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Winchester Syndrome: Differential Diagnoses & Workup

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Janusz E Urban, MD, Associate Professor, Head of Division of Pediatric Dermatology, Departments of Dermatology and Venereology, Medical University of Lublin, Poland; Vice-President of Pediatric Dermatology, Polish Dermatology Society
Contributor Information and Disclosures

Updated: Jun 1, 2009

Differential Diagnoses

Other Problems to Be Considered

The differential diagnosis of Winchester syndrome includes the following diseases.10

Juvenile rheumatoid arthritis

Juvenile rheumatoid arthritis (JRA) is also known as Still disease. An increased erythrocyte sedimentation rate, a positive rheumatoid factor test, the presence of rheumatoid nodules, the pattern of bone destruction, and painful periarticular inflammation help to differentiate JRA from Winchester syndrome.

Idiopathic multicentric osteolysis

Idiopathic multicentric osteolysis (IMO) has many synonyms, including hereditary multicentric osteolysis, carpal and tarsal osteolysis, acro-osteolysis, and idiopathic multicentric osteolysis.16,17,18 Tyler and Rosenbaum divided this disorder into 2 groups: (1) multicentric osteolysis with nephropathy and no hereditary tendency and (2) hereditary multicentric osteolysis inherited as an autosomal dominant trait. These authors excluded Gorham massive osteolysis because of its unicentric nature because it is often preceded by trauma, and because it may be a manifestation of aggressive hemangiomatosis or lymphangiomatosis.

According to Kozlowski et al and Lemaitre et al, specific radiologic findings should be the major criteria for classification of this disease.19,20 The clinical presentation, the pattern of bone lysis, and the laboratory findings differentiate IMO from Winchester syndrome, although some authors classify Winchester syndrome as a type of IMO.10

Juvenile hyaline fibromatosis

Juvenile hyaline fibromatosis is an autosomal recessive disorder with skin lesions that consist of multiple tumors in the face, palate, ears, and neck; gingival hyperplasia; joint contractures; and bone changes. Histologic findings from skin biopsy are pathognomonic.21,22,23 Infantile systemic hyalinosis has overlapping features with juvenile hyaline fibromatosis and must also be considered in the differential diagnosis of Winchester syndrome.24

Workup

Laboratory Studies

  • Morphologic and biochemical examinations of the blood show that the following values are within the reference range in Winchester syndrome (WS) patients:
    • White blood cell count
    • Red blood cell count
    • Erythrocyte sedimentation rate
    • Alkaline phosphatase level
    • Calcium level
    • Phosphate level
    • Potassium level
    • Blood glucose level
    • Urea concentration
    • Rheumatoid factor
  • No specific morphologic or biochemical examinations provide results that are characteristic of Winchester syndrome.
  • For a better understanding of the nature of this disease, studies should be conducted to assess the urine for abnormal oligosaccharides7 and increased para-amino-isobutyric acid, leucine, and proline levels.5
  • Determinations of IgM serum levels,4,5 rheumatoid factor tests, and other examinations are indicated to rule out rheumatoid arthritis.
  • The organic acid and mucopolysaccharide screening tests of the blood and urine are indicated to exclude mucopolysaccharidoses and mucolipidoses.10

Imaging Studies

  • Radiologic examination of the skeleton demonstrates generalized osteoporosis with progressive osteolysis in the carpal and tarsal bones. The intensity varies depending on the patient's age and the duration of the disease.
  • Radiographs of the long bones of the limbs show cortical thinning with widening of the marrow cavity and metaphyses.
    • Also present is flattening of the epiphyses, which have an irregular shape and visible erosions on the surfaces.
    • These changes result in ankylosis of the elbows, knees, and other joints.
  • Radiographs of the hand bones show osteoporosis of the phalangeal and metacarpal bones, which are enlarged in a cystic manner, with visible destruction of the interphalangeal and metacarpophalangeal joints.
  • Destructive changes of the hand bones with strong resorption and even osteolysis of the carpal bones and proximal part of the metacarpals can result in ankylosis.1,3,4,11
  • The radiographic changes observed in a 40-year-old female patient included the following: ankylosis between the radius and all the carpal bones, fusion of the carpals and metacarpals, and penciling and resorptive deformities of all the phalanges.10 Analogous osteoporotic and osteolytic changes were found in the tarsal, metatarsal, and phalangeal bones.
  • Intense osteoporosis in the vertebral bodies causes compressive fractures and vertebral curvatures; in the pelvic bones it causes deformation of the plate and hip joints.1,10

Procedures

  • To verify diagnosis of Winchester syndrome, skin and gum biopsy specimens should be collected for histologic and ultrastructural assessment.
  • Skeletal radiography is also indicated.

