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Hearing loss, X-linked 4(DFNX4)

MedGen UID:
376307
•Concept ID:
C1848204
•
Disease or Syndrome
Synonyms: DEAFNESS, NONSYNDROMIC SENSORINEURAL PROGRESSIVE 6; Deafness, X-linked 4; DEAFNESS, X-LINKED 6, PROGRESSIVE; DFNX4; DFNX4 (DFN6) Nonsyndromic Hearing Loss and Deafness
 
Gene (location): SMPX (Xp22.12)
 
Monarch Initiative: MONDO:0010238
OMIM®: 300066

Definition

X-linked deafness-4 is a nonsyndromic form of progressive hearing loss with postlingual onset. Affected males show earlier onset of hearing loss than affected females (summary by del Castillo et al., 1996). [from OMIM]

Clinical features

From HPO
High-frequency hearing impairment
MedGen UID:
42358
•Concept ID:
C0018780
•
Disease or Syndrome
A type of hearing impairment affecting primarily the higher frequencies of sound (3,000 to 6,000 Hz).
See: Feature record | Search on this feature
Sensorineural hearing loss disorder
MedGen UID:
9164
•Concept ID:
C0018784
•
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
See: Feature record | Search on this feature

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHearing loss, X-linked 4

Professional guidelines

PubMed

Alport syndrome: Expanding diagnosis and treatment.
Huang HX, Tsai IJ, Greenbaum LA
Pediatr Neonatol 2025 Feb;66 Suppl 1:S13-S17. Epub 2024 Oct 30 doi: 10.1016/j.pedneo.2024.10.005. PMID: 39521677
Renal, auricular, and ocular outcomes of Alport syndrome and their current management.
Zhang Y, Ding J
Pediatr Nephrol 2018 Aug;33(8):1309-1316. Epub 2017 Sep 1 doi: 10.1007/s00467-017-3784-3. PMID: 28864840
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article

Recent clinical studies

Etiology

Spectrum of Alport syndrome in an Indian cohort.
Yadav M, Jadon T, Singh G, Devi KG, Chandan M, Khandelwal P, Meena J, Geetha TS, Faruq M, Hari P, Sinha A, Bagga A
Pediatr Nephrol 2025 Feb;40(2):393-405. Epub 2024 Sep 16 doi: 10.1007/s00467-024-06507-1. PMID: 39278986
Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.
Bosman A, Appelman-Dijkstra NM, Boot AM, de Borst MH, van de Ven AC, de Jongh RT, Bökenkamp A, van den Bergh JP, van der Eerden BCJ, Zillikens MC
Calcif Tissue Int 2024 Mar;114(3):255-266. Epub 2024 Jan 16 doi: 10.1007/s00223-023-01172-2. PMID: 38226986Free PMC Article
X-linked deafness/incomplete partition type 3: Radiological evaluation of temporal bone and intracranial findings.
Parlak S, Gumeler E, Sennaroglu L, Ozgen B
Diagn Interv Radiol 2022 Jan;28(1):50-57. doi: 10.5152/dir.2021.20791. PMID: 34914607
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.
Colombo L, Maltese PE, Castori M, El Shamieh S, Zeitz C, Audo I, Zulian A, Marinelli C, Benedetti S, Costantini A, Bressan S, Percio M, Ferri P, Abeshi A, Bertelli M, Rossetti L
Invest Ophthalmol Vis Sci 2021 Feb 1;62(2):13. doi: 10.1167/iovs.62.2.13. PMID: 33576794Free PMC Article
Ocular features in Alport syndrome: pathogenesis and clinical significance.
Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D
Clin J Am Soc Nephrol 2015 Apr 7;10(4):703-9. Epub 2015 Feb 3 doi: 10.2215/CJN.10581014. PMID: 25649157Free PMC Article

Diagnosis

Alport syndrome: Expanding diagnosis and treatment.
Huang HX, Tsai IJ, Greenbaum LA
Pediatr Neonatol 2025 Feb;66 Suppl 1:S13-S17. Epub 2024 Oct 30 doi: 10.1016/j.pedneo.2024.10.005. PMID: 39521677
Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.
Bosman A, Appelman-Dijkstra NM, Boot AM, de Borst MH, van de Ven AC, de Jongh RT, Bökenkamp A, van den Bergh JP, van der Eerden BCJ, Zillikens MC
Calcif Tissue Int 2024 Mar;114(3):255-266. Epub 2024 Jan 16 doi: 10.1007/s00223-023-01172-2. PMID: 38226986Free PMC Article
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.
Colombo L, Maltese PE, Castori M, El Shamieh S, Zeitz C, Audo I, Zulian A, Marinelli C, Benedetti S, Costantini A, Bressan S, Percio M, Ferri P, Abeshi A, Bertelli M, Rossetti L
Invest Ophthalmol Vis Sci 2021 Feb 1;62(2):13. doi: 10.1167/iovs.62.2.13. PMID: 33576794Free PMC Article
Ocular features in Alport syndrome: pathogenesis and clinical significance.
Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D
Clin J Am Soc Nephrol 2015 Apr 7;10(4):703-9. Epub 2015 Feb 3 doi: 10.2215/CJN.10581014. PMID: 25649157Free PMC Article
X-linked mixed hearing loss: four case studies.
Bento RF, Miniti A
Laryngoscope 1985 Apr;95(4):462-8. doi: 10.1288/00005537-198504000-00017. PMID: 4039021

Therapy

Renal, auricular, and ocular outcomes of Alport syndrome and their current management.
Zhang Y, Ding J
Pediatr Nephrol 2018 Aug;33(8):1309-1316. Epub 2017 Sep 1 doi: 10.1007/s00467-017-3784-3. PMID: 28864840
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article
A note of caution on the diagnosis of Martin-Probst syndrome by the detection of the p.D59G mutation in the RAB40AL gene.
Ołdak M, Ruszkowska E, Pollak A, Sobczyk-Kopcioł A, Kowalewski C, Piwońska A, Drygas W, Płoski R
Eur J Pediatr 2015 May;174(5):693-6. Epub 2014 Nov 5 doi: 10.1007/s00431-014-2452-x. PMID: 25370018Free PMC Article
Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed.
Al Sawaf S, Mayatepek E, Hoffmann B
J Inherit Metab Dis 2008 Aug;31(4):473-80. Epub 2008 Jul 13 doi: 10.1007/s10545-008-0878-x. PMID: 18618289
Hearing loss in Fabry disease: the effect of agalsidase alfa replacement therapy.
Hajioff D, Enever Y, Quiney R, Zuckerman J, Mackermot K, Mehta A
J Inherit Metab Dis 2003;26(8):787-94. doi: 10.1023/B:BOLI.0000009948.86528.72. PMID: 14739683

Prognosis

Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.
Colombo L, Maltese PE, Castori M, El Shamieh S, Zeitz C, Audo I, Zulian A, Marinelli C, Benedetti S, Costantini A, Bressan S, Percio M, Ferri P, Abeshi A, Bertelli M, Rossetti L
Invest Ophthalmol Vis Sci 2021 Feb 1;62(2):13. doi: 10.1167/iovs.62.2.13. PMID: 33576794Free PMC Article
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article
Ocular features in Alport syndrome: pathogenesis and clinical significance.
Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D
Clin J Am Soc Nephrol 2015 Apr 7;10(4):703-9. Epub 2015 Feb 3 doi: 10.2215/CJN.10581014. PMID: 25649157Free PMC Article
Two novel mutations in the Norrie disease gene associated with the classical ocular phenotype.
Caballero M, Veske A, Rodriguez JJ, Lugo N, Schroeder B, Hesse L, Gal A
Ophthalmic Genet 1996 Dec;17(4):187-91. doi: 10.3109/13816819609057892. PMID: 9010869
Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4.
de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP
Science 1995 Feb 3;267(5198):685-8. doi: 10.1126/science.7839145. PMID: 7839145

Clinical prediction guides

Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.
Bosman A, Appelman-Dijkstra NM, Boot AM, de Borst MH, van de Ven AC, de Jongh RT, Bökenkamp A, van den Bergh JP, van der Eerden BCJ, Zillikens MC
Calcif Tissue Int 2024 Mar;114(3):255-266. Epub 2024 Jan 16 doi: 10.1007/s00223-023-01172-2. PMID: 38226986Free PMC Article
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article
Ocular features in Alport syndrome: pathogenesis and clinical significance.
Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D
Clin J Am Soc Nephrol 2015 Apr 7;10(4):703-9. Epub 2015 Feb 3 doi: 10.2215/CJN.10581014. PMID: 25649157Free PMC Article
Two novel mutations in the Norrie disease gene associated with the classical ocular phenotype.
Caballero M, Veske A, Rodriguez JJ, Lugo N, Schroeder B, Hesse L, Gal A
Ophthalmic Genet 1996 Dec;17(4):187-91. doi: 10.3109/13816819609057892. PMID: 9010869
Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4.
de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP
Science 1995 Feb 3;267(5198):685-8. doi: 10.1126/science.7839145. PMID: 7839145

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