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

Manal Khadora, M Zulf Mughal, Manal Khadora, M Zulf Mughal

Abstract

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a rare disorder caused by somatic mosaicism for the gain of function RAS mutations . Affected patients have segmental epidermal nevi, dysplastic cortical bony lesions, and fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic rickets. Herein, we describe a case of an Emirati girl with CSHS, whose hypophosphatemic rickets and osteomalcic pseudofractures and dysplastic bony lesions failed to recover due to poor adherence to treatment with oral phosphate supplements and alfacalcidol (conventional treatment). Treatment with burosumab, a fully human immunoglobulin G1 monoclonal antibody against FGF23 for 12 months, led to normalization of serum inorganic phosphate and alkaline phosphatase levels, radiographic healing of rickets, partial healing of pseudofractures, improvement in 6-minute walk test, and the physical scale of the Pediatric Quality of Life Inventory. We conclude that burosumab is effective in treatment of CSHS, however results of the ongoing phase 2 trial in adults (NCT02304367) are awaited.

Keywords: Burosumab; Cutaneous skeletal hypophosphatemia syndrome; Fibroblast growth factor 23; Hypophosphatemic rickets.

Conflict of interest statement

Both the authors were equally involved in writing & editing the manuscript.

© 2021 The Authors. Published by Elsevier Inc.

Figures

Fig. 1
Fig. 1
Photographs of the patient showing linear epidermal nevi distributed on the left side of her body.
Fig. 2
Fig. 2
Radiographic comparison of patient's condition after 10 months of conventional therapy and before treatment with burosumab. A. Radiographs of the knees before treatment with burosumab. Widening and fraying of the distal femoral metaphyses are consistent with rickets. Moreover, the sub-metaphyseal areas of lucency and vertical cortical striations are clearly visible in the left distal femoral radiograph. B. Radiographs of knees 12-months after treatment with burosumab. Radiograph of knees showing healing of radiological signs of rickets and improvement in bone texture. C. Radiograph of the left proximal femur before treatment with burosumab. Note the left medial cortical pseudofracture (arrow), with periosteal reaction. D. Radiograph of the left proximal femur 12 months after treatment with burosumab. Note cortical thickening and partial healing of left medial cortical pseudofracture (arrow). E. Radiograph of the left forearm before treatment with burosumab. Note the proximal ulnar pseudofracture (arrow). Also shown are diaphyseal areas lucency and sclerosis (dashed arrows). F. Radiograph of the left forearm 12-months after treatment with burosumab. Note the partial healing of the proximal ulnar pseudofracture (arrow) and improvement in the diaphyseal bone texture.
Fig. 3
Fig. 3
Fasting serum levels of phosphate (iP) and alkaline phosphatase (ALP). A. Fasting serum iP levels for 12-months of treatment with burosumab. B. Serum ALP levels for 12-months of treatment with burosumab.

