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A novel mutation in ITGB4 gene in a newborn with epidermolysis bullosa, pyloric atresia, and aplasia cutis congenita



Epidermolysis bullosa with pyloric atresia (EB-PA), also known as Carmi syndrome, is an uncommon, autosomal recessive genodermatosis that typically affects the skin and gastrointestinal tract. EB-PA is caused by homozygous or compound heterozygous mutations in the integrin alpha 6 (ITGA6) gene on chromosome 2q31.1 or in the integrin beta 4 (ITGB4) gene on 17q25.1.

Case presentation

A male premature infant was born with aplasia cutis, atresia of the pylorus, and bilateral hydronephrosis. His clinical and imaging findings were compatible with EB-PA. A novel, small deletion of the last two bases in exon 6 and the first two nucleotides of intron 6 (c.565_566+2del) in ITGB4 gene was identified.


EB-PA-aplasia cutis congenita is known to be a non-treatable condition with a poor prognosis as the reported case. The novel mutation reported in this patient may lead to the lethal form of this disease. Identification of underlying genetic abnormality is critical to give genetic counseling.


Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of inherited skin diseases characterized by blisters followed by skin and mucosal erosions. EB has subgroups based on the ultrastructural level. There are four subgroups: EB simplex, junctional epidermolysis bullosa (JEB), dystrophic EB, and Kindler syndrome [1,2,3].

JEB with pyloric atresia (JEB-PA, OMIM: 226730) is a rare form of EB with multisystem involvement. Cutaneous manifestations, congenital pyloric atresia, and ureteral and renal anomalies such as renal collecting system defects, multicystic/dysplastic kidney, hydronephrosis, and absent bladder are the characteristic features of the disorder [4]. Cutaneous manifestations of JEB-PA include severe mucocutaneus blisters, extreme skin fragility, atrophic scarring, and milia (small white spots). JEB-PA is caused by mutations in the ITGA6 or ITGB4 genes coding for subunit alpha 6 (α6) or beta 4 (β4) of integrin [5, 6]. Additional features shared by JEB-PA include aplasia cutis congenita (ACC) that means congenital localized absence of the skin affecting the extremities, head, nail dystrophy, scarring alopecia, enamel hypoplasia, contractures, and dilated cardiomyopathy [7,8,9].

ITGA6, mapped to 2q31.1, is one of the genes known to cause this phenotype. ITGA6 consists of 28 exons and encodes the integrin α6 which is a member of integrin alpha chain family. On the other hand, ITGB4 is located at 17q25.1 and encodes integrin β4 which is a component α6β4 integrin with integrin α6. Most of the patients with JEB-PA bear pathogenic variants in ITGB4 gene, while ITGA6 mutations are less common. Integrins are heterodimeric transmembrane receptors that play a critical role in cell surface adhesion and signaling. The α6β4 integrin is a hemidesmosomal protein, and its expression is altered by the mutations in ITGA6 and ITGB4 genes that cause structural defects in hemidesmosome [10,11,12].

Here, we describe a clinical case of a newborn with JEB-PA and ACC due to a novel mutation in ITGB4 gene.

Case presentation

A male preterm infant was born at 31 weeks’ gestation by vaginal delivery as the first child to consanguineous parents with a birth weight of 1620 g. On prenatal ultrasonography, gastric dilatation and unilateral hydronephrosis were described. He received positive pressure ventilation at the delivery room and transferred to neonatal intensive care unit after stabilization. On physical examination, the skin was absent on the face, anterior side of the left forearm, both legs, and scrotum. He had multiple bullous lesions on the right arm, along with dystrophic nails. The radiograph of the abdomen showed gastric bubble resembling that of pyloric stenosis (Figs. 1, 2, and 3). Bilateral hydronephrosis and left ureterocele were detected by abdominal ultrasonography. Echocardiography and cranial ultrasonography were normal. The patient was intubated due to respiratory failure at the 2nd day of his life. Skin biopsy was performed and confirmed the diagnosis of EB. During follow-up, intravenous hydration was increased and parenteral nutrition and intravenous albumin were administered. He could not achieve the required stability for surgery and died on the 4th day on his life.

Fig. 1
figure 1

Aplasia cutis from the left arm, legs, and scrotum of the patient

Fig. 2
figure 2

Dystrophic nails of the patient

Fig. 3
figure 3

Radiograph of the abdomen showing gastric dilatation due to pyloric atresia

Written informed consent was obtained from the parent of the patient.

