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Duane-radial ray syndrome(DRRS)

MedGen UID:
301647
Concept ID:
C1623209
Disease or Syndrome
Synonyms: Acro-Renal-Ocular Syndrome; Acrorenoocular syndrome; DR SYNDROME; DRRS; DUANE ANOMALY WITH RADIAL RAY ABNORMALITIES AND DEAFNESS; Duane-Radial Ray Syndrome/Okihiro Syndrome; Okihiro Syndrome; SALL4-Related Disorders
SNOMED CT: Okihiro syndrome (699867001); Duane-radial ray syndrome (699867001); DRRS - Duane-radial ray syndrome (699867001); Acrorenoocular syndrome (720415006); Acro-renal-ocular syndrome (720415006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SALL4 (20q13.2)
 
Monarch Initiative: MONDO:0011812
OMIM®: 607323
Orphanet: ORPHA93293

Disease characteristics

Excerpted from the GeneReview: SALL4-Related Disorders
SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features). [from GeneReviews]
Authors:
Jürgen Kohlhase   view full author information

Additional descriptions

From OMIM
Duane-radial ray syndrome, also known as Okihiro syndrome, is an autosomal dominant disorder characterized by upper limb anomalies, ocular anomalies, and, in some cases, renal anomalies. The combination of the 3 findings was earlier referred to as 'acro-renal-ocular syndrome.' The ocular anomalies usually include Duane anomaly (see 126800), but this finding may be absent in some patients (Kohlhase et al., 2003). Similarly, renal anomalies are not always seen and may not have been investigated, particularly in cases reported before routine renal imaging (Aalfs et al., 1996). Other less common features include sensorineural deafness and gastrointestinal anomalies, such as imperforate anus. The Holt-Oram syndrome (142900), caused by mutation in the TBX5 gene (601620) on chromosome 12q24, shows similar anomalies of the upper limb, but can be differentiated from Duane-radial ray syndrome by the absence of ocular and renal anomalies and the presence of severe congenital heart defects (Kohlhase, 2003).  http://www.omim.org/entry/607323
From MedlinePlus Genetics
Duane-radial ray syndrome is a disorder that affects the eyes and causes abnormalities of bones in the arms and hands. This condition is characterized by a particular problem with eye movement called Duane anomaly (also known as Duane syndrome). This abnormality results from the improper development of certain nerves that control eye movement. Duane anomaly limits outward eye movement (toward the ear), and in some cases may limit inward eye movement (toward the nose). Also, as the eye moves inward, the eye opening becomes narrower and the eyeball may pull back (retract) into its socket.

Bone abnormalities in the hands include malformed or absent thumbs, an extra thumb, or a long thumb that looks like a finger. Partial or complete absence of bones in the forearm is also common. Together, these hand and arm abnormalities are known as radial ray malformations.

People with the combination of Duane anomaly and radial ray malformations may have a variety of other signs and symptoms. These features include unusually shaped ears, hearing loss, heart and kidney defects, a distinctive facial appearance, an inward- and upward-turning foot (clubfoot), and fused spinal bones (vertebrae).

The varied signs and symptoms of Duane-radial ray syndrome often overlap with features of other disorders. For example, acro-renal-ocular syndrome is characterized by Duane anomaly and other eye abnormalities, radial ray malformations, and kidney defects. Both conditions are caused by mutations in the same gene. Based on these similarities, researchers suspect that Duane-radial ray syndrome and acro-renal-ocular syndrome are part of an overlapping set of syndromes with many possible signs and symptoms. The features of Duane-radial ray syndrome are also similar to those of a condition called Holt-Oram syndrome; however, these two disorders are caused by mutations in different genes.  https://medlineplus.gov/genetics/condition/duane-radial-ray-syndrome

