NBS is a rare chromosomal breakage syndrome which displays many overlapping features with other clinical entities such as: ataxia-telangiectasia, Bloom syndrome and Fanconi anemia[4
]. Generally, karyotypes of the patients with NBS are normal (46,XX or 46,XY). However, in a high proportion of them, spontaneous structural chromosomal rearrangements are observed, as well as other aberrations such as chromatid and/or chromosome breaks and acentric fragments. Most of these rearrangements specifically involve chromosomes 7 and 14, with breakpoints at bands 7p13, 7q35, 14q11, and 14q32, which are identical to those found in persons with ataxia-telangiectasia.
The product of NBS-1 gene is a protein, the nibrin that forms a complex with two cytoplasmic proteins. This complex needs phosphorylation by a protein kinase to be activated. This protein kinase is mutated in ataxia-telangiectasia[5
]. This is the molecular proof of the interrelation between NBS and ataxia-telangiectasia, and likely accounts for the relative homogeneity of clinical manifestations. Therefore, NBS is also known as an ataxia-telangiectasia variant 1[6
The granulomatous reaction pattern, described as an inflammatory reaction, may appear in persons with genetic or acquired immunodeficiency disorders (). Cutaneous granulomas have occasionally been reported to be a presenting sign of an immunodeficiency disorder[7
]. Clinically cutaneous granulomas manifest as erythematous plaques, nodules or papules. The lesions are often scaly, atrophic and ulcerated. The distribution of the lesions is most likely on the face and extremities as in our case. Spontaneous regression has been described[8
]. However, they can also be progressive as we have illustrated.
Immunodeficiency disorders associated cutaneous granulomas
Variable histological patterns may be described in cutaneous granulomas: non-necrotizing epitheloid granulomas (sarcoid-like), caseating (tuberculoid) granulomas and necrobiotic granulomas. Granuloma formation in patients with primary immunodeficiency is not yet elucidated.
The possibilities may include: functional imbalance of cellular immunity, diminution of humoral immunity and/or interleukin-2 deficiency.
Clinical manifestations such as cutaneous squamous lesions, and as histopathological being sarcoid-like granulomas have been well described in ataxia-telangiectasia and other primary immunodeficiency disorders[9
The main difference between sarcoidal granulomas and those from primary immunodefiency is that the last ones have a much lower CD4+ CD8+ T-cell ratio. Patients with primary immunodeficiency usually have hypogammaglobulinemia, meanwhile sarcoidosis is associated with hypergammaglobulinemia. Granuloma formation in primary immunodeficiency disorders may involve the lungs, spleen, liver, joints and skin. The isolated cutaneous involvement is very rare[10
Cutaneous sarcoid-like granulomas have been recently reported in patients with NBS[11
]. Based on the normal control breakage data in granulomatous inflammatory disease in patients without Nijmegen, in NBS granulomas may occur due to the chromosomal repair dysfunctions. Granulomas from primary immunodeficiencies may resemble those from sarcoidosis, because of the clinical and histological similarity[12
]. Sarcoidal granulomas are discrete, round to oval, are composed of epitheloid histiocytes and multinucleate giant Langhans cells. Although the granulomas may be in close proximity to one another, their confluence is not commonly found[14
]. Because of the aspects described above, many early reports of granuloma formation in patients with primary immunodeficiency were classified as sarcoidosis.
The treatment for cutaneous granulomas may not be necessary in very limited disease, but an important issue is to establish the medication responsible for the improvement of the skin manifestations. Methotrexate and dexamethasone are known to suppress granuloma formation[15
]. The cyclophosphamide has been used in the treatment of refractory noninfectious granulomas[16
Close follow-up is strongly suggested as cutaneous granulomas may be the first manifestation of systemic granulomas.