Bart-Pumphrey syndrome

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the GJB2 gene have been found to cause Bart-Pumphrey syndrome. This condition is characterized by a white discoloration of the nails (leukonychia), thickened skin on the palms of the hands and soles of the feet (palmoplantar keratoderma), wart-like growths (knuckle pads) on the knuckles of the fingers and toes, and hearing loss.

The GJB2 gene variants that cause Bart-Pumphrey syndrome lead to the substitution of a protein building block (amino acid) with another in the gap junction beta 2 protein. The altered protein disrupts the function of normal gap junction beta 2 in cells. This disruption affects skin growth and impairs hearing by disturbing the conversion of sound waves to nerve impulses.

Hystrix-like ichthyosis with deafness

A GJB2 gene variant has been identified in people with hystrix-like ichthyosis with deafness (HID), a disorder that is characterized by dry, scaly skin (ichthyosis) and hearing loss that is usually profound (meaning unable to hear very loud noises). This pathogenic variant is thought to cause cells to produce channels that constantly leak ions, which impairs the health of the cells and causes them to die. Death of cells in the skin and the inner ear may underlie the signs and symptoms of HID.

Often, the same variant that causes HID can also cause keratitis-ichthyosis-deafness (KID) syndrome. As a result, many researchers categorize KID syndrome and HID as a single disorder, which they call KID/HID.

Keratitis-ichthyosis-deafness syndrome

Pathogenic variants in the GJB2 gene have been identified in people with keratitis-ichthyosis-deafness (KID) syndrome. KID syndrome is characterized by keratitis, which is inflammation of the front surface of the eye (the cornea); ichthyosis; and deafness.

The pathogenic variants in the GJB2 gene that cause KID syndrome lead to the substitution of one amino acid for another in gap junction beta 2. These variants are thought to cause cells to produce channels that constantly leak ions, which impairs the health of the cells and causes them to die. Death of cells in the skin and the inner ear may underlie the ichthyosis and deafness that occur in people with KID syndrome. It is unclear how GJB2 gene variants affect the eye.

Nonsyndromic hearing loss

Several pathogenic variants in the GJB2 gene cause nonsyndromic hearing loss, which is a partial or total loss of hearing that is not associated with other signs and symptoms.

Most commonly, GJB2 gene variants cause a form of nonsyndromic hearing loss known as DFNB1A. DFNB1A is inherited in an autosomal recessive pattern, which means both copies of the GJB2 gene in each cell have pathogenic variants. This form of the condition accounts for about half of all cases of autosomal recessive nonsyndromic hearing loss, although this varies by population. DFNB1A is characterized by hearing loss that is present before a child learns to speak (prelingual), often being present at birth (congenital). DFNB1A varies in severity but typically does not worsen over time.

The pathogenic variants in the GJB2 gene that cause DFNB1A are described as "loss-of-function variants" because they lead to an altered or nonfunctional version of gap junction beta 2, which appears to disrupt the assembly or function of gap junctions. In the inner ear, the abnormal or missing gap junctions likely alter the availability of potassium ions, which may affect the function or survival of cells that are needed for hearing.

In very rare cases, GJB2 gene variants are inherited in an autosomal dominant pattern, which means only one altered copy of the gene in each cell is sufficient to cause hearing loss. This form of hearing loss is known as DFNA3A. It can be either prelingual or begin after a child learns to speak (postlingual) and often worsens over time.

The pathogenic variants in the GJB2 gene that cause DFNA3A likely lead to the production of an abnormal version of gap junction beta 2 that prevents the formation of any functional gap junctions. The absence of these channels probably affects the function or survival of cells in the inner ear that are essential for hearing.

Palmoplantar keratoderma with deafness

Pathogenic variants in the GJB2 gene have been identified in people with palmoplantar keratoderma with deafness, a condition that is characterized by hearing loss and unusually thick skin on the palms of the hands and soles of the feet (palmoplantar keratoderma). The pathogenic variants in the GJB2 gene that cause this condition lead to the substitution of one amino acid for another in gap junction beta 2. The altered protein probably disrupts the function of normal gap junction beta 2 in cells and may interfere with the function of other gap junction proteins. This disruption affects skin growth and impairs hearing by disturbing the conversion of sound waves to nerve impulses.

Vohwinkel syndrome

Pathogenic variants in the GJB2 gene have been identified in people with Vohwinkel syndrome, a condition that is characterized by hearing loss and skin abnormalities. In addition to abnormal patches of skin, affected individuals develop tight bands of abnormal fibrous tissue around their fingers and toes that may cut off the circulation to the digits and result in spontaneous amputation.

The pathogenic variants in the GJB2 gene that cause Vohwinkel syndrome lead to the substitution of one amino acid for another in gap junction beta 2. The altered protein probably disrupts the function of normal gap junction beta 2 in cells and may interfere with the function of other gap junction proteins. These abnormalities affect skin growth and impair hearing by disturbing the conversion of sound waves to nerve impulses.