Clinical characteristics.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by:

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

Suggestive Findings

Hyperphosphatemic familial tumoral calcinosis (HFTC) should be suspected in individuals with the following clinical, laboratory, and/or imaging findings.

Clinical Findings

Tumoral calcinosis or ectopic calcifications are typically seen in periarticular soft tissues exposed to repetitive trauma or prolonged pressure, such as the hips, elbows, and shoulders; they can also be observed in other locations ranging from the eyelid [Ichikawa et al 2006] to the submucosa of the large intestines (Figure 1A&D) [Ramnitz et al 2016].

Figure 1

A. Computed tomography (CT) scan showing calcifications in an adult with HFTC including shoulder and hip soft tissue calcifications (white arrows), aortic calcification (dashed arrow), papillary muscle calcification (black arrow), and submucosal gut calcifications (more...)

Hyperostosis. Some affected individuals experience transient but recurrent episodes of pain in the long bones, typically the tibia, associated with erythema, edema, and warmth of the overlying skin [Ichikawa et al 2007a, Gok et al 2009].

Vascular calcifications occur in both large and small vessels; they are often asymptomatic but can cause symptoms of peripheral vascular insufficiency (e.g., pain, cold extremities, and decreased peripheral pulses). Although rarely the presenting feature, the risk is likely increased over the general population; the true frequency is unknown.

Radiographs

Tumoral calcinosis. Radiographs of affected lesions show heterogeneous calcified masses (Figure 2A&B).

Figure 2

A&B. Radiographs in a child with hyperphosphatemic familial tumoral calcinosis showing tumoral calcinosis of the lateral proximal femur (A) and elbow (B) C. Radiograph of tibias/fibulas in a child showing hyperostosis with hypermineralization (more...)

Hyperostosis. When hyperostosis is symptomatic (i.e., causes pain, erythema, edema, and warmth), long-bone radiographs show hypermineralization of cortical bone, patchy sclerosis of the medullary cavities, diaphysitis, and marked periosteal reaction (Figure 2C) [Clarke et al 1984, Ichikawa et al 2007a, Olauson et al 2008, Gok et al 2009, Joseph et al 2010].

Dental radiographs often show the typical findings of short bulbous roots, obliteration of pulp chambers and root canals, abnormal curvature of the dental roots (known as root dilacerations), thistle-shaped dental pulps, and pulp stones (Figure 2D&E) [Foster et al 2014].

Computed Tomography (CT)

Tumoral calcinosis. Although CT is the preferred imaging modality to identify and measure calcifications and changes in size, it carries a risk of radiation exposure and should be used conservatively, especially in children (Figure 2A&B, Figure 3A).

Figure 3

A. CT 3D reconstruction in an adult with HFTC demonstrating bilateral vascular calcifications in superficial femoral arteries (solid arrows) and multifocal sheet-like calcification of the subcutaneous tissues at the level of the distal tibiae and fibulae (more...)

Vascular calcifications. CT can be particularly helpful in identifying vascular calcifications, which appear hyperattenuated when calcium is present (Figure 3A, C, D).

Establishing the Diagnosis

The diagnosis of HFTC is established in a proband with the clinical findings of tumoral calcinosis and/or characteristic laboratory findings of hyperphosphatemia, increased TRP, elevated or inappropriately normal 1,25D levels, and elevated C-terminal FGF23 levels.

Identification of biallelic germline loss-of-function variants in FGF23, GALNT3, or KL by molecular genetic testing (Table 1) confirms the diagnosis when clinical and laboratory findings are inconclusive.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, or comprehensive genomic testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized most commonly by tumoral calcinosis or ectopic calcifications (typically in periarticular soft tissues exposed to repetitive trauma or prolonged pressure) and hyperostosis (typically manifesting as painful swelling overlying the diaphyses of long bones). Onset of lesions typically occurs in the first two decades of life. The dental phenotype unique to HFTC includes enamel hypoplasia, short and bulbous roots, pulp chamber and canal obliterations, and pulp stones. Less frequently reported findings include large and small vessel calcifications, testicular microlithiasis, and angioid streaks of the retina.

