Morquio syndrome

Abstract

Spondyloepiphyseal dysplasia is a disorder characterized by abnormalities of growth. Previous studies of this disorder have identified a significant incidence of associated hearing loss. Hearing loss has been reported to occur in 25 to 30% of affected patients. To date, all reports of associated hearing loss have indicated the presence of a sensorineural component.

In this article, we report the case of a child who was diagnosed with spondyloepiphyseal dysplasia congenita and who was found to have a significant conductive hearing loss with a Carhart's notch, indicating the likely presence of stapes footplate fixation. We also review the diagnosis of this condition and the literature associated with hearing loss as it occurs with this disorder.

Introduction

Spondyloepiphyseal dysplasia (SED) is a rare, type II collagen disorder that is defined and diagnosed by its characteristic clinical and radiologic features. There are two variants of the disorder: SED congenita and SED tarda. They differ only in the inheritance pattern and age of onset; SED congenita is autosomal-dominant and occurs during early childhood, while SED tarda is autosomal-recessive and develops during teenage years. The patient described in this report had the congenita form.

The most consistent radiologic findings in SED are a dysplastic odontoid process, flattened vertebrae, and small and deformed femoral epiphyses (long-bone metaphyseal involvement is variable). [1-4] Clinically, SED is characterized by short stature (120 to 140 cm), often significant lordosis, pectus carinatum, and myopia (with or without retinal detachment). [1-4] Other associated anomalies include cleft lip or palate, muscular hypotonia, and sensorineural hearing loss. We describe the case of a patient with conductive hearing loss that was likely attributable to stapes fixation.

Case report

In 1988, a 2-year-old girl was brought to her pediatrician when her parents noticed that she was late in reaching developmental milestones. She had not crawled until the age of 12 months, and she had not begun walking until 19 months of age. She was the product of a normal pregnancy, and her perinatal and subsequent medical history was otherwise normal. There was no evidence of any delay in cognitive or language development, and there were no signs of abnormal social interaction. She did, however, experience a dropoff in her growth curves, declining from the 75th percentile to the 5th percentile in height and weight by the age of 21 months. Her head circumference remained above the 95th percentile.

She was referred by her pediatrician to an orthopedic surgeon, who noted delayed ossification of the femoral epiphyses on x-ray. The surgeon referred her to a pediatric orthopedic surgeon who specialized in growth disorders at The Children's Hospital of Boston. Based on further physical examination and a review of her films, a presumptive diagnosis of spondyloepiphyseal dysplasia was made. The physical examination revealed a short stature, head circumference as noted, an intact palate, broadening of her forehead, and flattening of her nasal bridge. She had significant lordosis and a mild thoracic kyphosis. Muscle strength was 5/5 in all extremities. Her gait was described as a wide-based waddle, with her feet rotated externally. X-ray examination revealed an absence of ossification of the femoral epiphyses and flattening of the metaphysis. Hypoplasia/dysplasia of the odontoid process and dysplasia at C4, C5, and L1 were also noted. Her forearm, particularly the radius, was unusually short. All of these featu res were consistent with a very narrow range of differential diagnoses, of which SED congenita was the most likely, followed by multiple epiphyseal dysplasia and type IV mucopolysaccharidosis (Morquio's syndrome).

Although multiple epiphyseal dysplasia was initially considered in the differential diagnosis, it was quickly ruled out because the involvement of the vertebral column was much more consistent with SED. Morquio's syndrome was also considered because it often has many of the same features. However, the results of the patient's mucopolysaccharide screen were within the normal range (3 units), and there was no involvement of the hands and no corneal opacification, which are characteristic of Morquio's syndrome. Thus, the diagnosis of SED was established. Because of the known associated anomalies, in 1989 she was referred for ophthalmologic and audiologic evaluations. Since 1995, she has been followed at the University of Massachusetts Medical Center by the Department of Otolaryngology.

In 1989, the patient had her first hearing evaluation (patient's age: 2 yr, 6 mo). The results of her behavioral audiologic tests suggested a mild to moderate hearing loss in the sound field at 0.25 to 4 kHz. Tympanometry results at that time were consistent with normal middle ear compliance and pressure (-100 daPa). An auditory brainstem response test was performed 1 month later in order to obtain an objective measurement of the hearing sensitivity in each ear. The results indicated a moderate bilateral hearing loss for clicks and 2- and 4-kHz tone bursts. Unmasked bone conduction responses to click stimuli indicated the presence of a conductive component in at least one ear. The patient was subsequently fitted binaurally with behind-the-ear hearing aids.

A followup behavioral audiologic evaluation with play audiometry was performed in early 1991 (patient's age: 4 yr, 7 mo). This test revealed the presence of a mild hearing loss in the right ear and a moderate hearing loss in the left ear, with normal bone conduction responses at 0.5 to 4 kHz.

