Novel compound heterozygous mutations of ECM1 in a Chinese family with lipoid proteinosis

Wei Wu; Jian-Qiang Shi; Ding Li; Fang-Gu Li; Yan-Xia Cai; Di-Qing Luo

doi:10.4103/ds.ds_23_18

CASE REPORT

Year : 2019 | Volume : 37 | Issue : 2 | Page : 82-85

Novel compound heterozygous mutations of ECM1 in a Chinese family with lipoid proteinosis

Wei Wu¹, Jian-Qiang Shi¹, Ding Li¹, Fang-Gu Li¹, Yan-Xia Cai¹, Di-Qing Luo²
¹ Department of Dermatology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
² Department of Dermatology, The Eastern Hospital of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Date of Submission	20-Jun-2018
Date of Acceptance	15-Sep-2018
Date of Web Publication	17-Jun-2019

Correspondence Address:
Prof. Di-Qing Luo
Department of Dermatology, The Eastern Hospital of The First Affiliated Hospital, Sun Yat-sen University, 183 Huangpu Rd. E., Guangzhou 510700
China
Prof. Jian-Qiang Shi
Department of Dermatology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524000
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_23_18

Abstract

Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by mutations of the ECM1 gene. The common variations of the ECM1 gene are nonsense and missense mutations, and in rare instance, compound heterozygotes may occur. We describe two siblings of LP from a nonconsanguineous family of China who were detected novel compound heterozygous mutations of c. 157C >T(p. R53X) in exon 3 and c. 857G >A (p. C286Y) in exon 7 of the ECM1 gene. Their mother was a carrier of missense mutation of c. 857G >A in exon 7 of ECM1, their father and one of the old sisters were the carriers of nonsense mutation of c. 157C >T in exon 3, respectively. All the carriers presented normally. The results support the opinion that the mutations of the ECM1 gene for LP are of varieties.

Keywords: Chinese, ECM1 gene, genodermatoses, lipoid proteinosis, mutation

How to cite this article:
Wu W, Shi JQ, Li D, Li FG, Cai YX, Luo DQ. Novel compound heterozygous mutations of ECM1 in a Chinese family with lipoid proteinosis. Dermatol Sin 2019;37:82-5

How to cite this URL:
Wu W, Shi JQ, Li D, Li FG, Cai YX, Luo DQ. Novel compound heterozygous mutations of ECM1 in a Chinese family with lipoid proteinosis. Dermatol Sin [serial online] 2019 [cited 2022 Aug 9];37:82-5. Available from: https://www.dermsinica.org/text.asp?2019/37/2/82/259677

Introduction

Lipoid proteinosis (LP), first described by Urbach and Wiethe in 1929 and also known as hyalinosis cutis et mucosae, is a rare autosomal recessive disease, characterized by generalized thickening and scarring of the skin and mucosa which are caused by deposition of hyaline material.^{[1],[2],[3],[4],[5]} It starts in early infancy with a hoarse voice along with various cutaneous manifestations including acneform scar and warty papules and progresses over the years. The beaded eyelid papules along the lid margins are considered to be its classic and most identifiable sign. Sometimes, dental anomaly, baldness, intracalvarium calcification, epilepsy, and mental symptoms may also occur.^[3],[4] LP is a worldwide disease, with high frequency in South Africa,^{[1],[2],[3],[6],[7]} but without gender preponderance.^{[1],[2],[3],[4]} Histology reveals acidophilia mass deposits widespread in dermal papilla and surrounding of blood vessels as well as adnexaes. Up to date, >300 cases have been reported,^[6] of them, about 30 were from India,^[4] and about 50 from China. We here reported two siblings in whom novel compound heterozygous mutations were identified.

Case Reports

Patients and Methods

The two affected patients, from a nonconsanguineous family of Guangdong province, China, were the 20-year-old sister and 18-year-old brother. No other family members including their parents and two other siblings were similarly affected.

The woman was referred for about 20 years' history of beaded papules on the eyelid margins. She was normal outcome at birth, but developed hoarse voice when she was 2 months, and presented transparent papules on her eyelids at the age of 1 year. Then, blisters and impetigoes presented over the face, trunk, and extremities, which cured with atrophic scar and pigmentation leaving behind. Cutaneous examination showed that discrete multiple soft-transparent papules looked like beads distributed bilaterally in the eyelid margins [Figure 1]a, and yellow plaques on the posterior wall of pharynx as well as on the buccal mucosa, with short lingual frenulum resulting in difficulty of tongue-rolling. Atrophic scars with reticular hyperpigmentation around distributed over the face, truck [Figure 1]b, extremities, and buttocks. Pharyngorhinoscopy revealed white pseudomembrane ecphymas and nodules on the commissura posterior of the left vocal cords. Biopsy from a nodule showed cells of stratified pavement epithelium-lined up in order and eosinophilic mass deposition in the dermis that was positively stained for anti-diastase periodic acid–Schiff (PAS) and weakly positive for Congo red. Biopsy from a papule on the eyelid revealed hyperkeratosis, irregular acanthosis, and homogenous eosinophilic material deposition in the dermis, with positive staining for anti-diastase PAS.

Figure 1: Multiple soft-transparent papules looked like bead distributed in the eyelid margins (a) and atrophic scar with reticular hyperpigmentation around on the truck (b) of the female. Yellow translucent, verrucous, keratotic plaques present on the knees (c) and elbows (d) of the male

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The man had similar clinical features with the same progression. However, he had more severe scarring and less serious mucous presentations and was absent for hoarse voice. Yellow translucent, verrucous, and keratotic plaques were also presented on the knees [Figure 1]c and elbows [Figure 1]d. No systemic involvements were present.

