Cutaneous Skeletal Hypophosphatemia Syndrome Research Articles

Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and FGF23-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels. This study aims to elucidate whether the source of FGF23 excess in CSHS is RAS mutation-bearing bone or skin lesions. Toward this end, we analyzed the expression and activity of Fgf23 in two mouse models expressing similar HRAS/Hras activating mutations in a mosaic-like fashion in either bone or epidermal tissue. We found that HRAS hyperactivity in bone, not skin, caused excess of bioactive intact FGF23, hypophosphatemia, and osteomalacia. Our findings support RAS-mutated dysplastic bone as the primary source of physiologically active FGF23 excess in patients with CSHS. This evidence informs the care of patients with CSHS, arguing against the practice of nevi removal to decrease circulating, physiologically active FGF23.

Response to Letter to the editor regarding, “Phacomatosis spilosebacea and cutaneous skeletal hypophosphatemia syndrome”

Response to Letter to the editor regarding, “Phacomatosis spilosebacea and cutaneous skeletal hypophosphatemia syndrome”

Phacomatosis spilosebacea and cutaneous skeletal hypophosphatemia syndrome

Phacomatosis spilosebacea and cutaneous skeletal hypophosphatemia syndrome

A case report to assess the safety and efficacy of Burosumab, an investigational antibody to FGF23, in a single pediatric patient with Epidermal Nevus Syndrome and associated hypophosphatemic rickets

Epidermal Nevus Syndrome (ENS), also known as Cutaneous Skeletal Hypophosphatemia Syndrome or Linear Sebaceous Nevus Syndrome, is caused by a mosaic somatic mutation of RAS (Rat Sarcoma genes) which leads to abnormally elevated levels of fibroblast growth factor 23 (FGF23). FGF23 is a major regulator in phosphate homeostasis. There are multiple disorders, along with Epidermal Nevus Syndrome (ENS), that result in unusually high circulating levels of FGF23. This increase ultimately leads to renal phosphate wasting and reduced levels of 1,25-dihydroxy vitamin D. Across these disorders, the clinical symptoms are similar and often include osteomalacia (hypophosphatemic rickets in children), muscle weakness, fatigue, joint deformities, bone pain, and fractures. Burosumab (KRN23), is an IgG1 monoclonal antibody that binds to the FGF23 receptor and inhibits the activity of FGF23. This leads to an increase in serum phosphate levels. Burosumab emerged as a potential therapy in FGF23 overactivity disorders. Burosumab was successful in the treatment of X-linked hypophosphatemia (XLH) and is now FDA-approved for its treatment. Studies have indicated that Burosumab therapy in subjects with XLH consistently increases and sustains serum phosphorus levels and tubular reabsorption of phosphate without a major impact on urine calcium levels or vitamin D metabolism. We studied the effect of Burosumab treatment in a single pediatric patient with Epidermal Nevus Syndrome. Serum phosphorus rose gradually as we titrated the dose of Burosumab upwards. During treatment, a persistent elevation of parathyroid hormone levels was noted along with a persistent elevation of serum calcium. We presumed the patient had tertiary hyperparathyroidism. However, after the removal of three parathyroid glands, the pathology came back with a single enlarged parathyroid adenoma. Subsequently, his calcium and PTH, and phosphorus levels stabilized while taking only Burosumab.ClinicalTrials.gov NCT04320316.

Cutaneous skeletal hypophosphatemia syndrome

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Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report

Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report

Rickets in association with skin diseases and conditions: A review with emphasis on screening and prevention.

Rickets is a common disease worldwide. In the developed world, its prevalence dramatically decreased but still diagnosed in at-risk populations. The skin plays a critical role in vitamin D synthesis. Therefore, several skin diseases, especially keratinization disorders, could lead to impaired vitamin D metabolism and vitamin D deficient rickets. The article aimed to summarize the current knowledge of skin diseases and conditions associated with rickets. To examine the association between rickets and skin diseases, we performed a systematic review of the literature using PubMed database. The search included studies published from the database inception to August 2019. A total number of 75 articles were included. Identified conditions associated with rickets were ichthyosis being a more common skin diseases, alopecia, epidermal and melanocytic nevi, xeroderma pigmentosum, mastocytosis, psoriasis, and atopic dermatitis. Three types of rickets were identified: vitamin D-dependent rickets, hypocalcemic vitamin D-dependent rickets type 2, and hypophosphatemic rickets. Cutaneous skeletal hypophosphatemia syndrome is a newly described and under-recognized condition. It is defined by the association of epidermal or melanocytic nevi, hypophosphatemic rickets, and elevated levels of fibroblast growth factor 23. Rickets in patients with ichthyosis was mainly due to impaired ability of ichthyotic skin to synthesize vitamin D, poor UV penetration of the skin caused by keratinocyte proliferation, and dark phototype. The latter may be considered a risk factor for rickets in patients with ichthyosis. Despite its rarity, these associations should be properly recognized by dermatologists. Early diagnosis of rickets is important to prevent growth retardation and skeletal deformities.

New Therapies for Hypophosphatemia-Related to FGF23 Excess.

FGF23 is a hormone produced by osteocytes in response to an elevation in the concentration of extracellular phosphate. Excess production of FGF23 by bone cells, or rarely by tumors, is the hormonal basis for several musculoskeletal syndromes characterized by hypophosphatemia due to renal phosphate wasting. FGF23-dependent chronic hypophosphatemia causes rickets and osteomalacia, as well as other skeletal complications. Genetic disorders of FGF23-mediated hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia of bone, McCune-Albright syndrome, and epidermal nevus syndrome (ENS), also known as cutaneous skeletal hypophosphatemia syndrome (CSHS). The principle acquired form of FGF23-mediated hypophosphatemia is tumor-induced osteomalacia (TIO). This review summarizes current knowledge about the pathophysiology and clinical presentation of the most common FGF23-mediated conditions, with a focus on new treatment modalities. For many decades, calcitriol and phosphate supplements were the mainstay of therapy. Recently, burosumab, a monoclonal blocking antibody to FGF23, has been approved for treatment of XLH in children and adults, and an active comparator trial in children has shown good efficacy and safety for this drug. The remainder of FGF23-mediated hypophosphatemic disorders continue to be treated with phosphate and calcitriol, although ongoing trials with burosumab for treatment of tumor-induced osteomalacia show early promise. Burosumab may be an effective treatment for the remainder of FGF23-mediated disorders, but clinical trials to support that possibility are at present not available.

OR29-06 Burosumab Improves Biochemical, Skeletal, and Clinical Features of Tumor-Induced Osteomalacia Syndrome

Tumor-induced Osteomalacia (TIO) is a rare condition in which excess FGF23 produced by a tumor leads to renal phosphate wasting, impaired 1,25(OH)2D synthesis, osteomalacia, fractures, weakness, fatigue, and decreased mobility. In an ongoing open-label Phase 2 study (NCT02304367), 17 adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS) were enrolled and received burosumab, a fully human monoclonal antibody against FGF23. Key endpoints were changes in serum phosphorus and osteomalacia as assessed from trans-iliac crest bone biopsies. This report excludes 3/17 subjects who did not have TIO: 2 subjects diagnosed with X-linked hypophosphatemia post-enrollment and 1 subject with CSHS. Serum phosphorus increased from baseline (BL; 1.60 mg/dL) and was maintained after titration, from Week (W) 22 (2.85 mg/dL, dosing cycle midpoint) to W144 (2.56 mg/dL, dosing cycle endpoint, p<0.0001). Serum TmP/GFR and 1,25(OH)2D also increased with burosumab. Eleven subjects underwent paired bone biopsies at BL and W48. Osteoid volume/bone volume decreased from a mean ± SE of 17.6% ± 5.9% at BL to 12.1% ± 4.7% at W48 (p=0.086). Mean ± SE osteoid thickness decreased from 16.5 ± 3.6 µm to 11.3 ± 2.8 µm (p<0.05). Using imputation (Dempster et al. 2012), mineralization lag time decreased from a mean ± SE of 1598 ± 420 days to 1032 ± 712 days (p=0.41). Osteoid surface/bone surface showed no change from BL (mean ± SE BL: 57% ± 9%, W48: 57% ± 7%). Of 249 areas identified with increased uptake on bone scan at BL, 68 (27%) and 81 (33%) were fully healed at W96 and W144, respectively; 56 (23%) and 32 (13%) were partially healed at W96 and W144, respectively. Mean (SD) Global Fatigue Score decreased from 5.6 (2.5) at BL to 3.5 (3.0) at W48, and to 3.8 (2.2) at W144 (both p<0.01). All 3 domains of the Brief Pain Inventory decreased with burosumab (W144 Pain Severity and Pain Interference p<0.05), indicating reduced pain. The SF-36 mean (SD) physical component summary score increased from 33 (10) at BL to 39 (10) at W48 (p<0.05) and to 41 (12) at W144 (p<0.01), indicating improved physical functioning. The mean (SD) number of sit-to-stand repetitions, an assessment of proximal muscle function, increased from 6.7 (4.2) at BL to 8.5 (4.2) at W48 (n=10; p<0.01). All subjects had ≥1 adverse event (AE). Two subjects discontinued: 1 to undergo chemotherapy to treat an AE of neoplasm progression and 1 failed to meet serum phosphorus dosing criteria and therefore received minimal burosumab dosing. There were 16 serious AEs in 7 subjects, all unrelated to drug. Of the 6 subjects with a serious AE of tumor progression/compression, 5 had a history of tumor progression prior to enrollment. There was 1 death, considered unrelated to treatment. In adults with TIO Syndrome, burosumab was associated with improvements in phosphate metabolism, osteomalacia, skeletal metabolism/fracture healing, physical functioning, fatigue, pain, and quality of life.

