Epidermolysis Bullosa Dystrophica Inversa: Case Report of a Novel Genetic Mutation, Involving a Rare Genodermatoses

Dear Editor,

A 9-year-old male patient, born out of a third-degree consanguineous marriage reported to our clinic with oral erosions and symmetrical erosive lesions involving the neck, armpits, waist, and groins. He was born with erosions involving his shins and feet. Throughout his infancy, he had recurrent episodes of blistering and erosions involving his trunk, extremities, and oral mucosa often triggered by minor trauma. The frequency and extent of blistering have declined with age, with involvement restricted to mucosa and flexures.

Clinical examination revealed erosions on the neck, axilla, waist, groins, and oral mucosa. Postlesional hypo- and hyperpigmented atrophic areas were present on the neck, axilla, waist, pubic regions, and dystrophic changes involving toenails [Figure 1a-d]. Immunofluorescence antigen mapping (IFAM) revealed a split below the level of lamina densa, with preserved immunoreactivity for type VII collagen [Figure 2]. The genetic testing report revealed a novel homozygous missense mutation in COL7A1 (exon 75), which was validated by Sanger sequencing in both parents [Figure 3a-c]. The patient was diagnosed with epidermolysis bullosa dystrophica inversa based on the clinical presentation, corroborated by the IFAM and genetic testing report. Family history was absent.

Figure 1.

(a) Erosions and bullae involving the axilla. (b) Waist and groin erosions. (c) Onychodystrophy of toe nails. (d) Oral mucosal erosions

Figure 2.

Split located below the level of lamina densa (IFAM)

Figure 3.

(a) The genetic testing report of the patient reveals homozygous missense mutation c. 6205C > T (p.Arg2069Cys) in COL7A1 gene in the patient. (b) Heterozygous missense mutation c. 6205C > T (p.Arg2069Cys) in COL7A1 gene in father. (c) Heterozygous missense mutation c. 6205C > T (p.Arg2069Cys) in COL7A1 gene in mother

Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous disorder characterized by skin fragility. It is due to mutations that affect the mucocutaneous structural proteins, leading to disruption at the dermo-epidermal junction or in the basal layer of the epidermis resulting in cutaneous vulnerability to mechanical stress.[1] Depending on the specific genetic defect and its molecular sequelae, it manifests as blisters, erosions, ulcers, and atrophic and hypertrophic scars following minor trauma.[1]

Dystrophic epidermolysis bullosa (DEB) manifests as mucocutaneous blistering resolving with atrophic scars. The 2020 consensus classification recognizes four major subtypes and several rare, dominant, or recessive subtypes of DEB.[1] The four major subtypes of DEB are localized-dominant dystrophic epidermolysis bullosa (localized-DDEB), intermediate-DDEB, intermediate-recessive dystrophic epidermolysis bullosa (intermediate-RDEB), and severe-RDEB. [Table 1 summarizes the clinical characteristics of major DEB subtypes].[1] The inverse subtype of recessive dystrophic epidermolysis bullosa is a rare genodermatosis characterized clinically by blistering, erosions, and atrophic scars primarily involving the flexural areas of the body (i.e., neck, axilla, infra-mammary groove, and inguinal folds), ultrastructurally by sub-lamina-densa split.[2,3] These typical clinical, ultrastructural, and genetic findings were identified in our patient.

Table 1.

Major subtypes of dystrophic epidermolysis bullosa1

DEB subtype	Gene mutation	Clinical features	Prognosis
Localized DDEB (Previously encompassing nails only, pretibial, and acral DDEB)	COL7A1 gene (Gene encoding Type VII collagen) Monoallelic missense, splice-site mutations within exon; deletion mutations within triple helical domain	Acral or pretibial skin fragility, with onset usually from birth or early childhood; mucosal erosions; onychodystrophy	Extensive scarring, contractures, and deformities are usually absent. Risk of cutaneous squamous cell carcinoma (SCC)
Intermediate DDEB (previously generalized DDEB)	COL7A1 gene Monoallelic missense, splice-site, or deletion mutations	Widespread mucocutaneous erosions with onset usually from birth or from early infancy (more marked over bony prominences)	Extensive scarring, contractures, and deformities; High risk of aggressive cutaneous SCC
Intermediate RDEB (previously RDEB generalized intermediate type and non-Hallopeau-Siemens RDEB)	COL7A1 gene Biallelic missense, nonsense, deletion, or insertion; Splice-site mutations with compound heterozygosity for a loss-of-function mutation on one COL7A1 allele and a non-loss-of-function mutation on the second allele	Generalized skin fragility with extensive mucocutaneous erosions with onset usually from birth or early childhood	Mutilating deformities are usually absent Mild flexion contractures of fingers may occur Striate pattern of keratoderma Increased risk of cutaneous SCC
Severe RDEB (previously RDEB generalized severe, Hallopeau-Siemens RDEB)	COL7A1 gene Biallelic nonsense, splice-site, deletion, or insertion; Missense mutations with homozygosity or compound heterozygosity	Widespread skin blistering onset from birth. Blistering is more marked over bony prominences with advancing age	Extensive scarring, flexion contractures of large joints, and mitten deformities involving extremities. High risk of aggressive cutaneous SCC

Identification of this distinctive subtype of epidermolysis bullosa is critical as it differs from other forms of EB types in terms of prognosis.[4] Homozygous mutations in the COL7A1 gene, encoding type-VII collagen, a major component of anchoring fibrils, underlie the pathogenesis of RDEB,[5] with arginine and glycine substitution within the triple helix domain (THD) leading to the inversa phenotype.[3]

The genetic testing report of our patient revealed a novel homozygous missense mutation c. 6205C > T (p.Arg2069Cys) in the COL7A1 gene, leading to a hydrophilic amino acid arginine being substituted by a strongly hydrophobic amino acid cysteine at position 2069 altering the protein sequence. The substitution of the large hydrophilic amino acid by a strongly hydrophobic amino acid in the THD of collagen VII alters both the tertiary and quaternary structures, leading to slightly weakened stability or folding of the molecule.[6] With respect to RDEB-inversa, the predominant distribution of lesions in the mucosa and flexures strengthens the hypothesis that the localization of the amino-acid substitutions in specific THD correlates with the synthesis of a thermo-labile type VII collagen, which is specifically less stable in the warmer areas on the patient's body.[2]

This study highlights the importance of genetic testing not only in precise diagnosis but also in the genotype-phenotype correlations in RDEB-Inversa, which is a first step toward understanding the pathophysiology of the flexural distribution of this rare DEB subtype. Further studies pertaining to the temperature-dependent pathophysiology are needed to help develop preventive strategies for this rare condition, which, although not fatal, is associated with significant morbidity and impact on the quality of life of the patient.

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