The Successful Treatment of Deep Soft-tissue Calcifications with Topical Sodium Thiosulphate and Acetazolamide in a Boy with Hyperphosphatemic Familial Tumoral Calcinosis due to a Novel Mutation in FGF23

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder. Topical sodium thiosulfate (STS) and acetazolamide can be a safe and effective treatment for patients who do not respond to conventional therapy for ectopic calcifications. We report the successful treatment of deep soft-tissue calcifications with topical STS and acetazolamide in a boy diagnosed with HFTC due to a novel homozygous mutation of FGF23.

Therapeutic success of sodium thiosulfate in treating cutaneous calciphylaxis in a patient with hyperphosphataemic familial tumoral calcinosis.

Calciphylaxis is a potencially disorder in patients with hyperphosphatemic familial tumoral calcinosis (HFTC). Patients commonly present livedo racemosa and retiform purpura, which may progress to necrosis and very painful ulcers. Treatment with sodium thiosulfate provides good results; however, intralesional and intravenous treatment can be limited by its adverse effects. Topical sodium thiosulfate has been successfully reported for cutaneous calcification associated with connective tissue diseases and calciphylaxis in patients with chronic kidney disease. We provide a case report of a patient with HFTC and calciphylaxis who was treated with topical sodium thiosulfate with a rapid and complete response with no side effects.

FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho.

The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts.

PURPOSE OF REVIEW: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

Hiperostosis cortical infantil: reporte de caso / Infantile cortical hyperostosis: Case report

La hiperostosis cortical infantil, o enfermedad de Caffey-Silverman, es una entidad clínica caracterizada por neoformación ósea perióstica secundaria a un proceso inflamatorio agudo. De baja frecuencia, su curso clínico es generalmente autolimitado y de excelente pronóstico. Objetivo: Presentar el caso de un lactante portador de un cuadro clínico compatible con una hiperostosis cortical infantil. Caso clínico: Lactante varón, 4 meses de edad, previamente sano, que consultó por presentar irritabilidad, llanto, aumento de volumen en la cara, los brazos y las piernas. Se observó aumento de volumen al nivel de la rama mandibular bilateral, simétrica, sensible, sin cambios en la coloración, la temperatura o la textura, hasta la región preauricular. El estudio bioquímico fue normal, y el estudio radiológico mostró reacción perióstica (periostitis e hiperostosis) al nivel de la rama mandibular, el fémur izquierdo, la tibia y el radio bilateral. Se manejó con antipiréticos, antiinflamatorios y analgésicos, y estuvo en observación en el servicio de urgencias durante 6 h, donde se decidió su egreso y el manejo ambulatorio. La sintomatología cedió por completo entre 4 y 6 semanas después del alta. Conclusión: La hiperostosis cortical es una colagenopatía que debe ser considerada como diagnóstico diferencial en cuadros agudos de inflamación ósea, irritabilidad y fiebre. Es indispensable conocerla para sospecharla y la correlación clínico-radiológica es notable.

Infantile Cortical Hyperostosis, or Caffey-Silverman disease, is a rare condition characterised by generalised bone proliferation mediated by an acute inflammatory process. Diagnosis can be made through clinical evaluation and X-ray studies. The course is generally self-limiting and prognosis is excellent. Objective: To present the case of a 4-month child with clinical and radiological symptoms compatible with Infantile Cortical Hyperostosis. Case report: A 4-month old male who presented with crying and irritability associated with swelling of the face, arms and legs was admitted to the Emergency Room of National Institute of Pediatrics. Bilateral mandibular swelling extending to periauricular region was observed, with no signs of inflammation. X-ray studies showed a periosteal reaction in the jaw, left femur and tibia, and radius bilateral. Clinical observation combined with analgesics and antipyretics was the only medical intervention. Four to six months after discharge from hospital, the symptoms disappeared, confirming the good prognosis of this condition. Conclusion: Infantile cortical hyperostosis is a collagenopathy, which must be considered as a differential diagnosis in acute bone inflammatory processes, irritability and fever. It is important to understand and identify this disease and clinical-radiological correlation is remarkable.

