Hallopeau (1898) was among the first to attempt to subclassify patients with inherited EB, using the terms simple and dystrophique, although nearly two decades passed before these terms became widely accepted. At that time, the name EB dystrophica was applied to those patients having nail dystrophy or skin atrophy after blistering or both, whereas the term EB simplex was reserved for those lacking evidence of these two cutaneous features. Of pertinence to the data to be presented in chapter 6, the presence of milia was considered to be a feature exclusively seen in EB dystrophica, and clinicians still frequently use it as an important diagnostic finding.

The earliest reported cases of EBS had generalized blister formation, conforming to the clinical phenotype that is now most often referred to as the Kobner (or Koebner) variant. As early as 1895, however, occasional patients were reported who had blisters confined to their feet or to both hands and feet and in whom scarring and nail dystrophy were lacking. One of Elliott's cases was sporadic, with blistering of the feet only, decades later shown to be the mutant stem-father to a large dominant pedigree. Weber (1926) named a similar sporadic, mainly localized case "recurrent bullous eruption of the feet," believing it to be separate from EBS, which was at that time thought to be a generalized disease process. In 1938, Cockayne presented a dominant family having a recurrent bullous eruption and admitted that it could he an allelomorph of EBS. Although some clinicians attempted to further separate patients with localized EBS into those having exclusively foot versus hand and foot involvement, such an overly restrictive distinction was eventually dropped. Since 1957 all of the latter patients have been designated as having the Weber- Cockayne variant of localized EBS.

Several other clinically distinctive forms of EBS have been reported. One such disease, described as "dystrophia bullosa hereditaria, typus maculatus" in 1908 by Mendes da Costa and van der Valk, based on the findings in a single affected Dutch family, was later shown to have intraepidermal rather than subepidermal skin cleavage, and therefore has been placed among the subtypes of EBS. This particular entity is unique among all other forms of inherited EB, due to its X-linked recessive transmission.. Additional unusual findings include microcephaly and reticulated dyspigmentation. Today, this distinctive group of patients is referred to as having the Mendes da Costa variant of generalized EBS.

A much more common type of generalized EBS, which is frequently associated with early infant mortality, was described in 1954 by Dowling and Meara. Initially this blistering disease, believed to be a variant of epidermolysis bullosa, was interpreted as autosomal recessive, but by the time of its rediscovery in the 1970s, it was proven to be autosomal dominant in transmission. This entity, now known as EB herpetiformis or Dowling-Meara EBS, is characterized by the presence of arcuate (or herpetiform) groups of vesicles or bullae. An unusual subtype of EBS, still referred to as the Ogna variant due to its naming after the origin in southern Norway of the single kindred re- ported by Gedde-Dahl in 1971, is characterized by the presence of generalized epidermal fragility (misnamed bruising in the original report). Another rare variant of generalized EBS, first reported by Fischer and Gedde-Dahl in 1979 is associated with the presence of mottled or reticulate hyperpigmentation; in some patients, punctate keratoderma of the palms and soles may also be found. Other, more recently defined, rare EBS subtypes include the autosomal recessive transmitted Kallin syndrome (1985), autosomal recessive generalized EBS associated with neuromuscular diseases (1972) (also reported under the term pseudojunctional EB) and EBS superficialis (1989).

Gossage (1908) was the first to note that patients with EBS had a pattern of Mendelian dominant inheritance. In 1921, Siemens expanded on this observation, showing the associations of dominant inheritance with EBS and recessive inheritance with patients having dystrophic skin findings. An apparent autosomal recessive form of Weber-Cockayne disease has also now been

reported. With rare other exceptions of autosomal recessive transmission and that of X-linked recessive transmission of the Mendes da Costa subtype, all other known forms of EBS continue to follow the rule of autosomal dominant transmission set forth by Gossage nearly 90 years ago.

During the early part of this century, all forms of DEB were believed to be transmitted as autosomal recessive traits. An autosomal dominant form of DEB was first described in 1926 by Hoffmann. Larger clinical series of DEB patients with dominant transmission were reported in 1933 by Cockayne and in 1942 by Touraine. Touraine further made the clinical distinction between " epidermolyse bulleuse hyperplasique (dominante)," which contained "hypertrophies"(which he defined as onychogryphoses, keratoses, and hyperpigmentation), and "epidermolyse bulicuse polydysplasique (recessive),"in which atrophy was a predominant feature.

Alhopapuloid lesions were independently described in a subset of dominant DEB (DDEB) patients in 1928 by Pasini and Maschkilicisson. In 1964, Schnyder and Eichoff proposed that patients meeting all clinical criteria for the Pasini variant of DDEB but lacking albopapuloid lesions be referred to as having the Cockayne-Touraine variant of DDEB, a clinical distinction still used today.

