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Duane-Radial Ray syndrome / Acro-Renal-Ocular syndrome
SALL4 (sal-like 4)
HSAL4 (human sal4)
Duane-Radial Ray syndrome (DRRS) is characterized by the Duane eye anomaly (a congenital disorder of eye movement) and radial ray malformations of the limbs including triphalangeal thumbs, preaxial polydactyly, hypoplasia/aplasia of the thumbs, hypoplasia/aplasia of the radii, and shortening and radial deviation of the forearms.
Acro-Renal-Ocular syndrome (AROS) is allelic to DRRS, and presents with radial ray malformations and Duane anomaly, along with other features such as ocular coloboma and renal abnormalities (renal hypoplasia, horseshoe kidney, vesico-utereral reflux, bladder diverticular, ectopia, and mild malrotation).
The limb anomalies characteristic of DRRS/AROS overlap with two other clinically defined genetic syndromes: Holt-Oram syndrome (HOS), which is due to mutations in the TBX5 gene, and Townes-Brocks syndrome (TBS), caused by mutations in the SALL1 gene. (see the chart below which outlines the overlapping and exclusive features of the three syndrome). Genetic testing for all three disorders is available at GeneDx, Inc.
DRRS/AROS is an autosomal dominant disorder caused by heterozygous mutations in the SALL4 gene. At least 1/3 of cases are sporadic.
Two recent studies demonstrated that SALL4 mutations can be identified in the vast majority of clinically diagnosed patients using a combination of full gene sequencing and deletion studies.
Using genomic DNA obtained from blood (1-5 mL in EDTA), combined analysis is performed by bi-directional sequencing of the coding regions (exons 1-4) and splice sites of the SALL4 gene as well as deletion/duplication testing using targeted array CGH analysis with exon-level resolution (ExonArrayDx). Mutation-specific testing in family members and prenatal diagnosis in at-risk pregnancies is available once a mutation in an affected person has been defined.
Genes and Associated Features/Malformations
TBS (SALL1)
DRRS/AROS (SALL4 gene)
HOS (TBX5 gene)
Limbs
Yes:
hands and feet (preaxial polydactyly, triphalangeal thumbs, bifid thumbs and toes, finger and toe syndactyly)
Exclusionary:
radial hypoplasia
Yes:
radial ray malformations including triphalangeal thumbs, preaxial polydactyly, hypoplasia/aplasia of the thumbs, hypoplasia/aplasia of the radii, shortening and radial deviation of the forearms; upper limb abnormalities
Yes:
most commonly triphalangeal or absent thumbs; upper limb abnormalities usually bilateral, frequently asymmentrical; spectrum ranges from severe (phocomelia) to mild (slight carpal bone abnormalities)
Exclusionary:
ulnar or lower limb involvement, syndactyly involving digits other than the thumb, polydactyly
Heart
Yes;
less common
Yes;
less common; less severe
Yes;
cardiac abnormalities occur in ~75% of patients, most commonly ASD or VSD
Eyes
Yes;
less common
Yes;
Duane Anomaly
No
Kidneys
Yes:
unilateral or bilateral hypoplastic or dysplastic kidneys, multicystic kidneys, renal agenesis, posterior urethral valves, vesico-uretal reflex
Yes:
renal hypoplasia, horseshoe kidney, vesico-utereral reflux, bladder diverticular, ectopia, and mild malrotation)
No
Ears
Yes:
external ear malformations (preauricular tags or pits, "lop" or "satyr" ear, microtia, abnormal helix); hearing loss (sensorineural, conductive or mixed)
Yes;
less common but can include hearing loss, ear malformations
No
Information Sheet, including prices and CPT codes
Consent Document
Genetic Test Sample Submission Form (Test Requisition Form) including Payment Options
SALL4, HSAL4, DRRS, AROS, Duane eye anomaly, congenital, eye movement, radial ray malformation, limb, coloboma, renal, hearing loss, ear, Holt-Oram syndrome, HOS, Townes-Brocks syndrome, TBS
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