HFTC results from a relative deficiency of or resistance to the phosphate-regulating hormone FGF23, leading to hyperphosphatemia due to increased renal phosphate reabsorption and elevated or inappropriately normal 1,25D production, which promotes gastrointestinal absorption of phosphorus and calcium (for more details see Pathophysiology).

In a review of the medical literature, Rafaelsen et al [2014] found 56 individuals with HFTC from 35 different families with a molecularly confirmed diagnosis of HFTC (i.e., biallelic germline loss-of-function pathogenic variants in FGF23, GALNT3, or KL).

Since the Rafaelsen et al [2014] review, 14 additional individuals with GALNT3-associated HFTC [Krstevska et al 2012, Favia et al 2014, Finer et al 2014, Demellawy et al 2015, Masi et al 2015, Vieira et al 2015, Jost et al 2016, Ramnitz et al 2016] and five individuals with FGF23-associated HFTC [Shah et al 2014, Keskar et al 2015, Jost et al 2016] have been reported.

For unknown reasons, the manifestations of HFTC vary among family members with the same pathogenic variants and genetic background and similar biochemical profiles. One member may have profound, extensive tumoral calcinosis while others are symptom free [Ramnitz et al 2016]. Of note, since HFTC has been reported in many pedigrees with multigenerational consanguinity, some phenotypic features found in association with HFTC may represent the expression of other autosomal recessive disorders.

Tumoral calcinosis represents ectopic calcification in the skin and/or subcutaneous tissue in periarticular locations consisting primarily of hydroxyapatite [Boskey et al 1983, Slavin et al 1993] and – in some reports – calcium carbonate [Annamunthodo 1960]. The lesions often occur at sites of repeat trauma and/or pressure, with the lateral hips being the most frequently reported site. However, the clinical spectrum of tumoral calcinosis is widely variable, ranging from no lesions [Ramnitz et al 2016], to isolated eyelid calcifications [Ichikawa et al 2006], to periarticular calcifications of significant size (Figure 2A&B).

These lesions can be extremely painful and debilitating; some may progress in size, perforate the skin, and drain liquid hydroxyapatite (also known as "milk of calcium"), which is often confused with purulent drainage. Such lesions often heal poorly.

Depending on the size and location, tumoral calcinosis can significantly impair range of motion or lead to frozen joints.

Hyperostosis typically presents as painful swelling in the areas overlying the diaphyses of the long bones (especially the tibiae), and can be the first observed manifestation of HFTC [Clarke et al 1984, Frishberg et al 2005, Ichikawa et al 2007a, Olauson et al 2008, Ichikawa et al 2010, Joseph et al 2010, Favia et al 2014, Jost et al 2016].

Some patients experience repeat episodes of diaphysitis (inflammation of the shaft of a long bone) involving a number of sites including the ulna, tibia, metacarpal bones, and radius [Clarke et al 1984, Campagnoli et al 2006b, Gok et al 2009].

Biopsies of hyperostosis lesions demonstrate reactive new bone surrounded by fibroblastic stroma infiltrated with plasma cells, lymphocytes, and polymorphonuclear cells; cultures are negative [Clarke et al 1984, Ichikawa et al 2010].

Vascular calcifications, identified in affected individuals ranging in age from three to 58 years, are rarely the presenting feature of HFTC. While the true frequency is unknown, the risk of vascular calcifications in HFTC is likely increased over that of the general population.

The calcifications are often incidental findings on radiologic studies, and patients are often asymptomatic. Some patients have significant symptoms of peripheral vascular insufficiency such as pain, cold extremities, and decreased peripheral pulses. Small to large vessel calcifications have been identified in variable anatomic locations including the cerebral vasculature, lower-extremity vasculature (Figure 3A&B), coronary arteries (Figure 3C), mesenteric arteries, renal arteries, carotid arteries, iliac vessels, and aorta [Martinez et al 1990, Li Voon Chong et al 1999, Ichikawa et al 2007c, Lammoglia & Mericq 2009, Rafaelsen et al 2014, Masi et al 2015, Ramnitz et al 2016]. The most severe reported consequences of vascular calcifications were below- and above-the-knee amputations in one man and digit amputations in the man's two affected sisters [Shah et al 2014].

