ESPE Abstracts

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-secreted hormone that regulates phosphorus homeostasis, result in renal phosphate wasting leading to rickets or osteomalacia. Patterns leading to FGF23 excess are still unknown. Recently, FGF23 elevated rickets has been associated with epidermal nevus syndrome, designating the cutaneous skeletal hypophosphatemia syndrome (CSHS). The clinical picture is not completely defined as, to date, only about fifty CSHS patients have been reported, all harbouring gain-of-function somatic mutations in HRAS or NRAS genes. RAS/MAPK signaling pathway is a key regulator of FGF23 production and the various clinical manifestations underscore its ubiquitous nature. We describe the first CSHS case molecularly confirmed, who developed a thyroid medullary carcinoma. The patient is an 11-year-old boy. At birth a large pigmented skin lesion involving the right hemisome was found. Dermatological evaluation diagnosed an extensive epidermal nevus, for which he underwent surgical treatment and laser therapy. Brain MRI and abdominal ultrasound were normal. At the age of two, he presented bilateral flatfoot and valgus knee, which progressively worsened. He was referred to our Pediatric Endocrinology Unit at 4 years old: from blood chemistry tests a picture of hypophosphatemic rickets emerged, so treatment with oral phosphate and calcitriol was started; growth was within the family target. Sequencing of genes associated with hypophosphatemic rickets and with RASopathies on DNA from blood was negative. Due to poor clinical response to standard rickets therapy, at the age of five he underwent bilateral femoral hemiepiphysiodesis surgery. At the age of seven he underwent total thyroidectomy because of a medullary carcinoma diagnosis. At 10 years old he started therapy with human monoclonal antibody burosumab, showing a particular good response, indeed he needs drug administration every 2-3 months. Based on the clinical picture, we repeated sequencing of the RAS/MAPK pathway genes on DNA from epidermal nevus biopsy and detected the pathogenic missense variant NM_005343.4:c.182A>G p.(Gln61Arg) in the HRAS gene, with an allele frequency of 35%. The HRAS variant was detected in DNA from urinary cells (at 4%), but not in saliva, confirming the mosaic and the CSHS diagnosis. In conclusion, in case of FGF23 increased hypophosphatemic rickets it is important to evaluate the presence of other particular clinical features and take into consideration a mosaic disorder of the RAS/MAPK signaling pathway. To reach the correct diagnosis allows to establish the more effective treatment and follow-up.