Genetic studies

Genomic DNA was isolated from 200 μL of peripheral blood sample of the patient and his parents using Magna Pure LC DNA Isolation Kit-Large Volume and Magna Pure LC instrument (Roche Applied Science, Mannheim, Germany). All exons and the flanking regions of ITGA6 and ITGB4 were amplified by polymerase chain reaction using the 100 ng genomic DNA (the 260/280 ratios of DNA samples were ~ 1.8) as a template for each PCR reaction. Conditions and primers for generating PCR products spanning all exons of the coding regions and flanking intronic sequences of the genes have been previously described elsewhere [6, 13]. After that, bidirectional Sanger sequencing analysis was performed using BigDye Terminator v3.1 Cycle Sequencing Kit on an ABI PRISM 3130 Genetic Analyzer (Thermo Fisher Scientific, Waltham, MA, USA).

A novel homozygous c.565_566+2del mutation was found in ITGB4 gene of the patient. His parents were found to be heterozygous for the same mutation (Fig. 4). This homozygous deletion in ITGB4 disrupts the intron 6 donor splice site and expected to result in aberrant splicing and loss of function for the encoded β4 integrin subunit. This variant was not listed in the 1000 Genomes ( or in the ExAC database (

Fig. 4
figure 4

Electropherogram of the index and his parents


Here, we describe a case with JEB-PA and ACC emerging from a novel splice site mutation in ITGB4 gene. EB is an inherited disease with an estimated frequency at 1 in 300,000, whereas pyloric atresia (PA) has an incidence of 1 in 100,000 live births. Familial PA with EB was first described in 1968, and pathophysiology was first described by Carmi, so the disease has been called as “Carmi syndrome.” Gastrointestinal, urinary, pulmonary, and eye involvement are also reported to be associated with EB-PA. ACC has been previously described with EB-PA in few reports. Literature shows that JEB-PA-ACC is the most severe spectrum of the disease and suggested that ACC is the poorest prognostic factor of the combination [7,8,9, 11, 14].

Mutations in ITGA6 and ITGB4 cause an altered expression of α6β4 integrin resulting in a structural defect of hemidesmosome which has an important role in stabilizing the association of the dermis with the epidermis. The defective hemidesmosomes cause blisters and erosions on the skin and gastrointestinal and urogenital abnormalities [11, 15]. Mutations in ITGA6 are less frequent than in ITGB4 [16]. There are more than 80 mutations that cause EB-PA and some of them are lethal. In lethal cases, the expression of α6β4 integrin is absent [17]. We identified a novel, small deletion of the last two bases in exon 6 and first two nucleotides of intron 6 (c.565_566+2del) in ITGB4 gene in our patient with Carmi syndrome and ACC. This mutation causes splicing defect and premature stop codon which is responsible for the clinical features of our patient.


EB-PA-ACC is known to be a non-treatable condition with a poor prognosis. There are few patients reported to be survived [16]. Although our patient was a premature baby and intestinal surgery could not be performed, we thought that the novel mutation reported in this patient may lead to a lethal form of the disease. Identification of underlying genetic abnormality is critical to give genetic counseling.

Availability of data and materials

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Aplasia cutis congenita


Epidermolysis bullosa


Epidermolysis bullosa with pyloric atresia


Junctional epidermolysis bullosa


Junctional epidermolysis bullosa with pyloric atresia


Junctional epidermolysis bullosa with pyloric atresia and aplasia cutis congenita


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GT and EO contributed to the conception. CDD, AG, EO, NYK, McGJ, and LL contributed to the acquisition and analysis. NYK, OE, McGJ, and LL contributed to the interpretation of the data. GT, CDD, and EO drafted the work. NYK, OE, BA, and SA critically revised the manuscript. GT, CDD, AG, EO, NYK, OE, BA, SA, McGJ, and LL approved the final manuscript.

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Correspondence to Emel Okulu.

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Okulu, E., Durmaz, C.D., Tunc, G. et al. A novel mutation in ITGB4 gene in a newborn with epidermolysis bullosa, pyloric atresia, and aplasia cutis congenita. Egypt J Med Hum Genet 21, 16 (2020).

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