For both patients, the laboratory tests including complete blood cell count, biochemical profiles, both stool and urine analysis, immunoglobulin and complements were within the normal limits or negative. Chest X-ray, electrocardiogram, B ultrasound for the abdomen and computed tomography scan for skull were also negative.

After signed informed consents, genomic DNA was extracted from peripheral blood samples obtained from all six individuals of the family, respectively. All exons groups of DNA for the affected woman were sequenced by chip capture high-flux sequencing. All mutations and potential pathogenic variants were validated using conventional Sanger sequencing methods. Other members from the family were validated mutable sites by the Sanger sequencing method.

DNA samples from 100 unrelated healthy Chinese individuals (under institutional approval and in concordance with the Declaration of Helsinki) were also collected as a control group. Polymerase chain reaction amplification of the ECM1 gene was performed for healthy individuals.

Results

Sequencing DNA from the affected individuals disclosed novel compound heterozygotes for a nonsense/missense combination of mutations of ECM1 gene which were c. 157C > T (p. R53X) in exon 3 and c. 857G > A (p. C286Y) in exons 7, respectively. Their mother was detected missense mutation of c. 857G > A on one allele, and their father, as well as one of their old sister, were nonsense mutation of c. 157C > T on one allele. No mutations were detected in the rests. The pedigrees of the patients with LP are shown in [Figure 2]. No similar mutations of ECM1 gene were detected in the control group.

Figure 2: Pedigrees of the patients with LP. Affected individuals are shown as filled both hemi-blue and hemi-black symbols, whereas heterozygous patients are shown as hemi-blue for c. 157C >T (p.R53X) in exon 3 and hemi-black for c. 857G >A (p.C286Y) in exon 7 of ECM1 gene, respectively (a). The results of sequencing EMC1 gene show compound heterozygous mutations of c. 157C >T (p.R53X) in exon 3 and c. 857G >A (p.C286Y) in exon 7 for the affected siblings, and heterozygous mutation of c. 157C >T in exon 3 for their father as well as their oldest sister, and heterozygous mutation of c. 857G >A in exon 7 for their mother (b)

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Discussion

LP primarily involves the larynx, skin, and tongue, with the possible involvement of all organs. Its diagnosis is based on the typical clinical features and histopathology as well as genetic investigation. Based on the clinical and histopathological manifestations and the genetic mutations, the present patients can be diagnosed with LP. Fortunately, both patients had cutaneous and mucosal involvement alone, without any systemic associations.

It is until 2002 that the mutations of ECM1 gene located on lq21, comprising 10 exons and encoding for the extracellular matrix protein, were revealed to be responsible for LP.^[8] The mutations of ECM1 in LP have been shown to affect both genders equally,^{[1],[2],[3],[4]} but are infrequent, variable, and recessive in nature.^[9] Up to date, >50 different mutations have been described,^[7],[10] including insertions/deletions, nonsense, missense, and splice site mutations. Among them, about 40 are homozygous mutations, and 13 compound heterozygotes, the most common mutations are located on exon 6, then exon 7.^[10] Therefore, these two exons are recommended as the initial targets to analyze in efficiently determining the molecular pathology in suspectable LP. As most mutations in the ECM1 gene are specific to individual families, it seems to be no clear paradigm for genotype-phenotype correlation.^[2] The present study showed that both patients were compound heterozygous mutations of ECM 1 gene with a pathogenic nonsense mutation c. 157C > T in exon 3 and a missense mutation c. 857G > A in exon 7. The C > T transition at nucleotide 157 in exon 3 of ECM1 gene, mimicking the previous report,^{[3],[11],[12]} changes the codon for arginine at amino acid position 53 into a stop codon (p.R53X), predicting premature termination of ECM1 with 52 amino acids instead of 540 amino acids of the its normal protein. The G > A transition at nucleotide 857 changes the codon for cysteine at amino acid position 286 into tyrosine (p.C286Y) in exon 7, which, to our knowledge, had never been reported before. However, with SIFT and polyphen analysis, the protein was predicted to be harmful. As the present mutations were not found in the control group, it is suggested that such kinds of mutation are not polymorphisms. Clinical manifestations of LP presented when the patient had compound heterozygotes while no presentations showed when the individuals had point mutation in one allele, suggesting that the present patients were autosome recessive inherited, and the compound heterozygotes were responsible for the disease. Of course, the mechanisms need further study. Although only a few compound heterozygotes in ECM1 gene have been reported up to date, based on the present cases, we supported the opinion that compound heterozygotes may be more frequent than we anticipated, especially in nonconsanguineous families.^[13]

The treatment of LP is still challengeable. Although various treatment modalities including dimethyl sulfoxide, etretinate, acitretin, penicillamine, surgical procedures, carbon dioxide laser, plastic surgery, and dermabrasion have been tried with different responses,^[4],[14] however, no recommended therapeutics have been established up to date. Fortunately, LP is a benign disorder with good prognosis.

Acknowledgments

The authors sincerely thank the patients and their parents as well as their siblings participating in the present work.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for 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

The present work was supported by the National Natural Science Foundation of China (number: 81472880).

Conflicts of interest

There are no conflicts of interest.

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