Recessive transmission of some forms of DEB (RDEB) has been known since Siemens's publication in 1921. In 1966, Schnyder proposed the term Hallopeau-Siemens RDEB to encompass all types of RDEB, including localized ones, to distinguish them from cases of DDEB. In 1971, Gedde-Dahl coined the term DEB inversa to describe those patients having relative sparing of the extremities, and therefore assumed a separate category for RDEB other than the Hallopeau-Siemens subtype. Today, the term Hallopeau-Siemens is confined to those RDEB patients having severe, generalized cutaneous and extra- cutaneous disease activity. Although not an absolutely specific finding, the presence of pseudosyndactyly (mitten deformity of the hand or foot) is also considered to be one of the more useful clinical criteria for this particular RDEB subtype. In 1971, Gedde -Dahl also described several cases of generalized RDEB of the nonlethal type, now referred to as generalized mitis RDEB. The existence of cases ascribed as RDEB with strictly localized disease have been partly based on observations no longer valid; for example, in 1938, Erichsen reported siblings having more localized disease activity, which was primarily confined to the extremities, and attributed their disease to RDEB. These were subsequently proven to have JEB. Most recently, McGrath, Schofield, and Eady (1994) coined the name EB pruriginosa to describe an unusual subset of DEB patients having intense pruritus and prurigo nodularis-like lesions

In 1901, Bettmann reported three brothers with DEB whom Wise and Lautman in 1915 included in the acquired group because of onset of disease at 12 years of age. In 1971, Gedde-Dahl reported three patients from two families with the same late onset of disease under the term EB dystrophica neurotrophica, using the term because of the presence of associated recessive hypoacusis. This name was subsequently revised to EB progressiva when the study of additional families showed the hypoacusis to be an independent but genetically linked trait.

In 1935, Herlitz described an autosomal recessive type of inherited EB that he believed differed from those cases of RDEB previously defined by Siemens by both its typically fatal course and its absence of clinical features (milia, scarring, atrophy, altered pigmentation, musculoskeletal deformities) that were considered to be highly characteristic of RDEB. Termed EB letalis, patients with this disorder were shown decades later to further differ from those with RDEB by the presence of blister formation in the lamina lucida rather than the sub-lamina densa region, of their skin. As will be discussed in greater detail in chapter 2, these patients are now most commonly referred to as having the Herlitz variant (or EB atrophicans generalisata gravis) of generalized JEB. In 1976, Hashimoto, Schnyder, and Anton-Lamprecht described a case of generalized non-Herlitz JEB. In 1982, Hintner and Wolff reported shared clinical findings in several patients with a nonlethal variant of generalized JEB. These authors suggested that their patients were phenotypically distinct from other known forms of JEB and referred to this condition as generalized atrophic benign EB (GABEB). A rare inverse variant of JEB was originally reported by Gedde-Dahl in his 1971 monograph. Another more localized variant of JEB was described in 1979 by Schnyder and Anton-Lamprecht. 1n 1985, Haber coined the term cicatricial JEB to describe rare patients with JEB who had hand deformities that were clinically indistinguishable from those observed in Hallopeau-Siemens RDEB. As early as 1968, rare patients with JEB were shown to have coexistent atresia of the upper gastrointestinal tract; all but two these have involved the pylorus. Although the distinction is not universally accepted, some authorities separate these patients from those having other forms of JEB but lacking this congenital anomaly.

In 1966, Bart and colleagues described a large kindred in which congenital localized absence of the skin was seen in conjunction with an autosomal dominant form of EB associated with nail dystrophy. Subsequently referred to by others as Bart's syndrome, this original family was recently proven to have DDEB by ultrastructural, immunohistochemical, and molecular biological means. Since Bart's original report, rare patients with associated congenital localized absence of skin and inherited EB have been found to have simplex, junctional, and recessive dystrophic forms of EB.

An acquired bullous disease with cutaneous features reminiscent of DEB was first described by Kablitz in 1904. At that time, the name EB traumatica aquisita was proposed. Additional early cases were reported by Wise and Lautman in 1915. In 1971, Roenigk suggested a series of specific criteria for the diagnosis of this disease, by then referred to as EB acquisita. Immunofluorescence and immunoelectron microscopy findings were further defined by Yaoita and colleagues in 1981, and they confirmed that EB acquisita is an autoimmune disease. In 1984, Gammon and colleagues showed that EB acquisita also may present as a nonscarring, autoimmune, bullous disease with clinical findings indistinguishable from those observed in bullous pemphigoid. The clinical spectrum of EB acquisita was later expanded to include those rare patients with clinical findings similar to those of cicatricial pemphigoid or porphyria cutanea tarda, in whom autoimmunity to type VII collagen could be shown to be present.