Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.

Dialysis as a Treatment Option for a Patient With Normal Kidney Function and Familial Tumoral Calcinosis Due to a Compound Heterozygous FGF23 Mutation.

Primary tumoral calcinosis is a rare autosomal recessive disorder characterized by ectopic calcified tumoral masses. Mutations in 3 genes (GALNT3, FGF23, and KL) have been linked to this human disorder. We describe a case of a 28-year-old man with a history of painful firm masses over his right and left gluteal region, right clavicle region, knees, and left elbow. Biochemical analysis disclosed hyperphosphatemia (phosphate, 9.0 mg/dL) and normocalcemia (calcium, 4.8 mg/dL), with normal kidney function and fractional excretion of phosphate of 3%. Parathyroid hormone was suppressed (15 pg/mL), associated with a low-normal 25-hydroxyvitamin D (26 ng/mL) concentration but high 1,25-dihydroxyvitamin D concentration (92 pg/mL). Serum intact FGF-23 (fibroblast growth factor 23) was undetectable. Genetic analysis revealed tumoral calcinosis due to a compound heterozygous mutation in FGF23, c.201G>C (p.Gln67His) and c.466C>T (p.Gln156*). Due to lack of other treatment options and because the patient was facing severe vascular complications, we initiated a daily hemodialysis program even in the setting of normal kidney function. This unusual therapeutic option successful controlled hyperphosphatemia and reduced metastatic tumoral lesions. This is a report of a new mutation in FGF23 in which dialysis was an effective treatment option for tumoral calcinosis with normal kidney function.

Hyperphosphatemic tumoral calcinosis caused by FGF23 compound heterozygous mutations: what are the therapeutic options for a better control of phosphatemia?

BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes encoding FGF23 or its regulators, and leading to functional deficiency or resistance to fibroblast growth factor 23 (FGF23). Subsequent biochemical features include hyperphosphatemia due to increased renal phosphate reabsorption, and increased or inappropriately normal 1,25-dihydroxyvitamin D (1,25-D) levels. CASE-DIAGNOSIS/TREATMENT: A 15-year-old girl was referred for a 1.2-kg-calcified mass of the thigh, with hyperphosphatemia (2.8 mmol/L); vascular impairment and soft tissue calcifications were already present. DNA sequencing identified compound heterozygous mutations in the FGF23 gene. Management with phosphate dietary restriction, phosphate binders (sevelamer, aluminum, nicotinamide), and acetazolamide moderately decreased serum phosphate levels; oral ketoconazole was secondary administered, leading to significantly decreased 1,25-D levels albeit only moderate additionally decreased phosphate levels. However, therapeutic compliance was questionable. Serum phosphate levels always remained far above the upper normal limit for age. The patient presented with two relapses of the thigh mass, requiring further surgery. CONCLUSIONS: We suggest that control of phosphate metabolism is crucial to prevent recurrences and vascular complications in HFTC; however, the medical management remains challenging.

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.

Hyperphosphatemic familial tumoral calcinosis: genetic models of deficient FGF23 action.

Hyperphosphatemic familial tumoral calcinosis (hFTC) is a rare disorder of phosphate metabolism defined by hyperphosphatemia and ectopic calcifications in various locations. To date, recessive mutations have been described in three genes involving phosphate metabolism: FGF23, GALNT3, and α-Klotho, all of which result in the phenotypic presentation of hFTC. These mutations result in either inadequate intact fibroblast growth factor-23 (FGF23) secretion (FGF23 or GALNT3) or resistance to FGF23 activity at the fibroblast growth factor receptor/α-Klotho complex (α-Klotho). The biochemical consequence of limitations in FGF23 activity includes increased renal tubular reabsorption of phosphate, hyperphosphatemia, and increased production of 1,25-dihydroxyvitamin D. The resultant ectopic calcifications can be painful and debilitating. Medical treatments are targeted toward decreasing intestinal phosphate absorption or increasing phosphate excretion; however, results have been variable and generally limited. Treatments that would increase FGF23 levels or signaling would more appropriately target the genetic etiologies of this disease and perhaps be more effective.

Enfermedad de Caffey: reporte de 2 casos / Caffey Disease: two cases´ report

En un período relativamente corto de tiempo se han hospitalizado en nuestro Servicio de Pediatría, dos lactantes pequeños (menores de 6 meses) con igual sintomatología: fiebre, irritabilidad y aumento de volumen de región mandibular, que al estudiarles y realizar diagnóstico diferencial se llega a la conclusión de estar afectados por una hiperostosis cortical infantil (Enfermedad de Caffey).

In a relatively short period of time, there has been hospitalized in the Pediatric Service, two little breast-fed infants (under 6 months) with same symptomatology: fever, irritability and volume´s increase of mandibular region, that when studying and doing the differential diagnosis, resulted of been affected by an infantile cortical hyperostosis (Caffey Disease).

Enfermedad de Caffey: reporte de 2 casos / Caffey Disease: two cases´ report

En un período relativamente corto de tiempo se han hospitalizado en nuestro Servicio de Pediatría, dos lactantes pequeños (menores de 6 meses) con igual sintomatología: fiebre, irritabilidad y aumento de volumen de región mandibular, que al estudiarles y realizar diagnóstico diferencial se llega a la conclusión de estar afectados por una hiperostosis cortical infantil (Enfermedad de Caffey) (AU)

In a relatively short period of time, there has been hospitalized in the Pediatric Service, two little breast-fed infants (under 6 months) with same symptomatology: fever, irritability and volume´s increase of mandibular region, that when studying and doing the differential diagnosis, resulted of been affected by an infantile cortical hyperostosis (Caffey Disease) (AU)

Sporadic congenital infantile cortical hyperostosis (Caffey's disease).

Prognosis of congenital infantile cortical hyperostosis (Caffey's disease) is poor particularly in premature babies. Two cases are presented of congenital Caffey's disease in premature babies. The first baby was hydropic at birth and had cortical hyperostosis involving the mandible and long bones of right upper limb and both lower limbs. The second baby had cortical hyperostosis of the nasal bones causing severe nasal nonchoanal stenosis that needed surgery, in addition to involvement of long bones of the four extremities. Both babies recovered from the disease and were discharged home well. These cases suggest that the improved outcome of congenital of infantile cortical hyperostosis may reflect improvement of neonatal mechanical ventilation and availability of neonatal total parenteral nutrition.

A 2-month-old infant with acute swelling of the extremities and mandible.

The following case is presented to illustrate the roentgenographic and clinical findings of a condition of interest to the orthopedic surgeon. The initial history, physical findings, and roentgenographic examinations are found on the first two pages. The clinical and roentgenographic diagnoses are presented on the following pages.

Antenatal-onset infantile cortical hyperostosis and nonimmune hydrops.

Infantile cortical hyperostosis antenatal onset is an uncommon disease characterized by polyhydramnios, anasarca or hydrops, pulmonary hypoplasia, hepatomegaly, bowed hyperostotic long bones, and a poor prognosis. Sonographically the intrauterine manifestations may be similar to those of osteogenesis imperfecta, type II.

Hiperostose cortical infantil / Infantile cortical hiperostosis

Relatam-se quatro casos de pacientes portadores de hiperostose cortical infantil, conhecida como doença de Caffey, na forma esporádica. Apresentam uma revisäo bibliográfica e discutem a etiologia, o diagnóstico, localizaçäo, manifestaçöes clínico-radiológicas e tratamento. Três pacientes apresentaram comprometimento dos ossos longos e um somente da escápula