Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found.

Purpose

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.

Methods

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.

Results

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.

Conclusion

An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lim YH et al (2014) Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet 23(2):397–407

    Article  CAS  PubMed  Google Scholar 

  2. Lim YH, Ovejero D, Derrick KM; Yale Center for Mendelian Genomics, Collins MT, Choate KA (2016) Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J Am Acad Dermatol 75(2):420–427. doi:10.1016/j.jaad.2015.11.012

  3. Aschinberg LC et al (1977) Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. J Pediatr 91(1):56–60

    Article  CAS  PubMed  Google Scholar 

  4. Dempster DW et al (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 28(1):2–17

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kuznetsov SA et al (1997) Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J Bone Miner Res 12(9):1335–47

    Article  CAS  PubMed  Google Scholar 

  6. Castilla EE, da Graca Dutra M, Orioli-Parreiras IM (1981) Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies. Br J Dermatol 104(3):307–15

    Article  CAS  PubMed  Google Scholar 

  7. Aggarwal S et al (2013) Hypophosphatemic rickets associated with giant hairy nevus. Indian J Endocrinol Metab 17(Suppl 1):S188–90

    Article  PubMed  PubMed Central  Google Scholar 

  8. Avitan-Hersh E et al (2014) Postzygotic HRAS mutation causing both keratinocytic epidermal nevus and thymoma and associated with bone dysplasia and hypophosphatemia due to elevated FGF23. J Clin Endocrinol Metab 99(1):E132–6

    Article  PubMed  Google Scholar 

  9. Bouthors J et al (2006) Phacomatosis pigmentokeratotica associated with hypophosphataemic rickets, pheochromocytoma and multiple basal cell carcinomas. Br J Dermatol 155(1):225–6

    Article  CAS  PubMed  Google Scholar 

  10. Cabanillas M et al (2009) Epidermal nevus syndrome associated with polyostotic fibrous dysplasia, CNS lipoma, and aplasia cutis. Dermatol Online J 15(10):7

    PubMed  Google Scholar 

  11. Carey DE et al (1986) Hypophosphatemic rickets/osteomalacia in linear sebaceous nevus syndrome: a variant of tumor-induced osteomalacia. J Pediatr 109(6):994–1000

    Article  CAS  PubMed  Google Scholar 

  12. Chou YY et al (2005) Hypophosphatemic rickets associated with epidermal nevus syndrome and giant hairy nevus. J Pediatr Endocrinol Metab 18(1):93–5

    Article  CAS  PubMed  Google Scholar 

  13. de Morais OO et al (2013) Phacomatosis pigmentokeratotica—a patient with hypophosphatemic rickets. Skinmed 11(2):125–8

    PubMed  Google Scholar 

  14. Feldmann JL et al (1990) Solomon’s syndrome associated with fibrous dysplasia of bone and vitamin-resistant rickets. Rev Rhum Mal Osteoartic 57(12):881–4

    CAS  PubMed  Google Scholar 

  15. Gathwala G et al (2013) Giant congenital melanocytic nevi: a rare association with hypophosphatemic rickets. Indian J Pediatr 80(5):430–1

    Article  PubMed  Google Scholar 

  16. Goldblum JR, Headington JT (1993) Hypophosphatemic vitamin D-resistant rickets and multiple spindle and epithelioid nevi associated with linear nevus sebaceus syndrome. J Am Acad Dermatol 29(1):109–11

    Article  CAS  PubMed  Google Scholar 

  17. Heike CL et al (2005) Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis? Am J Med Genet A 139(2):67–77

    Article  Google Scholar 

  18. Hoffman WH et al (2005) Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 134(3):233–6

    Article  PubMed  Google Scholar 

  19. Hosalkar HS et al (2003) Linear sebaceous naevus syndrome and resistant rickets. J Bone Joint Surg Br 85(4):578–83

    Article  CAS  PubMed  Google Scholar 

  20. Ivker R, Resnick SD, Skidmore RA (1997) Hypophosphatemic vitamin D-resistant rickets, precocious puberty, and the epidermal nevus syndrome. Arch Dermatol 133(12):1557–61

    Article  CAS  PubMed  Google Scholar 

  21. John M, Shah NS (2005) Hypophosphatemic rickets with epidermal nevus syndrome. Indian Pediatr 42(6):611–2

    PubMed  Google Scholar 

  22. Kishida ES et al (2005) Epidermal nevus syndrome associated with adnexal tumors, spitz nevus, and hypophosphatemic vitamin D-resistant rickets. Pediatr Dermatol 22(1):48–54

    Article  PubMed  Google Scholar 

  23. Klein GL et al (1998) Congenital linear sebaceous nevus syndrome. J Bone Miner Res 13(6):1056–7

    Article  CAS  PubMed  Google Scholar 

  24. Moorjani R, Shaw DG (1976) Feuerstein and Mims syndrome with resistant rickets. Pediatr Radiol 5(2):120–2

    Article  CAS  PubMed  Google Scholar 

  25. Moreira AI et al (2010) Epidermal nevus syndrome associated with hypophosphatemic rickets. Dermatol Online J 16(9):14

