Winchester Syndrome 

Updated: Apr 16, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

Overview

Background

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.

Pathophysiology

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]

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[5] and Cohen et al[12] emphasize the abnormal function of the fibroblasts, which causes some of the pathologic changes in this syndrome.

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).[8] See the Table in Background.

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

Race

No racial predisposition is recognized.

Sex

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]

Age

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).

Prognosis

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

 

Presentation

History

This rare genetic syndrome is one of the inherited osteolysis disorders characterized by destruction and resorption of affected bones with consequent skeletal deformities and functional impairment.[20] Dissolution of carpal and tarsal bones with generalized osteoporosis, progressive joint contractures, short stature, peripheral corneal opacities, and coarse facial features are often seen, although the clinical features vary. Cutaneous features may include diffusely thickened and leathery skin; hypertrichosis; patches of hyperpigmented, hypertrichotic leathery skin in an annular or linear distribution; subcutaneous nodules; gingival hypertrophy; and widespread progressive multilayered symmetrical restrictive banding of the skin.

Perinatal period

The gestation and delivery of children with later features of Winchester syndrome are normal. In the first case, as described by Winchester et al, closure of the frontal fontanel was delayed until the patient was aged 3 years; in the second case, eruption of the milk teeth was delayed until the patient was aged 12 months.[2]

Pathologic changes

The onset of pathologic changes occurred during the patient's first 2 months of life, as Winchester et al,[2] Hollister et al,[4, 5] and Nabai et al[6] described.

The first pathologic changes usually occurred during the patient's first year of life.[2, 5, 7] In the first stage of the disease, inflammatory conditions appeared with painful joints and limited mobility, which suggests rheumatoid arthritis. These inflammatory changes usually involved the small joints, such as the interphalangeal, metacarpophalangeal, and carpal joints. The changes occurred bilaterally and symmetrically.[2, 4, 5, 6, 7, 11] At the same time, changes may develop in the large joints, such as the knee and vertebral joints.[2]

In the second case, Winchester described findings in a 3.5-year-old girl who had changes in the joints that caused stiffness of the vertebral column and extremities. This stiffness was present before the patient was aged 20 months.

The progressive course of the disease may last for many years and lead to permanent flexion contractures in the small joints of the hands and feet, as well as in the knee, hip, elbow, and shoulder joints. Similar changes may be observed in the vertebral column. Inflammatory changes in the joints may result in a failure to thrive.

Peripheral corneal opacities occurred when patients were aged 2-5 years, or the opacities were found later.[2] In later years, the children had poor eyesight. In 5 reported cases in children aged 3 months, 13 months, 4 years, 12 years, and 16 years, cataracts were not found.[6, 7, 8, 10]

Craniofacial deformities

Deformities and coarsening of the facial features is found at different stages of the disease. In patients described by Winchester et al,[2] craniofacial deformities were visible when the patient was aged 20 months in the first case and at 8 years in the second case. In the third case described by Hollister et al,[4, 5] intense coarsening of the facial features was observed when the patient was aged 22 years.

Other abnormalities

Abnormalities also occur on the limbs and trunk. These abnormalities present different morphologic pictures. These abnormalities were not found in the 2 patients described by Winchester et al.[2] In other cases, thickening and hyperpigmentation of the skin occurred in the initial period of the disease or later.[6]

Physical Examination

In diagnosing Winchester syndrome, the following examination results and characteristic symptoms of the pathologic changes should be taken into account:

  • Case history with familial occurrence in siblings and cousins with a recessive autosomal inheritance pattern

  • Articular changes that occur when the patient is aged about 1 year, combined with complaints similar to those of rheumatoid arthritis

  • In older patients, permanent damages and deformities of the joints and short stature

  • Characteristic radiologic changes of the skeleton with features of multifocal osteoporosis, including a real lack of the carpal and tarsal bones

  • Peripheral corneal opacities

  • Coarsening of facial features

  • Gum hypertrophy

  • Focal or diffuse thickenings, with leathery skin, hyperpigmentation, and hypertrichosis

  • Characteristic histopathologic picture of skin lesions

In 1989, Winter[9] proposed diagnostic criteria for Winchester syndrome. These include the described skeletal radiologic characteristics (see Imaging Studies) combined with at least 2 of the following features: short stature and progressive articular contractures, corneal opacities, thickened hyperpigmentations or hirsutism of the skin, hypertrophy of the gums, and coarsened facial features.

Clinical changes in Winchester syndrome are multisystemic. They can be found in many tissues and organs.

Bony-articular system

Pathologic changes occur in small joints and large joints, as well as in the vertebral column. Involvement of these joints and the vertebral column is the basic feature of this pathologic syndrome. Deformities may occur as a consequence of changes in the bones that form the joints and edema of the periarticular tissues. These changes can be found in the joints of the hands and the digits of the feet, as well as in the wrists and metatarsi. Similar changes can occur in the knee, elbow, shoulder, and hip joints, and they can also involve the backbone. Note the image below.

(A) Case 1. Girl aged 2.5 years. Destruction of th (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.

