Ocular Manifestations Leading to the Diagnosis of Pseudoxanthoma Elasticum with a Novel Heterozygous ABCC6 Mutation: A Case Report

Abstract

Introduction

Pseudoxanthoma elasticum (PXE) is a progressive hereditary disease caused by the calcification and degeneration of elastic fibers, affecting the skin, retina, blood vessels, and gastrointestinal tracts. The gene responsible is the ATP-binding cassette subfamily C member 6 (ABCC6).

Case Presentation

A 47-year-old man presented to an ophthalmologist with a right eyelid contusion. Fundus examination revealed right macular hemorrhage and bilateral angioid streaks. PXE was suspected due to skin lesions around the neck and abdomen; he was referred to our dermatology department. Histopathological examination revealed degenerated anucleate elastic fibers with calcification in the mid-dermis. Genetic testing revealed a previously unreported heterozygous ABCC6 mutation. We established a diagnosis of PXE based on characteristic skin lesions and histopathological findings triggered by ocular manifestations. Based on in silico analysis, the ABCC6 gene mutation was predicted to be pathogenic.

Conclusion

In some PXE cases, the ABCC6 gene mutation can be undetectable or only one mutation is detected; PXE could be diagnosed based on clinical and histopathological symptoms. When characteristic skin and eye lesions are observed, appropriate evaluation is required. Genetic testing facilitates early diagnosis and the discovery of novel mutations, contributing to a deeper understanding of the disease spectrum.

Introduction

Pseudoxanthoma elasticum (PXE) is an autosomal recessive hereditary disorder characterized by progressive calcification and fragmentation of elastic fibers, leading to cutaneous, ocular, and cardiovascular manifestations [1]. This disorder is attributed to mutations in the ABCC6 gene [1]. This report describes a case of PXE that was first identified by an ophthalmologist due to macular hemorrhage and angioid streaks (AS), leading to a dermatological referral. This represents an unusual diagnostic pathway as the disease is usually first detected through dermatological involvement. Furthermore, a previously unreported heterozygous ABCC6 mutation was identified, providing novel insights into the genetic spectrum of PXE.

Case Report

A 47-year-old man noticed skin lesions on his neck since childhood but was left untreated as he was asymptomatic. He presented to a local ophthalmologist with a right eyelid contusion 3 months prior. Fundus examination demonstrated a right macular hemorrhage and bilateral AS. Due to the presence of yellowish papules on the neck and abdomen, PXE was suspected, and the patient was referred to the Dermatology Department. The patient had no relevant medical or family history. Physical examination revealed yellowish papules on the neck and abdomen (Fig. 1a and b). Dermoscopy was not performed during the initial dermatologic examination; therefore, dermoscopic images are not available. Laboratory workup, including blood coagulation studies, chest radiography, computed tomography (CT), and echocardiography, revealed unremarkable findings. Skin biopsy from the neck revealed rope-like, curled, and degenerated anucleate materials in the mid-dermis on hematoxylin and eosin staining (Fig. 1c, d). The degenerated material comprised elastic fibers that stained purple using the elastic Van Gieson stain and purple-black and showed calcium deposition using the Von Kossa stain with calcification (Fig. 1e, f). His fundus examination revealed AS (Fig. 1g, h). Direct sequencing identified a heterozygous ABCC6 mutation: Ex29, c.4070G>A, p.R1357Q. Multiplex ligation-dependent probe amplification showed no exon deletions. Based on the criteria described by Iwanaga et al. [1], the patient met the following aspects: characteristic skin lesions, fundoscopic examination, and histopathological features. The diagnosis of PXE was thereby established. The patient has undergone regular follow-ups for 4 years, with stable skin or ocular lesions, using topical corticosteroids as needed for pruritus. No systemic complications have been identified. A timeline is shown for clarity (Fig. 2).

Fig. 1.

a, b Yellowish papules on the neck and abdomen. c, d Hematoxylin-eosin-stained section shows altered anucleate material in the dermis (yellow circle): ×40 (c), ×200 (d). e The elastica Van Gieson staining shows degenerated elastic fibers (blue arrow) (×200). f The von Kossa staining shows calcification in degenerated elastic fibers (red arrow) (×200). g, h Fundus photographs of bilateral eyes showing AS (arrowheads): left (g), right (h).

Fig. 2.

Timeline of events.

Discussion

PXE is estimated at 1 per 25,000–100,000 habitants, with a 2:1 female preponderance and no racial or ethnic preferences [2]. It is a multisystem disorder involving mineralization and degeneration of elastic fibers in the skin, retina, and vascular system [3]. Cutaneous findings include yellowish-white papules and plaques, typically on the neck, axilla, cubital fossa, inguinal lesions, and around the umbilicus [1]. Differential diagnosis includes vitamin K-dependent coagulation factor deficiency, which was excluded based on normal coagulation tests, and ENPP1-related generalized arterial calcification of infancy: excluded due to the absence of vascular or periarticular calcification [3].

