Winchester Syndrome

Winchester Syndrome

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Winchester syndrome (WS) is a syndrome of pathologic changes consisting of dwarfism (resulting from disturbances of the skeletal-articular system), corneal opacities, coarsening of facial features, leathery skin, and hypertrichosis. It is one of the inherited osteolyses, or “vanishing bone” syndromes. [1]

In 1969, Winchester et al first described pathologic changes in 2 sisters aged 3.5 and 12 years, the offspring of first cousins. These sisters were reported to have “a new acid mucopolysaccharidosis” with skeletal deformities that simulated rheumatoid arthritis. [2] Later, Brown and Kuwabara [3] performed corneal biopsy in the younger sibling, whose case is discussed in the report by Winchester et al [2] ; the results were characteristic of the mucopolysaccharidoses.

In 1974, Hollister et al reported 3 cases of this disease in consanguineous relatives from Mexico: 2 sisters aged 8 and 9.5 years and their 22-year-old cousin. [4, 5] The authors first called the constellation of findings Winchester syndrome. In particular, they noted skin changes in the trunk and extremities that Winchester et al did not report. [2] In 1977, Nabai described a sixth patient, a 3-month-old boy from Iran. [6] In 1978, Irani et al reported a similar case in a 4-year-old boy from Bombay. [7] In both cases, the parents were first cousins.

In 1987, Dunger et al reported 2 additional cases. [8] The first patient had features similar to those of infantile systemic hyalinosis; Winter also emphasized these features. [9] The other patient was a 16-year-old male adolescent. Lambert et al presented a subsequent report on 2 cases in siblings, a girl aged 13 months and a girl aged 12 years, in France. [10] The most recent case of Winchester syndrome was in a 40-year-old woman from the United States; this woman had additional dental disorders with inflammation of the gums. The data in patients with Winchester syndrome are presented in the Table below.

Table. Clinical Features of Patients with Winchester syndromea (Open Table in a new window)

Clinical Feature

Winchester et al, 1969  [2]

Hollister et al, 1974  [4, 5]

Nabai et al, 1977  [6]

Irani et al, 1978  [7]

Dunger et al, 1987  [8]

Prapanpoch et al, 1992  [11]

Case 1

Case 2

Case 1

Case 2

Case 3

Case 1

Case 1

Case 1

Case 2b

Case

1

Sex

F

F

F

F

M

M

M

F

F

F

Age

12 y

3.5 y

9.5 y

8 y

22 y

3 mo

4 y

2

16 y

40 y

Onset

2 mo

1 y

1 y

1 mo

1 y

1 mo

1 y

1 mo

1 y

ND

Consanguinity

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

ND

Skin changes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Coarse face

Yes

Yes

No

No

Yes

Otherc

No

Yes

Yes

Yes

Thickened facial skin

No

No

Yes

Yes

Yes

Yes

No

Yes

No

Yes

Hyperpigmented

patches

No

No

Yes

Yes

Yes

Yes

Yes

No

No

No

Skin nodules

No

No

Yes

No

No

No

No

Yes

No

No

Corneal

opacity

Yes

Yes

Yes

Yes

Yes

No

No

No

No

Yesd

Gum hypertrophy

Yes

Yes

Yes

Yes

ND

Yes

No

Yes

Yes

No

Short stature

Yes

Yes

Yes

Yes

Yes

No

ND

Yes

Yes

Yes

Flexion

contractures

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Osteoporosis (visible on radiographs)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Osteolysis of the carpal and tarsal bones

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Abnormal test resultse

No

No

No

IgM

IgM

IgMf

No

Yesg

Yesg

No

Patient location

USA

USA

Mexico

Mexico

Mexico

Iran

India

Iranh

Indiah

USA

a Winter, 1989; completed by Urban. ND indicates no data.

b Additional clinical details obtained at repeat examination by Winter.

c Upper lip was hypertrophic.

d Glaucoma was present.

e Increased immunoglobulin M (IgM) levels were observed.

f Increased para-amino-isobutyric acid, leucine, and proline levels in the urine.

g Abnormal oligosaccharide in the urine.

h Cases reported in Great Britain.