DIAGNOSIS OF ENDOCRINE DISEASE: Mosaic disorders of FGF23 excess: Fibrous dysplasia/McCune-Albright syndrome and cutaneous skeletal hypophosphatemia syndrome.

Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.

FGF23, Hypophosphatemia, and Emerging Treatments.

ABSTRACTFGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co‐receptor Klotho, it modulates phosphate reabsorption and both 1α‐hydroxylation and 24‐hydroxylation in the renal proximal tubules. The most common FGF23‐mediated hypophosphatemia is X‐linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23‐mediated forms of hypophosphatemia are characterized by phosphaturia and low or low‐normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23‐mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor‐induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23‐mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

SAT-LB085 First Report of Burosumab (Anti-FGF23 Monoclonal Antibody) for Rickets Complicating HRAS-Associated Cutaneous Skeletal Hypophosphatemia Syndrome

Background: Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaicism of a RAS family gene (ie. HRAS, NRAS, KRAS). CSHS features: 1) congenital epidermal, melanocytic, or sebaceous nevi, 2) elevated circulating FGF23 levels that cause renal phosphate wasting and skeletal hypomineralization, and 3) focal bone lesions ipsilateral to the nevi as a possible source of excess FGF23. Conventional therapy for rickets in CSHS (phosphate salts and bioactive vitamin D) mirrors treatment for X-linked hypophosphatemia (XLH) with elevated circulating FGF23. Current therapy aims to treat signs and symptoms rather than the etiology. Clinical Case: A 21-month-old boy with left, widespread, unilateral nevus sebaceous developed bilateral lower extremity bowing with a wide-based gait. His serum phosphorus level was low at 2.1 mg/dl (Nl: 3-6) and FGF23 was elevated at 279 RU/mL (Nl: < 230). We prescribed conventional therapy for hypophosphatemic rickets and diagnosed linear sebaceous nevus syndrome, confirmed by mutation analysis of affected skin harboring HRAS p.Q61R (c.182A>G). Adherence to medical therapy was problematic, and he sustained 3 major long-bone fractures. By age 6 years, a walker was required to ambulate short distances with mostly wheelchair-dependence from pain and muscle weakness. Based on his elevated FGF23 level and clinical decline, burosumab (anti-FGF23 fully human monoclonal antibody), FDA-approved in 2018 for XLH, was initiated off-label. After weaning conventional therapy, burosumab was administered subcutaneously as a single dose of 0.8 mg/kg (20 mg) and decreased to 0.3 mg/kg (6 mg) two weeks later. Burosumab was then given every 2 weeks and adjusted by 0.1 mg/kg to maintain fasting serum phosphorus in the low-normal range for age (3.5 - 4.5 mg/dL). Laboratory and clinic follow-up occurred just prior to each injection for 3 months until serum phosphorus was stable as he received approximately 0.4 mg/kg (8 mg per dose). Biochemical testing and clinic visits will occur monthly for 3 months and are planned for quarterly afterwards, with repeat radiological imaging every 3-6 months for the first year of therapy. Duration of burosumab treatment has been 5 months. After his initial burosumab dose, serum phosphorus increased from 1.7 to 3.7 mg/dL and remained normal [Nl: 3.0 - 6.0 mg/dL] thereafter. Radiographs of his wrists and knees 3 months into therapy revealed striking improvement of his rickets but persisting focal bone lesions, characteristic of CSHS, on the left side. He now walks independently with endurance, strength, and resolving pain. Quality-of-life is markedly improved. Burosumab treatment is being tolerated well without side effects. Conclusion: Burosumab seems to be an effective therapy for FGF23-mediated rickets in pediatric CSHS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Epidermal nevus syndromes: New insights into whorls and swirls.

Knowledge of the molecular underpinnings of many epidermal nevi and epidermal nevus syndrome has expanded rapidly in recent years. In this review and update on epidermal nevus syndrome, we will cover recent genetic discoveries involving epidermal nevi, including nevus sebaceus, keratinocytic epidermal nevus, nevus comedonicus, congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome, phakomatosis pigmentokeratotica, Becker's nevus, porokeratotic adnexal ostial nevus, inflammatory linear verrucous epidermal nevi, and cutaneous-skeletal hypophosphatemia syndrome. We will discuss how newly defined mutations relate to the biology reflected in the cutaneous patterns seen in these mosaic disorders and how new molecular data has informed our understanding of these diseases and shaped management decisions.

Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment.

CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.