Clinical features

From HPO
Hydronephrosis
MedGen UID:
42531
Concept ID:
C0020295
Disease or Syndrome
Severe distention of the kidney with dilation of the renal pelvis and calices.
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Horseshoe kidney
MedGen UID:
65140
Concept ID:
C0221353
Congenital Abnormality
A connection of the right and left kidney by an isthmus of functioning renal parenchyma or fibrous tissue that crosses the midline.
Renal malrotation
MedGen UID:
68662
Concept ID:
C0238210
Congenital Abnormality
An abnormality of the normal developmental rotation of the kidney leading to an abnormal orientation of the kidney.
Renal hypoplasia
MedGen UID:
120571
Concept ID:
C0266295
Congenital Abnormality
Hypoplasia of the kidney.
Renal agenesis
MedGen UID:
154237
Concept ID:
C0542519
Congenital Abnormality
Agenesis, that is, failure of the kidney to develop during embryogenesis and development.
Crossed fused renal ectopia
MedGen UID:
372130
Concept ID:
C1835796
Congenital Abnormality
A developmental anomaly in which the kidneys are fused and localized on the same side of the midline. This anomaly is thought to result from disruption of the normal embryologic migration of the kidneys.
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Triphalangeal thumb
MedGen UID:
66029
Concept ID:
C0241397
Congenital Abnormality
A thumb with three phalanges in a single, proximo-distal axis. Thus, this term applies if the thumb has an accessory phalanx, leading to a digit like appearance of the thumb.
Preaxial polydactyly
MedGen UID:
87498
Concept ID:
C0345354
Congenital Abnormality
A form of polydactyly in which the extra digit or digits are localized on the side of the thumb or great toe.
Short thumb
MedGen UID:
98469
Concept ID:
C0431890
Congenital Abnormality
Hypoplasia (congenital reduction in size) of the thumb.
Radial deviation of the hand
MedGen UID:
108280
Concept ID:
C0575803
Finding
An abnormal position of the hand in which the wrist is bent toward the radius (i.e., toward the thumb).
Hypoplasia of the radius
MedGen UID:
672334
Concept ID:
C0685381
Congenital Abnormality
Underdevelopment of the radius.
Absent radius
MedGen UID:
235613
Concept ID:
C1405984
Congenital Abnormality
Missing radius bone associated with congenital failure of development.
Short humerus
MedGen UID:
316907
Concept ID:
C1832117
Congenital Abnormality
Underdevelopment of the humerus.
Sandal gap
MedGen UID:
374376
Concept ID:
C1840069
Finding
A widely spaced gap between the first toe (the great toe) and the second toe.
Aplasia of metacarpal bones
MedGen UID:
335431
Concept ID:
C1846473
Finding
Developmental defect associated with absence of one or more metacarpal bones.
Small thenar eminence
MedGen UID:
335432
Concept ID:
C1846474
Finding
Underdevelopment of the thenar eminence with reduced palmar soft tissue mass surrounding the base of the thumb.
Hypoplasia of the ulna
MedGen UID:
395934
Concept ID:
C1860614
Congenital Abnormality
Underdevelopment of the ulna.
Absent thumb
MedGen UID:
480441
Concept ID:
C3278811
Finding
Absent thumb, i.e., the absence of both phalanges of a thumb and the associated soft tissues.
Vascular dilatation
MedGen UID:
8076
Concept ID:
C0002940
Pathologic Function
Abnormal outpouching or sac-like dilatation in the wall of an atery, vein or the heart.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Imperforate anus
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.
Anal stenosis
MedGen UID:
82644
Concept ID:
C0262374
Anatomical Abnormality
Abnormal narrowing of the anal opening.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Slit-like opening of the exterior auditory meatus
MedGen UID:
339530
Concept ID:
C1846459
Finding
A type of stenosis of the external auditory meatus in which the opening of the external auditory meatus appears as a vertical slit.
Aganglionic megacolon
MedGen UID:
5559
Concept ID:
C0019569
Disease or Syndrome
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur. Genetic Heterogeneity of Hirschsprung Disease Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32. HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880). Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases. HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases (summary by Amiel et al., 2008).
Spina bifida occulta
MedGen UID:
36380
Concept ID:
C0080174
Congenital Abnormality
The closed form of spina bifida with incomplete closure of a vertebral body with intact overlying skin.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Shoulder dislocation
MedGen UID:
48655
Concept ID:
C0037005
Injury or Poisoning
A displacement or misalignment of the humerus with respect to the other bones of the should joint. Note that a subluxation is a partial dislocation.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Pectoralis hypoplasia
MedGen UID:
335435
Concept ID:
C1846477
Finding
Underdevelopment of the pectoral muscle.
Upper limb muscle hypoplasia
MedGen UID:
335436
Concept ID:
C1846478
Finding
Underdevelopment of muscles of the arm.
Fused cervical vertebrae
MedGen UID:
854386
Concept ID:
C3887527
Congenital Abnormality
A congenital anomaly characterized by a joining (fusion) of two or more cervical vertebral bodies with one another.
Abnormal nasopharynx morphology
MedGen UID:
871265
Concept ID:
C4025750
Anatomical Abnormality
A structural anomaly of the nasopharynx.
Choanal atresia
MedGen UID:
3395
Concept ID:
C0008297
Congenital Abnormality
Absence or abnormal closure of the choana (the posterior nasal aperture). Most embryologists believe that posterior choanal atresia results from a failure of rupture between the 35th and 38th day of fetal life of the partition which separates the bucconasal or buccopharyngeal membranes. The resultant choanal atresia may be unilateral or bilateral, bony or membranous, complete or incomplete. In over 90 per cent of cases the obstruction is bony, while in the remainder it is membranous. The bony type of atresia is commonly located 1-2 mm. anterior to the posterior edge of the hard palate, and the osseous septum varies in thickness from 1 to 10 mm. In the membranous form of choanal atresia the obstruction usually occurs further posteriorly. In approximately one third of cases the atresia is bilateral.
Choanal stenosis
MedGen UID:
108427
Concept ID:
C0584837
Finding
Abnormal narrowing of the choana (the posterior nasal aperture).
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Facial asymmetry
MedGen UID:
266298
Concept ID:
C1306710
Finding
An abnormal difference between the left and right sides of the face.
Palpebral fissure narrowing on adduction
MedGen UID:
375896
Concept ID:
C1846465
Finding
Duane retraction syndrome
MedGen UID:
4413
Concept ID:
C0013261
Disease or Syndrome
Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly results from failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle; globe retraction occurs as a result of abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Many individuals with Duane syndrome have strabismus in primary gaze but can use a compensatory head turn to align the eyes, and thus can preserve binocular vision and avoid diplopia. Individuals with Duane syndrome who lack binocular vision are at risk for amblyopia. The majority of affected individuals with Duane syndrome have isolated Duane syndrome (i.e., they do not have other detected congenital anomalies). Other individuals with Duane syndrome fall into well-defined syndromic diagnoses. However, many individuals with Duane syndrome have non-ocular findings that do not fit a known syndrome; these individuals are included as part of the discussion of nonsyndromic Duane syndrome.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Iris coloboma
MedGen UID:
116097
Concept ID:
C0240063
Anatomical Abnormality
A coloboma of the iris.
Impaired convergence
MedGen UID:
78768
Concept ID:
C0271379
Finding
Reduced ability to turn the eyes inward in order to focus on a nearby object.
Optic disc hypoplasia
MedGen UID:
224879
Concept ID:
C1298695
Finding
Underdevelopment of the optic disc, that is of the optic nerve head, where ganglion cell axons exit the eye to form the optic nerve.
Impaired ocular abduction
MedGen UID:
375894
Concept ID:
C1846462
Finding
An impaired ability of the eye to move in the outward direction (towards the side of the head).
Impaired ocular adduction
MedGen UID:
337588
Concept ID:
C1846463
Finding
Reduced ability to move the eye in the direction of the nose.
Retinal coloboma
MedGen UID:
761889
Concept ID:
C3540764
Disease or Syndrome
A notch or cleft of the retina.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVDuane-radial ray syndrome
Follow this link to review classifications for Duane-radial ray syndrome in Orphanet.