Winchester syndrome appears to be inherited in an autosomal recessive manner. [2, 12] The specific cause of the changes has not been clarified. The changes that occur in this syndrome are presumed to be a consequence of metabolic disturbances of glycosaminoglycans. The syndrome is believed to be a mucopolysaccharidosis with unknown enzymatic disturbances. [2, 11, 12] Dunger et al found an abnormal oligosaccharide consisting of a molecule of fucose and 2 molecules of galactose in the urine of 2 patients with Winchester syndrome. [8]

Studies performed by Hollister et al [4] and Cohen et al [12] did not reveal morphologic evidence of lysosomal storage. These authors believe that metachromasia of the fibroblasts and a 2-fold increase in the uronic acid content in these fibroblasts [2] are not sufficient evidence for diagnosing mucopolysaccharidosis because uronic acid is also observed in as many as 27% of healthy people.

In patients with established diagnosis of a disease that has features of mucopolysaccharidosis, the uronic acid level is 5-10 times greater than that of the control group. [4, 12] The authors believe that Winchester syndrome is a disease that should be classified as a nonlysosomal connective-tissue disturbance and not as a form of acid mucopolysaccharidosis. Their results suggest that fibroblasts play a major role in this syndrome of pathologic changes. Corneal opacities; leathery skin; abnormal collagen in the dermis; and, possibly, contractures are likely manifestations of anomalous fibroblast functions. The authors recommend further studies to determine the pathogenesis of this autosomal recessive disorder.

A homozygous missense mutation (E404K) in the active site of matrix metalloproteinase 2 was found in a 21-year-old woman with a severe form of osteolysis best compatible with a diagnosis of Winchester syndrome. [13] A novel homozygous MMP2 mutation was identified in a family with Winchester syndrome. [14] Torg syndrome, nodulosis-arthropathy-osteolysis, and Winchester syndrome may be allelic disorders. [15] These 2 syndromes are both associated with matrix metalloproteinase-2 deficiency and mutations in the metalloproteinase-2 gene. [16, 17] Five novel MMP2 mutations in 13 individuals with multicentric osteolysis nodulosis and arthropathy were identified in India. [18]

Homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14) were shown in one patient, an inactivating homoallelic mutation of MT1-MMP, with the resulting hydrophobic-region signal-peptide substitution (p.Thr17Arg) decreasing MT1-MMP membrane localization and with consequent impairment of pro-MMP2 activation. [1] MMP14 catalytic activity appears to be the main determinant of the Winchester syndrome phenotype. [19]

Winchester syndrome is an inherited familial disorder transmitted in an autosomal recessive manner. Isolated cases without familial occurrence are described. The molecular causes of the pathologic changes are unknown. Hollister et al [5] and Cohen et al [12] emphasize the abnormal function of the fibroblasts, which causes some of the pathologic changes in this syndrome.

United States

In the United States, 3 cases were described.

International

Cases in 3 Mexican patients are described (published in the United States). Two cases are described in France; 1 case, in India; 1 case, in Iran; and 2 cases, in Great Britain. The 2 cases in Great Britain involved patients from Iran (case 1) or India (case 2). [8] See the Table in Background.

In a 32-year period from 1969-2001, 12 cases of Winchester syndrome are described worldwide.

No racial predisposition is recognized.

Winchester syndrome appears to be more common in women than in men, with a female-to-male ratio of 3:1 (9 women, 3 men). The data presented in the Table in Background do not include 2 cases described by Lambert et al. [10]

The initial changes in the bony-articular system may be observed in infants usually when they are aged about 1 year. In 4 patients, the initial changes occurred earlier. In 3 patients, changes occurred when they were aged 1 month, the fourth patient was aged 2 months when the changes occurred. Winchester syndrome was usually diagnosed in the described cases when the patients were aged 3.5-16 years. In 1 case, the syndrome was recognized in an infant aged 3 months, [6] and in the other 2 cases, the patients were aged 22 and 40 years (see the Table in Background).

The disease has a progressive course with aggravating bony-articular, ocular, and cutaneous changes.

Evans BR, Mosig RA, Lobl M, Martignetti CR, Camacho C, Grum-Tokars V, et al. Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome. Am J Hum Genet. 2012 Sep 7. 91(3):572-6. [Medline]. [Full Text].

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. 1969 May. 106(1):121-8. [Medline].

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

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

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].

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

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

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

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

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. 1989 Sep. 37(3):231-6. [Medline].

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

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

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. 2005 Mar. 67(3):261-6. [Medline].

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

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. 2007 Feb. 22(2):329-33. [Medline].

Gok F, Crettol LM, Alanay Y, et al. Clinical and radiographic findings in two brothers affected with a novel mutation in matrix metalloproteinase 2 gene. Eur J Pediatr. 2010 Mar. 169(3):363-7. [Medline].

