From the Ulucanlar Training and Research Eye Hospital (TS, YO), Ankara; the Ankara Training and Research Hospital Department of Pediatric Endocrinology (ES), and the Tepecik Training and Research Hospital Department of Ophthalmology (GM), Izmir, Turkey.
The authors have no proprietary or financial interest in the materials presented herein.
Address correspondence to Tulay Simsek, MD, Turan Gunes Bulvari, 645, Sokak 8/20, 06450, Cankaya/Ankara, Turkey.
Usher syndrome is an inherited disorder characterized by different degrees of sensorineural hearing loss and progressive visual loss secondary to retinitis pigmentosa. It is the most common syndrome associated with retinitis pigmentosa.1 Various mental disorders and central nervous system defects have also been reported in association with Usher syndrome.2–5
Dandy–Walker malformation consists of a cystic expansion of the fourth ventricle in the posterior fossa resulting from failure of the roof of the fourth ventricle to develop during embryogenesis. A variety of central nervous system and systemic anomalies have been reported in association with Dandy–Walker malformation.6,7 We describe Usher syndrome associated with a variant of Dandy–Walker malformation in three siblings with consanguineous Turkish parents. To the best of our knowledge, no such association has been previously described.
Two of the siblings were female (cases 1 and 2) and one was male (case 3). They were 15, 12, and 5 years old, respectively, and had been admitted to a pediatric clinic with hearing problems.
The siblings underwent detailed ophthalmic, pediatric, and audiologic investigations. The ophthalmic examination included slit-lamp biomicroscopy, ophthalmoscopy, color fundus photography, electroretinography (ERG), and visual evoked potential (VEP). Best-corrected visual acuity measurement and visual field examination were not performed because two of the patients had mental retardation and the third would not cooperate during the examination.
The audiovestibular examination included standard pure tone audiometry, tympanometry, acoustic reflexes, and caloric test. Brain computed tomography (CT) was also performed. Pediatric examination revealed mental retardation in cases 1 and 2.
Cycloplegic retinoscopy revealed high myopia in cases 1 and 3. Biomicroscopic examination showed punctuate cortical crystalline opacities in both eyes of cases 1 and 3. A dilated fundus examination documented retinitis pigmentosa with attenuated retinal vessels, symmetric sparse intraretinal bone spicule pigment around the periphery, and optic atrophy in both eyes of cases 1 and 2 (Fig. 1). Ophthalmoscopy of case 3 revealed retinitis pigmentosa without any bone spicules. The ERG responses were completely subnormal in all of the patients (Fig. 2). Amplitudes of the a and b wave were reduced. VEP latencies were prolonged in cases 1 and 2, and normal in case 3.
Figure 1. Color Fundus Photograph of Case 1 Shows Intraretinal Bone Spicule Pigmentation.
Figure 2. Electroretinography Record of Case 3.
The pure tone audiogram revealed moderate sensorineural hearing loss in case 1 and mild sensorineural hearing loss in case 2. Case 3 refused to cooperate during the pure tone audiogram examination, although severe hearing loss was detected on clinical examination. Vestibular function was normal, except in case 1. Cranial CT revealed an irregular cystic lesion connected to the fourth ventricle by a thin gap crossing the cerebellar vermis, located posterior to the cerebellum in cases 1 and 2 (Fig. 3). This tomographic feature was considered a variant of Dandy–Walker malformation. The characteristics of the patients are documented in the table. Case 1 is presented in detail as a representative case.
Figure 3. Brain Computed Tomography of Case 1 Shows a Variant of Dandy–Walker Malformation.
Table: Clinical Characteristics of the Three Patients
A 15-year-old girl was admitted with hearing loss, vision difficulties, and night blindness for 10 years. Ophthalmic examination revealed high myopia, punctuate lens opacities, and vitreous degeneration in both eyes. Dilated fundus examination showed retinitis pigmentosa and optic atrophy bilaterally. The visual fields could not be determined because she had mental retardation. The ERG amplitudes were reduced and the VEP latencies were prolonged in both eyes. Her medical history revealed deafness and mental retardation.
Audiovestibular examination and brain CT were also performed. Moderate sensorineural deafness and minimal vestibular dysfunction were detected. Cranial CT showed an irregular cystic lesion connected to the fourth ventricle by a thin gap crossing the cerebellar vermis, located posterior to the cerebellum.
