active FGF23 or its action. The disease is described mainly in families from the Middle East, North and West Africa and parts of Asia.

Onset is in childhood or adolescence. A milder form with diaphysitis and cortical hyperostosis is called hyperostosis hyperphosphataemia syndrome and shares the same genes.

Pathophysiology.

Intact FGF23 is too low (GALNT3 prevents its cleavage) or fails to act on its receptor (KL, FGF23 variants), so renal phosphate reabsorption is high and calcitriol is inappropriately high. Raised calcium and phosphate product leads to ectopic calcification at sites of mechanical stress.

• Progressive periarticular masses over hips, elbows and shoulders, painless at first then painful, limiting movement. Skin ulceration and discharge of chalky material.
• Dental pulp stones, short roots and abnormal teeth. Diaphysitis with bone pain. Angioid streaks and vascular calcification are reported.

Red flags.

• Infected or discharging masses and sinus formation.
• Nerve compression.

• Fasting phosphate raised for age with normal calcium, normal or low parathyroid hormone, and normal or raised calcitriol. Alkaline phosphatase normal or raised.
• Tubular maximum reabsorption of phosphate to glomerular filtration rate raised, with normal kidney function.
• Intact FGF23 low (with C-terminal FGF23 raised in GALNT3 disease) or raised C-terminal and intact FGF23 in some FGF23 or KL disease.
• Radiographs and CT: lobulated, cystic, calcified masses with fluid levels (sedimentation sign). Dental radiographs. Genetic testing.

Differential diagnosis.

• Tumoural calcinosis from kidney disease or hyperparathyroidism (phosphate raised with parathyroid hormone high).
• Normophosphataemic tumoural calcinosis (SAMD9).
• Calcinosis from systemic sclerosis, dermatomyositis or vitamin D excess.
• Calcific periarthritis and pseudoxanthoma elasticum.

• Dietary phosphate restriction to under 800 mg daily.
• Phosphate binders with meals: sevelamer 800 to 1600 mg three times daily, or lanthanum 500 to 1000 mg three times daily. Aluminium hydroxide is used for short courses only because of aluminium accumulation.
• Acetazolamide 250 mg twice daily, up to three times daily, to increase phosphate excretion. Monitor bicarbonate and potassium, and avoid in sulphonamide allergy.
• Surgical removal of large, painful or ulcerated masses after phosphate is controlled; recurrence is common.
• Evidence is from case reports and small series.

Special groups. Children: growth, dental care and orthopaedic review. Genetic counselling for families.

Monitoring. Phosphate, calcium, parathyroid hormone, creatinine, alkaline phosphatase, bicarbonate and potassium every 3 months. Radiographs yearly.

Referral and escalation. Endocrinology or metabolic bone service with orthopaedics; urgent review for infection or neurological compression.