Because only one heterozygous mutation was identified, this result alone does not explain the development of PXE. Previous reports suggested the presence of secondary variants, including deep intronic variants, as a cause of the disease [4]. In vitro splicing assays have also shown that intronic variants outside canonical splice sites can disrupt normal splicing [5]. In addition, multiplex ligation-dependent probe amplification has technical limitations, including the inability to detect allelic variants that do not involve quantitative changes in the DNA as a whole [6] or identify variants located outside the probe target regions [7]. Furthermore, aberrant DNA methylation affecting multiple ABC transporter genes was observed [8], suggesting that epigenetic mechanisms, such as promoter methylation, may regulate ABCC6 expression and potentially act as disease modifiers in patient with PXE.

This case adds to the understanding of genotype-phenotype correlations in patients with PXE. Reviewing this case together with previous reports of Ex29 variants (Table 1) [9–11] suggest that missense variants around residue 1,357 and 1,400 are associated with typical skin manifestations and AS, indicating the functional importance of this region. Exon 29 of the ABCC6 gene apparently is a mutation hotspot; previously reported variants at codon 1,357 include p.R1357W, which has been associated with AS [12]. Our patient harbored a different substitution, p.R1357Q, which is located within the second nucleotide-binding domain (NBD), a region critical for ATP binding, hydrolysis, and NBD-NBD dimerization [13]. Taken together, these findings suggest that this sequence change represents a previously unreported ABCC6 mutation. The loss of positive charge resulting from the Arg→Gln substitution might disrupt the electrostatic environment, potentially impairing NBD folding or inter-domain interactions and thereby compromising transporter function.

Table 1.

Summary of reported ABCC6 exon 29 variants and associated clinical features

Author	Sex, age	Skin lesion	AS	CVD	ABCC6 mutation
Jin et al. [9]	F, 32	+	+	–	Ex29, c.4192C>T, p.R1357T
			​	​	Heterozygous
Noji et al. [10]	F, 23	+	+	+	Ex26, c.3661C>T, p.R1221C
			​	​	Ex29, c.4069C>T, p.R1357W
Chassaing et al. [11]	F, 26	+	–	–	Ex24, c.3421C>T, p.R1141X
			​	​	Ex29, c.4198G>A, p.E1400K
	F, 20	+	–	–	Ex29, c.4198G>A, p.E1400K
			​	​	Homozygous
	M, 18	+	–	+	Ex29, c.4198G>A, p.E1400K
			​	​	Homozygous

AS, angioid streaks; CVD, cardiovascular disease.

A possible explanation for the absence of cardiovascular manifestations in this patient is that greater arterial calcification volume on CT is associated with an increased risk of cardiovascular events [14]. In the present case, arterial calcification was not clearly detectable on CT imaging.

The effect of the ABCC6 mutation in the present case was predicted using in silico analysis with Ensemble (http://asia.ensembl.org). This mutation is a single-nucleotide polymorphism (SNP), rs201275608, with SIFT:0, Polyphen2:1. This mutation was considered a possible pathogenic mutation. A comprehensive review of the PubMed literature on PXE over the past 25 years revealed no instances of this substitution. Moreover, a search of the ClinVar database (accessed on December 22, 2025) identified no entries corresponding to ABCC6 Ex29, c.4070G>A, p.R1357Q. The mutation lacks a Variation ID, has no clinical significance submissions, and has not been reported by any contributing clinical laboratories. Furthermore, this variant was not found in major public variant databases, including the HGMD (public), gnomAD (v4.0), dbSNP, or LOVD. Taken together, these findings indicate that this sequence change represents a previously unreported ABCC6 mutation.

This case highlights the importance of clinical and histopathological evaluation in diagnosing PXE, particularly when genetic findings are inconclusive. Timely recognition and ongoing follow-up remain essential for detecting systemic complications. In some cases, the ABCC6 gene mutation is undetectable or only one mutation is detected; however, in others, PXE diagnosis is based on clinical symptoms. Importantly, dermatologists should not overlook the characteristic skin lesions of PXE and appropriately examine them. Genetic testing can detect new mutations. Further studies are needed to clarify the differences in the onset of symptoms and complications and determinants of prognosis and treatment strategies.

Patient Perspective

The patient felt reassured to receive an established diagnosis and expressed relief that his skin and ocular findings have remained stable during regular follow-up.

Statement of Ethics

This study was approved by the Ethics Review Committee of the Department of Dermatology at Fujita Health University, Japan (Approval No.: HG20-065/November 24, 2021). The study was approved by the Ethics Committee and informed consent was obtained from the patient before genetic analysis. Written informed consent was obtained from the patient for the publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material at https://doi.org/10.1159/000550862.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The sponsor or funder had no role in any of the above. No funding was received for this study.

Author Contributions

Akihiro Fukuta: conception and design of the case report; writing – original draft, drafting, review, and editing; and approving final version to be published. Yohei Iwata: clinical diagnosis, relevant paraclinical examination, conception and design of the case report, and writing and editing of the original draft review. Rena Yasuda: writing – original draft, drafting, review, and editing. Akira Iwanaga and Hiroyuki Murota: writing, review, and editing of the genetic mutation analysis. Kazumitsu Sugiura: conception and design of the case report and writing and editing of the original draft review.

Funding Statement

The sponsor or funder had no role in any of the above. No funding was received for this study.

Data Availability Statement

The data that support the findings of this report are not publicly available because they contain information that could compromise the privacy of the research participants. Further inquiries can be directed to the corresponding authors.