Dental phenotype characteristic of HFTC includes enamel hypoplasia, short and bulbous roots, pulp chamber and canal obliterations, and pulp stones (Figure 2D&E) [Lyles et al 1985, Burkes et al 1991, Benet-Pagès et al 2005, Laleye et al 2008, Krstevska et al 2012, Favia et al 2014].

Dental findings, reported to be the presenting sign in some individuals [Dumitrescu et al 2009, Vieira et al 2015], may be the most common imaging findings of HFTC as they can occur in the absence of calcinosis.

Renal calcifications have been described in two individuals, one of whom had mild impairment in renal function [Chefetz et al 2005, Bergwitz et al 2009].

Inflammation. The cause and role of inflammation in the pathogenesis of the calcific tumors is unclear. Microscopy of the lesions reveals macrophage engulfment of hydroxyapatite crystals, which probably release inflammatory cytokines, the likely etiology of the observed systemic inflammation [Ramnitz et al 2016].

Five individuals have had elevated markers of inflammation; i.e., C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) [Garringer et al 2006, Masi et al 2009, Masi et al 2015, Ramnitz et al 2016]. In one individual clinical symptoms of inflammation included recurrent acute inflammatory polyarthritis of the shoulders, hands, and feet [Garringer et al 2006]. Two others experienced increased fatigue, inflammation-mediated anemia of chronic disease, and thrombocytosis; one also had intermittent fevers and a cutaneous inflammatory calcific reaction [Ramnitz et al 2016].

Testicular microlithiasis was reported in a boy age 14 years. The ultrasound examination showed increased echogenicity with scattered hyperechogenic lesions. A biopsy of one testicle revealed diffuse intratubular calcifications; oligo-azoospermia was noted on spermiogram [Campagnoli et al 2006b]. Similar findings were reported in a man age 45 years [Garringer et al 2007].

Angioid streaks of the retina were reported in four individuals with HFTC [McPhaul & Engel 1961, Yancovitch et al 2011]. One had symptomatic sudden onset of blurred vision attributed to choroidal neovascularization secondary to angioid streaks 14 years after the initial diagnosis of HFTC [McGrath et al 2010].

Phenotype Correlations by Gene

Vascular calcifications appear to be more frequent in persons with biallelic FGF23 loss-of-function variants (5/12) compared to persons with biallelic GALNT3 loss-of-function variants (5/37). However, this observation is limited because not all reported individuals were evaluated for the presence of vascular calcifications.

Pathophysiology

Deficiency of or resistance to FGF23 leads to hyperphosphatemia resulting in increased renal phosphate reabsorption and elevated or inappropriately normal 1,25D production, which promotes gastrointestinal absorption of phosphorus and calcium. Thereby increased blood calcium X phosphate product, calculated by multiplying the blood calcium (mg/dL) by the blood phosphate (mg/dL), predisposes to ectopic soft-tissue calcification in tissues exposed to trauma or inflammation. In persons with renal insufficiency (where this product is most commonly clinically utilized), the incidence of soft-tissue calcification is increased when the calcium X phosphate product exceeds 70 mg²/dL² and decreased when the calcium X phosphate product is less than 50 mg²/dL² [Langman & Salusky 2005].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

• Sibs with the same GALNT3 pathogenic variants have been reported to have markedly different clinical courses [Ramnitz et al 2016].
• Treatment response does not appear to vary by genotype.

