Not yet certain. Most patients have at least lived through childhood; mortality in infancy in a minority.[5]
Frequency
Not yet known. 26 individuals known to be affected as of May 2019[update].[1][4]
Okamoto syndrome (OS), also known as Au–Kline syndrome (AKS), is a very rare autosomal dominant genetic condition characterised by congenital hydronephrosis, low muscle tone, heart defects, intellectual disability and characteristic facial features.[4][6] Those affected often have neurological and skeletal abnormalities, as well as frequent urinary tract infections. Language and walking are usually delayed. Facial features include prominent, downturned ears, an open, downturned mouth and drooping eyelids (ptosis).[4][5]
The syndrome is caused by mutations in the HNRNPK gene, which codes for heterogeneous nuclear ribonucleoprotein K. This protein is involved in the process of DNA transcription and translation into proteins. A mutation in this gene impairs DNA transcription, disrupting some developmental processes.[4][7] As an autosomal dominant disorder, only one faulty copy of the gene is required for the condition to occur. The syndrome is typically diagnosed based on the physical symptoms and then confirmed by genetic testing.[4][5]
Treatment has centred around the symptoms. Sign language and assistive language technology can aid communication.[4][7] The prognosis is not yet fully known, due to the lack of patients in literature, however most of the patients have at least lived through childhood. The urinary system defects have been the most significant contributors to mortality.[5] As of May 2019[update], 26 individuals worldwide were known to be affected.[1][4] The syndrome was first described in 1997 by Nobuhiko Okamoto et al.,[8] and the gene responsible was first identified in 2015 by Ping-Yee Billie Au, Antonie D. Kline et al.[7] In 2019, Okamoto proposed that Au–Kline syndrome and Okamoto syndrome were synonymous.[1]
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.[3][4][5]
Those affected may be born with low weight and size[7][8] and may display stunted growth in childhood,[3] although this symptom has been variable and not in every individual with Okamoto syndrome.[4][5]
Deletions in the region encompassing HNRNPK have been found in the cells of acute myeloid leukemia in approximately 2% of cases.[9] 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. The mice were also smaller, had less developed organs and had higher postnatal mortality (30%). The median lifespan of the mice that survived was less than 50% that of wild-type mice.[9] However, blood cancers had not yet been detected in any of the Okamoto syndrome patients as of 2018[update].[4][5]
Mutations in both copies of HNRNPK are embryonic lethal in mice. Mice with both copies of the gene knocked out die before the 14th day of embryonic development.[9]
The prognosis of the disorder is not yet fully known. A minority of patients have died in infancy due to complications from their urinary system defects, including infections in Okamoto's first two patients,[1] however most have lived through childhood and into adolescence.[5] Motor and language skills typically improve as the patient ages. The prognosis in adulthood is not yet known, due to the lack of known patients in this age group.[5]
As an autosomal dominant condition, there is little risk of recurrence in future conceptions from unaffected parents. However, there is a slight possibility (around 1%) due to germline mosaicism, a phenomenon in which some sperm cell precursors have the mutation and others don't. Genetic counselling may be offered for this.[4]
Epidemiology
The prevalence of the disorder is as yet unknown. As of May 2019[update], 26 individuals worldwide were known to be affected, with 13 of these reported in literature, mostly from 2010 to 2019.[1][4]
History
Okamoto syndrome was first described in 1997 by Nobuhiko Okamoto et al. from the Department of Medical Genetics at Osaka Women's and Children's Hospital after observing very similar symptoms and physical features in two unrelated Japanese infants. Both infants had congenital hydronephrosis due to ureteropelvic junction stenosis, low muscle tone, developmental delay and characteristic facial features including an open mouth and low-set ears.[8]
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. The practices were united with each other after both submitted the gene as a candidate to the online service GeneMatcher, which matched them together and allowed them to confirm the syndrome.[7]
In 2019, Okamoto proposed that Au–Kline syndrome and Okamoto syndrome were synonymous, because a mutation in the HNRNPK gene had been found in a new Okamoto syndrome patient, and the symptoms were virtually identical.[1]