A Rare Case of Singleton-Merten Syndrome Type II

Article: Family Finds Answers to Rare Genetic Glaucoma
Source: University of Michigan Medicine, Kellogg Eye Center
Published: June 4, 2021

The Gibson family, California transplants to Michigan, had for generations lived with an unusual constellation of symptoms for a condition for which they had no name. Those symptoms included childhood glaucoma and psoriasis-looking skin rashes, along with calcium build-up throughout the body, and arthritis or spontaneous tendon rupture. Some members of the family had additional symptoms such as light sensitivity (both ocular and dermatological) and teeth abnormalities (e.g., retained baby teeth). The Gibsons thought only male members of the family were affected. When their then 3-year-old daughter Rachel developed sudden eye pain, however, the family turned to C.S. Mott Children’s Hospital and the Kellogg Eye Center for more answers. Successful surgeries followed for Rachel, and also her father, Stan, for various ocular problems due to their condition. After their then 13-year-old son Adam experienced sudden vision loss from elevated eye pressure (which was mostly recovered thanks to emergency glaucoma surgery), an ophthalmic genetic specialist and a glaucoma geneticist became involved with the family's mysterious condition to dig deeper for an underlying cause. The answer ultimately came from genetic analysis (whole exome sequencing) in collaboration with the NEI/NIH of both immediate and distant family members, which determined that the condition has an autosomal dominant inheritance pattern. In particular, the data revealed a novel mutation in the DDX58 gene that had never been reported; this gene encodes for an RNA binding protein involved in the immune system. Genetic testing, and comparing notes about another family in Brazil with the same peculiar set of clinical findings and the same genetic variant of DDX58, helped the researchers to diagnose the case as Singleton-Merten syndrome type II, a rare autosomal dominant condition with only three families documented in the literature.

The team at Kellogg Eye Center then led an international study to provide the first complete molecular and histological assessment of the eye and skin findings in Singleton-Merten syndrome type II, demonstrating that the mutation in the DDX58 gene sets off an inflammatory cascade in the body in the absence of a definitive RNA trigger. Working with the Brazilian clinicians and researchers, who were studying a family with a more severe presentation of the condition, also improved understanding of how environmental factors could affect the presentation of Singleton-Merten syndrome type II, which could guide preventative measures for children who have the mutation but have yet to develop symptoms. Some individuals only present with common features, such as childhood glaucoma, so awareness of this rare condition's other features would be useful to clinicians, since these pediatric patients can go on to develop other, more severe symptoms later in life. While eventually finding a treatment for the disease would be a "miracle," the Gibsons are happy to simply put a name to their symptoms. Stan's wife, Eryn, applauds the research team, saying, "Their curiosity led to answers, but also helped us feel like we were finally being heard and cared about. Finally, after generations of unanswered questions and enormous health challenges someone took this seriously and had access to the resources to find answers about this condition." The U-M researchers next plan to generate an animal model to study targeted drug therapy, as well as study the connection between the RNA binding protein and glaucoma pathogenesis to hopefully find a way to block the receptor or the downstream signaling to prevent glaucoma from developing.

Personal commentary:  Shout out to the doctors at my brother's medical school, which he attends on a full scholarship, for the diagnosis of and novel insights about this exceptionally rare condition!

My rating of this study: ⭐⭐⭐🌸

Prasov L, Bohnsack BL, El Husny AS, et al. "DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation." Journal of Medical Genetics.  25 January 2021. https://doi.org/10.1136/jmedgenet-2020-107447