arthrogryposis

Arthrogryposis, Perthes Disease, and Upward Gaze Palsy

Clinical Characteristics
Ocular Features: 

Upward gaze is restricted and attempts to do so are associated with exotropia.

Systemic Features: 

Arthrogryposis with restricted joint mobility is present in both proximal and distal joints, including hips, elbows, hands, and knees.  It is usually evident early in infancy when parents note "tight joints".  Other joint deformities present to some degree are "trigger finger" deformities found in the middle fingers and thumbs.  Hip pain and difficulty walking as early as 3 years of age can be signs of avascular necrosis of the femoral head (Perthes disease).   

Pyloric stenosis can lead to severe, recurrent vomiting.  Pulmonic stenosis is commonly present and there are often cardiac septal defects as well as valvular malfunctions.  Bronchial asthma is a feature.

Genetics

One extended consanguineous Saudi family with three affected females has been reported.  No similar findings are present in the parents and the condition is most likely transmitted as an autosomal recessive.  A homozygous mutation in NEK9 (14q24) has been associated with this condition.

Heterozygous mutations in the same gene have been identified in 3 patients with nevus comedonicus (617025).  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Flexion deformities may be at least partially alleviated by surgery and is especially beneficial for digital function.  Pyloric stenosis and cardiac valve disease may respond to surgery.

References
Article Title: 

Mutations in NEK9 Cause Nevus Comedonicus

Levinsohn JL, Sugarman JL; Yale Center for Mendelian Genomics, McNiff JM, Antaya RJ, Choate KA. Somatic Mutations in NEK9 Cause Nevus Comedonicus. Am J Hum Genet. 2016 May 5;98(5):1030-7.

PubMed ID: 
27153399

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, ALMoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M, Alfaleh K, Alshammari M, Alhashem A, Alangari AA, Salih MA, Kircher M, Daza RM, Ibrahim N, Wakil SM, Alaqeel A, Altowaijri I, Shendure J, Al-Habib A, Faqieh E, Alkuraya FS. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med. 2016 Jul;18(7):686-95.

PubMed ID: 
26633546

Cerebrooculofacioskeletal Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts and microphthalmia are frequent findings in this disorder.  Delayed mental development and early death in childhood have limited full delineation of the ocular phenotype.  Photosensitivity, nystagmus, optic nerve atrophy, and pigmentary retinopathy have been reported.  The eyes may appear deeply-set.

Systemic Features: 

Microcephaly, flexion contractures, prominent nasal root and an overhanging upper lip are common features.  Severe developmental and growth delays are evident early followed by progressive behavioral and intellectual deterioration.  Both hypotonia and hyperreflexia have been described.    Kyphosis and scoliosis are common.  CT scans may show intracranial calcifications and brain histology shows severe neurodegeneration with neuronal loss and gliosis.  Respiratory distress may also occur and some individuals have died in the first decade of life.

Genetics

Homozygous mutations in the ERCC6 gene (10q11) seem to be responsible for this autosomal recessive disorder.  Several sets of parents have been consanguineous.  Mutations in the same gene are responsible for Cockayne type B syndrome (133540) and some suggest that the variable phenotype represents a spectrum of disease rather than individual entities. Cerebrooculofacioskeletal syndrome represents the more severe phenotype in this spectrum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 
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