From Seoul St. Mary’s Hospital, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Shin Hae Park, MD, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
Walker–Warburg syndrome is an autosomal recessive congenital malformation syndrome that was first described by Walker in 1942. The first case was characterized by lissencephaly (Greek, smooth brain, agyria), hydrocephalus, microphthalmia, and retinal dysplasia.1 Walker–Warburg syndrome has been also called HARD±E, characterized by hydrocephalus (H), agyria (A), and retinal dysplasia (RD) with or without encephalocele (±E). Warburg reported that the essential constellation indicating this syndrome is hydrocephalus, agyria, and retinal dysplasia.2 It has recently been determined that Walker–Warburg syndrome is the result of a defective O-glycosylation of α-dystroglycan, which plays a key role in neuronal migration. This defect is caused by mutations in the POMT1, POMT2, FKRP, and Fukutin genes.3–6
We describe an infant with Walker–Warburg syndrome who presented with microphthalmia, retinal detachment, and leopard spot retinopathy.
A male infant was brought to the ophthalmology clinic due to hydrocephalus and microphthalmia (Fig. 1). He was the first child of non-consanguineous parents and he had been noted to have fetal hydrocephalus on ultrasonography at 29 weeks’ gestation. He was delivered by caesarean section at 35 weeks’ gestation, at which time his weight was 2.83 kg and his head circumference was 38.5 cm. Severe hypotonia and hyporeflexia were noted at that time. His mother was a healthy 27-year-old primipara. There was no family history of brain or ocular anomalies. Serological analysis was negative for intrauterine infections. Chromosomal study revealed a normal male karyotype.
Figure 1. General Appearance of the Patient. Right Microphthalmia and Severe Hydrocephalus Are Seen.
Ophthalmic examination was performed 10 days after birth. Microphthalmia, retinal detachment, and leopard spot retinopathy were noted in his right eye (Figs. 2A and 3). The slightly dilated right pupil was not reactive to light. The red reflex in the right eye was dimmer than that seen in the left eye. A cataractous lens obscured the view of the right fundus. The left optic disc was pale and retinal arteries were extremely attenuated (Fig. 2B). Downbeat nystagmus was also noted.
Figure 2. Fundus Photography of the (A) Right Eye and (B) Left Eye. Typical Leopard Spot Retinopathy and Retinal Detachment Were Noted in the Right Eye, Although the Cataractous Lens Obscured the View. The Left Optic Disc Was Somewhat Pale. The Retinal Arteries Were Extremely Attenuated.
Figure 3. Ultrasound of Both Eyes. Microphthalmia and Retinal Detachment Was Apparent in the Right Eye.
On computed tomography scan, the patient was noted to have severe dilatation of the cerebral ventricular system and markedly decreased brain volume. A ventriculoperitoneal shunt was inserted 50 days after birth.
At 5 months after birth, laboratory examination revealed an elevation of creatine kinase level of 7,089 IU/L and lactate dehydrogenase level of 1.569 IU/L. Brain magnetic resonance imaging demonstrated a severe lissencephaly and hypoplastic cerebellum. The cerebral cortex was smooth and pachygyric with hydrocephalus (Fig. 4).
Figure 4. Brain Magnetic Resonance Imaging at 5 Months After Birth. (A) Axial T1-Weighted Magnetic Resonance Imaging Demonstrated a Thickened Cerebral Cortex and Increased Gray Matter. The Cerebral Cortex Was Smooth and Pachygyric with Hydrocephalus. (B) on Sagittal T1-Weighted Magnetic Resonance Imaging, the Cerebellar Hypoplasia Was Noted. (C) Axial T1-Weighted Magnetic Resonance Imaging Showed Microphthalmia of the Right Orbit.
Walker–Warburg syndrome is a rare disorder, although it has been reported in many countries.1,2,7–13 This is the first case reported in Korea. Type II lissencephaly, cerebellar malformation, retinal malformation, and congenital muscle dystrophy are essential to the diagnosis of Walker–Warburg syndrome.11 Any ocular malformation associated with a cerebral malformation should raise the suspicion of Walker–Warburg syndrome.12 In Walker–War-burg syndrome, the underlying genomic mutations have recently been described. A defect of neuronal migration, caused by the absence or alteration of alpha dystroglycan glycosylation, has been thought to be the important pathomechanism. Mutations in the POMT1 gene account for approximately 20% of patients with Walker–Warburg syndrome.3 Mutations in the POMT2, FKRP, FCMD, and LARGE genes have been reported in some cases of Walker–Warburg syndrome.3–6 Walker–Warburg syndrome is a genetic heterogeneous condition and the causative genes are still not clear. The diagnosis of Walker–Warburg syndrome is currently mainly based on the clinical and pathological findings.
