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. 
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.  Later, Brown and Kuwabara  performed corneal biopsy in the younger sibling, whose case is discussed in the report by Winchester et al  ; 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.  In 1977, Nabai described a sixth patient, a 3-month-old boy from Iran.  In 1978, Irani et al reported a similar case in a 4-year-old boy from Bombay.  In both cases, the parents were first cousins.
In 1987, Dunger et al reported 2 additional cases.  The first patient had features similar to those of infantile systemic hyalinosis; Winter also emphasized these features.  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.  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 syndrome* (Open Table in a new window)
|Clinical Feature||Winchester et al, 1969 ||Hollister et al, 1974 [4, 5]||Nabai et al, 1977 ||Irani et al, 1978 ||Dunger et al, 1987 ||Prapanpoch et al, 1992 |
|Case 1||Case 2||Case 1||Case 2||Case 3||Case 1||Case 1||Case 1||Case 2†||
|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|
|Thickened facial skin||No||No||Yes||Yes||Yes||Yes||No||Yes||No||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 results||||No||No||No||IgM||IgM||IgM¶||No||Yes#||Yes#||No|
* Winter, 1989; completed by Urban. ND indicates no data.
† Additional clinical details obtained at repeat examination by Winter.
‡ Upper lip was hypertrophic.
§ Glaucoma was present.
|| Increased immunoglobulin M (IgM) levels were observed.
¶ Increased para-amino-isobutyric acid, leucine, and proline levels in the urine.
# Abnormal oligosaccharide in the urine.
** 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. 
Studies performed by Hollister et al  and Cohen et al  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  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.  A novel homozygous MMP2 mutation was identified in a family with Winchester syndrome.  Torg syndrome, nodulosis-arthropathy-osteolysis, and Winchester syndrome may be allelic disorders.  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. 
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. 
In the United States, 3 cases were described.
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).  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. 
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,  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.
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