Topical Sodium Thiosulfate: A Treatment for Calcifications in Hyperphosphatemic Familial Tumoral Calcinosis?

CONTEXT: Hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperphosphatemia hyperostosis syndrome (HHS) are rare diseases characterized by hyperphosphatemia and ectopic calcifications or recurrent episodes of diaphysitis. In the setting of metabolic or inflammatory diseases, recent data suggest that systemic administration of sodium thiosulfate (STS) could be effective in the treatment of ectopic calcifications but may also be poorly tolerated (digestive symptoms, metabolic acidosis). Our group developed a topical formulation of STS to treat ectopic calcifications locally, therefore limiting patient exposure to the drug and its adverse effects. OBJECTIVE: We aimed at describing efficacy and tolerance for a topical formulation of STS in treated patients. DESIGN: We performed a retrospective study wherein clinical, radiological, and biological data before and after the application of the topical STS treatment were collected and analyzed. PATIENTS OR OTHER PARTICIPANTS: Three patients admitted to 3 different hospitals with an ectopic calcification secondary to HFTC or HHS were treated with topical STS. INTERVENTION: The topical STS was applied daily by the patients. RESULTS: A significant clinical and radiological decrease of ectopic calcifications was observed after at least 5 months of treatment. The STS treatment was well tolerated and no clinical or biological side effects were observed. CONCLUSION: Topical STS appears to be a promising treatment for ectopic calcifications secondary to HFTC or HHS.

[Infantile cortical hyperostosis: Case report]. / Hiperostosis cortical infantil: reporte de caso.

Infantile Cortical Hyperostosis, or Caffey-Silverman disease, is a rare condition characterised by generalised bone proliferation mediated by an acute inflammatory process. Diagnosis can be made through clinical evaluation and X-ray studies. The course is generally self-limiting and prognosis is excellent. OBJECTIVE: To present the case of a 4-month child with clinical and radiological symptoms compatible with Infantile Cortical Hyperostosis. CASE REPORT: A 4-month old male who presented with crying and irritability associated with swelling of the face, arms and legs was admitted to the Emergency Room of National Institute of Pediatrics. Bilateral mandibular swelling extending to periauricular region was observed, with no signs of inflammation. X-ray studies showed a periosteal reaction in the jaw, left femur and tibia, and radius bilateral. Clinical observation combined with analgesics and antipyretics was the only medical intervention. Four to six months after discharge from hospital, the symptoms disappeared, confirming the good prognosis of this condition. CONCLUSION: Infantile cortical hyperostosis is a collagenopathy, which must be considered as a differential diagnosis in acute bone inflammatory processes, irritability and fever. It is important to understand and identify this disease and clinical-radiological correlation is remarkable.

Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by enhanced renal phosphate absorption, hyperphosphatemia, and tumor-like extraosseous calcifications due to inactivating mutations in FGF23 or associated proteins. Surgical excision is needed when low phosphate diet and phosphate binders are ineffective. Sporadic reports have supported acetazolamide use. We report on a 7-year-old African American boy who presented with severe HFTC requiring numerous surgical excisions. Tumors continued to appear and others reoccurred despite phosphate restriction and sevelamer carbonate. At the age of 9.5 years, acetazolamide (40 mg/kg/day) was added and resulted in mild metabolic acidosis (bicarbonate 25.3 mEq/L vs. 21.4 mEq/L, P < 0.001; serum pH 7.38 vs. 7.31, P = 0.013, pre- and post-acetazolamide, respectively) but no change in tubular reabsorption of phosphate (TRP) (96.9% vs. 95.9%, P = 0.34) or serum phosphate (6.6 mg/dl vs. 6.9 mg/dl, P = 0.52 pre- and post-acetazolamide, respectively). Following the initiation of acetazolamide therapy, the patient experienced significant improvement in disease course as indicated by resolution of localized bone pain, cessation of tumor formation, and no tumor recurrence. Despite mild metabolic acidosis, our patient had improved linear growth and did not develop any other side effects related to therapy. Intact FGF23 remained abnormally low throughout disease course, while C-terminal FGF23 increased with acetazolamide. We conclude that acetazolamide can control severe HFTC by inducing mild metabolic acidosis despite no change in serum phosphate or TRP. This effect may be exerted though improved calcium-phosphate complex solubility and increased FGF23 locally.