Usher syndrome is both clinically and genetically heterogeneous, and there are three different types. Usher syndrome type 1 is characterized by profound congenital sensorineural hearing impairment, constant vestibular dysfunction, and pre-pubertal onset of retinitis pigmentosa. Patients with Usher syndrome type 2 have mild to moderate hearing loss, preserved vestibular function, and variable and slightly milder retinitis pigmentosa. Vision problems tend to progress more slowly than those in type 1, with the onset of retinitis pigmentosa often not apparent until adolescence. Usher syndrome type 3 involves post-lingual progressive sensorineural hearing loss with variable retinitis pigmentosa and progressive vestibular dysfunction.1,8 The ophthalmologic findings are an important way to distinguish the clinical types of Usher syndrome. Patients with Usher syndrome type 1 have more impaired visual acuity and visual fields than patients with types 2 and 3. Clinically significant hypermetropia and astigmatism are pathognomonic for patients with Usher syndrome type 3.8
Various mental disorders including schizophrenia-like disorder, atypical psychosis, recurrent depressive illness, and neurotic disorder have been reported with Usher syndrome.2,3 The cause of psychiatric symptoms in Usher syndrome remains unclear, but two etiological factors of mental disorders associated with Usher’s syndrome have been suggested. One is a stress-related illness imposed by progressive sensory impairment; the other is the direct consequence of a cerebral lesion. In addition, there are a few reports regarding central nervous system defects that were determined by magnetic resonance imaging or CT in patients with Usher syndrome.4,5,9
Bloom et al.4 demonstrated central nervous system abnormalities, including cerebellar atrophy, occipital lobe atrophy, cavum septum pellucidum, and cavum vergae by CT in patients with Usher syndrome types 1 and 2. However, no signs of cerebellar and occipital dysfunction were noted. They suggested that these central nervous system defects may be among the pleiotropic effects of the Usher syndrome gene. Piazza et al.5 showed midbrain and cerebellar lesions by magnetic resonance imaging in 7 patients with Usher syndrome type 2. Whether these finding were related to Usher syndrome was not clear. Tamayo et al.9 found cerebellar abnormalities in 50% of patients with Usher syndrome type 1 and 75% of patients with Usher syndrome type 2 using magnetic resonance imaging. Loundon et al.10 did not describe any abnormality on CT or magnetic resonance imaging of the brain in 13 patients with Usher syndrome, but they did not clearly identify a lesion like that seen in our patients.
Dandy–Walker malformation is a rare congenital malformation involving the cerebellum and fourth ventricle that is characterized by agenesis or hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle, and enlargement of the posterior fossa. Dandy–Walker variant is a subgroup of Dandy–Walker malformation and it represents the most wide-ranging set of symptoms and outcomes of Dandy–Walker malformation. It consists of vermian hypoplasia and cystic dilatation of the fourth ventricle without enlargement of the posterior fossa.6,7 Also, patients with Dandy–Walker malformation have concomitant abnormalities such as hearing loss, although it is not a primary characteristic of this malformation. Freeman and Jones reported an older age presentation of Dandy–Walker malformation associated with vestibular dysfunction.11
Mental retardation is found in approximately 50% of patients with Dandy–Walker malformation.12,13 Patients with Usher syndrome have delayed motor and impaired cognitive function, probably due to their ophthalmic and audiovestibular abnormalities. Nevertheless, mental retardation is not a constant finding in Usher syndrome.
Our patients were diagnosed as having Usher syndrome type 2 based on the findings of moderate hearing loss, milder retinitis pigmentosa, and minimally impaired vestibular function. Although classic bone spicule pigmentation was not seen in case 3, ERG response was subnormal in this patient. Retinitis pigmentosa tends to develop by adolescence in patients with Usher syndrome type 2. Our patient was only 5 years old and we thought that other clinical findings of retinitis pigmentosa might develop later. Although patients with Usher syndrome type 2 have normal vestibular functions, we observed vestibular dysfunction in case 1. Dandy–Walker malformation might have contributed to the mental retardation and vestibular dysfunction in one of our patients.
In this family, two of the three siblings presenting with the components of Usher syndrome had Dandy–Walker malformation. It may be a coincidental finding with Usher syndrome. Alternatively, it may be one of the associated findings of Usher syndrome. Two siblings had the same malformation. It is well known that some associated findings of rare syndromes may be identified later. For example, we found that delayed puberty in Wolfram syndrome may be secondary to primary gonadal failure or central pathology.14
Usher syndrome is a clinically heterogeneous syndrome, and genetic factors and associated malformations may contribute to this heterogeneity. Cranial investigations with imaging techniques may be effective for documenting any structural abnormality in pediatric Usher syndrome associated with mental retardation. Genetic factors should be investigated for the association of two different diseases and ophthalmologists should also be aware of central nervous system abnormalities in patients with Usher syndrome.
