Signs and symptoms
Kidneys
Individuals with Okamoto syndrome are usually born with hydronephrosis, or dilation of the internal structures of the kidneys, due to narrowing (stenosis) of the passage between the kidneys and the ureters (the ureteropelvic junction), leading to a build-up of urine. There is also often vesicoureteral reflux, in which urine passes backwards from the bladder to the ureters, and frequent urinary tract infections. Heart
Individuals with Okamoto syndrome are typically born with heart defects, which can include aortic valve stenosis, atrial or ventricular septal defect, bicuspid aortic valve or patent ductus arteriosus. Physical features
The syndrome has a characteristic facial appearance which is similar to that of Kabuki syndrome, including prominent, downward-displaced ears that are underdeveloped, long eyelids, epicanthic folds, a short, broad nose, an open, downturned mouth and a deep groove in the midline of the tongue. Cleft palate occurs in about half of those affected. There is sometimes webbing of the neck or bulging eyes, and less commonly there is excessive hair on the forehead or other parts of the body or a unibrow. Individuals with the syndrome may also have a broad first toe and crowding of the toes, and at least two affected individuals have had polydactyly of the fifth digit (postaxial polydactyly). Some of those affected have had undescended testicles (cryptorchidism). A small minority of those affected have had congenital joint contractures such as club foot. Neurological
Those with Okamoto syndrome typically have severe mental disability and are usually born with microcephaly.
Hearing and eyesight
A minority of those with Okamoto syndrome have had hearing loss of both sensorineural and conductive types, and a smaller minority have had optic nerve abnormalities. Cause
Okamoto syndrome is caused by a mutation in the HNRNPK gene, located on chromosome 9 at position q21.32. HNRNPK codes for heterogeneous nuclear ribonucleoprotein K. Ribonucleoproteins are proteins that form complexes with RNA, and they are involved in the transcription of DNA into RNA in the nucleus. They usually bind with precursor messenger RNA (pre-mRNA), which is messenger RNA that has not yet had its introns removed during splicing to be ready for translation. A mutation in one of the two copies of HNRNPK results in defects in DNA transcription, and therefore some developmental processes are disrupted or not completed.Mutations in HNRNPK that have been reported include nonsense mutations, in which the protein is truncated and usually non-functional as a result, frameshift mutations, splice-site mutations and microdeletions encompassing the gene. Rarely, missense mutations, in which one amino acid in the protein is replaced by another, have also been reported.Deletions in the region encompassing HNRNPK have been found in the cells of acute myeloid leukemia in approximately 2% of cases. Acute myeloid leukemia cells are immature white blood cells (myeloblasts) that remain in the stem-cell stage, dividing continually. Additionally, a 2015 study found that a majority of mice who had one of their HNRNPK genes artificially knocked out developed myeloid cancers, with a third developing lymphoid cancers and 4% developing hepatocellular carcinomas.