Spontaneous pain occurs in these joints. This pain is aggravated by movements and palpation at examination. Flexion contractures occur in these joints.

The hands are deformed as a consequence of osteoporosis and osteolysis of the wrist bones, metacarpals, and phalanxes of the hands. Shortening of the wrist metacarpals in the flexion position may be visible, with claw positioning of the fingers. In patients with chronic disease, shortening of the fingers with a deformation may occur as a consequence of total resorption of the phalangeal bones of the fingers.

In the foot region, osteoporosis of the metatarsals and the phalanges can be observed with osteolysis of the tarsal bones. Deformations of the feet with shortening of the tarsus and metatarsus,[2, 5, 6, 12] sometimes with features of equine foot,[11] are observed.

Short stature (below the third percentile) is a characteristic feature of patients with Winchester syndrome. Short stature is presumably a consequence of osteolytic and degenerative changes of the vertebral bodies of the backbone and the long bones of the limbs. The long bones may show osteolytic destruction with rarefaction and atrophy of the spongy and cortical bone tissue, sometimes with thinning of the cortical part to 1 mm.[10] Note the image below.

Case 1. Girl aged 12 years. The knees are ankylose 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.

The damage also involves the metaphyses and epiphyses of these bones. The metaphyses are flattened, and the epiphyses are widened. Erosions occur on the articular surfaces. In some cases, stiffening of the backbone and/or large joints occurs as a consequence of ankylosis.[2, 11]

Skin

Changes in the facial skin and the skin of the trunk and limbs are often characteristic of this syndrome. Facial features may be coarsened and deformed. The following characteristics may be found: protruding forehead, big fleshy nose with lowering of its dorsum, and thick lips.

The skin may be thickened and brownish, and sometimes, it may have a leathery consistency.[6, 7, 12]

On the trunk and extremities, the skin may be thickened with associated hyperpigmentation and, sometimes, associated hirsutism. Changes in the skin may be focal, oval shape, and 8-12 cm in diameter. The changes can be localized on the back in the scapular region, and smaller ones are symmetrically scattered in the medial and lower parts of the back, as well as on the lateral surfaces of the chest and arms.[4, 5]

In some patients, changes may be diffuse and occupy a larger surface area on the skin.

In the case of the 3-month-old infant described by Nabai et al, a diffuse symmetrical skin thickening occurred on the abdomen and both limbs.[6] The skin over the metacarpal joints of the phalanxes and phalanxes was thickened with brown hyperpigmentation. Widespread progressive multilayered symmetrical restrictive cutaneous banding has been noted in one patient.[4]

Eyes and oral cavity

Corneal opacities, which are also characteristic of this syndrome, are usually localized on the corneal peripheries. Corneal opacities may involve the Descemet membrane. Involvement of the Descemet membrane was found in 1 patient.[5] In a 40-year-old woman, the corneal opacities were accompanied by glaucoma.[11] Corneal damage depends on the duration of the disease and worsens as the patient ages.

Hypertrophy of the gums is found in most patients.

Internal organs

In the cases described to date, hepatosplenomegaly has not been shown. In the single cases of children, heart murmurs over the heart or ECG changes were present.[2, 5]

Complications

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.[5, 12] Multifocal bony-articular changes can lead to permanent disability.

Weakening of vision as a consequence of intensified cataracts can occur.

 

DDx

Diagnostic Considerations

The differential diagnosis of Winchester syndrome includes Hajdu-Cheney syndrome[21, 22] and the diseases described below.[11]

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.[23, 24, 25, 26] 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.[27]

According to Kozlowski et al and Lemaitre et al, specific radiologic findings should be the major criteria for classification of this disease.[28, 29] 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.[11]

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 specimens are pathognomonic.[30, 31, 32, 33] This disorder may result from mutations in the anthrax toxin receptor 2 gene (ANTXR2) located on 4q21.[34] Infantile systemic hyalinosis has overlapping features with juvenile hyaline fibromatosis and must also be considered in the differential diagnosis of Winchester syndrome.[35]

Infantile systemic hyalinosis

Infantile systemic hyalinosis is an allelic variant of juvenile systemic hyalinosis.[36] It tends to affect infants of consanguineous parents in Arab countries, with  painful joint contractures, cutaneous hyperpigmentation, and recurrent infections.

 

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 oligosaccharides[8] and increased para-amino-isobutyric acid, leucine, and proline levels.[6]

Determinations of IgM serum levels,[5, 6] 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.[11]

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.[2, 4, 5, 12]

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.[11] 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.[2, 11]

A case report documented the progression of radiological findings over a 23-year period.[37]

Procedures

To verify diagnosis of Winchester syndrome, skin and gum biopsy specimens should be collected for histologic and ultrastructural assessment.

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.[12] 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.[12]

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.[12]

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.[12] 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).

 

Treatment

Medical Care

To establish the final diagnosis of Winchester syndrome (WS), 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.[38]

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 backbone.

Long-Term Monitoring

Physiotherapy is advised. Some individuals with Winchester syndrome require orthopedic equipment.

 

Medication

Medication Summary

Treatment of the disease is symptomatic. The available literature provides little information regarding useful treatment modalities.