Hyperphosphatemic Familial Tumoral Calcinosis

Clinical characteristics: Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by:

1. Ectopic calcifications (tumoral calcinosis) typically found in periarticular soft tissues exposed to repetitive trauma or prolonged pressure (e.g., hips, elbows, and shoulders); and

2. Painful swellings (referred to as hyperostosis) in the areas overlying the diaphyses of the tibiae (and less often the ulna, metacarpal bones, and radius).

The dental phenotype unique to HFTC includes enamel hypoplasia, short and bulbous roots, obliteration of pulp chambers and canals, and pulp stones. Less common are large and small vessel calcifications that are often asymptomatic incidental findings on radiologic studies but can also cause peripheral vascular insufficiency (e.g., pain, cold extremities, and decreased peripheral pulses). Less frequently reported findings include testicular microlithiasis and angioid streaks of the retina.

Diagnosis/testing: HFTC results from a relative deficiency of – or resistance to – the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23). The clinical diagnosis of HFTC is established by the presence of tumoral calcinosis and/or characteristic laboratory findings of hyperphosphatemia in the setting of inappropriately increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D₃ (1,25D) levels, and elevated C-terminal FGF23 fragments. Identification of biallelic pathogenic variants in FGF23, GALNT3, or KL by molecular genetic testing confirms the diagnosis when clinical and laboratory findings are inconclusive.

Management: Treatment of manifestations: No randomized clinical trials have been performed; studies of the treatment of HFTC consist of case reports or case series. Since FGF23 replacement therapy is not available, treatment relies on lowering blood phosphorus by blocking absorption from the diet (i.e., use of low-phosphate diet and phosphate binders) and/or by increasing renal phosphate excretion (i.e., use of acetazolamide, probenecid, or niacinamide/nicotinamide); however, clinical responses vary. Surgical resection of tumoral calcinosis lesions – generally reserved for those patients with significant pain or functional impairment – has variable success. Treatment of pain associated with hyperostosis is symptomatic. No data on management of vascular calcification or testicular microlithiasis are available.

Surveillance: No specific guidelines address the issue of surveillance in HFTC. The frequency of monitoring depends on the clinical findings and medical treatment, as no data support an appropriate monitoring interval.

Agents/circumstances to avoid: It is prudent to avoid: use of calcium salts as phosphate binders; excessive dietary calcium intake; excessive vitamin D intake/supplements; foods high in phosphorus.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures to avoid development of ectopic calcifications.

Genetic counseling: HFTC is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FGF23, GALNT3, or KL pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.