GJB2-Related Conditions

Disease Overview

Summary

GJB2-related conditions are a group of genetic disorders primarily associated with hearing loss and/or deafness that result from changes (variants) in the GJB2 gene. Variants in the GJB2 gene are among the most common causes of hearing loss globally. While hearing loss is the main symptom in GJB2-related conditions, some conditions related to GJB2 variants can be multi-symptom disorders (syndromes) involving skin and hair abnormalities. Most people with GJB2-related conditions have hearing loss at birth, but the severity and age of onset can vary. The treatment for GJB2-related conditions focuses on managing symptoms since there is currently no cure. Early diagnosis can enhance the quality of life using hearing aids or cochlear implants. For syndromic forms of GJB2-related disorders, such as those affecting the skin, additional treatments may be necessary to manage these symptoms.^1-3

There are several conditions that can be caused by GJB2 variants including:

GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) is the leading genetic cause for severe-to-profound sensorineural hearing loss present at birth across many populations worldwide. It is also known as autosomal recessive deafness-1A (DFNB1A).¹
GJB2-related autosomal dominant hearing loss (GJB2-AD NSHL) is a much rarer cause of sensorineural hearing loss and typically associated with other findings (syndromic). When only associated with hearing loss (isolated or nonsyndromic) this can also be referred to as autosomal dominant deafness-3A (DFNA3A).⁴
Several syndromes include hearing loss and other problems.^1,2 These include:
- Keratitis-ichthyosis-deafness syndrome (KID) is present at birth and associated with eye conditions including light sensitivity and sores (ulceration) of the cornea and scarring. Skin changes include thickened plaques and thickened skin on the hands and feet (hyperkeratosis). Sensorineural hearing loss and sparse hair with nail differences can also be seen.^2,5
- Hystrix-like ichthyosis with deafness (HID) typically present in the first year of life with skin conditions including dry, scaly skin (ichthyosis) and red, scaly, inflamed skin on most or all of the body (erythroderma). Sometimes thinning hair and patches of balding are seen. Eye conditions can be found with HID including formation of small, pinpoint defects on the corneal surface (punctate keratitis). It is associated with sensorineural hearing loss.⁶
- Palmoplantar keratoderma (PPK) with deafness-typically starts in childhood with skin thickening (keratoderma) of the palms and soles along with varying degrees of sensorineural hearing loss.⁷
- Vohwinkel syndrome (VOWNKL) includes raised (papular) and honeycomb-like thickening of the skin (keratoderma). Affected people can have tightened areas (constrictions) in the fingers and toes that can result in loss of the fingers or toes (autoamputation). Additionally, there are unique starfish-shaped keratoses on the extremities and sensorineural hearing loss is typically moderate.⁸
- Bart-Pumphrey syndrome (BAPS) presents with palmoplantar keratoderma, white spots on the nails (leukonychia), painless nodules at the knuckles (knuckle pads), and sensorineural hearing loss.⁹

Introduction

GJB2 nonsyndromic hearing loss was among the first genetic causes of hearing loss to have its location in the genome found and then the gene identified in 1997. This was important in providing a genetic reason for a large group of people with hearing loss. Many studies have shown GJB2 variants as a frequent cause of nonsyndromic hearing loss.^10,11 PPK was identified that same year and further research published in the next few years provided a better understanding of variation in GJB2-related conditions.^12-14 Continued research led to the association of VOWNKL syndrome (1999) and KID syndrome (2002). These discoveries continued to highlight the role of GJB2 in both hearing and skin-related functions.^15-17 Given similarities between KID and HID, HID was quickly found to be associated with GJB2 variants as well. It was noticed that, on a molecular level, KID and HID look the same.¹⁸ BAPS was most recently associated with GJB2 variants. This finding continued to expand our understanding of associated conditions.¹⁹

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Subdivisions

GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) also known as:

autosomal recessive deafness-1A (DFNB1A)
autosomal recessive nonsyndromic deafness 1A
autosomal recessive nonsyndromic deafness type 1A
autosomal recessive nonsyndromic hearing loss 1A
deafness, autosomal recessive 1A
deafness, autosomal recessive type 1A
GJB2-related deafness
connexin 26 deafness
deafness nonsyndromic, connexin 26 linked
DFNB1

GJB2-related autosomal dominant nonsyndromic hearing loss (GJB2-AD NSHL) also known as:

autosomal dominant deafness-3A (DFNA3A)
autosomal dominant nonsyndromic deafness 3A
autosomal dominant nonsyndromic deafness type 3A
deafness, autosomal dominant 3A
deafness, autosomal dominant 3a
deafness, autosomal dominant nonsyndromic sensorineural 3
deafness, autosomal dominant type 3A
neurosensory nonsyndromic dominant deafness 1
autosomal dominant nonsyndromic deafness caused by mutation in GJB2
GJB2 autosomal dominant nonsyndromic deafness
DFNA3

keratitis-ichthyosis-deafness syndrome (KID) also known as:

KID syndrome
autosomal dominant keratitis-ichthyosis-deafness syndrome (KIDAD)
ichthyosiform erythroderma, corneal involvement, and deafness syndrome

hystrix-like ichthyosis with deafness (HID) also known as:

HID syndrome
ichthyosis, hystrix-like, with deafness

palmoplantar keratoderma (PPK) with deafness also known as:

keratoderma palmoplantar deafness
keratoderma palmoplantar, with deafness
keratoderma, palmoplantar, with deafness
palmoplantar keratoderma and sensorineural deafness
palmoplantar keratoderma-hearing loss syndrome
palmoplantar hyperkeratosis-deafness syndrome
palmoplantar hyperkeratosis-hearing loss syndrome
PPK-deafness syndrome
PPK with deafness
diffuse palmoplantar keratoderma with deafness
focal palmoplantar keratoderma with sensorineural deafness
hereditary palmoplantar keratoderma with deafness

Vohwinkel syndrome (VOWNKL) also referred to as:

keratoderma hereditarium mutilans (KHM)
mutilating keratoderma of Vohwinkel
mutilating keratoderma plus deafness
mutilating keratoderma
PPK mutilans and deafness
deafness, congenital, with keratopachydermia and constrictions of fingers and toes

Bart-Pumphrey syndrome (BAPS) also referred to as:

knuckle pads-leukonychia-sensorineural deafness-palmoplantar keratoderma syndrome
knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
knuckle pads, leukonychia, and sensorineural deafness
knuckle pads, leuconychia and sensorineural deafness

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Signs & Symptoms

Variants of the GJB2 gene can lead to a variety of symptoms associated with the following conditions:

GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL)

GJB2-AR NSHL is sensorineural, meaning it results from problems in the inner ear involving the cochlea or auditory nerves. GJB2-AR NSHL is typically severe to profound and usually present at birth (congenital). It is usually stable and not progressive. If an individual has mild to moderate hearing loss it may progress over time. The only symptom is hearing loss, with no other associated symptoms.¹

GJB2-related autosomal dominant nonsyndromic hearing loss (GJB2-AD NSHL)

GJB2-AD NSHL is sensorineural hearing loss caused by variants in the GJB2 gene and can vary significantly in terms of age of onset. It can present in infancy but often presents in adolescence or adulthood and can depend on the specific variant. The only symptom is hearing loss, with no other associated symptoms.^1,4,20

Keratitis-ichthyosis-deafness syndrome (KID)

Individuals with KID can have serious vision problems due to issues with blood vessels in the eyes, significant hearing loss and worsening skin thickening and redness. This happens because certain layers of skin and other tissues do not develop properly1.¹⁷ Some symptoms start at birth and others develop with time.²¹ Common symptoms include:

Sensorineural hearing loss
Blindness
Decreased tear production (keratoconjunctivitis sicca)
Limited hair
Eyelid and eyelash problems such as:
- Thickened eyelashes making it difficult to move the eyelids
- Eyelashes that grow inward toward the eye (trichiasis) which can damage the eye
Elbow or knee contractures
Tight heel cords
High arched feet (pes cavus)
Fissured tongue
White patches that form on certain areas of the mouth, such as the tongue, gums and inner cheeks (oral leukoplakia)
Nail differences
Skin differences such as:
- Extensive redness and scaling of the skin (erythroderma)
- Red patches that can change shape and location (erythrokeratoderma)
- Persistent, thickened, scaly areas (hyperkeratotic plaques)
- Skin that does not shed properly (lamellar ichthyosis)
- Decreased sweating
- Recurrent skin infections
Increased risk of squamous cell carcinoma of the skin and tongue^5,16,17

Hystrix-Like ichthyosis with deafness (HID) syndrome

HID syndrome presents with both sensorineural hearing loss and skin differences.

Common symptoms include:

Sensorineural hearing loss
No hair or limited hair
High arched feet (pes cavus)
Skin differences including erythroderma, spiky thickening of the skin (spiky hyperkeratosis), and ichthyosis
Eye conditions including punctate keratitis
Squamous cell carcinoma^6,18

Palmoplantar keratoderma with deafness

Palmoplantar keratoderma with deafness is a condition where thickened skin appears on the palms and soles (palmoplantar hyperkeratosis), accompanied by varying degrees of sensorineural hearing loss that progresses over time. Symptoms begin in childhood, and there are no other skin or systemic issues noted.^7,14,22

Vohwinkel syndrome (VOWNKL)

Classic Vohwinkel syndrome has a unique thickened pattern to the skin that is often described as honeycomb or starfish-like (honeycomb keratoderma or starfish-like keratoses). Constrictive bands can form on the fingers and toes (pseudoainhum) that can lead to loss of part or all of the fingers/toes involved (autoamputation). VOWNKL includes mild to moderate sensorineural hearing loss.^8,15

Bart-Pumphrey syndrome (BAPS)

People with BAPS have symptoms that affect the hearing, skin and nails. The presentation of these characteristics can vary significantly among individuals.

Common symptoms include:

Knuckle pads
Leukonychia
Sensorineural hearing loss
Palmoplantar keratosis^9,19

The severity of symptoms linked to GJB2-related conditions can differ significantly among individuals. Each person might experience a different set of symptoms.

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Causes

GJB2-related disorders are caused by changes (variants) in the GJB2 gene, which provides instructions for making a protein called connexin 26. This protein is a component of gap junctions, which are channels that allow the passage of ions and small molecules between cells. These channels are important for cell communication, especially in the inner ear as well as the skin and cornea. Variants in the GJB2 gene can lead to impaired production or function of connexin 26, disrupting cell communication and resulting in hearing loss and sometimes skin disorders and corneal defects.^2,19

Inheritance

GJB2-related conditions are inherited in two ways, depending on the specific disorder.

GJB2-AR NSHL is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

GJB2-AD NSHL, KID, HID, palmoplantar keratoderma with deafness, Vohwinkel syndrome, and BAPS are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either an affected parent or can be the result of a newly (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

In some individuals, a GJB2 variant can appear spontaneously, known as a de novo variant, meaning it is not passed down from either parent.^1,2 Such variants arise during the creation of reproductive cells (eggs and sperm) or at the early stages of embryonic development, resulting in the genetic change being present in the child without prior occurrence in the family.

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Affected populations

Variants in GJB2 are a well-known cause of nonsyndromic sensorineural hereditary hearing loss, particularly autosomal recessive forms. GJB2 variants are one of the most common genetic causes of congenital deafness worldwide.¹

Hearing impairment (HI) occurs in about 1 in 650 newborns.²⁴ Some of these are caused by genetic variants, while others are not. Approximately 80% of hearing loss caused by genetic variants have an autosomal recessive inheritance pattern. Of these, around 30% of the cases are linked to syndromes. The remaining 70% are classified as nonsyndromic hearing loss. Of these remaining cases, GJB2 variants account for up to 50% of autosomal recessive nonsyndromic hearing loss cases globally, making it the gene most frequently associated with this form of hearing loss.^25,26

The prevalence of GJB2-AR NSHL varies significantly among different populations. It is more common among certain ethnic groups, such as Ashkenazi Jews and some Asian and European populations.^1,20 For example, research has shown that the c.35delG variant in GJB2 is a prevalent cause of hereditary hearing loss in European populations.²⁷ Other variants appear more common in different populations, such as the 235delC variant observed more often in East Asian populations.^26,28

GJB2-related conditions can affect both males and females and have been observed in individuals from diverse ethnic groups. GJB2-AR NSHL is relatively common, but other GJB2-related conditions are considered rare. It is not known exactly how rare they are, but not many cases have been recorded in medical literature.^1,2,29 However, as awareness about these conditions grows, more people may be recognized, providing a better understanding of its actual occurrence in the general population.

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Disorders with Similar Symptoms

All GJB2-related conditions should be considered in their own differential as they all have a GJB2 variant. These conditions commonly present with varying degrees of sensorineural hearing loss as a central feature. GJB2-AR NSHL and GJB2-AD NSHL both present only with sensorineural hearing loss. Family history may show a recognizable inheritance pattern, however given the similarity with other hearing loss causes, final diagnosis requires genetic testing.

For other GJB2-related conditions, the symptoms can include hearing loss as well as skin abnormalities.^1,29 KID and HID share many common clinical features in their skin conditions and are caused by the same gene variants. This has led to discussions suggesting they are part of a spectrum of the same disease.¹⁸ Similarly, VOWNKL, PPK with deafness and BAPS all share palmoplantar keratoderma and hearing loss as symptoms. Given the genetic basis, the differential diagnosis of these conditions benefits not only from a detailed clinical examination but also from genetic testing and counseling to confirm the presence of GJB2 variants and provide guidance on inheritance patterns and family implications.^1,29

The following are GJB2-related conditions. For each of these conditions, the following list may be helpful when considering other diagnoses.

GJB2-AR NSHL

In general, autosomal recessive nonsyndromic sensorineural hearing loss can be caused by variants in more than 100 different genes. Presentation is very similar, and typically genetic testing is needed to differentiate between them.

Some genes that cause autosomal recessive non-syndromic hearing loss similar to GJB2 include:

SLC26A4 (DFNB4) autosomal recessive nonsyndromic hearing loss type 4
OTOF (DFNB9) autosomal recessive nonsyndromic hearing loss 9
TMC1 (DFNB7/11) autosomal recessive nonsyndromic hearing loss 7
MYO15A (DFNB3) autosomal recessive nonsyndromic hearing loss 3
TECTA (DFNB21) autosomal recessive nonsyndromic hearing loss 21

Many of these genes, like GJB2, play essential roles in cochlear cell function or structures, and disruption can lead to similar patterns of hearing loss.^1,30

GJB2-AD NSHL

Like autosomal recessive nonsyndromic sensorineural hearing loss, autosomal dominant nonsyndromic sensorineural hearing loss can be caused by at least 50 different genes that can have a similar presentation. Genetic testing is used to determine the final diagnosis.

Genes that cause autosomal dominant nonsyndromic hearing loss similar to GJB2 include but are not limited to:

KCNQ4 (DFNA2) autosomal dominant nonsyndromic hearing loss 2A
COCH (DFNA9) autosomal dominant nonsyndromic hearing loss 9
MYO7A (DFNA11) autosomal dominant nonsyndromic hearing loss 11
ACTG1 (DFNA20/26) autosomal dominant nonsyndromic hearing loss 20

These genes, like GJB2 in its dominant form, can lead to progressive or stable hearing loss and the variability can depend on specific variants. Genetic background and environmental factors can also impact hearing loss severity and onset in both recessive and dominant cases.^4,20,30

KID

The differential diagnosis for keratitis-ichthyosis-deafness (KID) syndrome should include conditions that present with similar features like skin differences, eye concerns and hearing loss. Although KID associated with GJB2 variants is inherited in an autosomal dominant pattern, KID can be inherited in an autosomal recessive pattern. Like GJB2-related KID, autosomal recessive KID is associated with sensorineural hearing loss, eye concerns, skin, nail and hair differences, but also includes failure to thrive, developmental delays, intellectual disability, abnormal teeth, gastrointestinal and liver concerns and brain differences. It is caused by variants in both copies of the AP1B1 gene.⁵

HID

HID syndrome has some similarities with KID but HID is not associated with significant eye findings such as the ones seen in KID.^5,6,9 Other skin conditions to consider can include types of autosomal recessive congenital ichthyosis.²¹ An accurate diagnosis typically involves a combination of clinical evaluation, genetic testing and sometimes biopsy of skin lesions to evaluate diagnosis.

Palmoplantar keratoderma with deafness

Palmoplantar keratoderma with deafness can also be caused by variants in the MTTS1 gene. This is a mitochondrial gene, meaning it is found within the mitochondria rather than in the nucleus. It has a different inheritance pattern known as mitochondrial inheritance.³² Palmoplantar keratoderma can be seen in Clouston syndrome (see below), along with nail differences and sparse hair. Clouston syndrome is caused by a variant in GJB6.³¹ Other GJB2-related conditions, particularly BAPS and Vohwinkel syndrome, should be considered in the differential with palmoplantar keratoderma with deafness, as these both have keratoderma associated with them. Diagnosis is determined by clinical evaluation along with genetic testing.^7-9,29

Vohwinkel syndrome (VOWNKL)

Classic Vohwinkel syndrome is caused by a variant in the GJB2 gene. There are two other forms of Vohwinkel syndrome caused by variants in LOR or TRPV3 genes:

Variants in the LOR gene cause Vohwinkel syndrome, variant form. This is also known as Vohwinkel syndrome with ichthyosis, mutilating keratoderma with ichthyosis, or loricrin keratoderma. People with this syndrome do not have hearing loss but have similar skin findings as classic Vohwinkel syndrome. It is inherited in an autosomal dominant pattern.³³
Variants in TRPC4 cause Olmsted syndrome 1 (OLMS1) or mutilating palmoplantar keratoderma with periorificial keratotic plaques 1 (PPKM1). It is inherited in an autosomal dominant pattern. Similar skin findings are noted, however hearing loss is not seen.³⁴ Other GJB2-related conditions, particularly BAPS and palmoplantar keratoderma with deafness syndrome, should be considered as these both have keratoderma associated with them. Clinical exam and genetic testing are used to determine diagnosis.^7-9,29

BAPS

As discussed above, people with BAPS have hearing, skin and nails problems. The differential should include all GJB2-related conditions, with extra attention given to Vohwinkel syndrome and palmoplantar keratoderma with deafness, since they share both hearing loss and palmoplantar keratoderma with BAPS.^7-9,29 To diagnose Bart-Pumphrey syndrome, a combination of clinical evaluation for characteristic symptoms, family history and genetic testing for GJB2 variants is used.

Other conditions that should be considered in the differential diagnosis of GJB2-related disorders include:

Clouston syndrome, which can present with palmoplantar hyperkeratosis, nail differences and hair loss. Clouston syndrome does not typically have eye findings or hearing loss. It is associated with variants in GJB6.³¹

Autosomal recessive congenital ichthyosis appears similar and should be included in the differential. Generally, other symptoms like hearing and vision concerns are not seen as in KID syndrome. This can be caused by variants in many different genes.²¹

Proper clinical assessment, genetic testing and involvement of dermatologists, audiologists and sometimes ophthalmologists are key to differentiating between these conditions. Sometimes biopsy of skin lesions is needed to help determine diagnosis.

Pachyonychia congenita should be considered and is characterized by severe nail differences, palmoplantar keratoderma and white patches with a thickened outer layer in the mouth (oral leukokeratosis). Pachyonychia congenita is associated with various genes, not including GJB2.³⁵

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Diagnosis

Diagnosing GJB2-related conditions involves a combination of clinical assessment and genetic testing. The first step involves collecting history and a physical examination to identify symptoms consistent with GJB2 variants. Findings discussed above may lead a doctor to suspect GJB2-related conditions. Gathering a detailed family history may suggest an inheritance pattern. For those with hearing loss, hearing (audiological) evaluations will measure the degree and type of hearing impairment. In people with skin symptoms, a skin biopsy may be taken to determine the skin disease present.^1,2,12,19,29

The definitive diagnosis as a GJB2-related condition is made through genetic testing, which involves analyzing the GJB2 gene for variants.¹

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Standard Therapies

As of now, there is no cure for genetic conditions caused by variants in the GJB2 gene. However, there are management and treatment options available to help manage symptoms and improve quality of life. These options include:

Hearing aids can amplify sound and help people with hearing loss to hear more clearly.
Cochlear implants: For individuals with severe or profound hearing loss, cochlear implants can provide a sense of sound by directly stimulating the auditory nerve.
Speech therapy can help improve communication skills.
Noise protection: Individuals who have confirmed hearing loss should receive proper counseling to refrain from repeated exposure to loud noises, which could worsen their hearing.^1,20

Skin conditions should be addressed by a dermatologist and treatment depends on condition present.³

People with eye conditions should have regular visits with an ophthalmologist to address the concerns.³⁶

Tailored educational plans and resources can assist people with hearing loss/vision loss in their learning and day-to-day activities.

Genetic counseling for individuals and their families is recommended to provide information about the genetic aspects of hearing loss.^1,20

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For more information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:https://www.clinicaltrialsregister.eu/

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References

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Programs & Resources

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/