Usher Syndrome Type 1 Associated With Primary Ciliary Aplasia

Usher syndrome (USH) is an autosomal recessive defect that affects both the inner ear and retina. It is regarded as the most frequent cause of deafness-blindness in humans. Three clinical subtypes have been described, of which the most severe form, USH type 1 (USH1), is characterized by profound congenital sensorineural hearing loss, constant vestibular dysfunction, and prepubertal onset of retinitis pigmentosa.

Primary ciliary aplasia, a rare form of primary ciliary dyskinesia, is a congenital disorder of the mucociliary apparatus characterized by a total absence of epithelial cilia in cells that show the other ultrastructural features of normal ciliated cells. It is characterized by chronic infections of the upper and lower respiratory tract and by male infertility. The absence of cilia and basal bodies in respiratory mucosa makes it possible to distinguish primary ciliary aplasia from acquired ciliary defects.

A 10-year-old boy whose speech was hardly intelligible had been diagnosed as having profound sensorineural deafness (120-dB loss) at the age of 20 months. His vestibular function was impaired, causing a loss of balance, and standard caloric testing showed the absence of nystagmic responses.

Best-corrected visual acuity on ophthalmologic evaluation, although determined with difficulty, was 20/80 in the right eye and 20/100 in the left eye; results of funduscopic examination showed arteriolar narrowing, slight pallor of the optic disc, and bone spicule pigment clumping spreading into the peripheral retina. The electroretinogram was markedly abnormal, showing severe reduction of the scotopic response.

On fluorescein angiography, both eyes showed diffuse hyperfluorescence due to pigment epithelial atrophy together with hypofluorescence, corresponding to bone spicule pigment clumping. These findings were consistent with retinitis pigmentosa. Consequently, the diagnosis of USH1 was made.

Since infancy, the patient had developed recurrent infections of the upper and lower respiratory tract; cystic fibrosis and severe immunodeficiency had been excluded. Ultrastructural analysis of samples of nasal and bronchial brushing, obtained at 3 different times when the patient was clinically well, showed that ciliated cells were completely replaced by columnar cells lacking cilia and basal bodies and bearing on their surface ciliumlike projections without any internal axonemal structure. Despite the absence of basal bodies and kinocilia, these cells showed mature striated roots and centriolar precursor material scattered throughout the apical cytoplasm. These morphologic features were consistent with a ciliary aplasia (Figure 1 and Figure 2).

Axonemal defects of nasal cilia associated with retinitis pigmentosa have been previously reported by Hunter et al, ¹ who showed axonemal abnormalities of sperm tails and photoreceptor epithelial cells in patients with USH. Barrong et al² corroborated the hypothesis of abnormal cilia involvement in the pathogenesis of USH by finding an alteration in axonemal structure in the retinas of 2 unrelated patients with USH2. Bonneau et al³ described the association of USH1 with bronchiectasis, chronic sinusitis, and reduced nasal mucociliary clearance in 2 brothers, speculating that USH1 could be a primary ciliary disorder. Hasson et al⁴ more recently reported that human USH1B phenotypes result from mutations in the gene encoding myosin VIIA, an actin-based motor protein that is a common component of cilia and microvilli, hypothesizing that blindness and deafness associated with USH are related to the lack of proper myosin VIIA function within the cochlear hairy cells and the retinal pigment epithelial cells.

Our case, showing primary ciliary aplasia, seems to indicate a role of abnormal ciliary axonemal structure in the pathogenesis of USH1.

Corresponding author and reprints: Pietro Luzi, MD, Department of Human Pathology and Oncology, University of Siena, Nuovo Policlinico "Le Scotte, "Via delle Scotte, 6, 53100 Siena, Italy (e-mail: luzi@unisi.it).