Nomenclature

In the past, hyperphosphatemic familial tumoral calcinosis (HFTC) has been referred to as the following:

• Lipocalcinogranulomatosis
• Teutschlaender's lipocalcinogranulomatosis
• Morbus Teutschländer

Prevalence

No formal study has estimated the prevalence of HFTC; the disorder is rare. To date, 75 individuals with a molecularly confirmed diagnosis of HFTC have been reported in the medical literature with an increased propensity in Africa and the Middle East and in populations originating from these regions [Sprecher 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hyperphosphatemic familial tumoral calcinosis (HFTC), the following evaluations are recommended if not done at the time of diagnosis:

• Physical examination with particular attention to:
  • Skin and joints to assess for tumoral calcinosis;
  • Lower extremities to assess for edema, erythema, and pain related to hyperostosis;
  • Peripheral pulses to assess for clinically significant vascular calcification.
  Use ankle-brachial systolic pressure index to confirm clinical suspicion of lower-extremity arterial occlusive disease.
• Metabolic work up including blood phosphorus, blood creatinine, urine phosphorus, urine creatinine to evaluate renal phosphate handling by measuring the tubular reabsorption of phosphorus (TRP) and the ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR)
• Duplex ultrasound examination, CT angiography, and/or magnetic resonance angiography (Figure 3B) to evaluate for vascular calcifications if there is a history of claudication or atypical leg symptoms, or clinical signs of vascular disease on physical examination (e.g., diminished pulses or cold extremities)
• Cardiac CT angiography (Figure 3C&D) to assess for coronary artery calcifications particularly in patients with documented vascular calcifications
• Consultation with a vascular specialist and/or cardiologist for patients with symptomatic vascular calcifications
• Complete blood count, erythrocyte sedimentation rate, and C-reactive protein to evaluate for evidence of systemic inflammation
• Dental consultation including dental radiographs to assess for the HFTC dental phenotype (Figure 2D&E)
• Testicular ultrasound examination to assess for microlithiasis (Figure 1C)
• Renal ultrasound examination to evaluate for medullary nephrocalcinosis
• Ophthalmologic consultation to evaluate for eyelid calcifications and angioid streaks of the retina
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No standard treatment for HFTC exists. No randomized clinical trials have been performed, and studies of the treatment of HFTC consist of case reports or case series.

Most reported therapies attempt to lower blood phosphorus; most patients with HFTC are treated with a combination of medical therapies. Clinical response to these treatments varies. No treatment regimen appears to consistently or universally decrease lesion size or prevent progression or recurrence of lesions after surgery.

