Harlequin ichthyosis and ABCA12

MD(Res)Harlequin ichthyosis (HI), a rare severe form of congenital ichthyosis is caused by recessive mutations in the ABCA12 gene. At birth, affected neonates have widespread, grossly thickened skin, separated by deep red fissures, bilateral ectropion, eclabium and a rudimentary nose and ears. Previously, most babies died shortly after birth but with improved neonatal care and the early introduction of oral retinoids, there is now a cohort of HI survivors. ABCA12 mutation analysis was performed and bi-allelic mutations were identified in 14 out of 17 cases, 9 of which were novel. In one consanguineous case, reverse transcriptase PCR on a parental skin biopsy and copy number analysis were used to identify a multiple exon deletion, when standard techniques failed. A previous study showed that in ABCA12 deficiency, epidermal differentiation is dysregulated. Staining of skin biopsies with RXR-α and PPAR-δ showed that both of these nuclear hormone receptors are up-regulated in the spinous and granular cell layers of HI skin compared to normal skin while ABCA1 is down regulated in the basal layer. The largest review to date of the outcomes of babies born with HI was performed. A retrospective clinical questionnaire was completed for 45 patients worldwide. Survivors’ ages ranged from 10 months to 25 years with an overall survival rate of 55.6%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% if cases. The early introduction of oral retinoids may improve survival as 83% of those treated survived, whereas 76% who were not given retinoids died. Recurrent skin infections in infancy affected one third. Problems maintaining weight affected 44%. Three children developed an inflammatory arthritis and developmental delay was reported in 32%. Mutation analysis revealed that 52% of survivors had compound heterozygous mutations whereas all deaths were associated with homozygous mutations

Omphaloliths: a case series and review of 29 cases in literature

Omphaloliths are uncommon benign umbilical lesions caused by the accumulation of sebum and keratin into a stone-like concretion. Recognition of this entity can prevent unnecessary procedures and imaging studies for uncomplicated cases. We present three cases of omphaloliths from our department and review all 26 cases previously reported in the English literature with regard to modes of presentation, potential risk factors, complications, and treatment options to guide clinicians. The mean age at presentation was 48 years. Of the 29 cases, 17 (59%) were asymptomatic. Male patients presented at a younger age and were more likely to present with complications compared to females who presented at an older age with asymptomatic lesions (P=0.006). Features of patients described included dementia, hirsutism, a deep or narrow umbilicus, multiple nevi, obesity, and poor hygiene. Two patients developed overlying pyogenic granulomas. Removal of asymptomatic lesions was uncomplicated and done using forceps or following irrigation, with no recurrence. Complications, including localized abscesses and peritonitis, were associated in 41% of patients who were treated surgically; recurrence was noted in one patient. Removal of omphaloliths is recommended, once identified, to reduce risks of complications and patients should be encouraged to improve their personal hygiene

Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions

M.P. is supported by a Fellowship from the Deutsche Forschungsgemeinschaft. This work was supported in part by a generous donation of Israel and Ruthi Ram (E.S.) and from a British Heart Foundation Programme grant (D.P.K.)

Omphaloliths: a case series and review of 29 cases in literature

Omphaloliths are uncommon benign umbilical lesions caused by the accumulation of sebum and keratin into a stone-like concretion. Recognition of this entity can prevent unnecessary procedures and imaging studies for uncomplicated cases. We present three cases of omphaloliths from our department and review all 26 cases previously reported in the English literature with regard to modes of presentation, potential risk factors, complications, and treatment options to guide clinicians. The mean age at presentation was 48 years. Of the 29 cases, 17 (59%) were asymptomatic. Male patients presented at a younger age and were more likely to present with complications compared to females who presented at an older age with asymptomatic lesions (P=0.006). Features of patients described included dementia, hirsutism, a deep or narrow umbilicus, multiple nevi, obesity, and poor hygiene. Two patients developed overlying pyogenic granulomas. Removal of asymptomatic lesions was uncomplicated and done using forceps or following irrigation, with no recurrence. Complications, including localized abscesses and peritonitis, were associated in 41% of patients who were treated surgically; recurrence was noted in one patient. Removal of omphaloliths is recommended, once identified, to reduce risks of complications and patients should be encouraged to improve their personal hygiene

Mutations in CSTA, Encoding Cystatin A, Underlie Exfoliative Ichthyosis and Reveal a Role for This Protease Inhibitor in Cell-Cell Adhesion

Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis

Harlequin Ichthyosis A Review of Clinical and Molecular Findings in 45 Cases

Objective: To assess the clinical outcomes of 45 cases of harlequin ichthyosis and review the underlying ABCA12 gene mutations in these patients

Mutations in CSTA, Encoding Cystatin A, Underlie Exfoliative Ichthyosis and Reveal a Role for This Protease Inhibitor in Cell-Cell Adhesion

Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis