Au-Kline Syndrome

Original Editor - Rucha Gadgil
Top Contributors - Rucha Gadgil and Uchechukwu Chukwuemeka

Introduction[edit | edit source]

Au–Kline syndrome (AKS), also called Okamoto syndrome is a multiple congenital malformation syndrome associated with intellectual disability. It is primarily caused by loss-of-function variants in the gene HNRNPK, which encodes the heterogeneous nuclear ribonucleoprotein K (hnRNP K). It can be categorized as a very rare autosomal dominant genetic condition.

Okamoto syndrome was first described in 1997 by Nobuhiko Okamoto et al. in Japan after observing similar symptoms and physical features in two unrelated Japanese infants.

Au–Kline syndrome was first described in 2015 by Ping-Yee Billie Au, Antonie D. Kline et al. after mutations in HNRNPK were found in two individuals with similar symptoms at their respective practices in Calgary, Alberta, Canada, and Baltimore, Maryland, United States. Both submitted the gene as a candidate to the online service GeneMatcher, which matched them together and allowed them to confirm the syndrome.

Okamoto, in 2019 proposed that Au–Kline syndrome and Okamoto syndrome were synonymous because of a mutation in the HNRNPK gene, and the symptoms were virtually identical[1][2].

Clinically Relevant Anatomy[edit | edit source]

There is a protein called heterogeneous nuclear ribonucleoprotein K (hnRNP K) which is a part of the HNRNPK gene, that binds to the DNA or its RNA and other proteins. By bringing certain proteins together with DNA or RNA, this 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[2].

Etiology[edit | edit source]

AKS is caused by mutations in the HNRNPK gene located on chromosome 9 at position q21.32, which produces little or no hnRNP K protein. This altered gene activity and protein production disrupt the normal development or functioning of several body systems. This may also cause affected brain development leading to intellectual disability, delayed development, and other neurological problems in people with the condition.

Autosomal Dominant Gene Structure.png

It is genetically inherited in an autosomal dominant pattern. Most cases of this condition result from new (de novo) mutations in the gene that occurs 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.

Clinical Presentation[edit | edit source]

This condition has been characterized by:

  1. Congenital hydronephrosis,
  2. Low muscle tone and reduced reflexes,
  3. Heart defects: like aortic valve stenosis, atrial or ventricular septal defect, bicuspid aortic valve or patent ductus arteriosus.
  4. Intellectual disability,
  5. Characteristic facial features: prominent, downturned ears, an open, downturned mouth, and drooping eyelids (ptosis)
  6. Neurological and skeletal abnormalities,
  7. Urinary tract infections,
  8. Language and walking
  9. Reduced growth: low weight and size.[3]

Diagnostic Procedures[edit | edit source]

The condition can be diagnosed by physical symptoms and confirmed by genetic testing. Genetic testing can be done by:

  1. whole exome sequencing, and
  2. comparative genomic hybridization (for microdeletions).

Sanger sequencing can confirm the nature of the mutation [4].

Management / Interventions[edit | edit source]

The management depends on the symptoms. Physiotherapy management may be suggested for low tone and functional growth. The rehabilitation team should include a team of cardiologists, neurologists, physiotherapists, occupational therapists, special educators, speech therapists, and other professionals associated with the symptoms.

Genetic counselling is an important aspect of management for this condition. Prenatal testing for pregnancies at increased risk is possible if the HNRNPK pathogenic variant in the family is known.

The prognosis of the condition is yet vague due to a handful of diagnosed individuals[4].

References[edit | edit source]

  1. Au PYB, You J, Caluseriu O, Schwartzentruber J, Majewski J, Bernier FP, et al. GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK. Hum Mutat. 2015;36:1009–14. doi: 10.1002/humu.22837.
  2. 2.0 2.1 Okamoto, N. "Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation". American Journal of Medical Genetics. Part A. May 2019, 179 (5): 822–826. doi:10.1002/ajmg.a.61079. ISSN 1552-4833
  3. Au, P; Innes, M; Kline,A.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Au-Kline Syndrome", GeneReviews®, University of Washington, Seattle, 2019, PMID 30998304
  4. 4.0 4.1 Au, P. Y., Goedhart, C; Ferguson, M; Breckpot, J; Devriendt, K; Wierenga, K; et al. "Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature". European Journal of Human Genetics. Sept. 2018. 26 (9): 1272–1281. doi:10.1038/s41431-018-0187-2. ISSN 1476-5438. PMC 6117294. PMID 29904177