    PubMed  Google Scholar 

  26. Narazaki R et al (2012) Linear nevus sebaceous syndrome with hypophosphatemic rickets with elevated FGF-23. Pediatr Nephrol 27(5):861–3

    Article  PubMed  Google Scholar 

  27. Olivares JL et al (1999) Epidermal naevus syndrome and hypophosphataemic rickets: description of a patient with central nervous system anomalies and review of the literature. Eur J Pediatr 158(2):103–7

    Article  CAS  PubMed  Google Scholar 

  28. O’Neill EM (1993) Linear sebaceous naevus syndrome with oncogenic rickets and diffuse pulmonary angiomatosis. J R Soc Med 86(3):177–8

    PubMed  PubMed Central  Google Scholar 

  29. Oranje AP et al (1994) Solomon’s epidermal nevus syndrome (type: linear nevus sebaceus) and hypophosphatemic vitamin D-resistant rickets. Arch Dermatol 130(9):1167–71

    Article  CAS  PubMed  Google Scholar 

  30. Pierini AM, Ortonne JP, Floret D (1981) Cutaneous manifestations of McCune-Albright syndrome: report of a case (author’s transl). Ann Dermatol Venereol 108(12):969–76

    CAS  PubMed  Google Scholar 

  31. Saraswat A et al (2003) Phakomatosis pigmentokeratotica associated with hypophosphataemic vitamin D-resistant rickets: improvement in phosphate homeostasis after partial laser ablation. Br J Dermatol 148(5):1074–6

    Article  CAS  PubMed  Google Scholar 

  32. Sethi SK, Hari P, Bagga A (2010) Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets. Pediatr Nephrol 25(8):1577–8

    Article  PubMed  Google Scholar 

  33. Shahgholi E et al (2011) Congenital rhabdomyosarcoma, central precocious puberty, hemihypertrophy and hypophosphatemic rickets associated with epidermal nevus syndrome. J Pediatr Endocrinol Metab 24(11–12):1063–6

    PubMed  Google Scholar 

  34. Shieh CC, Wang PJ (1991) Giant nevocellular nevi with rickets and brainstem tumor. Pediatr Neurol 7(6):452–4

    Article  CAS  PubMed  Google Scholar 

  35. Skovby F, Svejgaard E, Moller J (1987) Hypophosphatemic rickets in linear sebaceous nevus sequence. J Pediatr 111(6 Pt 1):855–7

    Article  CAS  PubMed  Google Scholar 

  36. Stosiek N et al (1994) Extensive linear epidermal nevus associated with hemangiomas of bones and vitamin-D-resistant rickets. Dermatology 189(3):278–82

    Article  CAS  PubMed  Google Scholar 

  37. Sukkhojaiwaratkul D, Mahachoklertwattana P, Poomthavorn P (2014) Epidermal nevus syndrome with hypophosphatemic rickets in a young girl. J Paediatr Child Health 50(7):566–9

    Article  PubMed  Google Scholar 

  38. Tokatli A, Coskun T, Ozalp I (1997) Hypophosphatemic vitamin-D resistant rickets associated with epidermal nevus syndrome. A case report. Turk J Pediatr 39(2):247–51

    CAS  PubMed  Google Scholar 

  39. Vidaurri-de la Cruz H et al (2004) Epidermal nevus syndromes: clinical findings in 35 patients. Pediatr Dermatol 21(4):432–9

    Article  PubMed  Google Scholar 

  40. Yu AC et al (1995) Epidermal naevus syndrome associated with polyostotic fibrous dysplasia and central precocious puberty. Eur J Pediatr 154(2):102–4

    Article  CAS  PubMed  Google Scholar 

  41. Zutt M et al (2003) Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets. Dermatology 207(1):72–6

    Article  CAS  PubMed  Google Scholar 

  42. Rustin MH et al (1989) Polyostotic fibrous dysplasia associated with extensive linear epidermal naevi. Clin Exp Dermatol 14(5):371–5

    Article  CAS  PubMed  Google Scholar 

  43. Bouwes Bavinck JN, van de Kamp JJP (1985) Organoid naevus phakomatosis: Schimmelpenning-Feuerstein-Mims syndrome. Br J Dermatol 113:491–492

    Google Scholar 

  44. Camacho Martinez F, Moreno Gimenez JC (1985) Epidermal nevus syndrome (of Solomon, Fretzin and Dewald). Ann Dermatol Venereol 112(2):143–7

