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Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 80-83

A mother with 3-month amenorrhea and 8-month-old dystrophic epidermolysis bullosa mitis child: Practical difficulties in genetic diagnosis

Department of Dermatology, Smt NHL Municipal Medical College, Ahmedabad, Gujarat, India

Date of Submission19-Aug-2020
Date of Decision15-Sep-2020
Date of Acceptance30-Sep-2020
Date of Web Publication27-Apr-2021

Correspondence Address:
Dr. Raju Chaudhary
Department of Dermatology, Smt NHL Municipal Medical College, Ahmedabad - 380 006, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpai.jpai_7_20

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Epidermolysis bullosa (EB) is a congenital blistering disorder, classified into three types based on the level of split in the skin as simplex, junctional and dystrophic. Here, the authors reports a mother who had 13 weeks of amenorrhea and brought an 8-month-old male infant presenting with multiple blisters and erosion all over the body, associated with nail changes since birth. On further investigations, histopathological data showed the changes of EB along with Sanger sequencing and next-generation sequencing (NGS) technique showing mutation in COL7A1 gene which is confirmatory for EB. Based on clinical, histopathological, and molecular genetics data, the diagnosis of dystrophic EB with less severe mitis variant was made. Screening for the unborn child showed similar mutation, and parents were counseled about the termination of pregnancy but due to social restrains, they refused and an affected child was born with similar features as that of index case.

Keywords: Blistering, COL7A1, dystrophic epidermolysis bullosa, epidermolysis bullosa, genetic diagnosis

How to cite this article:
Chaudhary R, Rathod S, Shah M, Kasundra D. A mother with 3-month amenorrhea and 8-month-old dystrophic epidermolysis bullosa mitis child: Practical difficulties in genetic diagnosis. J Pediatr Assoc India 2020;9:80-3

How to cite this URL:
Chaudhary R, Rathod S, Shah M, Kasundra D. A mother with 3-month amenorrhea and 8-month-old dystrophic epidermolysis bullosa mitis child: Practical difficulties in genetic diagnosis. J Pediatr Assoc India [serial online] 2020 [cited 2022 Sep 25];9:80-3. Available from: http://www.jpai.in//text.asp?2020/9/2/80/314815

  Introduction Top

Epidermolysis bullosa (EB) is an inherited disorder with severe blistering lesions presenting at birth which were classified by Koebner in 1886 as EB simplex, junctional EB and dystrophic EB (DEB).[1] DEB is due to mutation in COL7A1 gene coding for Collagen VII which anchors fibril and adhere Lamina densa with dermis.[2],[3] Patients of DEB present with multiple blisters all over the body, dystrophic nail changes, and dental abnormalities. Diagnosis is made clinically. Confirmation is done by histopathology and molecular genetics study.[4]

A mother with 13 weeks of amenorrhea presented with a 8-month-old child with multiple blisters all over body with superficial raw areas. Clinical suspicion of DEB was made and was confirmed by histopathology and genetic sequencing method when mother was 20 weeks amenorrheic, and screening of amniotic fluid of the unborn child also detected the mutation. Mother was advised for the termination of pregnancy at 24 weeks, but she refused, and affected child was born at full term with similar features as of index case.

  Clinical Case Top

An 8-month-old first-born male child of nonconsanguineous marriage with full term normally delivery, resident of Dahebavla, Ahmedabad – Gujarat presented to the skin outpatient department at our tertiary care center with a chief complaint of the absence of the skin of lower leg since birth and multiple fluid-filled skin lesions which appeared over body after 2 days of birth. Fluid-filled lesions appeared initially over the face, and then gradually over the hands, trunk, and lower limbs. Few were clear fluid filled lesions, and others were red-colored fluid-containing lesions which ruptured on their own within 2 days, leaving behind reddish raw area which healed leaving behind whitish-colored skin within 15 days, as shown in [Figure 1]. Incidentally, it was found that mother was having amenorrhea of unknown duration, and she could not remember her last menstrual cycle. On ultrasonography, she was found to have 13 weeks of amenorrhea. Parents were further investigated if there was similar kind of disease in any other family members or not, but there was no history of similar complaint in family members.
Figure 1: (a) Bullous lesions and superficial erosions show postinflammatory hypopigmentation on the body. (b) Milia formation on the face. (c) Bullous lesions and superficial erosions on the right lower leg. (d) Bullous lesion on the right foot

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As shown in [Figure 1], on examination, a single well-defined approximately 1 cm × 1 cm sized superficial erosion with erythematous base and peripheral brownish crusting was present over the right side of nasal bridge and right cheek. Multiple well-defined discrete superficial erosions with brownish crusting were present over trunk, both upper limbs, both lower limbs. Single well-defined clear fluid filled bulla of 3 cm × 2 cm sized was present over the right lower limb. Single well-defined hemorrhagic bulla of 5 cm × 4 cm sized was present over dorsal of the right foot. Multiple well-defined millet sized whitish papular lesions were present all over the face (mainly over forehead), trunk, back, both upper limbs, and both lower limbs. Multiple well-defined variously sized discrete superficial erosions with erythematous base were present over the tongue, palate, both buccal mucosae. Genital and anal mucosa were normal. Dystrophic changes were seen in the left ring finger nail.

