Abstract
Introduction
Lipoid proteinosis (LP), a rare autosomal recessive disorder typified by generalized thickening of the skin, mucosa, and certain viscera, is associated with pathogenic ECM1 variants. Skin lesions like beaded eyelid papules, acneiform scars, wavy, yellow papules and nodules typically appear in early childhood. Some patients may exhibit neurological abnormalities like temporal lobe or hippocampi-amygdala complex calcification, epilepsy, and neuropsychiatric abnormalities.
Methods
We included 15 individuals with LP from 10 unrelated families. The study includes clinical evaluations of family history, radiological findings, histopathological examination of the skin, and genetic investigations.
Results
All affected individuals exhibited skin and mucosal lesions. Among the 15 cases, five (33%) showed neurological symptoms, four (26%) presented neuropsychiatric findings, and three (20%) had diabetes mellitus. We observed characteristic intracranial calcifications in all patients with epileptic seizures. Four out of the five cases with epilepsy and intracranial calcifications also had neuropsychiatric findings. All patients with neurological and neuropsychiatric findings had a frame-shift variant, but the same frame-shift variant was not associated with these findings in other individuals. In our study, no patient with variants other than frame-shift variants exhibited neurological or neuropsychiatric findings. Adrenal calcification, which was observed in 1 patient, was not previously linked to LP.
Conclusion
Our study observed diverse variations in LP cases among the Turkish population, with varying clinical presentation even among individuals with identical variations within the same family. In our series, the lack of correlation between genotype and phenotype makes providing specific genetic counseling to families challenging.
Keywords: Lipoid proteinosis, ECM1, Genotype phenotype, Amygdala calcification
Introduction
Lipoid proteinosis (LP) is a rare genodermatosis, characterized by the accumulation of hyaline in the skin, mucous membranes, and internal organs, inherited in an autosomal recessive manner [1–3]. LP is histologically characterized by periodic Acid-Schiff (PAS)-positive but diastase-resistant hyaline accumulation in the dermal-epidermal junction, thickening of the basal membrane surrounding the vascular and adnexal epithelium, and hyaline deposition in the dermis [3]. Hyaline accumulation in the vocal cords leads to a hoarse voice. At the same time, it manifests as waxy, yellow papules and nodules, hyperkeratosis on the hands, elbows, knees, hips, and axillae exposed to mechanical friction, verrucous lesions, and thickening of the skin [3]. Some patients may exhibit neurological and neuropsychiatric findings, such as temporal lobe or hippocampal-amygdala complex calcifications, epilepsy, memory loss, executive function impairment, aggressive behavior, paranoia, hallucinations, and loss of fear [4, 5]. The incidence of bilateral and symmetric intracranial calcification in the temporal lobes, including the hippocampus and amygdala, remains unknown due to the absence of cranial imaging in all cases [6]. Epilepsy, observed in 25% of LP cases, is unrelated to the presence or absence of brain calcifications [7]. LP is not a life-threatening syndrome unless respiratory distress caused by hyaline accumulation in the upper respiratory tract results in fatality, with the exception of cases lost due to respiratory distress caused by superimposed infections due to hyaline accumulation [2]. The ECM1 gene is the only known gene associated with LP syndrome, encoding an extracellular matrix protein 1 [3]. ECM1 binds to specific sites in the dermal-epidermal junction to various hemidesmosome and extracellular matrix molecules [8]. The ECM1 gene, located at 1q21.2, contains 10 exons, and pathogenic variants are mainly detected on exons 6 and 7 [7]. Some studies do not support the view that variants in exons other than exon 7 are responsible for a more severe mucocutaneous LP phenotype [7]. Cranial imaging was not performed in some of the LP patients, and a definitive correlation between cerebral calcification and pathogenic ECM1 variations has yet to be established [7]. Additionally, there is no clear evidence showing a link between neurological and neuropsychiatric manifestations and a specific genotype [9]. The interpretation of the genotype-phenotype correlation is further complicated by the variable onset of clinical symptoms, the broad age range of affected individuals, and the observed intrafamilial variability [9].