References

    1. Al Juraibah F., Al Amiri E., Al Dubayee M., Al Jubeh J., Al Kandari H., Al Sagheir A., Al Shaikh A., Beshyah S.A., Deeb A., Habeb A., Mustafa M., Zidan H., Mughal M.Z. Diagnosis and management of X-linked hypophosphatemia in children and adolescent in the Gulf cooperationcouncil countries. Arch.Osteoporos. 2021;16(1):52. doi: 10.1007/s11657-021-00879-9.
    1. Aschinberg L.C., Solomon L.M., Zeis P.M., Justice P., Rosenthal I.M. Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. J.Pediatr. 1977;91(1):56–60. doi: 10.1016/s0022-3476(77)80444-7.
    1. Beck-Nielsen S.S., Mughal Z., Haffner D., Nilsson O., Levtchenko E., Ariceta G., de Lucas Collantes C., Schnabel D., Jandhyala R., Mäkitie O. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J. Rare Dis. 2019;14(1):58. doi: 10.1186/s13023-019-1014-8.
    1. Burosumab summary of product characteristics (Burosumab SmPC) ()
    1. Carpenter T.O., Whyte M.P., Imel E.A., Boot A.M., Högler W., Linglart A., Padidela R., Van’t Hoff W., Mao M., Chen C.Y., Skrinar A., Kakkis E., San Martin J., Portale A.A. Burosumab therapy in children with X-linkedhypophosphatemia. N.Engl.J.Med. 2018;378(21):1987–1998. doi: 10.1056/NEJMoa1714641.
    1. de Castro L.F., Ovejero D., Boyce A.M. DIAGNOSIS OF ENDOCRINE DISEASE: mosaic disorders of FGF23 excess: fibrousdysplasia/McCune-albright syndrome and cutaneous skeletal hypophosphatemia syndrome. Eur.J.Endocrinol. 2020;182(5):R83–R99. doi: 10.1530/EJE-19-0969.
    1. Geiger R., Strasak A., Treml B., Gasser K., Kleinsasser A., Fischer V., Geiger H., Loeckinger A., Stein J.I. Six-minute walk test in children and adolescents. J.Pediatr. 2007;150(4):395–399.e3992. doi: 10.1016/j.jpeds.2006.12.052.
    1. Heike C.L., Cunningham M.L., Steiner R.D., Wenkert D., Hornung R.L., Gruss J.S., Gannon F.H., McAlister W.H., Mumm S., Whyte M.P. Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis? Am.J.Med.Genet. A. 2005;139A(2):67–77. doi: 10.1002/ajmg.a.30915.
    1. Imel E.A., Glorieux F.H., Whyte M.P., Munns C.F., Ward L.M., Nilsson O., Simmons J.H., Padidela R., Namba N., Cheong H.I., Pitukcheewanont P., Sochett E., Högler W., Muroya K., Tanaka H., Gottesman G.S., Biggin A., Perwad F., Mao M., Chen C.Y., Portale A.A.… Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet (London, England) 2019;393(10189):2416–2427. doi: 10.1016/S0140-6736(19)30654-3.
    1. Ivker R., Resnick S.D., Skidmore R.A. Hypophosphatemic vitamin D-resistant rickets, precocious puberty, and the epidermal nevus syndrome. Arch.Dermatol. 1997;133(12):1557–1561.
    1. Jan de Beur S.M., Miller P.D., Weber T.J., Peacock M., Insogna K., Kumar R., Rauch F., Luca D., Cimms T., Roberts M.S., San Martin J., Carpenter T.O. Burosumab for the treatment of tumor-inducedosteomalacia. J. Bone Miner.Res.Off. J. Am. Soc. Bone Miner. Res. 2021;36(4):627–635. doi: 10.1002/jbmr.4233.
    1. Lim Y.H., Ovejero D., Sugarman J.S., Deklotz C.M., Maruri A., Eichenfield L.F., Kelley P.K., Jüppner H., Gottschalk M., Tifft C.J., Gafni R.I., Boyce A.M., Cowen E.W., Bhattacharyya N., Guthrie L.C., Gahl W.A., Golas G., Loring E.C., Overton J.D., Mane S.M., Choate K.A.… Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum.Mol.Genet. 2014;23(2):397–407. doi: 10.1093/hmg/ddt429.
    1. Lim Y.H., Ovejero D., Derrick K.M., Yale Center for Mendelian Genomics, Collins M.T., Choate K.A. Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J. Am. Acad. Dermatol. 2016;75(2):420–427. doi: 10.1016/j.jaad.2015.11.012.
    1. Moreira A.I., Ferreira G., Santos M., Baptista A., Ferreira E.O. Epidermal nevus syndrome associated with hypophosphatemic rickets. Dermatol. Online J. 2010;16(9):14.
    1. Mughal Z. Rickets in childhood. Semin.Musculoskelet.Radiol. 2002;6(3):183–190. doi: 10.1055/s-2002-36715.
    1. Narazaki R., Ihara K., Namba N., Matsuzaki H., Ozono K., Hara T. Linear nevus sebaceous syndrome with hypophosphatemic rickets with elevated FGF-23. Pediatr. Nephrol. 2012;27(5):861–863. doi: 10.1007/s00467-011-2086-4.
    1. Ovejero D., Lim Y.H., Boyce A.M., Gafni R.I., McCarthy E., Nguyen T.A., Eichenfield L.F., DeKlotz C.M., Guthrie L.C., Tosi L.L., Thornton P.S., Choate K.A., Collins M.T. Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment. Osteoporos. Int. 2016;27(12):3615–3626. doi: 10.1007/s00198-016-3702-8.
    1. Ramesh R., Shaw N., Miles E.K., Richard B., Colmenero I., Moss C. Mosaic NRAS Q61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets. Clin.Exp.Dermatol. 2017;42(1):75–79. doi: 10.1111/ced.12969.
    1. Sanmaneechai O., Wisuthsarewong W., Sawathiparnich P. Epidermal nevussyndromepresenting as hypophosphatemicrickets. Endocrinologist. 2006;16(3):145–149. doi: 10.1097/01.ten.0000218513.86979.d7.
    1. Saraswat A., Dogra S., Bansali A., Kumar B. Phakomatosis pigmentokeratotica associated with hypophosphataemic vitamin D-resistant rickets: improvement in phosphate homeostasis after partial laser ablation. Br.J.Dermatol. 2003;148(5):1074–1076. doi: 10.1046/j.1365-2133.2003.05273.x.
    1. Sukkhojaiwaratkul D., Mahachoklertwattana P., Poomthavorn P. Epidermal nevus syndrome with hypophosphatemic rickets in a young girl. J.Paediatr.ChildHealth. 2014;50(7):566–569. doi: 10.1111/jpc.12472.
    1. Upton P., Eiser C., Cheung I., Hutchings H.A., Jenney M., Maddocks A., Russell I.T., Williams J.G. Measurement properties of the UK-English version of the Pediatric Quality of Life Inventory 4.0 (PedsQL) generic core scales. Health Qual. Life Outcomes. 2005;3:22. doi: 10.1186/1477-7525-3-22.
    1. Welfringer-Morin A., Pinto G., Baujat G., Vial Y., Hadj-Rabia S., Bodemer C., Boccara O. Hypophosphatemic rickets: a rare complication of congenital melanocytic nevus syndrome. Pediatr.Dermatol. 2020;37(3):541–544. doi: 10.1111/pde.14139.
    1. Whyte M.P., Carpenter T.O., Gottesman G.S., Mao M., Skrinar A., San Martin J., Imel E.A. Efficacy and safety of burosumab in children aged 1–4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(3):189–199. doi: 10.1016/S2213-8587(18)30338-3.

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