Jeong SY, Kim BY, Kim HJ, Yang JA, Kim OH. A novel homozygous MMP2 mutation in a patient with Torg-Winchester syndrome. J Hum Genet. 2010 Nov. 55(11):764-6. [Medline].

Bhavani GS, Shah H, Shukla A, Gupta N, Gowrishankar K, Rao AP, et al. Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy. Am J Med Genet A. 2016 Feb. 170A (2):410-7. [Medline].

de Vos IJHM, Tao EY, Ong SLM, Goggi JL, Scerri T, Wilson GR, et al. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Hum Mol Genet. 2018 May 8. [Medline].

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

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

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

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

Al Kaissi A, Scholl-Buergi S, Biedermann R, Maurer K, Hofstaetter JG, Klaushofer K, et al. The diagnosis and management of patients with idiopathic osteolysis. Pediatr Rheumatol Online J. 2011 Oct 13. 9:31. [Medline]. [Full Text].

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

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

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. 1987 Jan. 26(1):123-31. [Medline].

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].

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. 1978 Dec. 35(10):1063-74. [Medline].

Haidar Z, Temanni R, Chouery E, Jitesh P, Liu W, Al-Ali R, et al. Diagnosis implications of the whole genome sequencing in a large Lebanese family with hyaline fibromatosis syndrome. BMC Genet. 2017 Jan 19. 18 (1):3. [Medline].

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

Krasuska-Sławińska E, Polnik D, Rokicki D, Koeber B. Treatment of Massive Labial and Gingival Hypertrophy in a Patient With Infantile Systemic Hyalinosis-A Case Report. J Oral Maxillofac Surg. 2015 Oct. 73 (10):1962.e1-5. [Medline].

Vanatka R, Rouzier C, Lambert JC, Leroux C, Coussement A. Winchester syndrome: the progression of radiological findings over a 23-year period. Skeletal Radiol. 2011 Mar. 40(3):347-51. [Medline].

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

Clinical Feature

Winchester et al, 1969  [2]

Hollister et al, 1974  [4, 5]

Nabai et al, 1977  [6]

Irani et al, 1978  [7]

Dunger et al, 1987  [8]

Prapanpoch et al, 1992  [11]

Case 1

Case 2

Case 1

Case 2

Case 3

Case 1

Case 1

Case 1

Case 2b

Case

1

Sex

F

F

F

F

M

M

M

F

F

F

Age

12 y

3.5 y

9.5 y

8 y

22 y

3 mo

4 y

2

16 y

40 y

Onset

2 mo

1 y

1 y

1 mo

1 y

1 mo

1 y

1 mo

1 y

ND

Consanguinity

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

ND

Skin changes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Coarse face

Yes

Yes

No

No

Yes

Otherc

No

Yes

Yes

Yes

Thickened facial skin

No

No

Yes

Yes

Yes

Yes

No

Yes

No

Yes

Hyperpigmented

patches

No

No

Yes

Yes

Yes

Yes

Yes

No

No

No

Skin nodules

No

No

Yes

No

No

No

No

Yes

No

No

Corneal

opacity

Yes

Yes

Yes

Yes

Yes

No

No

No

No

Yesd

Gum hypertrophy

Yes

Yes

Yes

Yes

ND

Yes

No

Yes

Yes

No

Short stature

Yes

Yes

Yes

Yes

Yes

No

ND

Yes

Yes

Yes

Flexion

contractures

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Osteoporosis (visible on radiographs)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Osteolysis of the carpal and tarsal bones

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Abnormal test resultse

No

No

No

IgM

IgM

IgMf

No

Yesg

Yesg

No

Patient location

USA

USA

Mexico

Mexico

Mexico

Iran

India

Iranh

Indiah

USA

a Winter, 1989; completed by Urban. ND indicates no data.

b Additional clinical details obtained at repeat examination by Winter.

c Upper lip was hypertrophic.

d Glaucoma was present.

e Increased immunoglobulin M (IgM) levels were observed.

f Increased para-amino-isobutyric acid, leucine, and proline levels in the urine.

g Abnormal oligosaccharide in the urine.

h Cases reported in Great Britain.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

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.

Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania 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, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society

Disclosure: Nothing to disclose.

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Albert C Yan, MD Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine

Albert C Yan, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology, Society for Pediatric Dermatology, American Academy of Pediatrics

Disclosure: Nothing to disclose.

Winchester Syndrome

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