Duane syndrome with radial ray anomalies

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One type of inherited Duane syndrome that is associated with other birth defects is Duane syndrome with radial ray anomalies. The association of Duane syndrome with radial ray anomalies is referred to in the literature as Duane/radial dysplasia syndrome, DR syndrome (acronym for Duane anomaly, deafness, radial dysplasia, renal dysplasia), and Okihiro syndrome. The familial association of Duane syndrome with radial ray anomalies appears to be autosomal dominant with incomplete penetrance and variable expressivity.

The Duane syndrome can be unilateral or bilateral. The radial dysplasia can range from hypoplasia of the thenar eminence (base of thumb) with or without thumb abduction and apposition weakness, hypoplasia or absence of the thumb, and hypoplasia or absence of the radial and ulnar bones to an absent forarem. In the picture to the right an individual with this disorder is attempting right and left gaze and thenar hypoplasia and thumb anomalies in affected individuals are displayed. Hearing loss, dysmorphic facies and cardiac, renal, and vertebral anomalies are variably expressed in some families.

In 2002 a publication that came out of our laboratory described the mapping of this disorder to Chromosome 20 and identification of the gene, SALL4, as being causative for the disorder1. One nonsense (a mutation (a change) in a base in the DNA that prematurely stops the translation (reading) of messenger RNA (mRNA) resulting in a polypeptide chain that ends prematurely and a protein product that is truncated (abbreviated) and incomplete and usually nonfunctional) and 2 frameshift (a mutational addition or deletion of a base pair in a gene that disrupts the normal reading frame of an mRNA, which is read in groups of three bases) mutations were identified in 3 families (2 US and 1 Japanese-the original Okihiro pedigree for which this disorder was named).

12 of the 13 affected participants had Duane syndrome (unilateral/bilateral; Type1 or 3). 12 affected participants had radial dysplasia (unilateral/bilateral) ranging from hypoplasia of the thenar eminence (ball of the thumb) to forearm foreshortening with absent radial bone, radial pulse and thumb. 2 affected's had sensorineural hearing loss and also in at least one affected: facial weakness, abnormal pinna, fused cervical vertebrae, pectoralis muscle aplasia and Hirschsprung disease existed.

Also, in July 2002, Kohlhase et al2 described the identification of 2 nonsense and 3 frameshift SALL4 mutations in 5 families and extended the DRR phenotype to include: anal stenosis, external ear malformations, deafness, thumb reduplication, unilateral renal agenesis, choanal stenosis and ventricular septal defect. Follow up papers3,4,5,6 described SALL4 mutations in individuals who had been diagnosed with Holt-Oram syndrome, acrorenalocular syndrome and also in whom thalidomide embryopathy had previously been reported.

One pedigree in which a SALL4 mutations was identified displayed VACTERL (vertebral, anal, cardiac, renal and limb anomalies) but without manifesting Duane syndrome. A total of 17 novel mutations have been identified to date in SALL4 and a wide phenotypic (clinical characteristics) spectrum has been identified in individuals manifesting this disorder.

Please contact Caroline Andrews to obtain further information on the genetic studies that we are undertaking and if you are interested in enrolling a patient or participating yourself.

References

Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last entry date 1/9/2004 (entry number #607323). 

  1. Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002 Nov;71(5):1195-9. Epub 2002 Oct 22.

  2. Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002 Nov 1;11(23):2979-87.

  3. Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, Newbury-Ecob R, Reardon W. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J Med Genet. 2003 Jul;40(7):473-8.

  4. Borozdin W, Wright MJ, Hennekam RC, Hannibal MC, Crow YJ, Neumann TE, Kohlhase J. Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum. J Med Genet. 2004 Aug;41(8):e102.

  5. Kohlhase J, Holmes LB. Mutations in SALL4 in malformed father and daughter postulated previously due to reflect mutagenesis by thalidomide. Birth Defects Res A Clin Mol Teratol. 2004 Aug;70(8):550-1.

  6. Borozdin W, Boehm D, Leipoldt M, Wilhelm C, Reardon W, Clayton-Smith J, Becker K, Muhlendyck H, Winter R, Giray O, Silan F, Kohlhase J. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet. 2004 Sep;41(9):e113.

 

Learn about SALL4

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SALL4 is the causative gene for Duane syndrome with radial ray anomalies (DRRS)-Okihiro syndrome.

The diagram to the right displays the predicted SALL1-4 protein structures. SALL4 contains one NH2-terminus C2HC-type finger (ZF; black circle) and 7 C2H2-type ZF (oval) domains. The latter are arranges as double ZFs (DZF), with a third finger associated with the second doublet (white oval). The first finger of each pair contains a somewhat variable sequence (yellow, orange and blue ovals), whereas the second finger of each pair contains the conserved SAL-box sequence, FT/STKGNLK (red ovals). The homologies to SALL1-3 are shown. SALL2 also contains three DZF motifs; the first two are highly similar to the other proteins, but the third is divergent (gray ovals).

In contrast, SALL1 and SALL3 each contain three DZF motifs located between the second and third DZF in SALL4. The positions of the SALL4 splice junctions and the three mutations identified by our laboratory in 3 pedigrees whose affected individuals had DRRS1 are superimposed on the schematic protein (V, FN and DA-referring to the 3 different pedigrees). The three mutations are predicted to result in unstable mRNAs or truncated proteins disrupting the fifth and/or lacking the sixth and seventh DZF motifs.

In a recent paper2 Kohlhase et al determined that Okihiro and acrorenalocular syndromes are the result of SALL4 haploinsufficiency (a situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally). These studies examined a loss of heterozygosity in DRS families in whom SALL4 mutations had not previously been identified. Their findings suggest that Duane syndrome with radial ray anomalies are not only caused by truncating(causing shortening of the derived protein) SALL4 mutations but also by deletions of either the whole gene or of single exons.

We are still interested in enrolling individuals with these disorders in our genetic studies and would screen your DNA for SALL4 mutations. Please contact Caroline Caroline Andrews for more information on enrollment. If we were to identify a SALL4 mutation in your DNA, and if you had indicated an interest in results being reported to you, Caroline can coordinate for the CLIA certified DNA Diagnostic Laboratory based at Boston Children's Hospital to undertake confirmatory testing such that results may be released to you.

References

Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, creation date 11/12/2003 (entry number *607343). Home page: http://www3.ncbi.nlm.nih.gov/Omim/

    1. Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002 Nov;71(5):1195-9. Epub 2002 Oct 22.

    2. Borozdin W, Boehm D, Leipoldt M, Wilhelm C, Reardon W, Clayton-Smith J, Becker K, Muhlendyck H, Winter R, Giray O, Silan F, Kohlhase J. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet. 2004 Sep;41(9):e113

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