Histologic Findings

Microscopic findings

In biopsy samples of leathery and hyperpigmented skin obtained from children aged 8 and 9.5 years, Cohen et al found characteristic changes in the deeper parts of the skin.11 The epidermis is normal, without atrophic changes. An increased amount of melanin was found only in cells of the basal layer. The dermis of the papillary, subpapillary, and medial layers had a mild inflammatory infiltration with features of chronic infection and an increased number of mast cells.

No pathologic changes were found in the collagen fibers. Elastic fibers were numerous. Within the deeper part of the dermis, down to the subcutaneous tissue, a diffuse proliferation of fibroblasts was observed, and collagen bands surrounded the skin appendages without causing their damage. Staining with periodic acid-Schiff (PAS), methylene blue, and colloidal iron did not reveal abnormal mucopolysaccharides or other pathologic substances.11

In the case of the 22-year-old man in whom the disease had a chronic course, a biopsy sample obtained from the upper arm showed a diffuse and somewhat hypocellular and dense homogenization of the collagen that extended from below the reticular dermis to the subdermal adipose tissue.11

Ultrastructural findings

Electron microscopic examinations of fibroblasts obtained from both pathologically changed skin and healthy skin, as well as from hypertrophic gums, showed the following changes: dilated and vacuolated mitochondria, varying amounts of myofilaments in the cytoplasm, and a prominent fibrous nuclear lamina.11 The described ultrastructural changes were visible only in fibroblasts. The changes were not found in other cells (eg, endothelial cells, mast cells, marrow cells, chondrocytes).

More on Winchester Syndrome

Overview: Winchester Syndrome
Differential Diagnoses & Workup: Winchester Syndrome
Treatment & Medication: Winchester Syndrome
Follow-up: Winchester Syndrome
Multimedia: Winchester Syndrome
References
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References

  1. Winchester P, Grossman H, Lim WN, Danes BS. A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis. Am J Roentgenol Radium Ther Nucl Med. May 1969;106(1):121-8. [Medline].

  2. Brown SI, Kuwabara T. Peripheral corneal opacification and skeletal deformities. A newly recognized acid mucopolysaccharidosis simulating rheumatoid arthritis. Arch Ophthalmol. Jun 1970;83(6):667-77. [Medline].

  3. Hollister DW, Rimoin DL, Lachman RS, Cohen AH, Reed WB, Westin GW. The Winchester syndrome: a nonlysosomal connective tissue disease. J Pediatr. May 1974;84(5):701-9. [Medline].

  4. Hollister DW, Rimoin DL, Lachman RS, Westin GW, Cohen AH. The Winchester syndrome: clinical, radiographic and pathologic studies. Birth Defects Orig Artic Ser. 1974;10(10):89-100. [Medline].

  5. Nabai H, Mehregan AH, Mortezai A, Alipour P, Karimi FZ. Winchester syndrome: report of a case from Iran. J Cutan Pathol. Oct 1977;4(5):281-5. [Medline].

  6. Irani A, Shah BN, Merchant RH. The Winchester syndrome: (a case report). Indian Pediatr. Oct 1978;15(10):861-3. [Medline].

  7. Dunger DB, Dicks-Mireaux C, O'Driscoll P, et al. Two cases of Winchester syndrome: with increased urinary oligosaccharide excretion. Eur J Pediatr. Nov 1987;146(6):615-9. [Medline].

  8. Winter RM. Winchester's syndrome. J Med Genet. Dec 1989;26(12):772-5. [Medline].

  9. Lambert JC, Jaffray JY, Michalski JC, Ortonne JP, Paquis V, Saunieres AM. [Biochemical and ultrastructural study of two familial cases of Winchester syndrome]. J Genet Hum. Sep 1989;37(3):231-6. [Medline].

  10. Prapanpoch S, Jorgenson RJ, Langlais RP, Nummikoski PV. Winchester syndrome. A case report and literature review. Oral Surg Oral Med Oral Pathol. Nov 1992;74(5):671-7. [Medline].

