[Type the document title]

EPIDERMOLYSIS BULLOSA JUNCTIONALIS WITH PYLORIC

ATRESIA

Alternative titles; symbols

EPIDERMOLYSIS BULLOSA, JUNCTIONAL, WITH PYLORIC ATRESIA
JUNCTIONAL EPIDERMOLYSIS BULLOSA WITH PYLORIC ATRESIA
JEB-PA
EPIDERMOLYSIS BULLOSA, JUNCTIONAL, WITH PYLORIC ATRESIA AND APLASIA
CUTIS CONGENITA
EB-PA-ACC
CARMI SYNDROME
APLASIA CUTIS CONGENITA WITH GASTROINTESTINAL ATRESIA

Phenotype-Gene Relationships
Phenotype Inheritance Phenotype Gene/Locus
Location Phenotype MIM number (in progress) mapping key Gene/Locus MIM number
Epidermolysis bullosa,
junctional, with pyloric
2q31.1 stenosis 226730 AR 3 ITGA6 147556
Epidermolysis bullosa,
junctional, with pyloric
17q25.1 atresia 226730 AR 3 ITGB4 147557

Clinical Synopsis

TEXT
A number sign (#) is used with this entry because of evidence that this disorder can be caused
by mutations in the integrin-beta-4 gene (ITGB4; 147557) or the integrin-alpha-6 gene
(ITGA6; 147556).

See also epidermolysis bullosa simplex with pyloric atresia (EBSPA), which is caused by
mutations in the PLEC1 gene (601282).

Description
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Traditionally, EB-PA has been classified as a form of junctional epidermolysis bullosa. Uitto et
al. (1997) andPulkkinen and Uitto (1998) proposed reclassification of the disorder as a
'hemidesmosomal' variant because ultrastructural findings can indicate cleavage in the
hemidesmosomal region of the skin. However, in subsequent reports of consensus
conferences, Fine et al. (2000, 2008) eliminated the term 'hemidesmosomal' because it added
undue confusion. The disorder is considered to be a form of junctional EB because skin
cleavage occurs within the lamina lucida. Hemidesmosome may be abnormal because the
integrins span this region.

In a study involving 265 cases of junctional or hemidesmosomal EB, Varki et al.

(2006) reviewed the clinical and molecular heterogeneity of these subtypes of EB, discussed
exceptions to the general rules on genotype-phenotype correlations, and noted unusual
phenotypes and genetics observed in patients and families with EB.

Clinical Features
Bull et al. (1980, 1983) reported a sister and brother with epidermolysis bullosa and pyloric
atresia at birth. Both died in early infancy of complications related to the skin disorder. An
older stillborn sister was probably affected. Both sibs also had bilateral stenosis at the
ureterovesical junctions with bilateral pyelonephrosis; this feature was present in an earlier-
reported case. Electron microscopic studies of skin biopsy specimens disclosed findings
consistent with a diagnosis of epidermolysis bullosa letalis, or the Herlitz form of JEB
(226700). The authors found 10 previously reported cases and 2 instances in which sibs were
affected, suggesting autosomal recessive inheritance.

Similar cases were reported by Adashi et al. (1980) and Berger et al. (1986). Death usually
occurred in the first few months of life despite surgical management of the pyloric
abnormality.

Carmi et al. (1982) described 2 sibs from consanguineous Bedouin parents with extensive
aplasia cutis congenita. Only 1 had pyloric atresia. Elevated amniotic fluid alpha-fetoprotein
was noted by Carmi et al. (1982) and byLeschot and Treffers (1975). Carey et al.
(1983) described a pair of dizygotic twins, a boy and girl, with extensive skin changes similar
to the changes observed in the patients of Carmi et al. (1982). Carey et al. (1983) suggested
that the designation 'aplasia cutis congenita' was inappropriate because it usually entails
involvement of the scalp predominantly or exclusively; they suggested the eponymic
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designation Carmi syndrome. One of the twins had axillary pterygia and bilateral lower lid
ectropion, whereas the other showed esophageal atresia.

Toriello et al. (1983) reported affected brother and sister, and Leschot (1983) called attention to
the similar case reported by Leschot et al. (1980). Frieden (1986) reported arthrogryposis and
ear and nose deformities.

Vivona et al. (1987) described a sister and brother with lethal congenital cutis aplasia. Only 1
had esophageal atresia with complete absence of the pyloris. In the view of Vivona et al.
(1987), the similarity between their cases and those of Carmi et al. (1982) strongly supported
the existence of a unique EB-like mutation, i.e., an autosomal recessive disorder with variable
involvement of skin, nails, and mucosa, with variable effects on the digestive system.

Rosenbloom and Ratner (1987) reported premature sibs with lethal epidermolysis bullosa
associated with congenital pyloric atresia. A review of other cases indicated that it is usually a
lethal condition with death due to the septic complications of EB.

Ishigami et al. (1990) described congenital pyloric atresia in a female infant with junctional EB
who, despite successful early surgical correction of the obstruction, died from intractable
diarrhea and protein-losing gastroenteropathy at the age of 4.5 months.

Lacour et al. (1992) described a case of lethal JEB in a newborn girl who also had pyloric
stenosis. Immunohistologic and electron microscopic studies showed cleavage through the
lamina lucida of the digestive basement membrane, as for the localized skin blisters. There
was normal immunostaining of the laminin glycoprotein BM600 at the dermoepidermal
junction.