- Pennings RJE, Huygen PLM, Orten DJ, et al. Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a. Acta Ophthalmol Scand. 2004;82:131–139. doi:10.1111/j.1600-0420.2004.00234.x [CrossRef]
- Koizumi J, Ofuku K, Sakuma K, Shiraishi H, Iio M, Nawano S. CNS changes in Usher’s syndrome with mental disorder: CT, MRI and PET findings. J Neurol Neurosurg Psychiatry. 1988;51:987–990. doi:10.1136/jnnp.51.7.987 [CrossRef]
- Mangotich M, Misiaszek J. Atypical psychosis in Usher’s syndrome. Psychosomatics. 1983;24:674–675.
- Bloom TD, Fishman GA, Mafee MF. Usher’s syndrome: CNS defects determined by computed tomography. Retina. 1983;3:108–113. doi:10.1097/00006982-198300320-00007 [CrossRef]
- Piazza L, Fishman GA, Kaplan RD, Horowitz AL, Hindo WA, Mafee MF. Magnetic resonance imaging of central nervous system defects in Usher’s syndrome. Retina. 1987;7:241–245. doi:10.1097/00006982-198707040-00009 [CrossRef]
- Parisi MA, Dobyns WB. Human malformations of the midbrain: review and proposed classification scheme. Mol Genet Metab. 2003;80:36–53. doi:10.1016/j.ymgme.2003.08.010 [CrossRef]
- Barkovich AJ, Kjos BO, Norman D, Edwards MS. Revised classification of posterior fossa cysts and cystlike malformations based on the results of multiplanar MR imaging. Am J Roentgenol. 1989;153:1289–1300.
- Tsilou ET, Rubin BI, Caruso RC, et al. Usher syndrome clinical types I and II: could ocular symptoms and signs differentiate between the two types?Acta Ophthalmol Scand. 2002;80:196–201. doi:10.1034/j.1600-0420.2002.800215.x [CrossRef]
- Tamayo ML, Maldonado C, Plaza SL, et al. Neuroradiology and clinical aspects of Usher Syndrome. Clin Genet. 1996;50:126–132.
- Loundon N, Marlin S, Busquet D, et al. Usher syndrome and cochlear implantation. Otol Neurotol. 2003;24:216–221. doi:10.1097/00129492-200303000-00015 [CrossRef]
- Freeman SRM, Jones PH. Old age presentation of the Dandy-Walker syndrome associated with unilateral sensorineural deafness and vertigo. J Laryngol Otol. 2002;116:127–131. doi:10.1258/0022215021909854 [CrossRef]
- Hirsch JF, Pierre-Kahn A, Renier D, Sainte-Rose C, Hoppe-Hirsch E. The Dandy-Walker malformation: a review of 40 cases. J Neurosurg. 1984;61:515–522. doi:10.3171/jns.1984.61.3.0515 [CrossRef]
- Klein O, Pierre-Kohn A, Baddaert N. Dandy-Walker malformation: prenatal diagnosis and prognosis. Childs Nerv Syst. 2003;19:484–489. doi:10.1007/s00381-003-0782-5 [CrossRef]
- Simsek E, Simsek T, Tekgül S, Hosal S, Seyrantepe V, Aktan G. Wolfram (DIDMOAD) syndrome: a multidisciplinary clinical study in nine Turkish patients and review of the literature. Acta Paediatr. 2003;92:55–61.
Clinical Characteristics of the Three Patients
|Characteristic||Case 1||Case 2||Case 3|
|Refraction||High myopia||Myopia||High myopia|
|Biomicroscopic examination||Punctuate lens opacities||Normal||Punctuate lens opacities|
|Ophthalmoscopy||Retinitis pigmentosa||Retinitis pigmentosa||Retinitis pigmentosa without bone spicules|
|Audiogram||Moderate SNHL||Mild SNHL||Not performed|
|Vestibular function||Minimally impaired||Normal||Normal|
|Brain computed tomography scan||Variant Dandy–Walker malformation||Variant Dandy–Walker malformation||Normal|