Because the severity of mucocutaneous lesions and/or the presence of neurological and neuropsychiatric findings vary among individuals affected by this syndrome, it is difficult to provide specific genetic counseling to families. Even if both partners with a known carrier status for LP request prenatal diagnosis, a clear foresight of the phenotype cannot be made even if the fetus has an affected genotype. This study aimed to genotype the LP cohort to identify associated variants, investigate possible genotype-phenotype correlations, contribute to the development of treatment modalities by revealing relationships at the cellular or protein level, and thereby add to the existing literature.
Materials and Methods
Samples
We examined 15 affected individuals from 10 families who were referred to the Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, with a clinical diagnosis of LP from different clinics. These cases were evaluated according to their clinical, histopathological, and radiological findings at the Medical Genetics outpatient clinics and were deemed suitable for the study. The study was approved by the Local Ethics Committee, and all patients provided written informed consent.
Molecular Analysis
2 mL of venous blood was collected for DNA isolation after obtaining patient consent. Sequence variants were investigated by Sanger sequencing of all 10 exons of the ECM1 gene (NM_004425.4), including exon-intron boundaries (±20 bp), using the ABI 3500 platform. In family 7, no PCR products were detected in affected individuals for exons 8–10, whereas detectable PCR products were detected in parents or unaffected siblings. Next-generation sequencing was performed to determine the mutation in family 7. Next-generation sequencing libraries of family 7 were enriched using the Swift 2S Turbo DNA Library Kit and the Swift Inherited Diseases Hyp Panel Kit, and these samples were sequenced on the NovaSeq platform (Illumina Inc., CA). Subsequently, these data were analyzed for single nucleotide variants and copy number variations using the SoPHiA DDM™ analysis tool (SOPHiA Genetics SA., Switzerland).
Results
We assessed 15 patients from 10 families diagnosed with LP based on clinical findings, histopathological analysis of skin, neuroimaging studies, and molecular analysis results. Additionally, we investigated potential genotype-phenotype relationships. Cutaneous and mucosal involvement findings were observed in all cases, including acneiform and/or atrophic lesions, papules at the base of the eyelashes, thickening of the tongue and lip mucosa, hoarseness due to laryngeal infiltration, and thickening of the skin on the knees and elbows. Verrucous lesions on the axillae, elbows, and knees were present in 11 of 15 patients (73%). Skin biopsies were performed on eight affected patients from eight families, and histopathological findings were consistent with those of LP. Lesions on the scalp caused patchy alopecia in 2 patients. Neurological and/or neuropsychiatric symptoms were observed in 5 of 15 patients (33%). Among the 5 patients with neurological and/or neuropsychiatric symptoms, brain CT/MR imaging revealed calcifications, whereas 6 out of 10 patients without these findings did not show any evidence of intracranial calcifications on brain CT or MR imaging. All patients with intracranial calcifications exhibited convulsions and/or episodes resembling absence of seizures, impairment of executive functions such as problem-solving and planning, memory loss, aggressive behavior in four out of five, paranoia/hallucination, and fear loss in three out of five (Table 1).
Table 1.
Summary of clinical findings and molecular analysis results of cases
| Family | LP01 | LP02 | LP03 | LP04 | LP05 | LP06 | LP07 | LP08 | LP09 | LP10 | % | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | |
| Consanguinity | + | + | + | + | − | + | + | + | + | + | 9/10 | |||||
| Age (physical examination) | 7 | 24 | 39 | 21 | 31 | 34 | 33 | 22 | 12 | 8 | 5 | 3 | 9 | 17 | 35 | |
| Gender | M | M | F | F | M | F | M | F | M | F | M | M | M | M | F | 6F/9M |
| Acneiform/atrophic lesions | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | 15/15 |
| Papules at the base of eyelashes | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | 15/15 |