Side-effects of long-term prostaglandin E(1) treatment in neonates.

BACKGROUND: In some neonates suffering from ductus arteriosus dependent congenital heart defect, a Prostaglandin E(1) (PGE1) therapy longer than 2 weeks may be needed. However, PGE1 analogue compounds may produce several adverse effects. METHODS: The authors retrospectively analyzed the data of nine patients who underwent a PGE1 treatment lasting longer than 14 days. RESULTS: The leukocyte count of the patients remained high throughout the treatment period, and the proportion of neutrophils was over 50%. Transient feeding difficulty and abdominal distension, and possible signs of gastric-outlet obstruction, were observed in two cases. In the case of three patients, cortical hyperostosis developed after different cumulative doses (1584, 3384 and 4320 microg). Significant correlations were found between the doses of PGE1 and serum K(+) levels (r=-0.770, P < 0.05) and between the blood standard bicarbonate levels and PGE1 doses (r= 0.889, P < 0.01). Bartter syndrome-like condition developed in those three patients who received the largest cumulative doses. CONCLUSIONS: Fluid-electrolyte parameters must be controlled frequently in the case of each patient treated with PGE1 for longer than 2 weeks. Although the dose, the length of the therapy and individual susceptibility may be equally important, fluid-electrolyte disturbances and the development of pseudo-Bartter syndrome seem to be more dose-dependent than cortical hyperostosis.

Indomethacin treatment of infantile cortical periostosis in twins.

Twin girls presented with infantile cortical periostosis (Caffey's disease) at 2 and 3 weeks of age, respectively. This disorder initially involved their upper and lower limbs and resulted in fever, irritability and tenderness. X-rays showed extensive periosteal new bone formation. Multiple relapses occurred in the first year of life and during some of these relapses mandibular and clavicular involvement was noted. Prednisolone, 1 mg/kg per day, was used to treat relapses until 9 months of age. Indomethacin therapy at this age at a dose of 3 mg/kg per day allowed the cessation of prednisolone therapy and disease flares were thereafter infrequent and responsive to indomethacin.

A case of recurrent Caffey's disease treated with naproxen.

Caffey's disease (infantile cortical hyperostosis) is considered to be a benign self-limiting disease of uncertain etiology that typically appears in early infancy. The following case of Caffey's disease in a young girl is significant from 2 standpoints. First, the course of the disease is atypical because of its severe recurrent nature. The patient experienced 6 highly symptomatic episodes of cortical hyperostosis involving multiple new sites and previously healed lesions. These recurrent episodes persisted into her fourth year of life. In general, the reported cases of late recurrence of Caffey's disease describe patients with minimal symptoms and mild bony involvement. The second area of significance involves the successful use of naproxen to control the symptoms and arrest the progression of the patient's disease. Reports of hyperostosis in patients receiving prostaglandin E to maintain a patent ductus arteriosus suggest that prostaglandins may play a role in the etiology of Caffey's disease. Given this evidence, it seems plausible that there may be a therapeutic role for prostaglandin inhibitors in the successful treatment of Caffey's disease. The patient in this case had immediate and complete resolution of her symptoms while receiving naproxen with no recurrent bone formation while being treated with antiinflammatory drugs.

Mineral balance in infantile cortical hyperostosis: effects of corticosteroids.

The effects on mineral metabolism of therapeutic doses of corticosteroids were investigated in infantile cortical hyperostosis; in four untreated cases the calcium, phosphorus, and magnesium balances were strongly positive. In one severe case, treatment with prednisolone was associated with an alteration to negative calcium and magnesium balance, and faecal losses of calcium were particularly high. This effect persisted for at least three months after the steroids had been discontinued, and during this period there was pronounced retardation of linear growth. Six months after the treatment had been stopped mineral balance was again positive and there was rapid 'catch up' in growth. In infancy, the negative effect of corticosteroids on calcium, phosphorus, and magnesium metabolism may contribute to inhibition of bone growth and steroid stunting.