eMedicine Specialties > Dermatology > Pediatric Diseases

Winchester Syndrome

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

Introduction

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.

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.¹ Later, Brown and Kuwabara² performed corneal biopsy in the younger sibling, whose case is discussed in the report by Winchester et al¹ ; 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.¹ 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.⁸ 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.⁹ 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.

Open table in new window

Pathophysiology

Winchester syndrome appears to be inherited in an autosomal recessive manner.^1,11 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, and the syndrome is believed to be a mucopolysaccharidosis with unknown enzymatic disturbances.^1,10,11 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 al³ and Cohen et al¹¹ 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 fibroblasts¹ 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.^3,11 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.¹² A novel homozygous MMP2 mutation was identified in a family with Winchester syndrome.¹³ Torg syndrome, nodulosis-arthropathy-osteolysis, and Winchester syndrome may be allelic disorders.¹⁴

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

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.⁹

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,⁵ and in the other 2 cases, the patients were aged 22 and 40 years (see the Table in Background).

Clinical

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.¹⁵ 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.¹
• Pathologic changes
  • The onset of pathologic changes occurred during the patient's first 2 months of life, as Winchester et al,¹ Hollister et al,^3,4 and Nabai et al⁵ described.
  • The first pathologic changes usually occurred during the patient's first year of life.^1,4,6
    • 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.^1,3,4,5,6,10
    • At the same time, changes may develop in the large joints, such as the knee and vertebral joints.¹
  • 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.¹ 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.^5,6,7,9
• Craniofacial deformities
  • Deformities and coarsening of the facial features is found at different stages of the disease.
  • In patients described by Winchester et al,¹ 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,^3,4 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.¹
  • In other cases, thickening and hyperpigmentation of the skin occurred in the initial period of the disease or later.⁵

Physical

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, Winter⁸ 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.

• 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,^1,4,5,11   sometimes with features of equine foot,¹⁰ 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.⁹

• 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.^1,10
• 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.^5,6,11
  • 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.^3,4
  • 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.⁵ The skin over the metacarpal joints of the phalanxes and phalanxes was thickened with brown hyperpigmentation.
• Eyes
  • 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.⁴
  • In a 40-year-old woman, the corneal opacities were accompanied by glaucoma.¹⁰
  • Corneal damage depends on the duration of the disease and worsens as the patient ages.
• Oral cavity: 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.^1,4

Causes

• 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 al⁴ and Cohen et al¹¹ emphasize the abnormal function of the fibroblasts, which causes some of the pathologic changes in this syndrome.

• Search for CME/CE on This Topic »