Deafness, Autosomal Dominant 34, With Or Without Inflammation

A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-34 (DFNA34) with or without inflammation is caused by heterozygous mutation in the NLRP3 gene (606416) on chromosome 1q44.

Heterozygous mutation in the NLRP3 gene can also cause several autoinflammatory disorders, including familial cold autoinflammatory syndrome-1 (FCAS1; 120100), Muckle-Wells syndrome (MWS; 191900), and CINCA syndrome (CINCA; 607115).

Description

DFNA34 is an autosomal dominant form of postlingual, slowly progressive sensorineural hearing loss with variable severity and variable additional features. Some patients have pure hearing loss without significant additional features, whereas some patients have features of an autoinflammatory disorder with systemic manifestations, including periodic fevers, arthralgias, and episodic urticaria. The disorder results from abnormally increased activation of the inflammatory pathway, and treatment with an IL1 receptor antagonist (see 147679) may be effective if started early (summary by Nakanishi et al., 2017).

Clinical Features

Kurima et al. (2000) reported a family (LMG113) with autosomal dominant postlingual nonsyndromic sensorineural hearing loss. The hearing loss became clinically detectable during the third or fourth decade of life and was slowly progressive.

Nakanishi et al. (2017) reported follow-up of family LMG113, which was a North American Caucasian family in which 3 generations were affected. Patients had onset of bilateral, symmetric, and progressive hearing loss between the late second and fourth decades of life. There were no consistent additional features, but 3 patients had some notable features as adults. One (subject 1285) developed multiple sclerosis, another (subject 1189) had episodic edema of her lower extremities, and a third (subject 1236) had a remote history of self-limited arthritis of unknown etiology. Laboratory investigations in subjects 1189 and 1236, both in their sixties with hearing loss, had serologic evidence of inflammation and pathologic enhancement of the cochlea on imaging. Another mutation carrier (subject 1238) in her thirties, who did not have hearing loss, had normal levels of inflammatory markers and normal cochlear imaging. However, peripheral blood cells from all 3 individuals secreted abnormally high levels of IL1B in response to stimulation with LPS.

Clinical Variability

Nakanishi et al. (2017) reported another family (LMG446) of North American descent with DFNA34 associated with a systemic inflammatory disorder. The patients included a 35-year-old father and his 3 children, 13, 10, and 6 years of age. The father had progressive hearing loss, episodic urticaria, periodic fevers, conjunctivitis, oral ulcers, cervical lymphadenopathy, arthralgias, and migraine headaches. All 3 children had similar inflammatory features, including periodic fevers, conjunctivitis, oral ulcers, cervical lymphadenopathy, episodic urticaria, and headaches, although only the 2 older children had evidence of mild hearing loss. Imaging showed variable abnormal cochlear signals in all 4 patients. Laboratory studies showed normal levels of inflammatory markers, but peripheral blood cells in all 3 children showed abnormally high secretion of IL1B in response to stimulation. Cells from the father were not tested.

Clinical Management

Nakanishi et al. (2017) found variably effective treatment of DFNA34 using anakinra, an IL1-receptor antagonist, if started early in the disease course. A 59-year-old woman from family LMG113 with hearing loss did not have subjective improvement of her hearing loss after treatment, but her serum markers of inflammation normalized. Treatment of 2 children from family LMG446 with anakinra resulted in significant improvement in hearing loss, whereas treatment of their father resulted in partial improvement. These improvements corresponded with decreased cochlear enhancement on imaging and improvement or resolution of signs and symptoms of autoinflammation.

Mapping

By genomewide linkage analysis of a family (LMG113) with autosomal dominant deafness, Kurima et al. (2000) found linkage to a 14-cM region on chromosome 1q44 between markers D1S102 and D1S3739 (maximum lod score of 3.33 at D1S2836). The locus was designated DNFA34. Kurima et al. (2000) noted that the locus overlapped that of Muckle-Wells syndrome (191900), and suggested that they may be allelic disorders.

Molecular Genetics

In affected members of 2 unrelated families from North America with DFNA34, Nakanishi et al. (2017) identified a heterozygous missense mutation in the NLRP3 gene (R918Q; 606416.0011). The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in both families. Haplotype analysis suggested a founder effect for the 2 families. Direct functional studies of the variant were not performed, but Nakanishi et al. (2017) postulated a gain-of-function effect because patient cells showed increased IL1B secretion in response to stimulation. Mouse cochlea showed expression of Nlrp3, Il1b, and other members of the Nlrp3 inflammasome, and Nlrp3 was specifically expressed in macrophage-like cells in the cochlea. Stimulation with LPS resulted in increased IL1B secretion in cochlear tissue, indicating that innate activation of the Nlrp3 inflammasome can occur specifically in the cochlea and theoretically result in local cochlear damage and hearing loss.