    CAS  PubMed  Google Scholar 

  45. Grun G, Didier MF (1972) Albright’s syndrome (apropos of 2 cases). Bull Soc Fr Dermatol Syphiligr 79(2):184–5

    CAS  PubMed  Google Scholar 

  46. Kaplan I, Metzker A, Calderon S (1993) Epidermal nevus syndrome with maxillary involvement. Int J Oral Maxillofac Surg 22(5):298–300

    Article  CAS  PubMed  Google Scholar 

  47. Muhle C et al (1998) Skeletal involvement and follow-up in linear nevus sebaceous syndrome. Eur Radiol 8(4):606–8

    Article  CAS  PubMed  Google Scholar 

  48. Sanmaneechai O, Wisuthsarewong W, Sawathiparnich P (2006) Epidermal nevus syndrome presenting as hypophosphatemic rickets. Endocrinologist 16(3):145–149

    Article  Google Scholar 

  49. Sugarman GI, Reed WB (1969) Two unusual neurocutaneous disorders with facial cutaneous signs. Arch Neurol 21(3):242–7

    Article  CAS  PubMed  Google Scholar 

  50. Shpall S et al (1994) Risk of malignant transformation of congenital melanocytic nevi in blacks. Pediatr Dermatol 11(3):204–8

    Article  CAS  PubMed  Google Scholar 

  51. Groesser L et al (2013) Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 133(8):1998–2003

    Article  CAS  PubMed  Google Scholar 

  52. Groesser L et al (2012) Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 44(7):783–U211

    Article  CAS  PubMed  Google Scholar 

  53. Hafner C et al (2012) Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J Med Genet 49(4):249–253

    Article  CAS  PubMed  Google Scholar 

  54. Kinsler VA et al (2013) Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Investig Dermatol 133(9):2229–2236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Boyce AM, Collins MT (1993) Fibrous dysplasia/McCune-Albright syndrome. In: Pagon RA et al (ed) GeneReviews(R). Seattle (WA)

  56. Lorenz-Depiereux B et al (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38(11):1248–50

    Article  CAS  PubMed  Google Scholar 

  57. Geller JL et al (2007) Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res 22(6):931–7

    Article  CAS  PubMed  Google Scholar 

  58. Carpenter TO et al (2014) Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest 124(4):1587–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wohrle S et al (2013) Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 28(4):899–911

    Article  PubMed  Google Scholar 

  60. Boyce AM, Bhattacharyya N, Collins MT (2013) Fibrous dysplasia and fibroblast growth factor-23 regulation. Curr Osteoporos Rep 11(2):65–71

    Article  PubMed  PubMed Central  Google Scholar 

  61. Kuznetsov SA et al (2008) Age-dependent demise of GNAS-mutated skeletal stem cells and “normalization” of fibrous dysplasia of bone. J Bone Miner Res 23(11):1731–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192(4):547–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Paller AS et al (1994) Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 331(21):1408–15

    Article  CAS  PubMed  Google Scholar 

  64. Chantorn R, Shwayder T (2011) Phacomatosis pigmentokeratotica: a further case without extracutaneous anomalies and review of the condition. Pediatr Dermatol 28(6):715–9

    Article  PubMed  Google Scholar 

  65. Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441(7092):424–30

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD (D.O., A.M.B., R.I.G., L.G.C., and M.T.C.). K.A.C. was supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, and Y.H.L. by a Doris Duke Charitable Foundation Medical Student Research Fellowship and the Yale Center for Mendelian Genomics (NIH U54 HG006504). YHL is also supported by the Medical Scientist Training Program at Yale University.

Author information

Authors and Affiliations

  1. Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National ADDRESSES, references BRACKETS, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA

    D. Ovejero, A. M. Boyce, R. I. Gafni, L. C. Guthrie & M. T. Collins

  2. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    D. Ovejero

  3. Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

    Y. H. Lim & K. A. Choate

  4. Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA

    E. McCarthy

  5. Albert Einstein College of Medicine, Bronx, NY, USA

    T. A. Nguyen

  6. Departments of Dermatology and Pediatrics, San Diego and Rady Children’s Hospital, University of California, San Diego, CA, USA

    T. A. Nguyen & L. F. Eichenfield

  7. Division Dermatology, Department of Medicine and Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA

    C. M. C. DeKlotz

  8. Bone Health Program, Division of Orthopaedics and Sports Medicine, Children’s National Health System, Washington, DC, USA

    L. L. Tosi

  9. Department of Endocrinology and Diabetes, Cook Children Medical Center, Fort Worth, TX, USA

    P. S. Thornton

Authors
  1. D. Ovejero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. H. Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. M. Boyce
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. I. Gafni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. A. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L. F. Eichenfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. M. C. DeKlotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. C. Guthrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L. L. Tosi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P. S. Thornton
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K. A. Choate
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M. T. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. T. Collins.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 493 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ovejero, D., Lim, Y.H., Boyce, A.M. et al. Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment. Osteoporos Int 27, 3615–3626 (2016). https://doi.org/10.1007/s00198-016-3702-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-016-3702-8

Keywords

Search

Navigation