Researchers describe long-term manifestations of CARMIL2 deficiency

Deficiencies in the CARMIL2 gene can lead to a variety of immunodeficiency complications, including cutaneous and respiratory allergies, necessitating clinician attention and further research, according to a study published in Allergy.

Patients with deficiencies in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene can present with eczematous lesions; early-onset inflammatory bowel disease (IBD); mucocutaneous candidiasis; skin abscesses; mycobacterial infections; smooth muscle tumors related to Epstein Barr virus (EBV); growth retardation; and recurrent bacterial, fungal and viral infections.

There have been fewer than 40 cases of CARMIL2 deficiencies reported around the world, according to Burcu Kolukisa, MD, of Marmara University in Istanbul, and colleagues. Because long-term follow-up and treatment options have not previously been described, the researcher sought to determine clinical and immunological manifestations of CARMIL2 deficiency, along with long-term efficacy of treatments.

The analysis included data of 15 patients (mean age, 14 years ± 3.3 years; female, n = 9), including 13 new and two previously reported patients, diagnosed by next-generation sequencing and confirmed by Sanger sequencing. Eight of the nine families involved had parental consanguinity.

At disease onset — which occurred at a mean age of 38 months (± 23 months) — cardinal symptoms included skin manifestation (n = 14; 93%), failure to thrive (n = 10; 67%), recurrent infections (n = 10; 67%), allergic symptoms (n = 8; 53%), chronic diarrhea (n = 4; 27%) and malignancy (n = 3; 20%).

All patients survived through the end of the study; median follow-up was 10.8 years (range, 3-17).

Sinopulmonary infections were the most common infections. With a mean age of onset of 3.5 years (± 1.9 years) for respiratory tract infections, 10 patients (67%) had recurrent upper respiratory tract infections, including otitis media and sinusitis.

Also, 12 of the patients (80%) had an active or previous history of eczema, with a mean age of onset of 2.7 years (± 2.1 years). Seven patients (47%) had HPV, making it the most common cutaneous infection.

Researchers also described skin manifestations including warts, molluscum contagiosum, recurrent herpes infections, cutaneous candidiasis, onychomycosis, persistent lingual and genital Candida rash, psoriasis vulgaris, early-onset psoriasis, psoriatic arthritis, skin abscesses and leukocytoclastic vasculitis.

Regarding systemic viral infections, three patients (20%) had low-level EBV viremia, and two patients (13%) had cytomegalovirus viremia.

Allergic manifestations included asthma in eight patients (53%), rhinitis with chronic nasal congestion and rhinorrhea in three patients (20%) and food allergies in two patients (13%).

Four patients (27%) diagnosed with IBD had chronic diarrhea with or without blood — two of whom were diagnosed with atypical Crohn’s disease — with a mean age of symptom onset of 4.6 years (± 3 years). Researchers described IBD as “the most severe clinical manifestation” they observed.

The researchers found seven distinct biallelic variants in the CARMIL2 gene among the nine families, including four missense mutations, one splice site mutation and three frameshift mutations. The mutations all were deleterious, leading to undetectable or reduced protein expression.

The patients generally experienced recurrent infections and dysgammaglobulinemia with poor antibody responses, prompting treatment with prophylactic antibiotics in five patients (33%) and immunoglobulin replacement therapy (IgRT) in seven (47%). The combined therapies, including IgRT and prophylaxis, effectively reduced infection frequency, according to the researchers.

Four patients received various systemic immunosuppressive therapies for IBD. Also, most patients received topical therapies to alleviate their skin manifestations.

The long-term evaluation showed most patients benefitted from drug therapies, although multistep therapy, including surgery, typically was necessary for refractory colitis, the researchers wrote.

“Overall, patients have low mortality compared to other combined immunodeficiencies,” the researchers wrote. “Infections and allergic manifestations like eczema, asthma and rhinitis are manageable and stable over the years, whereas gastrointestinal

manifestations are more severe, leading to severe growth failure, anemia and overall low quality of life, and requiring interventional treatments (corticosteroids, biologic agents, colectomy).

“Monitoring patients for smooth muscle tumors and providing earlier therapies might be life-saving,” the researchers added, noting that studies of hematopoietic stem cell transplantation for these patients are needed.