Au-Kline syndrome is a condition that affects many body systems. Individuals with this condition typically have weak muscle tone (hypotonia), intellectual disability, and delayed development. Speech is delayed in children with Au-Kline syndrome, and some are able to say only one or a few words or are never able to speak. In addition, affected children learn to walk later than usual, and some are never able to walk on their own.

Individuals with Au-Kline syndrome can have distinctive facial features, including long openings of the eyelids (long palpebral fissures), drooping eyelids (ptosis), and shallow eye sockets. Other common facial features in this condition include a broad nasal bridge, a mouth with the outer corners turned downward and often held in an open position, and a deep groove down the middle of the tongue. Less common abnormalities include premature joining of certain skull bones (craniosynostosis) in affected infants, an opening or unusually high arch in the roof of the mouth (cleft or high-arched palate), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and missing teeth (oligodontia).

Malformations of the heart, blood vessels, kidneys, or bones can also occur in people with Au-Kline syndrome. For example, in some affected individuals, the large blood vessel that distributes blood from the heart to the rest of the body (the aorta) becomes weakened and stretched (aortic dilatation), which can be life-threatening. Some people with Au-Kline syndrome have an abnormal curvature of the spine (scoliosis). In addition, affected individuals may have difficulty feeding or poor vision.

Au-Kline syndrome can sometimes affect the autonomic nervous system, which controls involuntary body functions, such as digestion and regulation of body temperature. In people with Au-Kline syndrome, abnormalities in this system can lead to digestive problems, difficulty feeling pain, abnormal sweating, and an inability to adjust to high heat in people with Au-Kline syndrome.

Au-Kline syndrome is caused by mutations in the HNRNPK gene. The protein produced from this gene, called heterogenous nuclear ribonucleoprotein K (hnRNP K), attaches (binds) to DNA or its chemical cousin RNA and to other proteins, acting as a docking station for these molecules so they can interact. By bringing certain proteins together with DNA or RNA, the hnRNP K protein helps control the activity of genes and the production of proteins. By regulating certain genes and proteins, the hnRNP K protein plays a role in the normal development and function of several body systems, including the brain.

HNRNPK gene mutations that cause Au-Kline syndrome result in the production of little or no hnRNP K protein. A shortage of this protein alters gene activity and protein production, which disrupts the normal development or functioning of several body systems, resulting in the varied features of Au-Kline syndrome. In particular, problems with brain development likely contribute to intellectual disability, delayed development, and other neurological problems in people with the condition.

Normal Function

The HNRNPK gene provides instructions for making a protein called heterogenous nuclear ribonucleoprotein K (hnRNP K). This protein attaches (binds) to DNA or its chemical cousin RNA and to other proteins. It acts as a docking site to bring together different molecules in the cell, which is important for relaying signals and controlling cellular functions. By bringing certain proteins together with DNA or RNA, the hnRNP K protein helps control the activity of genes and the production of proteins. By regulating gene activity and protein production, hnRNP K is involved in many cellular processes, including growth and division (proliferation) of cells, maturation of cells to take on specialized function (differentiation), and self-destruction (apoptosis) of cells when they are no longer needed.

The hnRNP K protein plays a role in the normal development or function of many body systems. In the brain, the protein may be involved in a process called synaptic plasticity, which is the ability of the connections between neurons (synapses) to change and adapt over time in response to experience. This process is critical for learning and memory. Another process in the brain involving the hnRNP K protein is the growth of nerve cell extensions called axons, which are essential for transmission of nerve impulses. While the protein is likely critical in other systems and processes, its role is not well understood.

Health Conditions Related to Genetic Changes

Au-Kline syndrome

More than 20 mutations in the HNRNPK gene have been found to cause Au-Kline syndrome. This condition is characterized by weak muscle tone (hypotonia), intellectual disability, delayed development of speech and walking, and distinctive facial features. Other body systems, such as the heart, kidneys, and bones, may also be affected.

The HNRNPK gene mutations that cause Au-Kline syndrome alter the blueprint for making hnRNP K protein, which results in the production of little or no hnRNP K protein from one copy of the gene. A shortage of this protein changes gene activity and protein production in cells. As a result, the normal development or function of cells, tissues, and organs in many parts of the body is disrupted, leading to the varied features of Au-Kline syndrome. In particular, problems with brain development likely contribute to intellectual disability, delayed development, and other neurological problems in people with the condition.

Cancers

Loss of the HNRNPK gene is thought to be involved in the development of a blood cancer known as acute myeloid leukemia (AML). A mutation that removes (deletes) DNA from the long (q) arm of chromosome 9 occurs in about 2 percent of AML cases. Such cases are referred to as del(9q) AML. The missing region of DNA includes the HNRNPK gene, among other genes. Researchers suspect that a shortage of hnRNP K protein alters the activity of genes that control cell growth, resulting in an excess of abnormal cells. When the del(9q) mutation occurs in certain blood cells, the shortage of hnRNP K may contribute to the uncontrolled cell growth that underlies AML.

Individuals with Au-Kline syndrome (described above) do not appear to have a higher risk of developing AML than does the general population.

Other Names for This Gene

• CSBP
• HNRPK
• transformation upregulated nuclear protein
• TUNP

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual’s parent or in early embryonic development. These cases occur in people with no history of the disorder in their family.

Au-Kline syndrome is a rare condition with an unknown prevalence. At least 25 cases have been diagnosed.