IMPE Abstracts

Introduction: Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy caused by postzygotic activating mutations in HRAS, NRAS or KRAS. It is characterised by the presence of congenital epidermal, melanocytic, or sebaceous nevi, elevated circulating FGF23 levels that causes renal phosphate wasting and rickets, skeletal hypomineralization and focal bone lesions ipsilateral to nevi.

Clinical Case: We report an 11 years old (yo) girl, third child of healthy non consanguineous parents, from Argentina with CSHS. At first appointment, at 5 months old, she presented with an extensive epidermal nevus (Phacomatosis Pigmentokeratotica) and normal height and weight. She developed leg length discrepancy at the age of 2 yo. On x-ray showed extended skeletal involvement, poorly defined cortical-medullary junctions and lytic lesion on the side of the skin lesion. All the metaphyseal showed signs of rickets. On biochemical evaluation, phosphatemia was persistently low 2.1 mg/dl (NV: 3-6) with hyperphosphaturia and elevated alkaline phosphatase (ALP) 661 IU/L (NV < 300). She received conventional treatment for hypophosphatemic rickets with oral phosphate salts and calcitriol with favourable metabolic control until she was 6 yo. At that time she developed a central precocious puberty which was treated with triptorelin acetate. Simultaneously, she evolved with a severe clinic compromise with asthenia, chronic pain, weakness, reduced functional capacity and compromise of independent walking. Orthopaedics procedures included repairing fractures and intramedullary rods. Due to clinical, radiological and biochemical worsening with decrease in phosphatemia (1.4 mg/dl) and increase in ALP (2117 IU/L) despite the good compliance to treatment with phosphate salts and calcitriol, she started treatment with Burosumab (monoclonal FGF23 antibody) at 11 yo. After changing treatment, phosphatemia and tubular phosphate reabsorption increased gradually with upward dose titration of burosumab. She has not presented adverse effects, maintaining normal calcemia, parathormone and renal function, with a progressive decrease in ALP and an increase in vitamin D requirements. After 3 months of this treatment, she spontaneously reported improvement in her physical abilities. Sanger sequencing of the main hot spots of HRAS, NRAS and KRAS was performed. A previously reported somatic variant, c.37G>C (p.Gly13Arg) in HRAS was detected from DNA isolated from the affected skin tissue. This variant was not present in DNA from peripheral blood or unaffected tissue.

Conclusion: We report a girl with CSHS confirmed by somatic HRAS mutation and the complications associated. She started treatment with Burosumab with good biochemical and clinical response after 3 months of treatment.