A variety of ophthalmic manifestations have been reported in association with Walker–Warburg syndrome.1,2,7–13 The usual external ocular presentation is microphthalmia. Anterior and posterior segment ophthalmic abnormalities such as iris coloboma, Peter’s anomaly, persistent fetal vasculature, retinal dysplasia, retinal detachment, optic nerve coloboma, and optic nerve hypoplasia are other major ocular manifestations. Buphthalmos has also been reported in one case. Leopard spot retinopathy has been described by Barth et al.13
In this case, typical leopard spot retinopathy was noted as demonstrated in Figure 2. The left eye showed less distinct retinal dysplasia; therefore, neither microphthalmia nor retinal detachment was noted.
Lissencephaly is a neuronal migration disorder. Type II lissencephaly in Walker–Warburg syndrome is characterized by severely disorganized cortex with extensive neuronal and glial ectopia in the leptomeninges. Meningeal thickening leads to obliteration of the subarachnoid space with secondary hydrocephalus.14
Walker–Warburg syndrome is usually fatal within the first few months of life. Diagnosis of this syndrome is important for counseling parents because the risk of occurrence among siblings is high. Considering its autosomal recessive genetic nature, there is a 25% risk of recurrence in families with an affected child. A history of Walker–Warburg syndrome should prompt thorough ultrasonographic investigation during later pregnancies. Prenatal ultrasonographic diagnosis of eye and brain malformations in at-risk families would be of significant benefit.
- Walker E. Lissencephaly. Arch Neurol Psychiatry. 1942;48:13–29.
- Warburg M. Hydrocephaly, congenital retinal non-attachment and congenital falciform fold. Am J Ophthalmol.1978;85:88–94.
- Beltran-Valero de Bernabé D, Currier S, Steinbrecher A, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 2002;71:1033–1043. doi:10.1086/342975 [CrossRef]
- van Reeuwijk J, Janssen M, van den Elzen C, et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet. 2005;42:907–912. doi:10.1136/jmg.2005.031963 [CrossRef]
- Beltran-Valero de Bernabé D, Voit T, Longman C, et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004;41:e61. doi:10.1136/jmg.2003.013870 [CrossRef]
- Cotarelo RP, Valero MC, Prados B, et al. Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker-Warburg syndrome. Clin Genet. 2008;73:139–145. doi:10.1111/j.1399-0004.2007.00936.x [CrossRef]
- Khalaf SS, Tareef RB. Walker-Warburg Syndrome. J AAPOS. 2006;10:486–488. doi:10.1016/j.jaapos.2006.06.016 [CrossRef]
- Denis D, Gambarelli D, Luciani A, Aymé S, Philip N, Saracco JB. Walker-Warburg syndrome: a report of 3 cases. Ophthalmologica. 1993;207:113–116. doi:10.1159/000310416 [CrossRef]
- Nabi NU, Mezer E, Blaser SI, Levin AA, Buncic JR. Ocular findings in lissencephaly. J AAPOS. 2003;7:178–184. doi:10.1016/S1091-8531(02)42005-8 [CrossRef]
- Asano Y, Minagawa K, Okuda A, et al. A case of Walker-Warburg syndrome. Brain Dev. 2000;22:454–457. doi:10.1016/S0387-7604(00)00181-9 [CrossRef]
- Dobyns WB, Pagon RA, Armstrong D, et al. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet. 1989;32:195–210. doi:10.1002/ajmg.1320320213 [CrossRef]
- Vohra N, Ghidini A, Alvarez M, Lockwood C. Walker-War-burg syndrome: prenatal ultrasound findings. Prenat Diag. 1993;13:575–579. doi:10.1002/pd.1970130707 [CrossRef]
- Barth RA, Pagon RA, Bunt-Milam AH. ‘Leopard spot’ retinopathy in Warburg syndrome. Ophthalmic Paediatr Genet. 1986;7:91–96. doi:10.3109/13816818609076115 [CrossRef]
- Kuchelmeister K, Bergmann M, Gullotta F. Neuropathology of lissencephalies. Childs Nerv Syst. 1993;9:394–399. doi:10.1007/BF00306191 [CrossRef]