Skip to main content

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

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

Fig. 2

Dystrophic nails of the patient

Fig. 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

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

Not applicable.



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


  1. 1.

    Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A et al (2008) The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 58:931–950

    Article  Google Scholar 

  2. 2.

    Fine JD (2010) Inherited epidermolysis bullosa: recent basic and clinical advances. Curr Opin Pediatr 22:453–458

    Article  Google Scholar 

  3. 3.

    Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, Heagerty A et al (2014) Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol 70:1103–1126

    Article  Google Scholar 

  4. 4.

    Pfendner EG, Lucky AW (1993) Epidermolysis bullosa with pyloric atresia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, Amemiya A (eds) . GeneReviews (R), Seattle

    Google Scholar 

  5. 5.

    Vidal F, Aberdam D, Miquel C, Christiano AM, Pulkkinen L, Uitto J et al (1995) Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet 10:229–234

    CAS  Article  Google Scholar 

  6. 6.

    Pulkkinen L, Kimonis VE, Xu Y, Spanou EN, McLean WH, Uitto J (1997) Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Hum Mol Genet 6:669–674

    CAS  Article  Google Scholar 

  7. 7.

    Maman E, Maor E, Kachko L, Carmi R (1998) Epidermolysis bullosa, pyloric atresia, aplasia cutis congenita: histopathological delineation of an autosomal recessive disease. Am J Med Genet 78:127–133

    CAS  Article  Google Scholar 

  8. 8.

    Birnbaum RY, Landau D, Elbedour K, Ofir R, Birk OS, Carmi R (2008) Deletion of the first pair of fibronectin type III repeats of the integrin beta-4 gene is associated with epidermolysis bullosa, pyloric atresia and aplasia cutis congenita in the original Carmi syndrome patients. Am J Med Genet A 146A:1063–1066

    CAS  Article  Google Scholar 

  9. 9.

    Kayki G, Bozkaya D, Ozaltin F, Orhan D, Kaymaz F, Kaymaz E et al (2017) Epidermolysis bullosa with pyloric atresia and aplasia cutis in a newborn due to homozygous mutation in ITGB4. Fetal Pediatr Pathol 36:332–339

    CAS  Article  Google Scholar 

  10. 10.

    Charlesworth A, Gagnoux-Palacios L, Bonduelle M, Ortonne JP, De Raeve L, Meneguzzi G (2003) Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. J Invest Dermatol 121:1344–1348

    CAS  Article  Google Scholar 

  11. 11.

    Chung HJ, Uitto J (2010) Epidermolysis bullosa with pyloric atresia. Dermatol Clin 28:43–54

    CAS  Article  Google Scholar 

  12. 12.

    Kim JH, Park HY, Lee HJ, Eom M, Choi EH (2011) Case of epidermolysis bullosa with pyloric atresia. Ann Dermatol 23 Suppl:S41–S44

    Article  Google Scholar 

  13. 13.

    Pulkkinen L, Kim DU, Uitto J (1998) Epidermolysis bullosa with pyloric atresia: novel mutations in the β4 integrin gene (ITGB4). Am J Pathol 152:157–166

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Pulkkinen L, Uitto J (1999) Mutation analysis and molecular genetics of epidermolysis bullosa. Matrix Biol 18:29–42

    CAS  Article  Google Scholar 

  15. 15.

    Geuijen CA, Sonnenberg A (2002) Dynamics of the alpha6beta4 integrin in keratinocytes. Mol Biol Cell 13:3845–3858

    CAS  Article  Google Scholar 

  16. 16.

    Nakano A, Pulkkinen L, Murrell D, Rico J, Lucky AW, Garzon M et al (2001) Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res 49:618–626

    CAS  Article  Google Scholar 

  17. 17.

    Pulkkinen L, Rouan F, Bruckner-Tuderman L, Wallerstein R, Garzon M, Brown T et al (1998) Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. Am J Hum Genet 63:1376–1387

    CAS  Article  Google Scholar 

Download references





Author information




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.

Corresponding author

Correspondence to Emel Okulu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written parental informed consent was obtained for the publication of this clinical report and images.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


  • Epidermolysis bullosa
  • Carmi syndrome
  • Integrin alpha 6
  • Integrin beta 4