Name: Otofaciocervical syndrome 2 | Acronym: OTFCS2
Alt. names: Fara-Chlupackova syndrome | OFC syndrome | PAX1 deficiency | Otofaciocervical syndrome

Gene: PAX1 | MOI: Autosomal recessive | Mechanism of action: Loss of Function

No. of cases in DB: 14 | First reported in: 2013

Last updated on: 2023-03-31 by Xiao P. Peng

OMIM: 615560

Orphanet: 2792

MONDO: 0014254

DOID: -

ClinGen: Definitive (2023-11-16)

Description

At least fourteen individuals from five unrelated families have now been described with this syndromic immunodeficiency resulting from biallelic PAX1 loss-of-function (LOF) mutations (PMID: 23851939, 28657137, 29681087, 32111619). Patients present with craniofacial dysmorphisms including microcephaly, a prominent forehead with frontal and parietal bossing, hypertelorism, nasolacrimal duct abnormalities, down-slanting palpebral fissures, epicanthal folds, long eyelashes, blue sclerae, small nose with depressed nasal bridge and hypoplastic nasal root, facial asymmetry due to facial nerve palsies, and retromicrognathia. Ears are particularly affected – patients show small, low-set malformed ears, with preauricular tags or pits, branchial fistulas and/or cysts, hypoplastic middle ear and internal auditory canals, and stenotic/atretic external auditory canals, often combining to result in mixed hearing loss. Additional musculoskeletal findings include low-set or malformed clavicles, protruding or sloping shoulders, winged scapulae, progressive weakness and hypotrophy of the scapular girdle, vertebral defects and kyphoscoliosis, as well as tapered fingers, bilateral clinodactyly and cutaneous syndactyly of the toes. Male patients may show bilateral cryptorchidism, while all patients may have short stature, developmental delays, and intellectual disability. From an immune perspective, thymic aplasia leads to a combined immunodeficiency picture, characterized by severe T cell lymphopenia (i.e. T− B+ NK+ SCID) and often resemblant of Omenn syndrome. Patients are affected by a broad spectrum of recurrent, early-onset infections of the bloodstream, skin, GI tract and sinorespiratory system including disseminated BCG infection after vaccination. In addition, they may show severe exfoliative dermatitis, chronic diarrhea, and lymphadenopathy. Labs are notable for markedly reduced proliferative responses to mitogens and antigens, variable hypogammaglobulinemia with often elevated serum IgE, and eosinophilia. Lymph node biopsy pathology may show severe lymphoid depletion with primary follicles without germinal centers.

Management

Antimicrobial prophylaxis is likely warranted for maximizing protection against infection. In the four patients for whom HSCT was tried, the profound T cell immunodeficiency of thymic origin failed to be corrected (PMID: 32111619). Only two patients were able to engraft with full donor chimerism but one failed to reconstitute T cells and developed severe autoimmune hemolytic anemia, requiring multiple courses of rituximab and immunosuppressive therapy. All T cells in the other patient showed a CD45R0+ phenotype, likely representing donor-derived T cells that had undergone peripheral expansion – this patient was awaiting thymic transplant at the time of report. Two others passed away from disease and/or transplant-related complications.