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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 24  |  Issue : 4  |  Page : 270-273

Nonmuscle myosin heavy chain IIA mutation and hearing loss in two cases of MYH9-related disease


Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Center of Porto, Porto, Portugal

Date of Web Publication15-Mar-2019

Correspondence Address:
Dr. Joana Raquel Correia Carvalho da Costa
Centro Hospitalar Universitario do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto
Portugal
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/indianjotol.INDIANJOTOL_66_18

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  Abstract 


MYH9-related disease is a rare disorder associated with the risk of developing progressive sensorineural hearing loss, nephropathy, cataracts, and/or liver enzyme alterations during childhood or adult life. To date, many reports on MYH9 disorder exist but only a few have provided a detailed description of the onset, degree of deafness, and shape of audiogram in individuals with this disorder. Further, the correlation between genotype–phenotype and hearing impairment and these descriptions were not very detailed. We described two particular cases that stand out from those described in the literature: two cases with an early diagnosis and an early auditory evaluation with the possibility to analyze the initial stages of hearing impairment. In addition, we confirm and reinforce the idea recently described in the literature that patients with mutations in the head domain have a higher risk of early-onset deafness than patients with mutations in the tail domain.

Keywords: Hearing loss, macrothrombocytopenia, MYH9-related disease


How to cite this article:
da Costa JR, Coutinho MB, Soares T, e Sousa CA. Nonmuscle myosin heavy chain IIA mutation and hearing loss in two cases of MYH9-related disease. Indian J Otol 2018;24:270-3

How to cite this URL:
da Costa JR, Coutinho MB, Soares T, e Sousa CA. Nonmuscle myosin heavy chain IIA mutation and hearing loss in two cases of MYH9-related disease. Indian J Otol [serial online] 2018 [cited 2019 Sep 19];24:270-3. Available from: http://www.indianjotol.org/text.asp?2018/24/4/270/254236




  Introduction Top


MYH9-related disease (MYH9-RD) is rare; the prevalence is around 1/400000, autosomal-dominant syndromic disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC-IIA).[1],[2]

All patients with MYH9-RD present since birth with thrombocytopenia and inclusions of NMMHC-IIA in leukocytes – macrothrombocytopenia.[3]

MYH9 disorder encompasses four syndromes that have been considered for many years to be distinct disorders: May–Hegglin anomaly (MHA; OMIM #155100), Sebastian syndrome (SBS; OMIM #605249), Fechtner syndrome (FTNS; OMIM #153640), and Epstein syndrome (EPTS; OMIM #153650).[4]

During infancy or adult life, most of them develop additional manifestations, mainly sensorineural hearing loss (SNHL), nephropathy, presenile cataract, and/or alterations of liver enzymes.[5],[6] SNHL is one of the most frequent manifestations of the MYH9-RD.[7],[8] NMMHC-IIA is extensively distributed in the inner ear in the sensory hair cells of the organ of Corti as well as in the spiral ligament and spiral limbus, with only minimal expression within the spiral ganglion.[7],[8]

A recent analysis of 255 patients showed that hearing impairment was present in about one-half of cases at a mean age at evaluation of 35 years and was expected to develop over time in almost all cases.[7],[8] The severity of hearing impairment is variable among different patients: while in some MYH9-RD, the hearing defect is mild or moderate even at advanced age, in other patients, hearing loss presents during childhood and progresses to profound deafness within the first decades of life.[7],[8]

To date, many reports on MYH9 disorder exist, but only a few have provided a detailed description of the onset (because the suspicion and diagnosis of the disease is often late), degree of deafness, and shape of audiogram in individuals with this disorder. Further, the correlation between genotype–phenotype and hearing impairment and these descriptions were not very detailed. Thus, we present the detailed description of two cases with early diagnosis of MYH9-RD and its hearing impairment as well as the genotype–phenotype correlation.


  Case Reports Top


Case 1

The patient was referred at the age of 1 year to a nephrology unit because of mild proteinuria without alteration of kidney function. There were no other complaints apart from easy bruising since birth.

Family history revealed that his grandfather had renal pathology requiring hemodialysis and thrombocytopenia. History of thrombocytopenia in more distant family members was also present. In view of these factors, the suspicion of MYH9-RD emerged. Consecutive genetic investigations confirmed the pathology. In subsequent urinalysis and imaging investigation by kidney ultrasound, renal dysfunction has not been confirmed.

At 4 years of age, the patient was referred to our otolaryngology unit for audiological screening, without any complaint or suspicion of hearing loss. Audiological evaluation showed bilateral mild symmetrical SNHL, more evident at higher frequencies, starting from 1000 Hz [Figure 1]. Imaging investigations by computerized tomography (CT) did not show inner ear malformations or retrocochlear pathologies. The patient presents an excellent psychomotor development, with good evolution of the language and learning; therefore, the patient does not benefit from auditory rehabilitation until now.
Figure 1: Pure-tone threshold audiometry with air and bone conduction masking

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Case 2

The patient was referred at the age of 2 years to a hematology unit because of severe thrombocytopenia and easy bruising.

Family history revealed that his mother and grandmother also had chronic thrombocytopenia. Due to her family history, she is evaluated and followed in genetics consultation. A diagnosis of MYH9-RD was suspected and successively confirmed at the age of 3 years.