In late 1991 (age: 5 yr, 3 mo), her air conduction thresholds and tympanograpy results were essentially unchanged (figure 1). Higher frequencies were also tested at that time. The results indicated the presence of a moderate to severe hearing loss in the right ear and a severe to profound hearing loss in the left ear at 6 to 8 kHz. Also, a slight depression (Carhart's notch) in the unmasked bone conduction threshold at 2 kHz was observed; this depression is often a characteristic of stapes fixation. Approximately 6 months later, her bone conduction at 2 kHz had worsened to a mild sensorineural component with stable air conduction thresholds.

By April 1993 (age: 6 yr, 7 mo), the patient's unmasked bone conduction thresholds had also worsened at 4 kHz, and she had a mild sensorineural component at 2 to 4 kHz in the right ear (figure 2). The worsening bone conduction line allowed us to obtain masked bone conduction responses for the left ear without the risk of overmasking. Results indicated the presence of a mixed hearing loss in the left ear, with air/bone gaps of approximately 30 dB at 0.5 to 4 kHz. Monaurally aided speech discrimination appeared to be excellent bilaterally. Air and bone conduction thresholds remained essentially unchanged through February 1995, except for recovery of the unmasked bone conduction threshold at 4 kHz.

In November 1995 (age: 9 yr, 3 mo), another evaluation indicated that her conduction thresholds in the right ear had decreased significantly since February 1995, but her bone conduction results were unchanged. Tympanometry continued to indicate normal middle ear compliance and pressure in both ears (0.8 cc static compliance at 0 daPa). Speech discrimination ability was excellent in both ears (100%).

In 1996, an evaluation was performed with insert phones, which permitted contralateral masking to each ear without overmasking and allowed us to better delineate bone conduction thresholds in each ear. An air/bone gap of approximately 40 dB was seen in the left ear at 0.25 to 4 kHz, and a gap of 15 to 20 dB was found in the right ear at 0.25 to 1 kHz and at 4 kHz. The hearing loss continued to be sensorineural in nature at 2 kHz in the right ear. Speech discrimination had worsened slightly (88%). Tympanometry was again normal (1.3 cc static compliance in the right ear, 1.7 cc in the left) at 0 daPa pressure, reflecting normal middle ear function. The patient underwent a Weber' s test, which lateralized to the left, and a Rinne' s test (512 Hz), which was negative on the left and positive on the right.

An evaluation conducted in June 1997 (age: 10 yr. 10 mo) indicated that the mild hearing loss in the right ear was primarily sensorineural, with a slight conductive component at 2 to 4 kHz (figure 3). Carhart's notch was still evident. Speech discrimination had continued to decline, as scores fell to 80% in the right ear and 72% in the left ear.

In summary, results obtained as early as 1989 indicated the presence of a bilateral hearing loss, as unmasked bone conduction results suggested that there was a conductive component in at least one ear. Air conduction thresholds remained relatively stable from 1989 to 1997, with no more than a 5- to l0-dB decline in the right ear and a 10- to 15-dB decline in the left ear. The hearing loss in the right ear was predominately sensorineural in nature. However, because of a masking dilemma, it was impossible to say whether there was a conductive component in the right ear prior to the onset of the sensorineural component. Speech discrimination appeared to have worsened significantly in both ears. At this point, the patient is doing well with bilateral behind-the-ear hearing aids, and corrective surgery for presumed left stapes fixation is being deferred until the child reaches adulthood.

Discussion

Spondyloepiphyseal dysplasia was first described by Spranger and Wiedmann in 1966. [1] Their original series did not highlight the incidence of associated hearing loss. Three years later, Fraser et al reported a large series of patients with this newly described disorder, and they did report a clear association with hearing loss. [2] In their series, 8 of 9 patients had a hearing loss that had begun during childhood (age range: 2 to 12 yr). The loss was most pronounced in the higher frequencies. All cases were sensorineural in nature. In 1982, Wynne-Davies and Hall reported a series of 17 patients and noted that roughly 25% of them had an associated hearing loss. [5] However, they did not document the nature of the loss or provide information on their patients' audiograms. In 1993, Cole et al published a report of a case of SED (associated with a specific amino acid substitution) in which the patient demonstrated a progressive hearing loss that eventually became moderate to severe bilaterally by the time the patient had reached 17 years of age. [6]

Data in the literature are limited by the rarity of the syndrome, but the overall estimate of hearing loss associated with SED is 30 %. [7] Most papers report a loss on the order of 30 to 70 dB at the higher frequencies (4 to 8 kHz). [2, 6] The sensorineural hearing loss might be explained by the fact that the inner ear has many structures that are derived from type II collagen. Type II collagen can be found on the apical and basal surfaces of the epithelium of most of the inner ear, including the cochlea. [6,8] More specifically, type II collagen is a significant component of the osseous spiral lamina, the spiral limbus, and the tectorial membrane. Abnormalities in these structures clearly result in a sensorineural hearing loss.

