Introduction
Gaucher's disease is the most common lysosomal storage disorder and was first described by Philippe Gaucher in 1882. It is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase, resulting in the accumulation of the glycolipid glucocerebroside in cells of the monocyte-macrophage system.Reference Zimran1 These glucocerebroside-engorged macrophages are known as Gaucher cells and are a cardinal feature of the disease. Principal features include hepatosplenomegaly, bone marrow involvement due to Gaucher cell infiltration and the resulting inflammatory response, and in some cases, neurological disease.Reference Deegan and Cox2
Three Gaucher subtypes have been described. In developed countries, type I (chronic, non-neuropathic) is the most common. Types II and III classically have neurological involvement; however, due to phenotypic variability, neurological involvement has also been described in the type I subtype.Reference Biegstraaten, van Schaik, Aerts and Hollack3
Approximately 1 in 100 Americans are carriers of the disease, with higher incidence in some ethnic groups, e.g. Ashkenazi Jews where up to 1 in 15 are carriers of the defective gene and 1 in 850 births have the type I disease, in comparison to a typical population incidence of 1 in 50 000.Reference Zimran1, Reference Deegan and Cox2 The type III disease is more common in Arab and Asian countries.Reference Zimran1
ENT manifestations
ENT manifestations are very unusual, although sensorineural hearing loss has been described due to neurological involvement of the auditory pathway in types II and III disease.Reference Kaga, Ono, Yakumaru, Owada and Mizutani4, Reference Uyama, Takahashi, Owada, Okamura, Naito and Tsuji5 All patients undergo audiological assessment to screen for sensorineural hearing loss as part of their multidisciplinary management.Reference Bamiou, Campbell, Liasis, Page, Sirimanna and Boyd6 Thrombocytopenia may also potentially contribute to other presentations such as epistaxis.
We describe the first detailed case report of conductive hearing loss secondary to middle-ear infiltration with Gaucher cells.
Case report
A five-year-old Spanish boy with known Gaucher's disease (type I) presented to our otolaryngology clinic with hearing impairment for the previous 18 months, with associated speech and language delay. On examination with otoscopy, the tympanic membranes were dull. Audiometry revealed bilateral conductive hearing loss, and tympanometry showed type B traces suggestive of bilateral middle-ear effusions. A clinical diagnosis of otitis media with effusion was made and after a period of watchful waiting he was listed for insertion of bilateral grommets.
While waiting for the procedure, he developed a right-sided, lower motor neuron facial palsy (House–Brackmann grade III) with an associated upper respiratory tract infection and right-sided otalgia. A diagnosis of right-sided, acute otitis media (with likely dehiscence of the tympanic portion of the facial nerve) was made. He was treated with oral steroids and broad-spectrum antibiotics, resulting in complete recovery of facial nerve function.
Subsequently, grommet insertion was attempted; however, both tympanic membranes were found to be featureless, unusually thickened and vascular. Myringotomy demonstrated no middle-ear fluid, but friable soft tissue material was found in the middle ear and the procedure was abandoned. A computed tomography scan was arranged which showed complete opacification of both middle-ear clefts, with no evidence of bony or ossicular erosion (Figure 1).
Axial computed tomography image showing bilateral middle-ear opacity.
Surgical management
The differential diagnosis included congenital cholesteatoma or possibly a manifestation of Gaucher's disease. Therefore, after discussion with the child's mother, an exploratory tympanomastoidectomy was performed on the child's right ear to allow direct inspection of the middle ear, exclude cholesteatoma, obtain biopsies for histology and collect tissue culture for microbiology. During surgery, the tympanic cavity and mastoid air cells were found to be filled with large amounts of abnormal, pale soft tissue that was hyperaemic and not consistent with congenital cholesteatoma (Figure 2). The long process of the incus (removed) and the stapes superstructure were eroded. Representative biopsies were taken and atticoantral drainage was established. There was good post-operative recovery with normal facial nerve function. There was no improvement in hearing thresholds.
Intra-operative view into the right middle ear showing the chorda tympani (A) and Gaucher cell infiltrates in the middle ear (B).
Pathology
Microbiology samples revealed Enterococcus faecalis. Histological analysis revealed histiocytic aggregates with foamy and ‘wrinkled tissue paper’ cytoplasm. In two specimens (incus and sample from the mastoid cavity), the histiocytes were in direct contact with the bone (Figure 3). Although Perls' Prussian blue stain did not reveal any iron deposits, these infiltrates were in keeping with Gaucher's disease within the middle ear. This view was also shared by the reviewing pathologist at a regional multidisciplinary meeting (Semon Club, ENT Department, Guy's and St Thomas' NHS Foundation Trust, London, UK).
Histiocytes (A) in close proximity to the incus (B) (H & E; × 100).
Discussion
A brief description of a possible otological manifestation of Gaucher's disease was provided by Brunner in 1928.Reference Brunner7 He presented a patient who had tinnitus, otalgia and hearing impairment and commented that there were Gaucher cells present in the petrous portion of the temporal bone of a case diagnosed as otosclerosis. However, we believe ours is the first fully reported case in the english language literature of Gaucher's disease with middle-ear infiltrates causing conductive hearing loss.
Clinical manifestations of Gaucher's disease vary. The otolaryngologist or audiological physician may be involved in the multidisciplinary assessment of cases of suspected Gaucher's disease, but patient management is predominantly led by paediatric endocrinologists.