Tumoral calcinosis

• Low-phosphate diet. Many patients are instructed to follow a low-phosphate diet in combination with other medical therapies. Limited benefit was reported in use of low-phosphate diet alone [Carmichael et al 2009].
• Phosphate binders, such as sevelamer and aluminum hydroxide, are used to decrease absorption of dietary phosphorus. Response is mixed, including: (1) decrease or no change in blood phosphorus; (2) decrease, no change, or increase in the size of the tumoral calcinosis [Steinherz et al 1985, Yamaguchi et al 1995, Campagnoli et al 2006a, Garringer et al 2006, Ichikawa et al 2007b, Lammoglia and Mericq 2009, Ichikawa et al 2010, Finer et al 2014, Keskar et al 2015, Ramnitz et al 2016].
  Note: (1) Aluminum-containing phosphate binders can probably be used safely in patients with HFTC as opposed to patients with renal failure, in whom the risk of aluminum toxicity is increased due to impaired renal clearance. (2) Calcium salts, used in the past, have fallen out of favor because of their potential to increase the calcium X phosphate product, as defined in Pathophysiology.
• Acetazolamide, a carbonic anhydrase inhibitor, increases urinary phosphate excretion. While some reports describe improvement or resolution of tumoral calcinosis following treatment with acetazolamide alone or – most often – in combination with phosphate binders, other reports describe no change in lesions. Similarly, blood phosphorus levels decreased or remained unchanged [Yamaguchi et al 1995, Garringer et al 2006, Dumitrescu et al 2009, Lammoglia & Mericq 2009, Ichikawa et al 2010, Finer et al 2014, Ramnitz et al 2016].
• Probenecid (which promotes renal phosphate excretion) has been used along with other phosphate-lowering medications. Note: Because probenecid prolongs the half-life of a number of drugs, physicians should assess for drug interactions prior to starting this medication.
  • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [McPhaul & Engel 1961, Lammoglia & Mericq 2009].
  • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [Ichikawa et al 2010].
  • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [Ramnitz et al 2016].
• Niacinamide/nicotinamide, shown to decrease renal phosphate reabsorption, has been evaluated as a short-term treatment in two patients: one showed decreased blood phosphorus during a 48-hour treatment [Dumitrescu et al 2009]; one showed no change in blood phosphorus during an approximately three-week treatment [Ramnitz et al 2016]. Of note, there are no long-term treatment data.
• Topical sodium thiosulfate applied to skin overlying the tumoral calcinosis lesions has been shown to decrease ectopic calcifications after at least five months of treatment in three patients [Jost et al 2016]. The mechanism by which topical or systemic sodium thiosulfate inhibits mineralization is unclear.
• Risedronate, a bisphosphonate with anti-osteoclast activity, was used in one patient for one year, after which no change in blood phosphorus level or obvious improvement in tumoral calcinosis burden was observed [Ichikawa et al 2010]. Of note, there is no mechanistic support for the use of second-generation bisphosphonates in the treatment of HFTC.
• Synthetic salmon calcitonin, a hormone that inhibits osteoclast activity and rental tubular reabsorption of calcium and phosphorus, was administered subcutaneously to one patient in combination with a low-phosphate diet and phosphate binder. The patient had a decrease in blood phosphorus on treatment; tumoral calcinosis lesions remained stable in size while no new ectopic calcifications developed [Candrina et al 1989].
• Surgical resection of tumoral calcinosis lesions has variable outcomes. Some patients have complete resolution of the lesions while others have required multiple surgeries due to lesion recurrence [Carmichael et al 2009, Ichikawa et al 2010, Ramnitz et al 2016]. Given the risks of surgical morbidities and recurrence of lesions, surgical resection of tumoral calcinosis may be reserved for those with significant pain or functional impairment.

Hyperostosis

• Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat the pain and edema associated with hyperostosis [Ichikawa et al 2007a].
• Acetaminophen in combination with NSAIDs has been shown to improve the symptoms of hyperostosis [Ichikawa et al 2010].
• Steroids – prescribed for a brief course in one patient with hyperostosis – reduced edema [Masi et al 2015].

Vascular calcification

• No data are available on the management of vascular calcification in HFTC.
• Patients with vascular calcification should be evaluated by a vascular specialist and/or cardiologist for further assessment and treatment including optimizing other modifiable cardiovascular risk factors.

Systemic inflammation. Interleukin-1 (IL-1) antagonists (canakinumab, a monoclonal IL-1β antibody; or anakinra, a recombinant IL-1 receptor antagonist) were used to treat two patients with overwhelming systemic inflammation after one patient failed treatment with NSAIDs and glucocorticoids. In both, inflammatory markers significantly decreased; in one, calcinosis cutis resolved and perilesional edema of hip tumoral calcinosis improved. Both subjectively reported improved energy, appetite, and overall sense of well-being [Ramnitz et al 2016].

Dental abnormalities. Patients should receive routine dental care.

Testicular microlithiasis

• No data are available on the management of testicular microlithiasis.
• Men with impaired fertility may be referred to a reproductive specialist for further evaluation.

Angioid streaks

• Patients should be referred to an ophthalmologist for evaluation, treatment, and monitoring of angioid streaks of the retina.
• Intravitrial ranibizumab injections improved visual acuity in the only individual reported to experience sudden worsening of vision due to choroidal neovascularization associated with an angioid streak [McGrath et al 2010].

Surveillance

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

Tumoral calcinosis. When initiating medical therapy the following should be monitored regularly:

• Blood phosphorus to help manage medication doses
• Blood calcium and intact parathyroid hormone because levels of 1,25D can be elevated
• Complete blood count, ESR, and CRP to assess for evidence of inflammation
• Renal function because hyperphosphatemia can contribute to development of kidney disease

In patients treated with acetazolamide, blood chemistries to assess for evidence of metabolic acidosis.

