Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. CONCLUSIONS: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

Acute localised exanthematous pustulosis (ALEP) induced by clindamycin in pregnancy.

Acute generalised exanthematous pustulosis (AGEP) or toxic pustuloderma (TP) is an uncommon though well-recognised cutaneous hypersensitivity reaction that is usually drug-induced. It presents with a triad of scattered sterile pustules, fever and malaise. Acute localised exanthematous pustulosis (ALEP) is a rare and unusual variant of AGEP. We describe a case of ALEP triggered by oral clindamycin that occurred during pregnancy.

Patch testing in patients treated with systemic immunosuppression and cytokine inhibitors.

BACKGROUND: Currently, there is little data available on the reliability of patch testing in patients taking immunosuppressive agents other than systemic corticosteroids. OBJECTIVES: We present data from 38 patients who were patch tested whilst taking various immunomodulating agents to determine if positive reactions can be elicited. PATIENT/MATERIALS/METHODS: Between September 2006 and May 2009, 38 patients attending the St John's Institute of Dermatology were patch tested whilst taking immunosuppressive agents including azathioprine, ciclosporin, infliximab, adalimumab, etanercept, methotrexate, mycophenolate mofetil, and tacrolimus. RESULTS: Positive patch test reactions of varying degrees and significance were elicited in: 2 of 10 patients on azathioprine; 5 of 11 patients on ciclosporin; 1 patient on ciclosporin and Fumaderm; 1 patient on infliximab; 1 patient on infliximab and methotrexate; 1 of 2 patients on adalimumab; 1 patient on etanercept and methotrexate; 3 of 4 patients on methotrexate; 1 of 3 patients on mycophenolate mofetil; and 1 patient on mycophenolate mofetil and tacrolimus. Negative patch test reactions occurred in 1 patient on azathioprine and ciclosporin; 1 patient on infliximab and azathioprine; and 1 patient on mycophenolate and ciclosporin. CONCLUSIONS: Positive patch test reactions can be elicited in patients taking azathioprine, ciclosporin, infliximab, adalimumab, etanercept, methotrexate, mycophenolate mofetil, and tacrolimus. However, it remains unclear what effect these immunosuppressive drugs may have on suppressing allergic patch test reactions and further studies should be carried out to determine the reliability of testing in these circumstances.

A limited form of proteus syndrome with bilateral plantar cerebriform collagenomas and varicose veins secondary to a mosaic AKT1 mutation.

IMPORTANCE: Proteus syndrome is an extremely rare disorder of mosaic postnatal overgrowth affecting multiple tissues including bone, soft tissue, and skin. It typically manifests in early childhood with asymmetric and progressive skeletal overgrowth that leads to severe distortion of the skeleton and disability. The genetic basis has recently been identified as a somatic activating mutation in the AKT1 gene, which encodes an enzyme mediating cell proliferation and apoptosis. OBSERVATIONS: We present a 33-year-old man who developed plantar cerebriform collagenomas on the soles of both feet and varicose veins in early childhood, in the absence of any skeletal or other connective tissue abnormality. Although the patient did not meet the diagnostic criteria for Proteus syndrome, he was found to have the c.49G>A, p.Glu17Lys AKT1 mutation in lesional skin but not in his blood. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the mildest molecularly confirmed case of Proteus syndrome, occurring in the absence of the characteristic skeletal overgrowth. These findings extend the spectrum of Proteus syndrome pathological characteristics and suggest that somatic mutations late in development and restricted in distribution cause subtle clinical presentations that do not meet the published clinical criteria.