key: cord-0734770-m8othzwy
authors: Diociaiuti, Andrea; Guerriero, Cristina; Cesario, Claudia; Rossi, Sabrina; Rotunno, Roberta; Zambruno, Giovanna; El Hachem, May
title: Self-improving dominant dystrophic epidermolysis bullosa: phenotypic variability associated with COL7A1 mutation p.Gly2037Glu
date: 2021-02-12
journal: Eur J Dermatol
DOI: 10.1684/ejd.2020.3922
sha: b4898b9c58647d0651009770bcd88294997d8568
doc_id: 734770
cord_uid: m8othzwy

nan

Dystrophic epidermolysis bullosa (DEB) is one of the four major types of inherited epidermolysis bullosa, the prototypic skin fragility disorder [1] . DEB is characterized by blister formation below the lamina densa of the cutaneous basement membrane zone (BMZ) and by mutations in the COL7A1 gene, encoding type VII collagen (colVII). DEB is inherited as a dominant or recessive trait and several subtypes are distinguished based on clinical features. A peculiar subtype, self-improving DEB (previously referred to as "bullous dermolysis of the newborn"; OMIM #131705), is characterized by major improvement or com- plete resolution of skin fragility within the second year of life [1] . Self-improving DEB blisters are predominantly acral and heal with no or minimal scarring. Laboratory diagnostic features are granular colVII deposits within the epidermis, and specific cytoplasmic inclusions (stellate bodies) in keratinocytes [2, 3] . Self-improving DEB can be dominantly or recessively inherited [1] . We describe the clinical, immunopathological and ultrastructural features of a case of self-improving dominant DEB (SI-DDEB) due to the glycine substitution p.Gly2037Glu in colVII and discuss the phenotypic variability associated with this mutation. A full-term female infant, the third child of healthy non-consanguineous Chinese parents, developed tense blisters on the extremities from the fifth day of life ( figure 1A) . The oral mucosa was also affected and subungual haemorrhages were present. Lesions healed with milia and minimal atrophic scarring. Muco-cutaneous fragility rapidly improved in the first months of life. Following informed consent, a skin biopsy and blood sample were taken at three months of age. Immunofluorescence mapping (IFM) showed colVII-positive granular deposits within the epidermis, and linear labelling at the BMZ ( figure 1C) . Ultrastructural examination demonstrated cleavage below the lamina densa and a few rudimentary anchoring fibrils. Rough endoplasmic reticulum (RER)-bound perinuclear inclusions were present mainly within suprabasal keratinocytes ( figure 1D) . These were partially filled with granular content and some elongated electron-dense structures, compatible with stellate bodies ( figure 1D) . Molecular testing performed in the patient and healthy parents revealed a de novo heterozy-gous missense mutation, c.6110G>A (p.Gly2037Glu), in exon 73 of the COL7A1 gene [4, 5] . In the child, who is now 18 months old, spontaneous blisters no longer develop, although milia are still present on extremities ( figure 1B) .

Our patient was diagnosed with SI-DDEB based on laboratory findings and clinical course. In self-improving DEB, colVII cytoplasmic inclusions are regularly observed by IFM and correspond to colVII retention within the RER [2, 3, 6] . Usually, staining for colVII is reduced to such an extent that it is absent at the BMZ. The epidermal inclusions resolve over time, with parallel increase in colVII expression [7, 8] . The concomitant reduction or cessation of skin fragility is thought to be secondary to normalization of colVII secretion from keratinocytes. However, persistence of intraepidermal colVII in the presence of normal BMZ labelling has been observed after resolution of skin fragility [8] . In our patient, the skin biopsy was performed at three months of age, when disease was already markedly attenuated. At that time, IFM for colVII showed granular labelling throughout the epidermis but also linear staining at the BMZ, and ultrastructural examination revealed cytoplasmic inclusions mainly localized within suprabasal keratinocytes, containing few elongated dense structures. We hypothesize that these features capture an intermediate phase in self-improving DEB pathology, corresponding to initial secretion of colVII concomitant with residual retention within keratinocytes.

The dominant colVII glycine substitution, p.Gly2037Glu, identified in our patient has been previously reported. The mutation causes colVII retention within HaCaT keratinocytes and is associated with granular labelling in the basal epidermis [4, 5] . In previous cases, the mutation p.Gly2037Glu resulted in a phenotype of intermediate DDEB; a 12-year-old female had acral and oral blisters together with albopapuloid lesions [4] and a two-yearold child continued to develop blisters on the trunk and lower extremities (supplementary table 1 ). In contrast, in our patient, oral involvement rapidly resolved in infancy and skin blisters were strictly localized to extremities and ceased by the second year of life. However, our relatively short follow-up does not allow to formally exclude that some skin fragility signs recur in the future, a limitation shared by other self-improving DEB cases reported in the literature [6] . In conclusion, comparison of our patient with the other cases carrying the missense p.Gly2037Glu mutation shows that the same mutation may result in a variable phenotype, possibly due to individual genetic backgrounds and environmental factors.

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa

Frequent occurrence of aplasia cutis congenita in bullous dermolysis of the newborn

Dominant dystrophic epidermolysis bullosa (Pasini) caused by a novel glycine substitution mutation in the type VII collagen gene (COL7A1)

COL7A1 mutation G2037E causes epidermal retention of type VII collagen

Intraepidermal type VII collagen by immunofluorescence mapping: A specific finding for bullous dermolysis of the newborn

Intracytoplasmic retention of type VII collagen and dominant dystrophic epidermolysis bullosa: reversal of defect following cessation of or marked improvement in disease activity

Transient bullous dermolysis of the newborn in three generations

Acknowledgements: the patient's parents provided written informed consent to the publication of their child's case details. We thank Mr. Gabriele Bacile for the preparation of the images. Conflicts of interest: none.

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