The Complexities and Challenges of Managing Genetic Causes of Hyperphosphataemia, a Case Report

Hyperphosphataemic familial tumoral calcinosis (HFTC) is a rare, disabling disorder caused by a relative deficiency of or resistance to the phosphate regulating hormone—fibroblast growth factor 23 (FGF23) [1], resulting in hyperphosphataemia with ectopic calcification. This leads to inflammatory pain, reduced range of movement, and impairment in physical function [1].

Patient one, a 14-year-old healthy Caucasian boy, active in sports, who presented to an orthopaedic surgeon with a painful lump around his left elbow (Figure 1A,B) without a preceding history of trauma. He was systemically well with an unrestricted range of movement. Initial investigations included X-ray and MRI, which demonstrated a calcified mass around the triceps insertion (Figure 1C,D), elevated serum phosphate 2.0 mmol/L (1.10–1.80 mmol/L), normal serum calcium 2.5 mmol/L (2.10–2.60 mmol/L) and inappropriately normal tubular reabsorption of phosphate 95% (82%–95%) (Table 1). He was referred for endocrinologic assessment.

He had no relevant past or family history in a non-consanguineous family. Detailed questioning revealed only previous observation of short tooth roots by his dentist (Figure 1E). HFTC was confirmed on genetic testing, which demonstrated compound heterozygosity for two diagnostic variants in GALNT3 (c.892delT;p.(Tyr298Thrfs*5)) classified as pathogenic and c.1312C>T;p.(Arg438Cys) classified as likely pathogenic.

Dietary phosphate restriction was commenced on consultation with a paediatric renal dietician. Compliance was limited by his dairy preference. Sevelamer 800 mg three times a day, was added, as a phosphate binder, to decrease enteral phosphate absorption. Despite this, his condition progressed and the elbow mass increased in size over the next 8 months (Figure 1F,G). He subsequently developed a second 9 mm area of calcification medial to the left greater trochanter (Figure 1H,I). The resulting hip pain and restricted mobility limited his sporting ability and was associated with a significant mental health deterioration.

Biochemically elevated phosphate levels persisted with inappropriately normal tubular reabsorption of phosphate (Table 1) and low intact FGF23 (iFGF23)—19.8 ng/L (23.2–95.4 ng/L) consistent with the GALNT3 mutation. Following nephrology advice, Acetazolamide 250 mg QID (carbonic anhydrase inhibitor) was added to increase urinary phosphate loss.

As restricted movement of his left arm worsened, he underwent surgical excision of the calcinosis of the left elbow lesion. Despite serum hyperphosphataemia due to dietary non-compliance, tubular reabsorption of phosphate has reduced and is stable with acetazolamide (Table 1). Following 2 years of medical treatment, his calcinosis has not recurred in his elbow and has completely resolved in his hip, and his return to sport has improved his mental state (Figure 1J,K).

Patient 2 is a 10-year-old boy of Middle Eastern descent, with fourth degree consanguineous parents. He presented with right hip pain, limiting the range of movement. Figure 1L shows a calcified mass at the right greater trochanter. Similar to Case 1, he had persistently elevated serum phosphate level 2.2 mmol/L (0.9–1.65 mmol/L), an inappropriately low iFGF23 level 16.1 ng/L (23.2–95.4 ng/L) (Table 2). He had an unexpectedly normal 1,25-dihydroxyvitamin D of 130 nmol/L (60–208 nmol/L) with a low 25-hydroxyvitamin D 29 nmol/L (50–150 nmol/L), consistent with the lack of the inhibitory effect of iFGF23 on 1 alpha hydroxylase function. Genetic testing confirmed a homozygous pathogenic variant of GALNT3 (c.1524 + 1G>A transition in IVS8).

He was treated with sevelamer and acetazolamide. Probenecid was trialled but not tolerated due to severe nausea. The right hip calcification completely resolved (Figure 1M). During 2019, he was non-compliant with medication, resulting in increased serum phosphate 2.4 nmol/L (NR 0.9–1.65) and serum calcium 2.5 mmol/L (NR 2.1–2.5) (Table 2). Two discrete calcific lesions were documented on CT scan in the middle third of the right coronary artery, the left having no calcification. He was recommenced on sevelamer and acetazolamide with improvement in serum phosphate and calcium levels, with no evidence of subcutaneous calcification. Cardiology consultation suggested 5 yearly CT if phosphate is well controlled and 2 yearly if not. Following intercountry relocation, regular cholecalciferol was commenced due to low 25-dihydroxyvitamin D level (16 nmol/L), resulting in an increase in his 1,25-dihydroxyvitamin D level 466 pmol/L (60–208 pmol/L), 25-hydroxyvitamin D 33 nmol/L (50–150) and increase in phosphate load 2.3 (1-2 mmol/L) corrected Ca 2.4 (2.4–2.55 mmol/L) (Table 2). The cholecalciferol was ceased. Due to intermittent compliance, serum phosphate and calcium levels remain elevated, with a normal tubular reabsorption of phosphate with ongoing surveillance of cardiac lesions; he has not developed further soft tissue or eye lesions.

HFTC is a rare group of autosomal recessive conditions, characterised by hyperphosphataemia in the setting of inappropriately increased tubular reabsorption of phosphate [2]. There are less than 100 genetically confirmed cases reported [2]. It has a broad phenotype with significant heterogeneity in the clinical profile [1]. In children or adolescents, it often presents as painful, firm, tumour-like calcified lesions in soft tissue exposed to repetitive trauma or prolonged pressure such as in the hips, elbows and shoulders [2, 3]. The calcified swellings may grow and become very large, causing severe limitation in joint movements, resulting in significant disability [2]. Non-specific inflammatory symptoms such as joint pain, fever and anaemia have been described with associated elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). This is due to macrophages secreting inflammatory cytokines after engulfing hydroxyapatite crystals in the calcified deposits [2].

The dental phenotype is unique to this condition and is the most penetrant feature, including enamel hypoplasia with short bulbous roots (resembling a thistle), pulp stones and obliteration of pulp chamber (Figure 1E). These changes are most commonly seen in premolar teeth [2]. The dental changes are often the first reported manifestations of HFTC before the development of tumoral calcinosis, and are thus important for early recognition by dentists [1, 2].

Less common features include cardiac calcification, including coronary vessels or muscular structures, with increased risk of cardiac events [2]. Small vessel calcification results in peripheral vascular insufficiency (which may require amputation). The phenotype is variable, with case reports describing deposition in small, medium, and large vessels [4]. Deposition also occurs in visceral structures such as the tongue, intestine, dura mater, nephrocalcinosis, and testicular microlithiasis [1, 2]. Eye involvement includes angioid retinal streaks with risk of sudden vision loss or calcific deposits in the eyelids, conjunctiva, or cornea [2]. Computed tomography (CT) imaging provides detailed anatomical information for the detection and monitoring of lesions; however, given the significant phenotypic variability, clinicians should carefully weigh the benefits of imaging against the risks associated with radiation exposure [1].

FGF23, an osteocyte-derived hormone, plays a critical role in phosphate and vitamin D homeostasis [5]. In the proximal tubule of the kidney, FGF23 binds the FGF receptor 1 and its co-receptor KLOTHO, downregulating expression of the sodium-phosphate co-transporters, resulting in phosphaturia [2, 3, 6, 7]. Additionally, FGF23 inhibits 1-alpha-hydroxylation and stimulates 24-hydroxy vitamin D hydroxylase, resulting in decreased 1,25-dihydroxyvitamin D (calcitriol) synthesis, lowering serum phosphate levels by reducing intestinal absorption [1]. Hyperphosphataemia causes FGF23 release from osteocytes, inducing phosphaturia as well as reducing 1,25-hydroxyvitamin D synthesis. Defects in FGF23 action or secretion can therefore not only result in hyperphosphataemia, but also hypercalcaemia and low parathyroid hormone levels due to increased 1,25-hydroxyvitamin D levels [1].

HFTC is caused by either a deficiency of active intact FGF23 or a defect in signalling of pathological variants (GALNT3, FGF23 or KLOTHO) [1]. The resultant defect in all types of HFTC is an increased activity of the sodium-phosphate co-transporter and increased activity of 25-hydroxyvitamin D 1-alpha hydroxylase in the kidney [2]. The hyperphosphataemia and high-normal calcium levels lead to an increased calcium × phosphate product, contributing to ectopic calcifications. Alkaline phosphatase (ALP) which in bone plays a role in its formation, is within the normal range in HFTC as the primary issue is not bone turnover, a key distinguishing feature from other metabolic disorders involving ectopic calcification [8].

Given the rarity of the condition and the absence of controlled trials, clinical management relies heavily on individual case reports. This highlights the essential role of publishing rare disease cases and promoting international collaboration to enhance collective knowledge and guide evidence-informed care in rare diseases. Current treatment primarily targets inflammatory pain control and phosphate depletion through either a low phosphate diet, which is difficult for most patients as phosphate is in most food, or the use of phosphate lowering therapies [1]. Phosphate lowering therapies work by either reducing phosphate intestinal absorption with phosphate binders or by increasing renal excretion. Phosphate binders (sevelamer, lanthanum, aluminium hydroxide) decrease dietary phosphate intestinal absorption, so they need to be taken with each meal [2]. Phosphate binders prevent dietary phosphate absorption within the intestine by exchanging a cation with the anion phosphate, creating a non-absorbable compound that is excreted in the stool [9]. There are a number of avenues to increase phosphate excretion. These include diuretics (furosemide, hydrochlorothiazide), aminoglycoside antibiotics (gentamicin), tyrosine kinase inhibitors (sirolimus), glucocorticoids, probenecid, and carbonic anhydrase inhibitors (acetazolamide). Carbonic anhydrase inhibitors increase urinary phosphate loss by renal tubular acidification and increase urinary phosphate excretion [2, 10, 11]. By lowering the serum pH, it also contributes to increasing the solubility of calcium phosphate salts found in tumoral calcinosis [2]. A major side effect is metabolic acidosis.

Surgery is reserved for extreme cases, often needing to be repeated when regrowth of calcification occurs [2, 10].

25-hydroxyvitamin D supplementation not advised in this condition, even if low, as it results in further increase in 1,25-dihydroxyvitamin D and phosphate, and may exacerbate calcium deposition, as seen in Case 2 [2]. Indeed, given the increased secretion of 1,25-dihydroxyvitamin D, maintaining lower than normal levels of 25-hydroxyvitamin D would be preferable to reduce intestinal calcium and phosphate absorption.

The strengths of this case report are that it highlights a rare condition where detailed history results in early and accurate diagnosis. If misdiagnosed, patients' symptoms worsen due to the pathogenesis of this condition or due to incorrect therapy such as 25-hydroxyvitamin D supplementation. The limitation of this case report is its inability to establish causality, provide information on epidemiological quantities, and is limited to the compliance of the patients that are described.

The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by the Melbourne Children's Hospital, Royal Children's Hospital, Melbourne, Victoria—Ethics approval was not required for this case report. All procedures involving human participants were conducted in accordance with the ethical standards of the Royal Children's Hospital, Melbourne, Victoria, Australia and the Declaration of Helsinki (1964), as revised in 2013.

Consent was obtained from the human participants prior to the production of this report.

The authors declare no conflicts of interest.