| Thickening of the tongue/lip mucosa | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | 15/15 |
| Hoarse voice | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | 15/15 |
| Thickened skin on elbows/knees | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | 15/15 |
| Verrucous lesions | − | + | + | − | + | + | − | + | + | + | + | − | + | + | + | 11/15 |
| Accumulation of hyaline in skin biopsy material | + | + | + | NA | NA | + | NA | NA | + | NA | NA | NA | + | + | + | 8/8 |
| Patchy alopecia | − | − | − | + | − | − | − | − | − | − | − | − | + | − | − | 2/15 |
| Memory loss | − | − | + | − | + | − | + | − | − | − | − | − | − | + | − | 4/15 |
| Convulsion | − | − | + | − | + | − | + | + | − | − | − | − | − | + | − | 5/15 |
| Intracranial calcification | − | − | + | − | + | NA | + | + | − | NA | NA | − | NA | + | − | 5/11 |
| Impaired executive function | − | − | + | − | + | − | + | − | − | − | − | − | − | + | − | 4/15 |
| Paranoia/hallucination | − | − | + | − | + | − | − | − | − | − | − | − | − | + | − | 3/15 |
| Aggressive behavior | − | − | + | − | + | − | + | − | − | − | − | − | − | + | − | 4/15 |
| Loss of fear | − | − | + | − | + | − | − | − | − | − | − | − | − | + | − | 3/15 |
| ECM1 mutation | c.1305-2A>G | c.1305-2A>G | c.735_736delTG | c.735_736delTG | c.709-2A>G | c.826delC | 1163-bp deletion 1163-bp deletion | c.507delT | c.507delT | c.806G>A | ||||||
| c.1441C>T | c.1305-2A>G | c.735_736delTG | c.735_736delTG | c.1411_1412insAT | c.826delC | c.507delT | c.507delT | c.806G>A | ||||||||
The study encompassed ten families, within which a total of nine distinct variants associated with LP were identified; one nonsense (c.1441C>T/p.(Arg481*)/rs370285146), one missense (c.806G>A/p.(Cys269Tyr)/rs756977475), two splicing site substitutions (c.709-2A>G; c.1305-2A>G/rs779368723), three small deletions (c.507delT/p. Arg171Glyfs*7/rs869025565, c.735_736delTG, p.(Cys245*)/rs757039185; c.826delC/p.(Gln276Serfs*40)), and one insertion (c.1411_1412insAT/p.(Leu472Ilefs*19)) resulting in frame-shift to early stop. Additionally, a gross deletion involving exons 9–10 of the ECM1 gene was observed (shown in Fig. 1). In Family LP07, a homozygous 1163-base pair (bp) seq[GRCh38]1q21.2(150512605-150513767) deletion spanning exons 9–10 of the ECM1 gene was detected. In our study, we identified three novel variants (c.709-2A>G, c.826delC, c.1411_1412insAT) associated with LP.
Fig. 1.
Mutations identified in the cases and their localization in the ECM1 gene. Three new mutations are indicated with a star, and homozygous mutations are marked with a double arrow.
Discussion
LP, characterized by the deposition of hyaline-like material in various tissues, is a rare disease worldwide, with over 400 cases reported [10]. It is expected to become more common in populations with a high consanguinity rate, such as in Turkiye. In this study, which examined 15 patients with LP from 10 families across different cities in Turkiye and their clinical and molecular findings, we demonstrated variant diversity in Turkiye.
LP is caused by a homozygous or compound heterozygous loss-of-function mutation in the ECM1 gene [11]. To date, 81 pathogenic variants of ECM1 have been reported in the Human Gene Mutation Database. The variants reported in the literature include missense, nonsense, frame-shift, small, and large deletions/insertions, and splice site variants.
With this study, a total of 13 different variants related to LP have been reported in publications from Turkiye to date. The variants identified in the Turkish population are as follows: c.157C>T (p. Arg53*), c.507delT (p. Arg171Glyfs*7), c.727C>T (p. Arg243*), c.93_94delGCinsTT (p. Arg31delinsSer*), c.826delC (p. Gln276Serfs*40), c.735_736delTG (p. Cys245*), c.806G>A (p. Cys269Tyr), c.1246C>T (p. Arg416*), c.1411_1412insAT (p. Leu472Ilefs*19), c.1305-2A>G, c.709-2A>G, c.1304+33_*300del (1163-bp deletion), c.1441C>T (p. Arg481*) [12–15]. The c.507delT (p. Arg171Glyfs*7) and c.1304+33_*300del (1163-bp deletion) variants were the most frequent variants in Turkiye. In our study, 10 families originating from different provinces in Turkiye were investigated, and 9 different pathogenic variants were identified. The distribution of the detected variants by province is shown in Figure 2.
Fig. 2.
