Au-Kline Syndrome

Disease Overview

Summary

Au-Kline syndrome is a rare genetic condition associated with intellectual disability, global developmental delay, low muscle tone and other features. As of 2025, there have been more than 75 individuals identified to have Au-Kline syndrome worldwide.^1,2

Many people with Au-Kline syndrome have specific facial features such as eyes that look longer or more open, droopy eyelids, shallow eye sockets, a wide nose with a wide bridge, a downturned mouth and a tongue with a deep groove. Other features may include early fusion of the skull bones, heart problems, abnormalities of the roof of the mouth such as cleft palate, swelling or other abnormalities of kidneys, and differences of the genitals and bones. Some people may have problems with automatic body functions such as unusual sweating, problems with digestion, reduced or absent reflexes, a high sensitivity to heat and a high pain tolerance. Feeding difficulties, vision and hearing problems, reduced growth and muscle weakness may also occur.^1-3

Au-Kline syndrome is an autosomal dominant condition caused by changes (variants) in one copy of the HNRNPK gene. All affected individuals to date have Au-Kline syndrome because of a random (de novo) variant that was not inherited from a parent.¹

The diagnosis is suspected based on signs and symptoms and confirmed with a genetic test. There is currently no cure, but a diagnosis allows for appropriate monitoring and treatment of associated symptoms.¹

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Synonyms

• AUKS
• AKS
• Au-Kline-Okamoto syndrome
• HNRKPK-related neurodevelopmental disorder
• Okamoto syndrome

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Signs & Symptoms

Au-Kline syndrome can cause a wide range of physical and developmental symptoms. Symptoms of Au-Kline syndrome may start to appear in a newborn and some differences may be identified before birth. These symptoms can vary from person to person but the most common symptoms include:^1-3

• Intellectual disability / developmental delay has been seen in all affected individuals to date but the level of delay ranges from moderate to severe.
  • Many individuals can move around on their own but some may require assistive devices for longer distances.
  • Many can speak but some may use sign language or communication devices to help them express themselves.
• Low muscle tone (hypotonia) has also been seen in all affected individuals and can continue into adulthood.

Many individuals have characteristic facial features that include:^1,3

• A long face
• Ears that stick out
• Shallow eye sockets
• Eyes that look longer or more open (long palpebral fissures)
• Droopy eyelids (ptosis) which may occur on just one side
• A broad nose with a wide bridge
• A downturned mouth often held in an open position
• A deeply grooved tongue that may be larger than usual (macroglossia)

Many individuals have heart problems that are present from birth (congenital heart defects):^1,3

• The most common is a hole in the wall between the lower heart chambers (ventricular septal defect).
• Some people may have a hole between the upper chambers of the heart (atrial septal defect) or have a heart valve with only two flaps instead of the usual three (bicuspid aortic valve).

Other features include:^1-3

• Neurologic features:
  • Differences in how the brain and spinal cord are formed
  • Muscle weakness and easy fatigability
  • Weak or absent reflexes (hyporeflexia or areflexia)
  • Problems with automatic body functions (autonomic dysfunction) which can include problems with digestion, sensitivity to heat, a high pain tolerance, frequent fevers and unusual sweating
  • Neurobehavioral and psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder and issues with impulse control; more rarely, autism spectrum disorder
  • Seizures (rare)
• Other head and facial features:
  • Early fusion of the skull bones (craniosynostosis) which may require surgery
  • Differences in the roof of the mouth (palate) such as a cleft palate, split uvula (bifid uvula) or a high/narrow palate
• Genital and urinary features:
  • Swelling of the kidneys caused by a blockage in the urinary tract (hydronephrosis)
  • Undescended testicles in males (cryptorchidism)
• Bone and joint differences:
  • A smaller-than-average head size (microcephaly) in some individuals, usually noted by early childhood
  • Problems with how the bones in the spine form (vertebral segmentation defects)
  • A sideways curve in the spine (scoliosis) which can range from mild to severe
  • Tight and stiff joints (contractures) are occasionally reported
  • Extra flexibility in some joints (hypermobility)
  • Improper hip joint development (congenital hip dysplasia) which may cause the hips to be unstable or dislocate
  • Clubfoot (talipes equinovarus) and/or flat feet (pes planus) are common
  • Extra fingers or toes on the outside of the hands and feet (postaxial polydactyly) have been reported rarely
• Gastrointestinal and feeding difficulties:
  • Most newborns can feed normally but some might struggle with feeding and require short- or long-term tube feeding
  • Many individuals have constipation
• Growth differences:
  • Most newborns have normal growth, but some have reduced growth over time, affecting both height and weight
• Vision issues:
  • Some individuals have nearsightedness (myopia) or farsightedness (hyperopia)
  • Optic nerve anomalies
• Dental differences:
  • Teeth may not line up properly (malocclusion and sometimes open bite)
  • Some people are missing six or more permanent teeth (oligodontia)
  • Teeth grinding or clenching (bruxism)
• Ear and hearing problems:
  • Hearing loss may happen due to fluid in the middle ear (conductive hearing loss) or problems with the nerves or inner ear (sensorineural hearing loss) or both
• Endocrine differences:
  • Low bone density (osteopenia)
  • Low thyroid hormone levels (hypothyroidism)
• Respiratory differences:
  • Some people may have slow or shallow breathing (hypoventilation) and obstructive sleep apnea (rare)
• Skin differences:
  • Loose or stretchy skin (skin laxity)
  • Extra nipples (supernumerary nipples) or nipples that are turned inward

