ROSAH syndrome
Genetic disease of innate immune activation with ocular and systemic features.
ROSAH syndrome is a genetic condition that causes the innate immune system to be overactive. Its name is an acronym for retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache, though these are not the only features of the disorder. The condition follows an autosomal dominant inheritance pattern and is triggered by heterozygous missense mutations in the ALPK1 gene, which normally acts as an innate immune sensor for bacterial sugars.
Signs and symptoms originally focused on eye problems, but it is now recognized that the syndrome can also involve recurrent fever, uveitis, deforming arthritis, AA amyloidosis, meningeal enhancement, and premature mineralization of the basal ganglia, substantia nigra, and red nuclei visible on MRI. Other reported features not typically linked to inflammation include short dental roots, enamel defects, and reduced saliva flow.
The underlying mechanism involves ALPK1, a pattern recognition receptor that detects the bacterial metabolite ADP-heptose. Samples from patients and lab experiments using mutated ALPK1 show immune activation, with increased NF-κB signaling, STAT1 phosphorylation, and an interferon gene expression signature.
Genetically, the condition is caused by mutations in the ALPK1 gene on the long arm of chromosome 4 (4q25). The most common change replaces the amino acid threonine with methionine at position 237 in the protein. Inheritance is autosomal dominant.
Diagnosis currently depends on a physician’s suspicion. Genetic testing can be done through targeted single-gene Sanger sequencing or broader methods like whole exome or whole genome sequencing.
Management includes immunomodulatory therapy for some features, though more research is needed to see if this approach can reduce the risk of progressive vision loss.
The prevalence is unknown. Fewer than 70 individuals have been described in medical literature. The term ROSAH syndrome was first used in 2019, and since then nearly 70 patients from 29 unrelated families have been identified.
The condition was first described in 2012, before its genetic cause and name were established. The genetic basis appeared in an ARVO abstract in 2013 and a full article in 2019. In 2022, the ROSAH Syndrome Foundation was created to support patients by sharing information and connecting them with others living with the syndrome.
Quick Facts
- Causes
- Mutation in ALPK1 gene
Facts from the source article.
Lore & Background
ROSAH syndrome was first described in 2012 prior to the discovery of its genetics and naming. The genetic basis was first published in an ARVO abstract in 2013 and in a complete article in 2019. The name ROSAH was coined in 2019. Since then, almost 70 patients have been identified from 29 unrelated families. In 2022, the ROSAH Syndrome Foundation was established to serve patients by providing information and connecting them to others living with the syndrome.
Reader's Guide
ROSAH syndrome represents a recently characterized disorder of innate immune dysregulation. Its significance lies in linking a specific mutation in the ALPK1 gene—an innate immune sensor for bacterial sugars—to a broad spectrum of inflammatory and non-inflammatory features. While initial descriptions emphasized ocular manifestations, subsequent reports have revealed systemic involvement including recurrent fever, uveitis, deforming arthritis, AA amyloidosis, meningeal enhancement, and premature mineralization of basal ganglia, substantia nigra, and red nuclei. Non-inflammatory features such as short dental roots, enamel defects, and decreased salivary flow have also been noted. The pathophysiology involves increased NF-κB signaling, STAT1 phosphorylation, and an interferon gene expression signature. Diagnosis relies on physician judgment and genetic testing via Sanger sequencing, whole exome, or whole genome sequencing. Some features are amenable to immunomodulatory therapy, though whether this can mitigate progressive vision loss remains uncertain. With fewer than 70 reported individuals, the prevalence is unknown, highlighting the need for further research and clinical awareness.
Did You Know?
- ROSAH stands for retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and headache, but the name emphasizes some, not all, features.
- The condition is caused by heterozygous missense mutations in the ALPK1 gene, most commonly changing threonine to methionine at position 237.
- Less than 70 individuals with ROSAH syndrome have been described in the medical literature.
- The ROSAH Syndrome Foundation was established in 2022 to serve patients and connect them to others living with the syndrome.
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