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GeNeViSTA
Type of DA | Clinical features | Intelligence | Synonyms | Inheritance | Genes
|
DA type 1 (1A & 1B) | Typical involvement of hands and feet | Normal | – | AD# | |
DA type 2A | Typical involvement of hands and feet, typical facies* | Normal | Freeman-Sheldon syndrome | AD | MYH3 7 |
DA type 2B | Typical involvement of hands and feet, typical facies* | Normal | Sheldon-Hall syndrome | AD | |
DA type 3 | Finger contractures, cleft palate, talipoequinovarus | May have intellectual disability | Gordon syndrome | AD | – |
DA type 4 | Finger contractures, scoliosis | May have intellectual disability | – | AD | – |
DA type 5 | Finger contractures, ophthalmoplegia, ptosis | Normal | – | AD, ARθ | ECEL1 (AR)4 |
DA type 6 | Finger contractures, sensorineural hearing loss | Normal | – | AD | – |
DA type 7 | Trismus, camptodactyly on dorsiflexion of wrist | Normal | Trismus-pseudo-camptodactyly syndrome | AD | MYH8 8 |
DA type 8 | Typical involvement of hands and feet, multiple pterygia, typical facies* | Normal | – | AD | – |
DA type 9 | Finger contractures, arachnodactyly, external ear deformity | Normal | Congenital contractural arachnodactyly (Beals syndrome) | AD | FBN2 |
* For facial description see text.
# AD – Autosomal dominant.
θ Autosomal recessive.
TNNI2 – Troponin I; TMP2 - Tropomyosin 2; TNNT3 – Troponin T3; MYH3 – Myosin heavy chain 3; MYBPC1 –
Myosin-binding heavy protein C; MYH8 - Myosin heavy chain 8; FBN2 – Fibrillin 2.
DA type 4 manifests with finger contractures and scoliosis. Variable features include intellectual disability and limitation of elbow joint movements.3,5
DA type 5 is inherited as both an autosomal dominant and autosomal recessive disorder. Along with finger contractures and feet involvement, eye findings are peculiar to patients with DA5. Variable eye features include ophthalmoplegia, strabismus, ptosis, pigmentary maculopathy, keratoconus and an abnormal electroretinogram. Some cases are known to have pulmonary hypertension secondary to restrictive lung disease.3,5 Based on the eye and other findings, DA5 has been classified into four subtypes (DA5A-D).4 DA5D is inherited as an autosomal recessive disorder.
DA type 6 is characterized by distal limb contractures and sensorineural hearing loss.3,5
DA type 7 is characterized by inability to open the mouth and flexion of fingers on dorsiflexion of the wrist. Variable clinical features include talipes equinovarus, hip involvement, short leg muscles and short stature.3,5
In DA type 8, along with typical manifestations in the hands and feet, patients present with multiple pterygia, scoliosis with vertebral segmentation defects, facial features, short neck and short stature. Facial features include ptosis, downslanting eyes, low set ears, and high arched palate. It is an autosomal dominant disorder, with most cases occurring sporadically due to de novo mutations. The other conditions which present with similar clinical features include autosomal recessive multiple pterygium syndrome (Escobar syndrome), X-linked multiple pterygium syndrome and a lethal form.3,5
DA type 9 is characterized by finger contractures and crumpled ears. Variable clinical features include scoliosis, limitation of elbow and hip joint movements, valvular heart disease and talipes equinovarus.3,5 DA9 is caused by FBN2 (fibrillin 2) gene mutations, with most of the mutations occuring in exon 23 to exon 34. Some patients with the severe form of DA9 can simulate neonatal Marfan syndrome.11 Crumpled ear is used as a hallmark to identify patients with DA9.
Management of patients with DA should involve various specialties (clinical genetics, orthopedics, neurology, pediatrics and physiotherapy). Joint contractures and skeletal complications (scoliosis) are managed by physical therapy and/or surgery. Patients requiring surgery might face difficult intubation and are at risk of malignant hyperthermia (documented in some of the subtypes). Inheritance is autosomal dominant in most of the cases. Mutations can occur de novo (sporadic), in which case the risk of recurrence in siblings is negligible. If the mutation is inherited from one of the parents, the risk of recurrence is 50% for the siblings. Molecular genetic testing and identification of the causative gene mutation help in providing an accurate risk of recurrence and appropriate genetic counseling. In cases with autosomal recessive inheritance, the risk of recurrence in siblings of an affected individual is 25%.
Prenatal diagnosis can be achieved by ultrasound (less accurate) and molecular genetic testing, if the underlying gene mutation is known (more accurate).
Author suggests readers the recent article on Arthrogryposis: Diagnostic approach to etiology, classification, genetics and general principles by Dr Judith G Hall published in E J Med Genet (2014) for updated clinical approach and list of genes.
1. Hall JG. Clin Orthop Relat Res 194: 44-53.
2. Hall JG. Am J Med Genet A 2012; 158A: 2214-20.
3. Bamshad M, et al. Am J Med Genet 1996; 65: 277-81.
4. McMillin MJ, et al. Am J Hum Genet 2013; 92: 150-6.
5. Beck AE, et al. Am J Med Genet A 2013; 161: 550-5.
6. Gurnett CA, et al. Hum Mol Genet 2010; 19: 1165-73.
7. Toydemir RM, et al. Nat Genet 2006; 38: 561-5.
8. Toydemir RM, et al. Am J Med Genet A 2006; 140: 2387-93.
9. Beals RK. Clin Orthop Relat Res. 2005; 435: 203-10.
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