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Causes

Au-Kline syndrome is caused by changes (variants) in a gene called HNRNPK. This gene gives instructions to make a protein called heterogenous nuclear riboprotein K, or hnRNP K. This protein helps control how genetic information is used in the body. It works by attaching to single strands of DNA or RNA and helps other proteins do their jobs, like turning genes on or off and making proteins from RNA. Disease-causing variants in HNRNPK prevent hnRNP K from doing its job, leading to the physical and developmental features seen in Au-Kline syndrome.^1,3

Inheritance

Au-Kline syndrome follows autosomal dominant inheritance. 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 parent or can be the result of a new (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. All individuals reported with Au-Kline syndrome whose parents have undergone genetic testing have the condition because of a de novo disease-causing HNRNPK variant.^1,2

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Affected populations

Au-Kline syndrome is a very rare disorder that was first described in 2015.^1,3 It was recognized shortly afterwards that Au-Kline syndrome is the same condition described clinically as Okamoto syndrome in 1997.⁴ The exact number of affected individuals is currently unknown, but as of 2025, more than 75 individuals have been identified worldwide. Over 40 of these individuals have been written about in medical reports.¹

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Disorders with Similar Symptoms

Symptoms of Au-Kline syndrome overlap with the following disorders. Comparisons may be useful when doctors are trying to determine a diagnosis.¹

Kabuki syndrome has symptoms that include reduced growth, congenital heart defects, genital and urinary abnormalities, characteristic facial features, intellectual disability (mild-to-moderate) and skeletal differences.^1,3

Noonan syndrome has symptoms that include short stature, genital and urinary abnormalities, coarse facial features and droopy eyelids (ptosis).^1,3

Simpson-Golabi-Behmel syndrome type 1 has symptoms that include coarse facial features, an enlarged tongue (macroglossia), intellectual disability (mild-to-severe), extra fingers and/or toes on the outside of the hands or feet (postaxial polydactyly), extra nipples (supernumerary nipples) and differences in the bones of the spinal column.¹

Shprintzen-Goldberg syndrome has symptoms that include early fusion of the skull bones (craniosynostosis), shallow eye sockets, palate abnormalities, intellectual disability (mild-to-moderate) and skeletal anomalies.^1,3

Some affected individuals may only have subtle differences with few or minor abnormalities. The diagnosis of a mild case of Au-Kline syndrome may be considered for an individual with “nonsyndromic” intellectual disability, particularly when they also have low muscle tone (hypotonia).¹

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Diagnosis

Au-Kline syndrome may be suspected when a young child has global developmental delay and/or intellectual disability, low muscle tone (hypotonia) and at least four of the following six characteristic facial features:¹

• Eyes that look longer or more open (long palpebral fissures)
• Droopy eyelids (ptosis)
• Shallow eye sockets
• Deeply grooved tongue
• Broad nose with a wide bridge
• Downturned mouth

The diagnosis of Au-Kline syndrome is confirmed with the identification of a disease-causing variant in the HNRNPK gene by genetic testing.¹

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Standard Therapies

There is currently no cure for Au-Kline syndrome. Treatment involves managing symptoms through a multidisciplinary approach to improve quality of life, maximize function and reduce complications. Several different specialists may be involved in a patient’s care to address specific symptoms.^1,2

A consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate resources and to support parents in maximizing quality of life. Early intervention programs are recommended for access to occupational, physical, speech and feeding therapies.¹

Referrals to other specialties may include neurology, neurosurgery, otolaryngology (ENT), cardiology, nephrology, urology, gastroenterology, orthopedics, ophthalmology, audiology and endocrinology to address specific symptoms or concerns.^1,2

Genetic counseling is recommended for individuals affected by Au-Kline syndrome and their families. The genetic counselor can provide information about how this condition can be passed down in families, coordinate genetic testing and offer additional resources and support.^1,2

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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 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

1. Au PYB, McNiven V, Phillips L, et al. Au-Kline Syndrome. 2019 Apr 18 [Updated 2024 Feb 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540283/ Accessed April 15, 2025.
2. Au-Kline syndrome. Genetic and Rare Diseases Information Center (GARD). https://rarediseases.info.nih.gov/diseases/4064/x Accessed April 15, 2025.
3. Au PYB, Goedhart C, Ferguson M, et al. Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature. Eur J Hum Genet. 2018;26(9):1272-1281. doi:10.1038/s41431-018-0187-2
4. Okamoto N, Matsumoto F, Shimada K, Satomura K. New MCA/MR syndrome with generalized hypotonia, congenital hydronephrosis, and characteristic face. Am J Med Genet. 1997;68(3):347-349.

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Programs & Resources

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