Vidal et al. (1995) reported an infant who presented at birth with pyloric atresia and
cutaneous aplasia of the left hand. Perioral blistering and erosions of the mucosa of the
mouth, upper esophagus and cornea were noted shortly after birth. Gastric erosions were
found later. The infant died at the age of 8 months as the result of infection of skin blisters
and generalized infection.

Chavanas et al. (1999) reported a patient who represented a rare instance in which JEB-PA
showed improvement with age. The proband was a 14-year-old boy, the child of
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nonconsanguineous parents, who at birth presented all the hallmarks of severe JEB-PA,
including extensive skin blistering, pyloric atresia, and urethrovesical occlusion. However, as
the child grew, the blistering tendency decreased and his skin and epithelia acquired
resistance to trauma. At the age of 14, induction of blisters required prolonged rubbing of the
skin.

Pathogenesis
Lestringant et al. (1992) found that the GB3 monoclonal antibody, which reacts to laminin-5
subunits, was normally expressed in skin biopsies from 3 of 3 cases of JEB-PA, thus excluding
it as a form of Herlitz JEB, which is due to mutations in genes encoding laminin-5
subunits. Lestringant et al. (1992) concluded that the pyloric atresia/epidermolysis bullosa
association represents an autosomal recessive entity of JEB, and that pyloric atresia is a
primary manifestation rather than a scarring process secondary to JEB. The authors noted
that patients with JEB-PA often have erosions and/or subepithelial cleavage in the
respiratory, gastrointestinal, and urinary tracts. Obstruction of the ureterovesical junction and
a high incidence of a peculiar form of aplasia cutis congenita were considered to be additional
features.

Maman et al. (1998) provided detailed clinical and histopathologic information on 8 cases of
the triple syndrome epidermolysis bullosa/pyloric atresia/aplasia cutis congenita (EB-PA-
ACC). The affected individuals were members of the extended Bedouin family first described
by Carmi et al. (1982). All affected infants were found to have mixed skin lesions, including
blisters and patchy lack of skin. In 7 of the 8, intestinal obstructions, especially pyloric atresia
or stenosis, were found. Skin lesions involved all layers with marked dystrophic changes. The
intestinal obstruction was the result of overproliferation of connective tissue. In view of the
clinical and histopathologic findings, Maman et al. (1998) postulated that the condition is
caused by an autosomal recessive mutation affecting the integrity of the basement membrane
and hemidesmosomes and the control of the normal process of fibrosis occurring during
wound healing. The sequence of events appeared to be initiated by the separation of the
epidermis or the intestinal mucosal layer. An inflammatory reaction then takes place and
proceeds with massive fibrosis penetrating the deep layers and causing damage to skin and
obstruction of the intestinal lumen. Maman et al. (1998) postulated a mutation in one of the
integrin genes.

Diagnosis
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Prenatal Diagnosis

Nazzaro et al. (1990) made the prenatal diagnosis of JEB-PA by ultrastructural demonstration
of dermal-epidermal separation at the lamina lucida level in fetal skin obtained at 18 weeks of
gestation. Fetal ultrasound showed marked gastric dilatation, and light microscopy of pyloric
tissue obtained after termination showed that the pyloric lumen was replaced by loose
connective tissue with no inflammatory reaction. Skin biopsy studies showed a positive
reaction with the GB3 antibody, thus excluding the Herlitz form of JEB. In the family studied,
2 previous children had died during the first months of life of the same disorder despite
surgery for the pyloric abnormality.

Although AFP and skin biopsy had been used for prenatal diagnosis of this
condition, Achiron et al. (1992) found normal levels of amniotic AFP at 16 weeks' gestation in
a woman at risk for this disorder in her fetus. However, 10 weeks later, ultrasonography
showed hydramnios, dilated stomach, deformed external ear, and contracted fisted hand, all
of which were confirmed postnatally.

Molecular Genetics
In an infant with JEB-PA, Vidal et al. (1995) demonstrated compound heterozygosity for 2
mutations in the integrin beta-4 gene (147557.0001, 147557.0002).

In a patient with nonlethal JEB-PA and survival until 14 years of age, Chavanas et al.
(1999) found compound heterozygosity for 2 splice site mutations in the ITGB4 gene
(147557.0007 and 147557.0011).

In an infant with epidermolysis bullosa with pyloric atresia and esophageal stenosis, Ruzzi et
al. (1997, 1997) identified a homozygous deletion in the ITGA6 gene (147556.0001).

In members of the original inbred Bedouin kindred from southern Israel with EB-PA-ACC
described by Carmi et al. (1982) and Maman et al. (1998), Birnbaum et al. (2008) identified a
homozygous 2,279-bp in-frame deletion in exons 27-30 of the ITBG4 gene (147557.0016). They
stated that this was the largest deletion in the ITBG4 gene to date and included the first pair
of fibronectin III repeats.

Genotype/Phenotype Correlations
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Pulkkinen et al. (1998) identified novel lesions of both ITGB4 alleles in the probands of 5
families with JEB-PA, 2 of them with lethal and 3 of them with nonlethal variants of the
disease. Of the 2 patients with lethal JEB-PA, one was a compound heterozygote for
premature termination codon mutations, and the other was homozygous for a missense
mutation involving a cysteine residue (C61Y; 147557.0005). The 3 patients with nonlethal JEP-
PA had missense mutations on both alleles.

See Also:
Egan et al. (1985); Schnur et al. (1985)

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Contributors: Kelly A. Przylepa - updated : 2/5/2009

Creation Date: Victor A. McKusick : 6/3/1986

Edit History: alopez : 07/28/2015