A novel NEMO/IKBKG mutation identified in a primary immunode
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A 38-year-old Caucasian male reported a history of recurrent sinus and otitis media infections, multiple staphylococcal skin infections, and pneumonia since childhood. He never had problems with hair development, perspiration, or problems with his skin. This patient first noted a rash that appeared as papules and plaques on his trunk, limbs, and face.

Physical exam demonstrated absence of thickened skin, abnormal nails, or sparse hair. He was treated empirically for psoriasis, atopic dermatitis, and tinea infection without complete resolution of the rash. Biopsies of the arm and back revealed a sarcoidal granulomatous dermatitis, which were negative for infectious organisms by PAS and Fite stains. The patient was tentatively diagnosed with cutaneous sarcoidosis and treated with topical steroids and a prednisone taper and was lost to followup.

After two years the patient presented with widespread red brown papules and plaques involving most of his body and worsening numbness of his hands and feet. Biopsies of lesions on the thigh and forearms revealed granulomas and lymphohistiocytic infiltrates with prominent perineural involvement.

Fite stain revealed numerous acid fast bacilli consistent with the clinical diagnosis of lepromatous leprosy. Mycobacterium leprae was confirmed in the biopsy by molecular testing. Treatment with dapsone, rifampin, clofazimine, and prednisone improved most lesions, but a distinctive 8x5cm, red-brown plaque with regions of hypopigmentation, hyperpigmentation, and scale on his posterior left calf persisted.

A biopsy and Fite stain of this lesion revealed abundant acid fast bacilli with a culture showing Mycobacterium haemophilum. Azithromycin was added to his existing lepromatous leprosy regimen which was continued for 24 months. After completing therapy, the rash on his posterior left calf began to recur and the patient developed many new skin lesions, including a red-brown papule with keratotic plug on his left forearm. Biopsy with Fite stain of the lesion on the left calf revealed yet another mycobacterial infection, with cultures now revealing Mycobacterium fortuitum on both upper and lower extremities.

After reporting respiratory symptoms in 2016, CT chest revealed granulomatous changes in the lungs concerning for an infectious etiology. Sputum studies revealed both Mycobacterium avium complex (MAC) and Mycobacterium fortuitum.

Whole-exome sequencing did not identify any mutations. However, RNA sequencing (RNA-Seq) identified a hemizygous missense change in NEMO/IKBKG exon 8, c.923A more than G causing p.Y308C. While mutations at this site have not previously been reported in patients, the tyrosine residue at this site is evolutionarily conserved and the presence of a hydrophobic residue at tyrosine 308 has been demonstrated to be essential to polyubiquitin binding and NF-B activation in independent studies.

Source: https://www.jaadcasereports.org/article/S2352-5126(20)30754-2/fulltext?rss=yes
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