Distribution of mutations detected in our cases by province in Turkey.
In cases of LP, causative variations in ECM1 generally occur in exons 6 and 7, and any other exon 7 outside exon 7 may lead to a more severe mucocutaneous phenotype [11]. Based on the results of a study of 60 cases with different ECM1 alterations, Chan et al. [7] concluded that the phenotype of cases with exon 7 mutations was not milder in terms of skin and mucosal involvement, neurological, and neuropsychiatric findings compared with other cases. In another study investigating the role of genotype-phenotype relationship among South Africans of German origin carrying the same variant (p. Gln276*) in ECM1 due to a founder effect, intrafamilial variability was observed, and no relationship was established between the type and position of the pathogenic mutation and the phenotype [9]. The 1163-bp deletion variant of ECM1 encompassing exons 9 and 10 was found in seven LP families from Şanlıurfa province in Turkiye and has been suggested to be a founder variant in this region [15]. Due to the emergence of LP clinical findings over time and variability in phenotype at the age of onset among individuals, the evaluation of the phenotype has been noted to be challenging [9]. Although brain imaging was not performed in all patients with LP, no association was observed between unique ECM1 variants and cerebral calcifications [7].
In our cohort, nine different variations were associated with LP, and six of them have already been reported in the literature. The c.1305-2A>G gene was reported in a Turkish individual with skin lesions of LP [16]. A neuropsychological evaluation conducted at the age of 17 revealed mild deficits in effect interpretation and visual memory construction, whereas brain MRI at the age of 21 was reported to be normal [16]. In our case (LP02), a 24-year-old man with homozygous c.1305-2A>G, no neurological or neuropsychiatric findings were detected. LP03 and LP04 were found to have a homozygous c.735_736delTG in exon 7 of the ECM1 gene. When the clinical findings of these two cases were compared, LP03 aged 39 years was diagnosed with temporal lobe epilepsy at 18 years of age, and bilateral amygdala calcification was detected. Epigastric sensation, déjà vu, palpitation, macropsia, paresthesia, cognitive decline, hallucination, aggression, and impaired recognition of facial emotional expressions were also observed in this case. Additionally, LP03 had a history of sialadenitis, angioedema, and type 2 diabetes mellitus. LP04, aged 21, did not have calcification on brain imaging and did not exhibit neurological or neuropsychiatric findings. Although there were no differences in other skin involvement findings, LP04 did not exhibit verrucous lesions like LP03 but had more prominent patchy alopecia. In the literature, the c.735_736delTG mutation has been reported in two Turkish siblings aged 14 and 4 years with skin, mucosal, and temporal lobe calcifications showing intrafamilial variability [11]. Neurological and neuropsychiatric findings were present in the LP05 case carrying the compound heterozygous novel mutations c.709-2A>G and c.1411_1412insAT. In family LP06, three affected siblings were found to have different clinical findings, and all had the novel homozygous c.826delC mutation in exon 7. Among the three cases with skin and mucosal involvement, a female patient aged 34 years had no neurological or neuropsychiatric findings, whereas a male sibling aged 33 years had intracranial calcifications, convulsions, memory loss, executive function loss, and aggressive behaviors. The 22-year-old younger sister had more pronounced skin manifestations than her siblings, along with a history of intracranial calcification and seizures, without neuropsychiatric symptoms. Additionally, a male sibling aged 33 years had type 1 diabetes mellitus and a history of cerebrovascular events, and a sister aged 22 years had type 1 diabetes mellitus. This family demonstrates intrafamilial phenotypic variability in patients carrying the same mutation (shown in Fig. 3). Family LP07: Four affected siblings carrying the homozygous deletion involving exons 9–10 of the ECM1 gene were found to have skin and mucosal involvement but did not exhibit any neurological or neuropsychiatric findings. Salih et al. [17] reported a family with a homozygous 1163-bp deletion encompassing exons 9–10 of the ECM1 gene. Three siblings (aged 5, 12, and 18 years) had skin scarring and hoarseness of voice from early childhood but had no gross neurologic, neurodevelopmental, or neuroimaging abnormalities [17]. Neurological findings were also observed in seven LP families from Turkiye who were reported to have this variant [15]. LP08 and LP09, both with the homozygous c.507delT mutation in exon 6 of the ECM1 gene, exhibited skin and mucosal involvement. LP08 (aged 9 years) showed no neurological or neuropsychiatric findings, whereas LP09 (aged 17 years) displayed all the neurological and neuropsychiatric features of the syndrome. Additionally, LP08 developed adrenal calcification. Given the varying ages of individuals with the same mutation and the onset of neurological and neuropsychiatric symptoms in LP09 at the age of 13, it can be concluded that the interpretation of genotype-phenotype relationship is challenging. LP09 two siblings, aged 12 and 19, who had the same mutation presented with milder skin manifestations and no neurological or neuropsychiatric symptoms. A cohort study revealed extensive phenotypic variability in three Iranian families with the same homozygous c.507delT mutation in ECM1 [18]. LP10 (aged 35), manifesting skin and mucosal findings, had no neurological or neuropsychiatric findings, and the c.806G>A mutation was identified. This mutation was previously reported in two siblings aged 12 and 19 with skin and mucosal lesions but no neurological or neuropsychiatric findings [17].
