BackgroundFilaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations.ObjectiveWe hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease.ResultsWe describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype.ConclusionOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.
Summary
Background
Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer. Standard treatment in the UK is either wide local excision (WLE) or Mohs micrographic surgery (MMS). It is unclear which approach has the lower recurrence rate.
Objectives
We undertook a retrospective comparative review of surgical management of DFSP in the UK National Health Service in order to define (i) current surgical practice for primary and recurrent DFSP, (ii) local recurrence rates for primary DFSP and (iii) survival outcomes for DFSP.
Methods
A retrospective clinical case‐note review of patients with histologically confirmed DFSP (January 2004 to December 2013) who have undergone surgical treatment.
Results
The surgical management of 483 primary and 64 recurrent DFSP in 11 plastic surgery and 15 dermatology departments was analysed. Almost 75% of primary DFSP (n = 362) were treated with WLE and 20% (n = 97) with MMS. For recurrent DFSP, 69% (n = 44) and 23% (n = 15) of patients underwent WLE and MMS, respectively. Recurrent primary DFSP occurred in six patients after WLE and none after MMS. The median follow‐up time was 25·5 months (interquartile range 6·8–45·1) for new and 19·8 (IQR 4·5–44·5) for recurrent DFSP [Correction added on 1 Feb 2021, after first online publication: 4.8 years (interquartile range 3.5‐5.8) was incorrect], with eight reported deaths during the follow‐up analysis period (one confirmed to be DFSP related).
Conclusions
WLE was the most common surgical modality used to treat DFSP across the UK. The local recurrence rate was very low, occurring only after WLE. Although a prospective randomized controlled trial may provide more definitive outcomes, in the absence of a clearly superior surgical modality, treatment decisions should be based on patient preference, clinical expertise and cost.
The authors have reviewed their institutional experience of peripheral nerve sheath tumors over a 10-year period. Their results will help to focus clinical and radiologic investigation of patients presenting with these tumors.
Background:
In FGFR2 craniosynostosis, midfacial hypoplasia features oculo-orbital disproportion and symptomatic exorbitism. Clinical consequences may mandate surgery at a young age to prevent globe subluxation, corneal ulceration, and potential loss of vision. Monobloc osteotomy and distraction osteogenesis (monobloc distraction) seek to correct exorbitism. A report of the age-related impact of monobloc osteotomy and distraction osteogenesis on orbital volume, globe volume, and globe protrusion is presented.
Methods:
Computed tomographic scan data from 28 Crouzon-Pfeiffer patients were assessed at preoperative, early postoperative, and 1-year follow-up time points. Orbital volumes, globe volumes, and globe protrusions were measured by manual and semiautomatic segmentation techniques, and these were compared to 40 age-matched controls.
Results:
Crouzon-Pfeiffer syndrome orbital volumes are significantly small, and are significantly overexpanded by distraction to endpoints correcting symptomatic exorbitism. Globe volumes are significantly larger than controls under 5 years, do not independently correlate with globe protrusion, and are unaffected by surgery. Correlation between orbital volume expansion and reduction of globe protrusion is not significant. Age-related variations of postoperative growth potential occur to 1 year postoperatively. The Crouzon-Pfeiffer syndrome FGFR2 orbit exhibits early growth acceleration followed by premature growth arrest at 10 to 14 years.
Conclusions:
Orbital volume expansion by monobloc osteotomy and distraction osteogenesis is not the sole determinant of reduced globe protrusion. Mean volume relapse of the orbit at 1 year is insignificant across the series. Derived Crouzon-Pfeiffer growth curves suggest that “early functional monobloc” in infants occurs on a background of dynamic orbital growth, which remains programmed to a Crouzon-Pfeiffer FGFR2 phenotype and aligns with the incidence of delayed clinical regression and later secondary surgery.
CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
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