First, shave biopsy from bullae over the left thigh was sent for histopathology and was diagnostic of EB, as shown in [Figure 2]. We counseled about the availability of genetic testing for the index case ad despite economic constraints parents agreed for testing. Clinical exome analysis by the next generation sequencing (NGS) was done on Index case EDTA blood after 1 week of the biopsy report which took about 6 weeks to process and pathogenic heterozygous variant c. 7051G >A (p.Gly2351Arg) mutation in COL7A1 gene was found which was later confirmed by Sanger Sequencing within the period of 2 weeks, as shown in [Figure 3]a. Meeting up to the financial requirement and certain social restriction, the chromosomal analysis by karyotyping (ISCN format) was done from Amniotic Fluid after NGS report of Index case, and no abnormality in number as well as structure was found as shown in [Figure 3]b. A little delay due to economic status of patient was done in prenatal mutation confirmation by Sanger Sequencing on amniotic fluid sample which indicated that Mutation c. 7051G >A (p.Gly2351Arg) in COL7A1 gene was heterozygous positive, as shown in [Figure 3]c. Parents were counseled about the termination of pregnancy at 20 weeks, but they refused to terminate because of some social reason. Testing of index case parent's sample was done when mother was 22 weeks amenorrheic, mutation in father's blood as confirmed by NGS after the processing period of 2 weeks, as shown in [Figure 4]. Index case died at 14 months of age due to unknown cause.
Figure 2: Histopathological section from shave biopsy of fluid-filled bulla showing epidermis and dermis. There is the presence of subepidermal bullae formation with mild inflammatory cells infiltrate

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Figure 3: (a) Sanger sequencing of EDTA blood of the patient shows pathogenic heterozygous variant c. 7051G >A (p.Gly2351Arg) mutation in COL7A1 gene. (b) Cytogenetic analysis of long-term fibroblast culture revealed a normal karyotype with no structural and numerical chromosomal abnormalities in amniotic fluid. (c) Testing of amniotic fluid sample indicates that mutation c. 7051G >A (p.Gly2351Arg) in COL7A1 gene looks heterozygous positive

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Figure 4: Testing of EDTA blood of patient's father shows pathogenic heterozygous variant c. 7051G >A (p.Gly2351Arg) mutation in COL7A1 gene

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Index case's younger sister was born after 20 weeks of testing the index case, and she was also having the similar features as the patient, as shown in the [Figure 5]a and [Figure 5]b, she died at 8 weeks after birth due to unknown cause.
Figure 5: (a) Similar bullous lesions and superficial erosions on the face and hands since birth in younger sister of the patient. (b) Similar bullous lesions and superficial erosions over the hand and buttock since birth in younger sister of the patient. (c) The flowchart of clinical and laboratory workup along with time line

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In the following flow chart as shown in [Figure 5]c, we have mentioned the clinical and laboratory work up with its time line.

  Discussion Top

Inherited epidermolysis bullous is divided into three types depending on the level of split in the cutaneous layer. They are EB simplex (EBS), junctional EB and DEB. DEB is further divided into dominant DEB, recessive DEB, and severe generalized recessive DEB.[1] DEB is due to split in sublamina densa with epidermis and lamina lucida forming the roof and dermis forming the floor. It is caused by the mutation in COL7A1 gene, and its subtypes are Cockaine-Touraine, Pasini, Hallopeau-Siemens and the recessive mitis dystrophic form.[3],[4],[5] From the epidemiological data obtained from the United states of America, the incidence of inherited EB is 50/100,000 population 92% being EB simplex, 5% DEB, 1% EB junctionalis, and 2% are nonclassified EB.[6] Previously known as Hallopeau-Siemens type, severe generalized recessive DEB present manifest at birth with the formation of fluid-filled bulla at trauma prone site which heals with minimal scarring and milia formation. Fluid-filled bulla over the hands which ruptures and heals by stricture leads to “mitten hand”. They can be oral bullous lesions, adhesion of tongue to the floor, dystrophic teeth and dental caries, associated with chances of developing squamous cell carcinoma.[7] In the recessive variant, there is less serious blistering, dental abnormalities, and nail changes. Dominant variant of DEB starts at birth with blistering at trauma prone sites. Oral and esophageal lesions in DEB can lead to malnutrition, leading to abnormal facial growth, marked dentoalveolar development, and dental crowding.[8] Mitis form shows the mutation in COL7A1 with replacement of glycine (most frequent mutation), and there can be quantitative or qualitative mutation which can lead to phenotypic variation.[3],[9] Investigations include a skin biopsy, immunofluorescence antigen mapping, transmission electron microscopy, and EB-related monoclonal antibodies. New diagnostic modalities include next-generation whole-exome sequencing of EDTA blood.[10] According to Sampaio and Rivitti, treatment includes Vitamin supplementation, Hydantoin (believed to be inhibitor of collagenase), and steroid therapy. However, according to Pai S and Marinkovich, there is no role of steroids as this is a genetic disorder. Treatment includes basic barrier nursing including care of ulceration and wounds and nutritional supplementation.[11] Ortiz-Urda et al. tried injection intraepidermal fibroblast injection which was thought to increase the expression of type VII collagen.[12] Complications include the development of squamous cell carcinoma which can be due to increase proliferation of keratinocytes due to repeated trauma, and it mostly occurs in the extremities.[13]

