Practice Essentials
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]
A 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] |
Nabai et al, 1977 [5] |
Irani et al, 1978 [6] |
Dunger et al, 1987 [7] |
Prapanpoch et al, 1992 [8] |
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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. |
Etiology
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 [4] and Cohen et al [9] emphasize the abnormal function of the fibroblasts, which causes some of the pathologic changes in this syndrome.
Prognosis
The disease has a progressive course with aggravating bony-articular, ocular, and cutaneous changes.
Complications
Anesthesia management can be challenging in these patients. [10]
Intensified symptoms of osteoporosis, including osteolysis of the carpal and tarsal bones, causes destructive changes in the joints of the hands and wrists, as well as in the joints of the tarsus and foot. Aggravated osteoporosis of the vertebral bodies may lead to compressive fractures of the backbone. In the knee and hip joints, strong contractures can hinder movement. [4, 9] Multifocal bony-articular changes can lead to permanent disability.
Weakening of vision as a consequence of intensified cataracts can occur.
Diagnostics
To verify diagnosis of Winchester syndrome, skin and gum biopsy specimens should be collected for histologic and ultrastructural assessment.
Also see Workup.
Treatment
To establish the final diagnosis of Winchester syndrome, patients with findings suggestive of this pathologic syndrome should undergo examination by many specialists (see Consultations). Pamidronate does not improve peripheral osteolysis in multicentric osteolysis and nodular arthropathy caused by a mutation in the matrix metalloproteinase 2 gene. [11]
Consultations
To establish the final diagnosis and to plan further medical care, patients with findings suggestive of this pathologic syndrome require examinations by specialists, including a pediatrician, a radiologist, a rheumatologist, an orthopedist, an ophthalmologist, a neurologist, a dermatologist, a stomatologist, and a psychologist.
Families with this syndrome should be referred for adequate genetic counseling and consultations.
Activity
The activity of patients is limited because of the pathologic changes that occur in the joints of the limbs and in the spine.
Physiotherapy is advised. Some individuals with Winchester syndrome require orthopedic equipment.
Background
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 [12] 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. [3, 4] 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. [5] In 1978, Irani et al reported a similar case in a 4-year-old boy from Bombay. [6] In both cases, the parents were first cousins.
In 1987, Dunger et al reported 2 additional cases. [7] The first patient had features similar to those of infantile systemic hyalinosis; Winter also emphasized these features. [13] 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. [14]
Pathophysiology
Winchester syndrome appears to be inherited in an autosomal recessive manner. [2, 9] 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, 8, 9] 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. [7]
Studies performed by Hollister et al [3] and Cohen et al [9] 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. [3, 9] 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. [15] A novel homozygous MMP2 mutation was identified in a family with Winchester syndrome. [16] Torg syndrome, nodulosis-arthropathy-osteolysis, and Winchester syndrome may be allelic disorders. [17] These 2 syndromes are both associated with matrix metalloproteinase-2 deficiency and mutations in the metalloproteinase-2 gene. [18, 19] Five novel MMP2 mutations in 13 individuals with multicentric osteolysis nodulosis and arthropathy were identified in India. [20]
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] A homozygous frameshift variant of MMP2 gene has been described. [21] MMP14 catalytic activity appears to be the main determinant of the Winchester syndrome phenotype. [22]
Epidemiology
Frequency
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). [7] See the Table in Background.
In a 32-year period from 1969-2001, 12 cases of Winchester syndrome are described worldwide.
Race-, sex-, and age-related information
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. [14]
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, [5] and in the other 2 cases, the patients were aged 22 and 40 years (see the Table in Practice Essentials).
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(A) Case 1. Girl aged 2.5 years. Destruction of the carpal ossification centers that have appeared early is visible. (B) Case 1. Girl aged 6 years. The carpals are totally destroyed, and erosion of the proximal metacarpals is seen. The phalanges are expanded and appear cystic. Destructive arthritis is observed in the metacarpal, phalangeal, and interphalangeal joints. (C) Case 1. Girl aged 12 years. Only small portions of the metacarpals remain, and destruction of the phalanges of the fifth finger has occurred. The distal radius and ulna are flared. Courtesy of Patricia Winchester, MD, Departments of Radiology, Pediatrics, and Medicine, Cornell University Medical College and the New York Hospital, Cornell Medical Center, 525 East 68th Street, New York, NY 10021.
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Case 1. Girl aged 12 years. The knees are ankylosed. The ends of the long bones are flared. The bone density is markedly diminished. The left distal fibula is eroded. Destruction of the small bones of the foot is seen. Courtesy of Patricia Winchester, MD, Departments of Radiology, Pediatrics, and Medicine, Cornell University Medical College and the New York Hospital, Cornell Medical Center, 525 East 68th Street, New York, NY 10021.