Okihiro syndrome and acro-renal-ocular syndrome: clinical overlap, expansion of the phenotype, and absence of PAX2 mutations in two new families
- 1Genetics Centre, Guy's and St Thomas's NHS Trust, 7th Floor New Guy's House, Guy's Hospital, London SE1 9RT, UK
- 2Department of Ophthalmology, Guy's Hospital, London SE1 9RT, UK
- 3Centre for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
- 4Molecular Medicine Unit, Institute of Child Health, University College, London WC1N 1EH, UK
- Correspondence to: Dr K Becker, The Kennedy-Galton-Centre, Level 8V, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK;
The Okihiro syndrome consists of Duane anomaly, radial ray defects, and deafness. There are similarities with the acro-renal-ocular syndrome in which there are radial ray and renal abnormalities and colobomas which mostly involve the optic nerve. Both malformation syndromes are dominantly inherited. We report two families with an overlapping phenotype, suggesting a common aetiology. The combination of optic nerve coloboma and renal disease is also seen in families with mutations of the PAX2 gene. We did not find any evidence of PAX2 involvement in our families.
The main features of the autosomal dominant Okihiro syndrome are radial ray defects of variable severity and Duane anomaly.1,2 Sensorineural hearing loss and spinal and other skeletal abnormalities also occur, and polydactyly, hemifacial microsomia with skin tags, cardiac defects, and Hirschsprung disease have also been reported.1,3–5 The radial ray defects may be associated with vascular abnormalities such as hypoplasia of the radial artery6 and abnormal nerve conduction studies with reduced or absent motor response from the median nerve.1,6 The acro-renal-ocular syndrome, which is also autosomal dominant, consists of radial ray defects, renal anomalies, and ophthalmological abnormalities, mainly colobomas, but also microphthalmia, ptosis, and Duane anomaly.7–12 There is considerable overlap between the two syndromes, and it has been suggested previously that they are one clinical entity.8 In addition, mutations in the PAX2 gene have been documented in patients with optic nerve colobomas and renal malformation.13–15 There are also similarities to Wildervanck syndrome, Goldenhar syndrome, and thalidomide embryopathy. This can lead to considerable difficulties with classification in individual families. We describe four affected subjects in two new families with features of both Okihiro syndrome and the acro-renal-ocular syndrome and investigate the possibility of PAX2 involvement.
The female proband was the second child of unrelated parents. She was born with severe upper limb defects, had a preaxial extra digit surgically removed from the right hand, and was diagnosed as having bilateral Duane anomaly in early childhood. She was referred to the Genetics Centre at the age of 24 years. On examination, she had a longer arm on the right with an elbow, a shortened forearm, and a hand with four digits. The left upper arm was severely shortened and three digits were directly attached to the shortened forearm. The thumbs were absent bilaterally. Both humeri were shortened and the radii were absent. Ophthalmological examination showed bilateral latent fine nystagmus and slightly dysplastic optic discs, and orthoptic assessment showed bilateral Duane anomaly with severe limitation of eye abduction (fig 1A, B, C). ECG and renal ultrasound did not show any abnormalities and an audiogram showed mild bilateral conductive hearing loss only. Her karyotype was 46,XX.
The mother of case 1 was noted to have absent thumbs and shortened forearms at birth (fig 2). She was otherwise well and ophthalmological examination was normal. A renal ultrasound showed a normal right kidney and a smaller left kidney in pelvic position, situated in the left iliac fossa.
An audiogram showed bilateral, moderate, low frequency conductive loss and significant bilateral, high frequency sensorineural hearing loss, of which the patient had previously been unaware. An ECG was normal and chromosomes were 46,XX. Her parents had died and no other family members were known to have any limb abnormalities.
The female proband was the second child of unrelated parents. She presented as a neonate with absent left thumb and hypoplastic right thumb (fig 3A, B). Visual inattention and abnormal eye movements were noted by the parents in the first few weeks of life. Ophthalmological examination showed a right “morning glory” optic disc (a major dysplastic disc with a deep central pit) and a left dysplastic optic disc with a large inferior retinal coloboma. In the Genetics Clinic, unilateral, left Duane anomaly was noted, which was subsequently confirmed by detailed ophthalmological and orthoptic assessment.
She has since then developed bilateral nystagmus secondary to the visual impairment. Her development has otherwise been age appropriate to date.
An EEG, ERG/VER, cranial ultrasound, and MRI scan of the brain were all normal. A renal ultrasound showed mild left pelvicalceal dilatation and an MCUG showed grade 1 vesicoureteric reflux. Audiometry showed bilateral moderate hearing impairment which appeared to be conductive in origin, as there was middle ear effusion on the left and right total meatal occlusion with wax; a sensorineural component, however, cannot be excluded at present. The karyotype was 46,XX.
The father of case 3 presented with severe upper limb defects at birth which were thought to be the result of thalidomide exposure in utero (fig 4A, B). His mother had taken one single thalidomide tablet during the pregnancy. He was noted to have unilateral, right Duane anomaly in the Genetics Clinic, which was later confirmed by the orthoptist. Ophthalmological examination showed bilateral segmental optic disc hypoplasia. A renal ultrasound was normal. The patient declined a hearing test. His mother had a hearing impairment from an early age, and a female cousin had a left hypoplastic optic disc, but did not have the Duane anomaly.