Congenital blistering disorders should be carefully examined and diagnosed with all the molecular and genetic facilities that are available. It is necessary to counsel parents regarding its inheritance in future generation. It is also necessary to make the diagnosis in time in such cases, when diagnosis of one child could lead to proper decision regarding future child.

In countries like India where the facilities for diagnosing a rare genetic disease are limited, and people are restrained to their social orthodoxy it is must to formulate a plan for diagnosing the disease. Termination of pregnancy was advised at 24 weeks of pregnancy which could have been done legally according to 2014 amendment of MTP Act in India but parents refused.[14]

This case is reported because of rarity of the disease occurrence, and a mitis variant which is less frequent presentation and only few cases have been reported so far as per author's knowledge, economic, and social difficulties related to the process of diagnosis in our country as well as the importance of timely diagnosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, et al. The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008;58:931-50.  Back to cited text no. 1
de Almeida Jr HL. Genética Molecular das Epidermólises Bolhosas Molecular Genetics of Epidermolysis Bullosa. An Bras Dermatol 2002;77:519-32.  Back to cited text no. 2
Ryoo YW, Kim BC, Lee KS. Characterization of mutations of the type VII collagen gene (COL7A1) in recessive dystrophic epidermolysis bullosa mitis (M-RDEB) from three Korean patients. J Dermatol Sci 2001;26:125-32.  Back to cited text no. 3
Vaccaro M, Moretti G, Guarneri F, Cannavò S, Magaudda L. “Sporadic” dystrophic epidermolysis bullosa: A new dominant or mitis recessive mutation? Eur J Dermatol 2000;10:436-8.  Back to cited text no. 4
Hashimoto I, Kon A, Tamai K, Uitto J. Diagnostic dilemma of “sporadic” cases of dystrophic epidermolysis bullosa: A new dominant or mitis recessive mutation? Exp Dermatol 1999;8:140-2.  Back to cited text no. 5
Horn HM, Tidman MJ. The clinical spectrum of dystrophic epidermolysis bullosa. Br J Dermatol 2002;146:267-74.  Back to cited text no. 6
Bruckner-Tuderman L. Dystrophic epidermolysis bullosa: Pathogenesis and clinical features. Dermatol Clin 2010;28:107-14.  Back to cited text no. 7
Shah H, McDonald F, Lucas V, Ashley P, Roberts G. A cephalometric analysis of patients with recessive dystrophic epidermolysis bullosa. Angle Orthod 2002;72:55-60.  Back to cited text no. 8
Betts CM, Posteraro P, Costa AM, Varotti C, Schubert M, Bruckner-Tuderman L, et al. Pretibial dystrophic epidermolysis bullosa: A recessively inherited COL7A1 splice site mutation affecting procollagen VII processing. Br J Dermatol 1999;141:833-9.  Back to cited text no. 9
Shinkuma S. Dystrophic epidermolysis bullosa: A review. Clin Cosmet Investig Dermatol 2015;8:275-84.  Back to cited text no. 10
Pai S, Marinkovich MP. Epidermolysis bullosa: New and emerging trends. Am J Clin Dermatol 2002;3:371-80.  Back to cited text no. 11
Ortiz-Urda S, Lin Q, Green CL, Keene DR, Marinkovich MP, Khavari PA. Injection of genetically engineered fibroblasts corrects regenerated human epidermolysis bullosa skin tissue. J Clin Invest 2003;111:251-5.  Back to cited text no. 12
Bosch RJ, Gallardo MA, Ruiz del Portal G, Snchez P, Arce MF, Herrera E. Squamous cell carcinoma secondary to recessive dystrophic epidermolysis bullosa: Report of eight tumours in four patients. J Eur Acad Dermatol Venereol 1999;13:198-204.  Back to cited text no. 13
Draft Medical Termination of Pregnancy (Amendment) Bill, 2014. New Delhi: Maternal Health Division, Ministry of Health & Family Welfare, Government of India; 2014. p. 5. Available from: https://mohfw.gov.in/sites/default/files/74582186651414643779.pdf. [Last accessed on 2020 Feb 13].  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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