Arthrogryposis, Perthes Disease, and Upward Gaze Palsy

Alternative Names

  • APUG
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations and deformations of the musculoskeletal system

OMIM Number

614262

Mode of Inheritance

Autosomal recessive

Description

APUG is a novel congenital disorder so far reported only in a single consanguineous Saudi family. It is a syndromic form of arthrogryposis affecting both distal and proximal joints. The disorder is characterized by avascular necrosis of capital femoral epiphysis i.e. Perthes disease, upward gaze palsy associated with exotropia, atopy manifesting as severe bronchial asthma, pyloric stenosis, congenital heart disease and subtle facial dysmorphism.

It is interesting to note that thus far, all reported cases of APUG have been female even though one of its features, pyloric stenosis, has generally shown a higher association with males. Management of this disorder involves a multistep approach to deal with each of the symptoms. This includes physiotherapy to relieve joint contractures and surgery to correct pyloric stenosis.

Molecular Genetics

APUG bears the hallmarks of an autosomal recessive disorder due to it affecting the children of healthy consanguineous parents, the presence of unaffected siblings and its highly consistent phenotype in female patients. While a Mendelian cause is strongly suspected, a clear genetic defect is yet to be identified. The PRG4 gene, associated with CACPS syndrome, was not found to be mutated in any of the APUG patients.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Alkuraya (2011) reported a novel autosomal recessive disorder affecting three females of a consanguineous Saudi family. Patient 1, aged 12 years, and her sister, aged 15, were born to healthy parents who were first cousins. Patient 3, aged 7.5 years was the cousin of patients 1 and 2 and was also born to healthy consanguineous parents. All three patients were found to have limited joint mobility as infants and were diagnosed with arthrogryposis of the hands, elbows, knees, hips and ankles. Physiotherapy was carried out in all cases but flexion deformity of knees and elbows remained. Patients 1 and 2 also required surgery for flexion deformities of their fingers. All patients showed disability in gait due to limited hip mobility and Perthes disease. All patients showed upward gaze palsy and exotropia when attempting to look upward. All three had severe, difficult to treat bronchial asthma. The patients showed normal growth and did not have any developmental delays. However, patient 2 did report academic difficulties but this can be attributed to foetal distress at birth. Patients 1 and 2 were found to have pulmonary stenosis after delivery. During infancy, both patients 2 and 3 had to undergo surgery to correct pyloric stenosis. Other symptoms of note include pericardial effusion for patient 1 and sleep apnea for patient 2. Slight facial dysmorphism was reported; this included mildly raised eyebrows, full cheeks and folded upper third of left helix for patient 1; micrognathia and full cheeks for patient 2; and long philtrum and full cheeks for patient 3. All patients were tested for mutations in the PRG4 gene, associated with CACPS syndrome, but no genetic defect was uncovered. After ruling out all possible diagnoses of known diseases, the author concluded that this was a novel disorder combining arthrogryposis, Perthes disease and upward gaze palsy.

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