MUTATIONAL ANALYSIS OF THE PAX2 GENE
Exons 2, 3, and 4 (containing the paired box domain) and exon 5 (containing the octapeptide sequence) of the PAX2 gene were investigated for mutations with a combination of single strand conformation polymorphism analysis and direct sequencing as previously described.15 No mutations in the two functional domains were found in patients 2 and 4.
Six families with Okihiro syndrome and six families with acro-renal-ocular syndrome have been reported. Radial ray defects, vertebral anomalies, pre- and postaxial polydactyly, Duane anomaly, and deafness occur in families with either syndrome. Urinary tract anomalies have been described in two families with some features of Okihiro syndrome. One family presented with upper limb defects, Duane anomaly, renal agenesis, and malrotation, but the report preceded delineation of the Okihiro syndrome and the acro-renal-ocular syndrome.7 In the second family, the affected family members were found to have a supernumerary bisatellited marker chromosome derived from chromosome 22. In addition to renal agenesis, the proband in this family showed other features such as absence of the cervix and uterus with blind ending fallopian tubes, which have not been reported in other Okihiro syndrome families.16 The lack of reports of renal abnormalities in Okihiro syndrome families may be a reflection of the lack of renal investigations in this patient cohort. Urinary tract abnormalities are a defining feature of the acro-renal-ocular syndrome. Colobomas of the iris, choroid, and optic nerve and other ophthalmological findings such as optic nerve hypoplasia, microphthalmia, microcornea, cataract, ptosis, and nystagmus are only mentioned in connection with the acro-renal-ocular syndrome, but retinal abnormalities may not have been specifically looked for in the Okihiro patients. The “morning glory” optic disc anomaly has not previously been reported in either syndrome; the association of the Duane anomaly and the “morning glory” anomaly is rare, but has been reported previously.17 The “morning glory” optic disc anomaly also occurs in renal-coloboma syndrome, which is caused by mutations in the PAX2 gene, in combination with renal disease. A locus for isolated autosomal dominant Duane anomaly has been mapped to chromosome 2q31.18,19 It also occurs as part of a contiguous gene syndrome in patients with interstitial deletions of chromosome 8q.20,21
Both our families show a combination of radial ray defects, Duane anomaly, renal abnormalities (malrotation, vesicoureteric reflux), and abnormal retinal findings (optic nerve hypoplasia or dysplasia, retinal coloboma, and “morning glory” anomaly of the optic nerve). One of four affected subjects had a significant sensorineural hearing loss and two had preaxial polydactyly. Radiological examinations of the spine were not carried out in our families. No cardiac lesions were identified.
Our two families are the first to show an overlapping phenotype clinically, which suggests that the two syndromes are one clinical entity. To date, no mapping studies have been published and molecular confirmation of this clinical hypothesis is awaited. It has been pointed out by Naito et al9 and Aalfs et al11 that the pattern of malformations is consistent with a disturbance of embryonic development around the fourth to eighth week. The phenotypic resemblance to the pattern of malformations induced by thalidomide is interesting. The mode of action of this well known teratogen is still poorly understood, but as in chondrodysplasia punctata and warfarin embryopathy22 teratogens and genes can act through common pathways.
Diagnostic difficulties often arise when not all features are present in an affected subject or within a family. In Okihiro syndrome, subjects with radial ray defects only3,4 or Duane anomaly only1,2,4 have been described. Clinically normal obligate gene carriers also occur.4 In the acro-renal-ocular syndrome, renal abnormalities are frequent, but radial ray defects and/or ophthalmological findings may be absent.8,9 The main features distinguishing Goldenhar syndrome from Okihiro syndrome and the acro-renal-ocular syndrome are the hemifacial microsomia and epibulbar dermoid; in Wildervanck syndrome, it is the absence of limb abnormalities. Epibulbar dermoid and preauricular tags have been described in acro-renal-ocular syndrome8 and facial asymmetry and microtia have been reported in a subject with Okihiro syndrome.4 Goldenhar-like features including Duane anomaly can occur in subjects with Townes-Brocks syndrome and mutations in the SALL1 gene.23 Renal anomalies, sensorineural hearing loss, and thumb abnormalities are also part of this syndrome, but our families did not show any anal anomalies, and the limb involvement was more extensive. Until molecular studies are carried out to identify the gene(s) involved in the pathogenesis of these syndromes, careful clinical examination and further investigation of affected subjects and family members are the only means of attempting classification. We have excluded a coding sequence mutation in exons 2-5 of the PAX2 gene in our families by single strand conformation polymorphism analysis and direct sequencing. Most of the mutations reported to date in PAX2 are within exons 2-5 for as yet unknown reasons.24,25
Renal and retinal anomalies need to be specifically looked for in subjects presenting with Duane anomaly and/or radial ray defects.
We thank Dr Keith Pohl and Dr P N P Devlin for referring the families to us, Liz Tomlin for orthoptic evaluation, and Professor Michael Eccles for his helpful comments.