Okamoto syndrome

History

Okamoto syndrome was identified in 1997 by Nobuhiko Okamoto and his team at Osaka Women's and Children's Hospital, based on two unrelated Japanese infants who shared the same set of symptoms: congenital hydronephrosis caused by ureteropelvic junction stenosis, low muscle tone, developmental delay, and distinctive facial features like an open mouth and low-set ears. In 2015, Au–Kline syndrome was recognized by Ping-Yee Billie Au, Antonie D. Kline, and colleagues after HNRNPK mutations turned up in two patients with similar presentations, one in Calgary and one in Baltimore; the researchers connected through GeneMatcher. By 2019, Okamoto had proposed that the two syndromes are the same, since a new Okamoto syndrome patient also carried an HNRNPK mutation and the symptoms were nearly identical.

Signs and symptoms

Individuals with Okamoto syndrome are usually born with hydronephrosis due to narrowing of the ureteropelvic junction, leading to urine buildup. Vesicoureteral reflux and frequent urinary tract infections are common. Heart defects present at birth may include aortic valve stenosis, atrial or ventricular septal defect, bicuspid aortic valve, or patent ductus arteriosus. The facial appearance resembles that of Kabuki syndrome, with prominent downward-displaced underdeveloped ears, long eyelids, epicanthic folds, a short broad nose, an open downturned mouth, and a deep groove in the midline of the tongue.

About half of those affected have a cleft palate. Other features can include webbed neck, bulging eyes, excessive hair on the forehead or body, a unibrow, broad first toe, toe crowding, and occasionally postaxial polydactyly. Some individuals have undescended testicles or congenital joint contractures such as club foot.

Severe mental disability and microcephaly are typical, along with language and walking delays, very low muscle tone, and decreased reflexes. Neural tube defects such as lipomyelomeningocele or syringomyelia may occur. Dysautonomia can cause gastrointestinal dysmotility, gastroesophageal reflux disease, neurogenic bladder dysfunction, high pain tolerance, and reduced sweating. An underdeveloped corpus callosum has been found in some patients.

Cause

Okamoto syndrome results from a mutation in the HNRNPK gene located on chromosome 9 at position q21.32. This gene codes for heterogeneous nuclear ribonucleoprotein K, a protein that forms complexes with RNA and is involved in transcribing DNA into RNA within the nucleus. The protein typically binds to precursor messenger RNA before introns are removed during splicing.

A mutation in one copy of HNRNPK disrupts DNA transcription, causing some developmental processes to be impaired or incomplete. Reported mutations include nonsense mutations that truncate the protein, frameshift mutations, splice-site mutations, and microdeletions encompassing the gene. Missense mutations, where one amino acid is replaced by another, have rarely been reported.

Deletions in the region containing HNRNPK have been found in about 2% of acute myeloid leukemia cases. In a 2015 study, most mice with one HNRNPK gene knocked out developed myeloid cancers, and the mice were smaller with less developed organs and higher postnatal mortality. Mutations in both copies of HNRNPK are embryonic lethal in mice, causing death before the 14th day of embryonic development.

Prognosis

Okamoto syndrome's long-term outlook remains uncertain. While most affected children survive into their teens, a small number have died in infancy from urinary tract infections or other kidney-related complications. As children grow, their motor and language abilities tend to improve.

No adults with the condition are known, so the outlook beyond adolescence is unclear. Because the disorder follows an autosomal dominant inheritance pattern, the chance of it recurring in a future child of unaffected parents is very low. However, there is roughly a 1% risk due to germline mosaicism, and genetic counseling may be recommended.

Did You Know?

• Diagnosis is usually based on physical symptoms and confirmed by genetic testing methods such as whole exome sequencing, comparative genomic hybridization, or Sanger sequencing.
• Atrial or ventricular septal defects are usually treated with observation but can be surgically corrected in severe cases.
• Some patients have used sign language or assistive language devices to facilitate communication.