  11. Cohen AH, Hollister DW, Reed WB. The skin in the Winchester syndrome. Arch Dermatol. Feb 1975;111(2):230-6. [Medline].

  12. Zankl A, Bonafe L, Calcaterra V, Di Rocco M, Superti-Furga A. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2. Clin Genet. Mar 2005;67(3):261-6. [Medline].

  13. Rouzier C, Vanatka R, Bannwarth S, et al. A novel homozygous MMP2 mutation in a family with Winchester syndrome. Clin Genet. Mar 2006;69(3):271-6. [Medline].

  14. Zankl A, Pachman L, Poznanski A, et al. Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome. J Bone Miner Res. Feb 2007;22(2):329-33. [Medline].

  15. Sidwell RU, Brueton LA, Grabczynska SA, Francis N, Staughton RC. Progressive multilayered banded skin in Winchester syndrome. J Am Acad Dermatol. Feb 2004;50(2 Suppl):S53-6. [Medline].

  16. Hemingway AP, Leung A, Lavender JP. Familial vanishing limbs: four generations of idiopathic multicentric osteolysis. Clin Radiol. Sep 1983;34(5):585-8. [Medline].

  17. Pai GS, Macpherson RI. Idiopathic multicentric osteolysis: report of two new cases and a review of the literature. Am J Med Genet. Apr 1988;29(4):929-36. [Medline].

  18. Tyler T, Rosenbaum HD. Idiopathic multicentric osteolysis. AJR Am J Roentgenol. Jan 1976;126(1):23-31. [Medline].

  19. Kozlowski K, Barylak A, Eftekhari F, Pasyk K, Wislocka E. Acroosteolysis. Problems of diagnosis--report of four cases. Pediatr Radiol. Apr 19 1979;8(2):79-86. [Medline].

  20. Lemaitre L, Remy J, Smith M, et al. Carpal and tarsal osteolysis. Pediatr Radiol. 1983;13(4):219-26. [Medline].

  21. Fayad MN, Yacoub A, Salman S, Khudr A, Der Kaloustian VM. Juvenile hyaline fibromatosis: two new patients and review of the literature. Am J Med Genet. Jan 1987;26(1):123-31. [Medline].

  22. Landing BH, Nadorra R. Infantile systemic hyalinosis: report of four cases of a disease, fatal in infancy, apparently different from juvenile systemic hyalinosis. Pediatr Pathol. 1986;6(1):55-79. [Medline].

  23. Nezelof C, Letourneux-Toromanoff B, Griscelli C, Girot R, Saudubray JM, Mozziconacci P. [Painful disseminated fibromatosis (systemic hyalinosis): a new hereditary collagen dysplasia]. Arch Fr Pediatr. Dec 1978;35(10):1063-74. [Medline].

  24. Grover S, Grewal RS, Verma R, Mani NS, Mehta A, Sinha P. Winchester syndrome: a case report. Int J Dermatol. Feb 2009;48(2):175-7. [Medline].

  25. Phadke SR, Ramirez M, Difeo A, Martignetti JA, Girisha KM. Torg-Winchester syndrome: lack of efficacy of pamidronate therapy. Clin Dysmorphol. Apr 2007;16(2):95-100. [Medline].

  26. Ball GV, Koopman WJ. Rheumatoid arthritis. In: Kelley WN, DeVita VT, DuPont HL, Harris ED, JR, et al, eds. Textbook of Internal Medicine. Philadelphia, Pa: Lippincott-Raven; 1989:974-81.

  27. Myers LK, Pinals RS. Arthritis in childhood. In: Summit RL, ed. Comprehensive Pediatrics. Toronto, Canada: Mosby; 1990:526-33.

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Further Reading

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Keywords

WS, Winchester's syndrome, mucopolysaccharidosis, dwarfism, bony-articular changes, corneal opacities, coarsened facial features, leathery skin, hypertrichosis

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Janusz E Urban, MD, Associate Professor, Head of Division of Pediatric Dermatology, Departments of Dermatology and Venereology, Medical University of Lublin, Poland; Vice-President of Pediatric Dermatology, Polish Dermatology Society
Disclosure: Nothing to disclose.

Medical Editor

Albert C Yan, MD, Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia and University of Pennsylvania
Albert C Yan, MD is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, Society for Investigative Dermatology, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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