In patients treated with probenecid, blood uric acid levels to help manage medication doses. Probenecid should be increased until the blood uric acid level is suppressed or the maximum dose for age is reached.

Radiographs of affected areas can be performed intermittently to evaluate and assess the presence or change in size of lesions of tumoral calcinosis (with the goal of minimizing radiation exposure).

Hyperostosis. Routine surveillance of hyperostosis without clinical symptoms is unnecessary; however, if long-bone pain, erythema, and/or edema develop, obtain radiographs to assess for hyperostosis.

Vascular calcifications. No data are available regarding surveillance for vascular calcifications.

Dental abnormalities. Provide dental surveillance as part of routine dental care.

Testicular microlithiasis. No data are available regarding surveillance for testicular microlithiasis.

Angioid streaks of the retina. Patients with angioid streaks of the retina should be followed by an ophthalmologist.

Agents/Circumstances to Avoid

Because phosphorus-lowering medications are aimed at lowering the calcium X phosphate product, it is prudent to avoid the following:

• Use of calcium salts as phosphate binders
• Excessive dietary calcium intake
• Excessive vitamin D intake and/or 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.

Evaluations can include:

• Blood phosphorus, the most cost-effective approach
• Molecular genetic testing if the pathogenic variants in the family are known
• Evaluation of phosphorus and calcium metabolism including blood phosphorus, blood creatinine, blood calcium, parathyroid hormone, 1,25D, 25-OH vitamin D, C-terminal FGF23, urine phosphorus, and urine creatinine if initial blood phosphorus level is inconclusive or if the pathogenic variants in the family are not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

While there is a lack of information regarding pregnancies in women with HFTC, calcifications of the placenta have been noted post delivery [Li Voon Chong et al 1999, McGrath et al 2010]. Therefore, pregnancy is best managed by a specialist in high-risk maternal-fetal obstetrics.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Hyperphosphatemic familial tumoral calcinosis (HFTC) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The normophosphatemic parents of an affected child are obligate heterozygotes (i.e., carriers of one FGF23, GALNT3, or KL pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder; however, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [Ichikawa et al 2005].
• Rarely, when there is consanguinity this autosomal recessive condition can be reported in consecutive generations.

Siblings of a proband

• 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.
• Because of intrafamilial clinical variability, it is not possible to predict the phenotype in sibs who have inherited biallelic pathogenic variants (see Clinical Description).
• Although heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [Ichikawa et al 2005].

Offspring of a proband

• Unless an individual with HFTC has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an FGF23, GALNT3, or KL pathogenic variant.
• HFTC has been reported in many families with multigenerational consanguinity. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous or homozygous for pathogenic variants in the same HFTC-related gene.
• The offspring of a proband and an individual heterozygous for a pathogenic variant in the same HFTC-related gene have a 50% chance of being affected and 50% chance of being heterozygotes.

Other family members. Each sib of the proband's heterozygous parents is at a 50% risk of being a carrier of a FGF23, GALNT3, or KL pathogenic variant. If there is a history of consanguinity, the risk of being a carrier may be higher.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the FGF23, GALNT3, or KL pathogenic variants in an affected family member.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the FGF23, GALNT3, or KL pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Author Notes

Dr Collins' web page

Our research focuses on bone biology and mineral metabolism, which are studied through clinical and translational studies. Specific areas of interest include the role of PTH, G-proteins, and cAMP in bone cell biology, and FGF23 in mineral metabolism. The primary approach is the study and treatment of patients with rare disorders of bone and mineral metabolism as models through which to understand human bone and mineral biology and physiology. Current models of focus include fibrous dysplasia of bone, hypoparathyroidism, and disorders of FGF23 excess such as tumor-induced osteomalacia and X-linked hypophosphatemic rickets and deficiency such as hyperphosphatemic familial tumoral calcinosis.

Acknowledgments

This research was supported by the Intramural Research Program of the NIH, NIDCR.

Revision History

• 1 February 2018 (bp) Review posted live
• 14 November 2016 (msr) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Hyperphosphatemic Familial Tumoral Calcinosis" is in the public domain in the United States of America.