Fig. 3.
Clinical features of three affected siblings in family LP06. a, d (aged 34 years) Skin thickening on the face, verrucous thickening on the elbows, and atrophic lesions. b, e (aged 33 years) Skin thickening on the face and atrophic lesions on the elbows. c, f, g (aged 34 years) Pronounced skin thickening on the face and acne-like lesions, verrucous thickening on the elbows, and atrophic lesions in the axilla.
In our cases, patient LP03 had type 2 diabetes mellitus, whereas 2 affected individuals in LP06 had been diagnosed with type 1 diabetes mellitus. The ECM acts as a reservoir for matricellular proteins and growth factors that can enhance β-cell proliferation and survival [19]. In our series, the frequency of DM was 20%. LP10 reported using medication containing pancreatic enzymes for constipation complaints, which resulted in improved symptoms. In patient LP08 at the age of 6 years, upon nephrological evaluation due to edema in the feet, oliguria, and hypertension, calcification was detected in the adrenal gland. The adrenal calcification has not been reported to be associated with LP.
In our study, all patients with neurological and neuropsychiatric findings had a frame-shift variant, but this same frame-shift variant was not associated with these findings in other individuals. In our study, no patient with variants other than frame-shift variants exhibited neurological or neuropsychiatric findings. This situation raises the question of whether there is an association between the presence of neurological and neuropsychiatric symptoms and the type of the identified variant, specifically whether it is a frame-shift variant. More research is needed to answer this question. The frame-shift variants found in neurological and neuropsychiatric cases affect different domains of ECM1. In a study by Hamada et al. [11], frame-shift variants were identified in 8 out of 10 patients with LP, and neurological findings were reported in 5 of these cases. In contrast, 2 patients with nonsense and missense variants (aged 2 and aged 53) did not exhibit neurological findings [11]. Publications on LP often focus on skin and mucosal findings and sometimes do not address whether neurological findings are present in patients. The patient age may also influence the detection of these findings. In our patients, skin and mucosal symptoms appeared earlier, and neurological symptoms emerged at ages 17, 6, 15, 6, and 13. In the LP06 family, one of the two siblings, aged 33 years, had a hoarse voice since birth and mild skin findings, with seizures beginning at age 15. The sibling that was currently 22 years old had more pronounced skin lesions and began having seizures at the age of 6 years. A 34-year-old sibling who carries the same ECM1 variant did not present with neurological or neuropsychiatric findings. Variable expressivity is common in autosomal dominantly inherited syndromes but is seldom observed in autosomal recessively inherited syndromes [20]. The severity of the mutation’s phenotypic impact can be influenced by allelic heterogeneity, epigenetic factors, gene-environment interactions, age and gender effects, modifier genes, copy number variations, and SNPs [20]. LP03 and LP04, despite carrying the same homozygous mutation and homozygous rs11801190 polymorphism, are discordant in terms of neurological and neuropsychiatric findings. Different phenotypes were observed in cases with the same mutation, and no relationship was established between the type or location of the mutation and the phenotype.
In conclusion, our study demonstrated the clinical findings and variant diversity among 15 patients with LP from different cities in Turkiye. