Auriculo-condylar syndrome is a condition that affects facial development, particularly development of the ears and lower jaw (mandible).

Most people with auriculo-condylar syndrome have malformed outer ears ("auriculo-" refers to the ears). A hallmark of this condition is an ear abnormality called a "question-mark ear," in which the ears have a distinctive question-mark shape caused by a split that separates the upper part of the ear from the earlobe. Other ear abnormalities that can occur in auriculo-condylar syndrome include cupped ears, ears with fewer folds and grooves than usual (described as "simple"), narrow ear canals, small skin tags in front of or behind the ears, and ears that are rotated backward. Some affected individuals also have hearing loss.

Abnormalities of the mandible are another characteristic feature of auriculo-condylar syndrome. These abnormalities often include an unusually small chin (micrognathia) and malfunction of the temporomandibular joint (TMJ), which connects the lower jaw to the skull. Problems with the TMJ affect how the upper and lower jaws fit together and can make it difficult to open and close the mouth. The term "condylar" in the name of the condition refers to the mandibular condyle, which is the upper portion of the mandible that forms part of the TMJ.

Other features of auriculo-condylar syndrome can include prominent cheeks, an unusually small mouth (microstomia), differences in the size and shape of facial structures between the right and left sides of the face (facial asymmetry), and an opening in the roof of the mouth (cleft palate). These features vary, even among affected members of the same family.

Auriculo-condylar syndrome can be caused by mutations in either the GNAI3 or PLCB4 gene. These genes provide instructions for making proteins that are involved in chemical signaling within cells. They help transmit information from outside the cell to inside the cell, which instructs the cell to grow, divide, or take on specialized functions.

Studies suggest that the proteins produced from the GNAI3 and PLCB4 genes contribute to the development of the first and second pharyngeal arches, which are structures in the embryo that ultimately develop into the jawbones, facial muscles, middle ear bones, ear canals, outer ears, and related tissues. Mutations in these genes alter the formation of the lower jaw: instead of developing normally, the lower jaw becomes shaped more like the smaller upper jaw (maxilla). This abnormal shape leads to micrognathia and problems with TMJ function. Researchers are working to determine how mutations in these genes lead to the other developmental abnormalities associated with auriculo-condylar syndrome.

In some people with the characteristic features of auriculo-condylar syndrome, a mutation in the GNAI3 or PLCB4 gene has not been found. The cause of the condition is unknown in these individuals.

Normal Function

The GNAI3 gene provides instructions for making one component, the inhibitory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). G proteins are composed of three protein subunits: alpha, beta, and gamma. Each of these subunits is produced from a different gene.

Through a process called signal transduction, G proteins trigger a complex network of signaling pathways within cells. These pathways help transmit information from outside the cell to inside the cell. Specifically, G proteins made with the GNAI3 inhibitory alpha subunit reduce (inhibit) the activity of an enzyme called adenylyl cyclase, which is an important chemical messenger within cells. G protein signaling ultimately influences many cell activities, instructing the cell to grow, divide, or take on specialized functions.

Studies suggest that G protein signaling involving the GNAI3 inhibitory alpha subunit contributes to the development of the first and second pharyngeal arches. These embryonic structures ultimately develop into the jawbones, facial muscles, middle ear bones, ear canals, outer ears, and related tissues.

Health Conditions Related to Genetic Changes

Auriculo-condylar syndrome

At least two mutations in the GNAI3 gene have been found to cause auriculo-condylar syndrome, a disorder that primarily affects the development of the ears and lower jaw (mandible). The identified mutations change single protein building blocks (amino acids) in the inhibitory alpha subunit. These mutations likely alter the structure of the inhibitory alpha subunit and impair G protein signaling. Abnormal signaling alters the formation of the lower jaw: instead of developing normally, the lower jaw becomes shaped more like the smaller upper jaw (maxilla). The abnormal shape leads to an unusually small chin (micrognathia) and problems with jaw function. Researchers are working to determine how mutations in this gene lead to the other developmental abnormalities associated with auriculo-condylar syndrome.

Other Names for This Gene

• 87U6
• ARCND1
• g(i) alpha-3
• GNAI3_HUMAN
• guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3
• guanine nucleotide-binding protein G(k) subunit alpha

Genomic Location

Normal Function

The PLCB4 gene provides instructions for making one form (the beta 4 isoform) of a protein called phospholipase C. This protein is involved in a signaling pathway within cells known as the phosphoinositide cycle, which helps transmit information from outside the cell to inside the cell. Phospholipase C carries out one particular step in the phosphoinositide cycle: the conversion of a molecule called phosphatidylinositol 4,5-bisphosphate (PIP2) to two smaller molecules, inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol. These smaller molecules relay messages into the cell that ultimately influence many cell activities.

Studies suggest that the beta 4 isoform of phospholipase C contributes to the development of the first and second pharyngeal arches. These embryonic structures ultimately develop into the jawbones, facial muscles, middle ear bones, ear canals, outer ears, and related tissues. This protein is also thought to play a role in vision, particularly in the function of the retina, which is a specialized tissue at the back of the eye that detects light and color.

Health Conditions Related to Genetic Changes

Auriculo-condylar syndrome

At least nine mutations in the PLCB4 gene have been found to cause auriculo-condylar syndrome, a disorder that primarily affects the development of the ears and lower jaw (mandible). The identified mutations change single protein building blocks (amino acids) in the the beta 4 isoform of phospholipase C. These changes likely alter the structure of the protein and impair the phosphoinositide cycle. Abnormal signaling alters the formation of the lower jaw: instead of developing normally, the lower jaw becomes shaped more like the smaller upper jaw (maxilla). The abnormal shape leads to an unusually small chin (micrognathia) and problems with jaw function. Researchers are working to determine how mutations in this gene lead to the other developmental abnormalities associated with auriculo-condylar syndrome.

Other Names for This Gene

• 1-phosphatidyl-D-myo-inositol-4,5-bisphosphate
• 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4
• ARCND2
• dJ1119D9.2 (Phopholipase C, beta 4 (1-Phosphatidylinositol-4,5-Bisphosphate Phosphodiesterase Beta 4))
• inositoltrisphosphohydrolase
• monophosphatidylinositol phosphodiesterase
• phosphoinositidase C
• phosphoinositide phospholipase C-beta-4
• phospholipase C, beta 4
• PI-PLC
• PLC-beta-4
• PLCB4_HUMAN
• triphosphoinositide phosphodiesterase

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is typically sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Some people who have one altered copy of the GNAI3 or PLCB4 gene have no features related to auriculo-condylar syndrome. (This situation is known as reduced penetrance.) It is unclear why some people with a mutated gene develop the condition and other people with a mutated gene do not.

Auriculo-condylar syndrome appears to be a rare disorder. More than two dozen affected individuals have been described in the medical literature.