A search and review of the literature written since Spranger and Wiedmann's original description in 1966 yielded no reports of an associated hearing loss in the absence of a middle ear infection or middle ear fluid. One case report did describe a conductive loss in the presence of middle ear fluid, which improved following myringotomy and drainage of the ear. [6] Our patient clearly had a mixed bearing loss in the left ear, even in the absence of middle ear fluid or other middle or outer ear abnormalities.

Based on the documented presence of type II collagen in the cochlea, it is no surprise that SED is associated with sensorineural hearing loss. [6'8] However, it is also believed that type II collagen is present in the cartilage that gives rise to the ossicles. [8] Therefore, it is surprising that there are no reports of SED associated with mixed hearing loss.

One possible mechanism of conductive hearing loss is damage to the synovial joints of the ossicles. In a case series of the synovial joint complications of SED, Sambrook et al noted cases of chronic synovitis and radiologically evident chondrocalcinosis in multiple joints. [9] They reported such complications in larger joints, but they did not specifically address the ossicles or hearing status. Nonetheless, it is not implausible that the same mechanism, which is driven by the underlying dysplasia and consequent abnormalities in the joint, could affect the ossicles and result in hearing loss.

Several studies in animal models have shown an association between type II collagen autoimmunity and otosclerosis. [10-12] The described mechanism is a logical one: immunologic tissue damage to the cartilaginous components of the ossicles produces otospongiotic lesions. These lesions in turn yield the clinical finding of otosclerosis. These studies were of autoimmune diseases rather than hereditary dysplasias, such as SED. Even so, knowing that SED results in dysplastic and hypoplastic type II collagen structures, one might expect structures similar to those described in otosclerosis. Thus the clinical findings--namely the pattern of hearing loss--would also be expected to be similar.

Either mechanism would explain the observed pattern of mixed hearing loss. Moreover, it is more reasonable to think that a disease of abnormal type II collagen, which is known to be associated with sensorineural hearing loss, is also associated with conductive hearing loss rather than not. With the overwhelming problems in growth and gait that SED presents patients and their physicians, perhaps there are other cases of associated conductive hearing loss that are being overlooked. Our young patient's hearing status has been closely followed and clearly demonstrates a mixed hearing loss with what appears to be stapedial fixation.

From the Department of Otolaryngology (Dr. Dahiya and Dr. Megerian) and the Department of Audiology (Ms. Cleveland), University of Massachusetts Medical Center, Worcester.

References

(1.) Spranger JW, Wiedmann HR. Dysplasia spondyloepiphysaria congenita. Helvetica Paediatrica Acta 1966;21:598-611.

(2.) Fraser GR, Friedmann AI, Maroteaux P. Dysplasia spondyloepiphysaria congenita and related generalized skeletal dysplasias among children with severe visual handicaps. Arch Dis Child 1969;44:490-8.

(3.) Harris NH, Birch R. Postgraduate Textbook of Clinical Orthopaedics. Cambridge, Mass.: Blackwell Science Press, 1995.

(4.) Resnick D, Niwayama G. Diagnosis of Bone and Joint Disorders. Vol. 6. Philadelphia: W.B. Saunders, 1988.

(5.) Wynne-Davies R, Hall C. Two clinical variants of spondyloepiphysial dysplasia congenita. J Bone Joint Surg 1982;64:435-41.

(6.) Cole WG, Hall RK, Rogers JG. The clinical features of spondyloepiphyseal dysplasia congenita resulting from the substitution of glycine 997 by serine in the alpha 1(II) chain of type II collagen. J Med Genet 1993;30:27-35.

(7.) Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and Its Syndromes. New York: Oxford Press, 1995.

(8.) Wood A, Ashhurst DE, corbett A, Thorogood P. The transient expression of type II collagen at tissue interfaces during mammalian craniofacial development. Development 1991;l11:955-68.

(9.) Sambrook PN, de Jager JP, Champion GD, et al. Synovial complications of spondylepiphyseal dysplasia of late onset. Arthritis Rheum 1988;31:282-7.

(10.) Yoo TJ, Tomoda K, Stuart JM, et al. Type II collagen-induced autoimmune otospongiosis: A preliminary report. Ann Otol Rhinol Laryngol 1983;92:103-8.

(11.) Joliat T, Seyer J, Bernstein J, et al. Antibodies against a 30 kilodalton cochlear protein and type II and IX collagens in the serum of patients with inner ear diseases. Ann Otol Rhinol Laryngol 1992;101:1000-6.

(12.) Yoo TJ, Stuart JM, Kang AH, et al. Type II collagen autoimmunity in otosclerosis and Meniere's Disease. Science 1982;217:1153-5.

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