A number sign (#) is used with this entry because of evidence that retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH) is caused by heterozygous mutation in the ALPK1 gene (607347) on chromosome 4q25.

Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH) is an autosomal dominant disorder in which affected individuals present in childhood with reduced vision associated with papilledema and low-grade ocular inflammation. Progressive deterioration of visual acuity results in counting fingers to no light perception by the third decade of life. Patients also show anhidrosis, as well as splenomegaly and mild pancytopenia, and most experience headaches that may be migraine-like in nature (Williams et al., 2019).

Tantravahi et al. (2012) studied a mother and 2 daughters, who were half-sisters, who had massive splenomegaly, cytopenia, anhidrosis, chronic optic nerve edema, and vision loss. The patients presented in the first decade of life with chronic optic nerve edema followed by slowly progressive vision loss, particularly central, and loss of color vision. In all cases, despite continued optic nerve head edema, lumbar puncture did not show elevated pressure. Although uveitis was seen in 2 patients, it was not present at all exams and testing for common causes of uveitis was negative. Disease progression was similar to a cone or cone-rod dystrophy, with electroretinography (ERG) showing loss of photopic (cone) responses with maintenance of scotopic (rod) responses into the teenage years in 2 patients; however, by ages 15 years to early twenties, all 3 patients had completely extinguished full-field ERGs. In addition, splenomegaly and mild pancytopenia developed in all 3 patients, at ages 9, 12, and 15 years; bone marrow evaluations were normal and splenectomy normalized their complete blood count values, indicating that the cytopenias were due to splenic sequestration. Splenic pathology showed congestion without infiltration or extramedullary hematopoiesis. Both daughters also reported migraine headaches and anhidrosis, and 1 also had episodic urticaria. Immunologic and autoimmune evaluations were negative.

Williams et al. (2019) restudied the family from Utah (family 1) with splenomegaly, cytopenia, and vision loss that was originally reported by Tantravahi et al. (2012), and ascertained 5 more similarly affected families, including 1 family from Australia (family 2), 1 from the Netherlands (family 3), 1 from Virginia (family 4), and 1 from Delaware (family 5). In the 16 affected individuals, the most frequent earliest feature was decreased vision associated with optic nerve edema, evident as early as 4 years of age and present by age 12 years in all cases. Low-grade ocular inflammation, unresponsive to steroids or other forms of immunosuppression, was common in affected individuals. In later childhood or in the second decade of life, patients had increasing visual impairment, with abnormal cone function and later loss of rod function in most. By the third decade of life, visual dysfunction was severe with visual acuity ranging from counting fingers to no light perception. In addition to the ocular findings, patients generally had splenomegaly, beginning in the first or second decade of life; 1 patient underwent splenectomy. Hematologic assessment showed chronic mild pancytopenia, which was sometimes exacerbated during periods of viral or other infection. Peripheral smears frequently showed leukopenia with reactive lymphocytosis; bone marrow was normocellular with trilineage hematopoiesis and relative erythroid hyperplasia. Affected individuals also experienced anhidrosis, and migrainous headache was a frequent feature, often associated with episodic fever and back pain. Mild renal impairment was present in some members of family 2, but was not a consistent feature in all patients. Williams et al. (2019) designated the disorder 'ROSAH syndrome' based on the retinopathy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache observed in these patients.

Zhong et al. (2020) described 2 unrelated Chinese girls with ROSAH syndrome. In addition to retinal dystrophy, papilledema, splenomegaly, and pancytopenia, both experienced intermittent febrile episodes and were anhidrotic. One patient had undergone elective splenectomy due to concerns about spontaneous rupture, and splenectomy was planned in the other patient.

Kozycki et al. (2022) reported clinical features in 27 patients with ROSAH syndrome. Almost all patients had inflammatory features, including fever, malaise, episodic abdominal pain, headache, cytopenia, and/or retinal vasculitis. Ophthalmologic findings in the cohort included optic nerve elevation, uveitis, retinal vasculitis, and retinal degeneration. Twenty patients had arthralgias, which started in childhood in some patients. Fourteen patients had gastrointestinal symptoms, including pain, gastroesophageal reflux, dysphagia, and/or reflux. Thirteen patients had recurrent headaches, and 7 patients had brain abnormalities seen on brain MRI, including calcification of the globi pallidi, red nucleus, and substantia nigra. Dental abnormalities included multiple caries in 23 patients and enamel defects in 7 patients; 5 patients were edentulous. Almost all patients had hyperhidrosis or anhidrosis, and 4 parous women had dysfunctional breast milk production. Laboratory findings included variably elevated C-reactive protein (CRP; 123260), transient neutropenia, and cytopenias.

Kozycki et al. (2022) reported that 7 of 10 patients with ROSAH syndrome treated with anticytokine therapy had subjective improvement in 1 or more clinical symptoms.

The transmission pattern of ROSAH in the family reported by Tantravahi et al. (2012) was consistent with autosomal dominant inheritance. Genetic analysis by Williams et al. (2019) confirmed autosomal dominant inheritance in this family; Williams et al. (2019) also showed that the mutation occurred de novo in the mother. The heterozygous mutations in other patients reported by Williams et al. (2019) and Zhong et al. (2020) occurred de novo.

In all 16 patients from 5 unrelated families with ROSAH syndrome, Williams et al. (2019) identified heterozygosity for the same missense mutation in the ALPK1 gene (T237M; 607347.0001). The mutation segregated with disease in all families and was not found in the gnomAD database.

In 2 unrelated Chinese girls with ROSAH syndrome, Zhong et al. (2020) identified heterozygosity for the previously reported recurrent T237M mutation in the ALPK1 gene. The mutation arose de novo in both probands.

Kozycki et al. (2022) reported molecular findings in 21 patients from 13 unrelated families with ROSAH. Twenty of the patients were heterozygous for the recurrent T237M mutation in the ALPK1 gene, and 1 patient (patient 13.1) was heterozygous for a Y254C mutation (607347.0002). In in vitro studies, Kozycki et al. (2022) found that both mutations resulted in increased NF-kappa-B (see 164011) signaling and STAT1 (600555) phosphorylation.