Development of 3 autoimmune diseases over a 14-year period in one patient led us to ask whether other BBS patients were at risk of developing chronic inflammatory and autoimmune disorders, especially IBD, and to review the cohort of BBS patients in our hospital.
BBS is estimated to occur in 1/125.000 to 160.000 inhabitants of European countries and in 1/13.500 to 1/17.500 people of Middle East countries and Newfoundland [12
]. The spectrum of the clinical features is large because of the affection's phenotypic variability with intrafamilial as well as interfamilial disparity. This disorder appears, at least by some gene mutations, as being in the frontier between classical monogenic Mendelan heredity and multifactorial heredity [13
]. A new model of triallelic heredity is current since the pioneer work of Katsanis et al. who reported that in some families, heterogeneous mutations can influence the penetrance and the expressivity of the phenotypes [14
]. Hence, the latter can be extremely different when mutations on a second BBS gene exist. For this reason, BBS became the first example of triallelic inheritance described in humans.
The genetic defect found in the reported patient is a frameshift mutation on chromosome 12q21.2, described in almost 50% of patients with BBS 10
]. The BBS 10
gene, incriminated in almost 20% of BBS cases, encodes a vertebrate-specific chaperoninlike protein [15
]. As member of the chaperonines type II, a family of multistructured proteins, BBS10
is implicated in the folding and spatial conformation of target proteins [4
], and in the BBsome assembly [8
], a protein complex responsible for the vesicular trafficking of membrane proteins to the primary cilium. The possible relationship between this genetic defect and chronic inflammatory or autoimmune diseases reported in BBS patients is not established. But, 20% of patients with BBS in our cohort presented with chronic inflammatory or autoimmune disorders. Admittedly, this observation should be first confirmed in larger cohorts of patients with BBS or congenital ciliopathy. However, some observations are relevant. It has been demonstrated that the adipose tissue of some obese individuals produces higher levels of the proinflammatory cytokine TNF and other proinflammatory factors [16
]. Obesity in BBS seems more specific, and pathophysiologicial theories are recent. Studies clearly suggest that ciliary dysfunction is associated with human obesity, despite the fact that adipocytes are not considered as a ciliated cell (http://www.bowserlab.org/primarycilia/cilialist.html
). First, it has been demonstrated that obesity in BBS mice was associated with hyperleptinemia and LepR [9
]. Subsequently, it has been found that BBS proteins were required for LepR signaling in the hypothalamus, by using a BBS knockout mouse model [10
] which reproduce the major features of the human phenotype, including obesity. These data suggest that BBS genes mediate LepR trafficking and that impaired LepR signaling induces energy imbalance in BBS [10
]. A defect in BBS10
gene impairing the ciliogenesis and activating proadipogenic pathways was also evidenced [17
]. Therefore, it seems that the pathogenesis of BBS-associated obesity by a defect of ciliary cells is unique in BBS patients. Are the adipocytes of these patients different, and do they have precise abilities in order to induce specific impairment in specific conditions? Further studies are necessary to assess this hypothesis and to explore accurately the relationship between BBS and autoimmune disorders. In the case of reported patient with CD, PSC, and HT, the morbid obesity without any hyperlipidemia could be due to central leptin resistance. However, this boy also carries a HLA DQ8
antigen, an antigen commonly linked to autoimmune diseases in the human population.
In conclusion, we described a patient with BBS, ileal CD without family history of IBD, PSC, and Hashimoto thyroiditis, and found a 20% prevalence of chronic inflammatory or autoimmune diseases in our cohort of patients with BBS. These observations should encourage physicians to explore carefully and rule out chronic inflammatory or autoimmune disorders, including IBD, in the followup of BBS patients.