Kellogg Leads International Team Linking Family’s Symptoms to Rare, Inherited Syndrome

Stan Gibson has struggled his whole life with an unusual collection of symptoms—symptoms that plagued his father and grandfather before him.

All developed glaucoma as young children, and all battled similar rheumatologic, dermatologic and musculoskeletal problems.

The condition seemed to be passed down only to males, and symptoms seemed to present in early childhood. Based on that pattern, Stan Gibson and his wife Eryn initially thought their daughter was not at risk, and that the disorder had bypassed their sons, who reached adolescence without developing symptoms.

The first indication that that was “not the case came when, at age three, their daughter Rachel was diagnosed with glaucoma. At the time, the family lived in California, where Rachel underwent multiple corrective procedures.

Rachel’s eye problems persisted after the family relocated to Michigan. When the iris of one eye slipped into the sclera, she was referred to Kellogg, where pediatric glaucoma surgeon Brenda Bohnsack, M.D., Ph.D., performed a complex reconstructive procedure that saved her vision. Dr. Bohnsack is now head of ophthalmology at the Lurie Children’s Hospital of Chicago.

Impressed by the level of care his daughter received, Stan Gibson soon began seeing Kellogg glaucoma surgeon Sayoko Moroi, M.D., Ph.D., and cornea and refractive surgeon Shahzad Mian, M.D., to manage his ongoing eye problems. After elevated eye pressure caused an initial cornea transplant to fail, Gibson underwent a second transplant procedure at Kellogg.

The mysterious condition struck the family again when, at age 13, their son Adam experienced sudden and dramatic vision loss. Dr. Bohnsack performed an emergency procedure to normalize his eye pressure, restoring most of Adam’s vision, save a small peripheral loss.

At that point, ophthalmic geneticist Lev Prasov, M.D., Ph.D., along with Dr. Bohnsack and glaucoma geneticist Julia Richards, Ph.D., began looking for the genetic origins of the seemingly random symptoms shared by Stan, Rachel and Adam.

In collaboration with colleagues at the National Eye Institute of the National Institutes of Health (NIH), where Dr. Prasov completed a clinical fellowship, all of the protein-coding of the fellowship, all of the protein-coding DNA from affected and unaffected members of the extended Gibson family was sequenced.

This whole exome sequencing revealed a never-before observed misspelling in the gene DDX58. Stan, Rachel and Adam all share this mutation.

A search of a public database of reported patient information linked to genetic variants led to the identification of another family in Belém, Brazil, with a similar set of clinical findings and the same DDX58 variant. “

We concluded that the disease is Singleton-Merten syndrome type II,” says Dr. Prasov, “an extremely rare, autosomaldominant condition with only three previously documented families.”

Further genetic, clinical and epidemiological research followed to better understand the syndrome. An international team led by Dr. Prasov included specialists from Kellogg and six other departments at U-M, academic medical centers in Boston, Chicago and Columbus in the U.S., Belém and Sao Paulo in Brazil, and seven different units of the NIH.

In addition to the most prominent symptoms — pediatriconset glaucoma and a psoriasis-like skin rash, other symptoms include arthritis, spontaneous tendon ruptures, and aortic, skeletal and dental calcifications. The team described how the DDX58 variant triggers an inflammatory cascade in the body responsible for many of the symptoms.

The tendency to develop calcifications explained some of the puzzling symptoms experienced by Stan, Rachel and Adam Gibson. All three endured dental problems caused by retaining baby teeth long after they are normally lost. Also likely due to a calcium buildup, Adam suffered a carotid artery rupture at age 21.

“This work highlights how a genetic diagnosis can have a big impact on clinical practice and patient outcomes,” says Dr. Prasov, who now leads a multidisciplinary clinic to care for families with inherited ophthalmic conditions. “Understanding all the factors that drive this syndrome may help us prevent some of its more severe consequences, and eventually develop effective treatments.”

The Gibsons came to Kellogg for sight-saving care. In the process, a family mystery was finally solved.

“If it wasn’t for the Kellogg Eye Center, two of our kids would be blind,” says Eryn Gibson. “Because of the communication between these doctors, this condition is now better understood. Their curiosity led to answers, and helped us feel like we were finally being heard and cared about. After generations of unanswered questions and enormous health challenges, someone took this seriously and had access to the resources to find answers. We are grateful beyond words.”

Left to right—Samuel, Stan, Rachel, Rulon, Eryn, Ammon, Adam, Lauren, Spencer. Photo courtesy of the Gibson family.