Debilitating hip degeneration in trichothiodystrophy: Association with ERCC2/XPD mutations, osteosclerosis, osteopenia, coxa valga, contractures, and osteonecrosis.

Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder of DNA repair and transcription with developmental delay and abnormalities in brain, eye, skin, nervous, and musculoskeletal systems. We followed a cohort of 37 patients with TTD at the National Institutes of Health (NIH) from 2001 to 2019 with a median age at last observation of 12 years (range 2-36). Some children with TTD developed rapidly debilitating hip degeneration (DHD): a distinctive pattern of hip pain, inability to walk, and avascular necrosis on imaging. Ten (27%) of the 37 patients had DHD at median age 8 years (range 5-12), followed by onset of imaging findings at median age 9 years (range 5-13). All 10 had mutations in the ERCC2/XPD gene. In 7 of the 10 affected patients, DHD rapidly became bilateral. DHD was associated with coxa valga, central osteosclerosis with peripheral osteopenia of the skeleton, and contractures/tightness of the lower limbs. Except for one patient, surgical interventions were generally not effective at preventing DHD. Four patients with DHD died at a median age of 11 years (range 9-15). TTD patients with ERCC2/XPD gene mutations have a high risk of musculoskeletal abnormalities and DHD leading to poor outcomes. Monitoring by history, physical examination, imaging, and by physical medicine and rehabilitation specialists may be warranted.

Misclassification of Aggressive Basal Cell Carcinoma Subtypes and Implications for Management.

BACKGROUND: Management of basal cell carcinoma (BCC) varies by histopathologic subtype; however, biopsies may inadequately characterize them as nonaggressive, risking potential suboptimal treatment. OBJECTIVE: To characterize the rate of undetected aggressive BCC subtypes by size, location, and histopathology type. MATERIALS AND METHODS: Retrospective cohort study of 928 BCCs treated with Mohs Micrographic Surgery (MMS) at a tertiary academic institution from 2015 to 2017, comparing patient and tumor characteristics and histopathologic subtype on biopsy versus Mohs. RESULTS: Among the 825 BCCs with known subtypes on biopsy, 68% (561/825) were classified as nonaggressive, 28% (159/561) of which were subsequently found to have aggressive subtypes on MMS. Aggressive features were more often underrepresented in biopsy samples taken from Area H compared with Area M/L (odd ratio [OR] 2.65, 95% confidence interval [CI] 1.73-4.08, p < .001) or those with nodular subtypes (OR 2.19, CI 1.08-4.45, p = .03). Of concern, these unsuspected aggressive BCCs required more Mohs stages for clearance (mean 2.37, SD 0.72, p < .001) compared with BCCs that remained nonaggressive on both biopsy and Mohs (mean 1.50, SD 0.75). CONCLUSION: Given the high percentage of BCCs with unsuspected aggressive subtypes, higher clinical suspicion for undiagnosed high-risk BCCs should be given to nodular BCCs and to BCCs on Area H.

Exploring mechanisms of IgE-mediated autoimmunity through the lens of bullous pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease characterized by pathogenic autoantibodies targeting collagen XVII (col XVII), a hemidesmosomal adhesion molecule. Early studies utilizing IgG were critical for establishing col XVII-specific antibodies as primary mediators of blister formation; however, these studies lacked key features of the disease, including urticarial erythema and eosinophilic infiltration, which are often associated with IgE. Although it was recognized that BP patients often had elevated circulating IgE, investigations into the pathogenicity of these antibodies was delayed until discovery of col XVII-specific IgE in BP sera. Since then, a variety of in-vivo and in-vitro studies have provided clear evidence that IgE autoantibodies are a key component of BP. Furthermore, studies utilizing IgE receptor blockade in BP patients were the first to confirm a pathogenic role of IgE autoantibodies in human autoimmunity. In this review we will utilize BP as a prototypical autoimmune disease to better understand how IgE autoantibodies participate in human autoimmunity.