The main diagnostic tool for Gaucher's disease remains the measurement of β-glucocerebrosidase levels in the blood. However, most patients also undergo genetic testing to confirm the diagnosis. In equivocal cases, response to enzyme replacement is considered in addition to bone marrow aspirate, which may point to an alternate haematological pathology.Reference Zimran1 Routine blood tests may show evidence of anaemia and thrombocytopenia, as well as possible elevation of liver enzymes, angiotensin converting enzyme and ferritin.Reference Zimran1, Reference Biegstraaten, van Schaik, Aerts and Hollack3 Abnormal brainstem auditory evoked potentials have been described in Gaucher's disease type II and type III.Reference Bamiou, Campbell, Liasis, Page, Sirimanna and Boyd6 Campbell et al. described the case of two children with type II disease with normal peripheral hearing and otoacoustic emissions, but abnormal auditory brainstem response.Reference Campbell, Harris, Sirimanna and Vellodi8
Magnetic resonance imaging (MRI) is a useful modality for identifying bone involvement.Reference Mikosch and Hughes9 We did not perform MRI scanning in this case because MRI is not routinely performed in a child for a suspected case of congenital cholesteatoma in our department.
Type I disease is the most variable subtype and our patient had an unusual combination of genetic mutations. However, type I is widely considered to be non-neuropathic and therefore we would not expect disturbance of the neural pathways. Our case had an episode of sudden onset, partial, lower motor neuron facial nerve palsy during an episode of acute otitis media. As the facial nerve palsy completely recovered after steroids and antibiotics, this is in keeping with neuropraxia from middle-ear inflammation rather than direct neuronal involvement from Gaucher's disease.
Our case also had persistent intra-abdominal lymphadenopathy thought to be secondary to Gaucher's disease and it seems feasible that Gaucher cell infiltrates could appear elsewhere. One of the sites typically involved in Gaucher's disease is the bone marrow, but Mikosch and Hughes described the additional possibility of extraosseous extension of Gaucher cells.Reference Mikosch and Hughes9 This is a rare phenomenon that involves infiltrates spreading into the surrounding tissue after cortical destruction.Reference Mikosch and Hughes9 In our case, histiocytic aggregates in the middle ear were in direct contact with the bone and this mechanism could be responsible for the microscopic appearances.
Current management of Gaucher's disease is mainly in the form of enzyme replacement therapy. This has been shown to be beneficial in controlling systemic disease in the type I subtype but less so in controlling neuropathic disease.Reference Mikosch and Hughes9, Reference Hughes and Pastores10 Hůlková et al. suggested that following enzyme replacement therapy, smaller Gaucher cell infiltrates may be noted at post-mortem.Reference Hůlková, Ledvinová, Poupetová, Kohout, Malinová and Elleder11 Splenectomy may be considered in some patients, while bone marrow transplantation is no longer routinely used due to the associated risks. Possible future options include reducing substrate synthesis, using enzyme chaperones, altering intracellular calcium and stem cell therapy. Gene therapy is another possibility and trials are already under way.Reference Zimran1, Reference Hughes and Pastores10
This case presented in an identical fashion to that of more common diagnoses, such as otitis media with effusion or bilateral congenital cholesteatoma. We attempted grommet insertion and then proceeded to tympanomastoid exploration to exclude congenital cholesteatoma and to obtain tissue biopsy. In retrospect, grommets were not necessary. It may be more appropriate that a more conservative strategy be adopted for the future management of otological symptoms in known cases of Gaucher's disease, possibly with the use of advanced imaging techniques, to exclude cholesteatoma and avoid the need for surgical intervention. However, until reliable diagnostic imaging techniques are available, we would recommend that common diagnoses be excluded before settling on a conservative management strategy.
• Gaucher's disease is a rare autosomal recessive lysosomal storage disease
• We have described a unique case of middle-ear involvement presenting with conductive hearing loss
• Histological analysis of middle-ear infiltrates confirmed Gaucher cells
• This is the first detailed report in the english language literature of Gaucher's disease affecting the middle ear and mastoid
• A conservative management strategy is recommended for future cases
Following multidisciplinary discussion, it has been decided that further clearance of middle-ear infiltrates in this child is not warranted due to likely recurrence. Middle-ear ventilation tubes are also not indicated, as they would be unlikely to improve middle-ear ventilation or alter infiltrate accumulation. Options for audiological rehabilitation include conventional hearing aids or a bone-anchored hearing aid.
Currently, the child has shown significant improvement in hearing, speech and language function using conventional hearing aids. His mother has reported that his educational abilities have improved significantly after hearing aid fitting. The mainstay of treatment remains continued intravenous enzyme replacement therapy, titrated according to the symptoms. The long-term prognosis is difficult to ascertain given the variability of clinical course in type I disease.
Conclusion
Gaucher's disease is the most common lysosomal storage disorder and results in lipid-laden macrophages accumulating in body tissues. Otolaryngological manifestations are rare, but sensorineural hearing loss has been described with the neuropathic forms of the disease. We reported the first case in the english language literature of a child with type I Gaucher's disease presenting with conductive hearing loss secondary to Gaucher cell infiltrates of the middle ear and mastoid. Early auditory rehabilitation is important to maximise the child's educational progress. A conservative strategy may be most appropriate for the future management of such cases once more common diagnoses have been excluded. Long-term management requires the guidance of a multidisciplinary team.
Acknowledgements
We would like to thank Dr Ashok Vellodi for his expert input regarding the management of Gaucher's disease in children.