Professional guidelines

PubMed

Kalevar A, Ong Tone S, Flanders M
Can J Ophthalmol 2015 Aug;50(4):310-3. doi: 10.1016/j.jcjo.2015.05.005. PMID: 26257226
Maya JF, de Liaño RG, Catalán MR, Rayward O
Strabismus 2013 Mar;21(1):4-7. doi: 10.3109/09273972.2012.762530. PMID: 23477770
Helveston EM, Neely DE, Cherwek DH, Smallwood LM
Telemed J E Health 2008 Aug;14(6):531-8. doi: 10.1089/tmj.2007.0086. PMID: 18729751

Recent clinical studies

Etiology

Ajam-Hosseini M, Parvini F, Angaji A
BMC Med Genomics 2023 Feb 24;16(1):33. doi: 10.1186/s12920-023-01467-1. PMID: 36829172Free PMC Article

Diagnosis

Ajam-Hosseini M, Parvini F, Angaji A
BMC Med Genomics 2023 Feb 24;16(1):33. doi: 10.1186/s12920-023-01467-1. PMID: 36829172Free PMC Article
Garcia-Martin E, Pinilla I, Almarcegui C, Fernandez J, Engle EC, Ramos FJ
Binocul Vis Strabolog Q Simms Romano 2012;27(4):235-42. PMID: 23234485Free PMC Article
Demer JL, Clark RA, Lim KH, Engle EC
Invest Ophthalmol Vis Sci 2007 Dec;48(12):5505-11. doi: 10.1167/iovs.07-0772. PMID: 18055799Free PMC Article

Therapy

Vargesson N
J Hand Surg Eur Vol 2019 Jan;44(1):88-95. Epub 2018 Oct 18 doi: 10.1177/1753193418805249. PMID: 30335598

Prognosis

Alves LU, Perez AB, Alonso LG, Otto PA, Mingroni-Netto RC
Eur J Med Genet 2016 Feb;59(2):80-5. Epub 2016 Jan 11 doi: 10.1016/j.ejmg.2015.12.015. PMID: 26791099

Clinical prediction guides

Kodytková A, Amaratunga SA, Zemková D, Maratová K, Dušátková P, Plachý L, Průhová Š, Koloušková S, Lebl J
Horm Res Paediatr 2024;97(2):203-210. Epub 2023 Aug 23 doi: 10.1159/000531996. PMID: 37611564
Alves LU, Perez AB, Alonso LG, Otto PA, Mingroni-Netto RC
Eur J Med Genet 2016 Feb;59(2):80-5. Epub 2016 Jan 11 doi: 10.1016/j.ejmg.2015.12.015. PMID: 26791099
Garcia-Martin E, Pinilla I, Almarcegui C, Fernandez J, Engle EC, Ramos FJ
Binocul Vis Strabolog Q Simms Romano 2012;27(4):235-42. PMID: 23234485Free PMC Article

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