At the time of diagnosis, the main symptoms were as follows: easy bruising, recurrent epistaxis, easy gum bleeding, and prolonged bleeding after eruption of teeth.

Hearing impairment was referred from the age of 13 years. The first audiological evaluation showed bilateral moderate symmetrical SNHL, more evident at higher frequencies [Figure 1]. Consecutive imaging investigations (CT) did not show inner ear malformations or retrocochlear pathologies. The patient received benefit from bilateral hearing aids.

No signs of kidney impairment, cataract, or chronic elevation of transaminases were found.

The basic clinical features and patients' clinical presentation at diagnosis are summarized in [Table 1].
Table 1: Basic clinical features and patients' clinical presentation at diagnosis

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  Discussion Top


MYH9-RD is a rare autosomal dominant disorder associated with the risk of developing progressive SNHL, nephropathy, cataracts, and/or liver enzyme alterations during childhood or adult life.[2]

In the experience of the Italian Registry for MYH9-RD, diagnosis was reached at a mean age of 36 years with a diagnostic delay of about 28 years after the first clinical manifestation of MYH9-RD.[3] Mean age at onset of hearing impairment was 21 years and severe-to-profound deafness occurred after a mean age of 11.5 years.[3]

We described two particular cases that stand out from those described in the literature. In the first place, we described two cases that obtained a suspicion and early diagnosis of the pathology (at 1 and 3 years old). In addition, they had an early referral and evaluation by otorhinolaryngology (at 13 and 4 years old). This reflects the better recognition of this disease by clinicians and a more timely reference, sometimes even before the onset of symptoms or some degree of hearing loss.

Hearing impairment is limited to high frequencies at clinical onset and in mild forms, but it progressively involves all frequencies in severe phenotypes.[3] In the present study, we analyzed the initial stages of hearing impairment in both cases. We found a bilateral mild symmetrical SNHL, more evident at higher frequencies, which is consistent with previous reports.

SNHL is one of the most frequent manifestations of the MYH9-RD.[7],[8] In our study, in addition to reporting two cases of MYH9-RD with hearing loss, we showed that hearing impairment often arises earlier than other pathologies with renal, hepatic, or visual involvement.

The analysis of high-resolution temporal bone CT scans ruled out middle and inner ear malformation in both cases, which is in accordance with the cases described in the literature.[9]

As all conventional myosins, it has a hexameric structure formed by one heavy chain (NMMHC-IIA) dimer and two pairs of light chains. Each NMMHC-IIA molecule recognizes an N-terminal head domain (HD) responsible for enzymatic activity and a C-terminal tail domain (TD) mainly responsible for myosin assembly.[10] Genotype–phenotype studies showed that patients with mutations in the HD have a higher risk of early-onset and severe deafness than patients with mutations in the TD 10. This idea, recently described in the literature, is reinforced by our two cases. In both cases, there is an involvement of the HD and an early hearing impairment was found.


  Conclusion Top


From the otolaryngologist's point of view, the association of bilateral sensorineural deafness with a personal or familiar history of thrombocytopenia, possibly associated with the other nonhematological manifestations of the disease, represents the key element for raising diagnostic suspicion of MYH9-RD.

For us, the desired and ideal in MYH9 disorder, after diagnosis, would be the immediate reference to otorhinolaryngology, even in asymptomatic cases, for the early identification of hearing impairment and subsequent follow-up.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, et al. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet 2000;26:103-5.  Back to cited text no. 1
    
2.
Balduini CL, Pecci A, Savoia A. Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol 2011;154:161-74.  Back to cited text no. 2
    
3.
Canzi P, Pecci A, Manfrin M, Rebecchi E, Zaninetti C, Bozzi V, et al. Severe to profound deafness may be associated with MYH9-related disease: Report of 4 patients. Acta Otorhinolaryngol Ital 2016;36:415-20.  Back to cited text no. 3
    
4.
Kunishima S, Saito H. Advances in the understanding of MYH9 disorders. Curr Opin Hematol 2010;17:405-10.  Back to cited text no. 4
    
5.
Balduini CL, Pecci A, Savoia A. Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol 2011;154:161-74.  Back to cited text no. 5
    
6.
Pecci A, Biino G, Fierro T, Bozzi V, Mezzasoma A, Noris P, et al. Alteration of liver enzymes is a feature of the MYH9-related disease syndrome. PLoS One 2012;7:e35986.  Back to cited text no. 6
    
7.
Pecci A, Klersy C, Gresele P, Lee KJ, De Rocco D, Bozzi V, et al. MYH9-related disease: A novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. Hum Mutat 2014;35:236-47.  Back to cited text no. 7
    
8.
De Rocco D, Zieger B, Platokouki H, Heller PG, Pastore A, Bottega R, et al. MYH9-related disease: Five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations. Eur J Med Genet 2013;56:7-12.  Back to cited text no. 8
    
9.
Ganaha A, Kaname T, Shinjou A, Chinen Y, Yanagi K, Higa T, et al. Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH 1 related disease. Am J Med Genet A 2017;173:2826-30.  Back to cited text no. 9
    
10.
Eddinger TJ, Meer DP. Myosin II isoforms in smooth muscle: Heterogeneity and function. Am J Physiol Cell Physiol 2007;293:C493-508.  Back to cited text no. 10
    


    Figures

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    Tables

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