Immunodeficiency 58 due to Carmil2 deficiency D82.3

Immunodeficiency 58 is a very rare, autosomal recessive primary immune disorder characterized by early-onset skin manifestations (eczematous dermatitis, infectious abscesses, and viral warts), recurrent respiratory infections or allergies, and chronic persistent infections with Candida, Molluscum contagiosum, mycobacteria, and also other bacteria, as well as persistent EBV infections. Gastrointestinal involvement has been demonstrated in some patients (inflammatory bowel disease, EBV+ smooth muscle tumors, esophagitis). Immunologically, impaired T-cell function can be demonstrated with decreased Treg cells and deficient CD3/CD28 costimulation responses in both CD4+ and CD8+ T cells. B-cell function may also be impaired (see below Wang et al. 2016 ).

Worldwide, the incidence is estimated to be <1/1000,000.

Wang et al (2016) reported 6 patients from three unrelated families. Two families were consanguineous with Moroccan (family A) and Tunisian (family B) ancestry, while the third was an unrelated Turkish family (family C). Patients presented with chronic mucocutaneous candidiasis, including onychia and perionychia of the nails and thrush, and severe eczematous dermatitis during the first years of life. Furthermore, variable skin involvement with scaling of the scalp with limited cicatricial alopecia, hyperlinearity of the palms, inflammatory plaques on the soles with pustular lesions, ichthyosis, psoriasis-like plaques, seborrheic dermatitis, diffuse hyperpigmented lesions with atrophic and ulcerated scars, and red inflammatory plaques on the face, trunk, back, elbows, and legs. Histologically: psoriasiform hyperplastic epidermis. Two siblings suffered from severe recurrent subcutaneous staphylococcal abscesses, 1 patient from molluscum contagiosum and 2 from mycobacterial infections. Most patients had recurrent bacterial lung infections and chronic bronchitis, and some had asthma and bronchiectasis. Furthermore, allergic symptoms (food allergies, allergic bronchial asthma) were found. The most severely affected patient had multifocal tuberculosis of the lungs, lymph nodes, and intestines, viral meningoencephalitis, and overall poor growth. He died at the age of 17 years. All patients had normal circulating B-cell, neutrophil, monocyte, and NK-cell counts. All patients except one had increased levels of CD8+ T cells, and two unrelated patients had increased levels of CD4+ T cells. However, patients had decreased levels of certain T-cell subtypes, including regulatory T cells, follicular T helper cells, and certain subsets of memory T cells, including Th1 and Th17. All patients responded poorly to vaccination with antibodies and had fewer memory B cells.

Sorte et al (2016) reported four patients aged 18 to 52 years from three unrelated Norwegian families with IMD58. All had onset of symptoms in early childhood, including widespread viral warts on the hands and feet. Furthermore, hyperkeratosis of the palms and soles, psoriatic lesions, seborrheic dermatitis, atopic eczema, photodermatitis, dermatophytic lesions, fungal skin infections, and viral skin infections (HSV and VZV) were found. All patients had asthma, 3 had recurrent respiratory infections, and 2 developed chronic obstructive pulmonary disease (COPD. Three patients suffered from gastrointestinal compromise: neonatal necrotizing enterocolitis, gastroesophageal ulcers, chronic diarrhea, colitis, and Crohn's disease. Other features included aphthous stomatitis, BK viral cystitis (2 patients), and molluscum contagiosum. One patient developed malignant leiomyosarcoma without signs or symptoms of EBV infection, although she had recurrent HSV and VZV infections. Three patients had low levels of Th17 cells. CD4+ and NK cells showed low expression of gamma interferon. Treg cell numbers were decreased in all patients.

Shayegan LH et al described a child with skin lesions they termed "actinic prurigo-like photodermatitis." Furthermore, an allergic diathesis as well as recurrent infections were detectable.

1. Schober T et al. (2017) A human immunodeficiency syndrome caused by mutations in CARMIL2. Nature Commun. 8: 14209.
2. Shayegan LH et al (2020) CARMIL2-related immunodeficiency manifesting with photosensitivity. Pediatr Dermatol 37:695-697.
3. Sorte HS et al. (2016) A potential founder variant in CARMIL2/RLTRR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. Molec Genet Genomic Med. 4: 604-616.
4. Wang Y et al (2016) Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations. J Exp Med 213: 2413-2435.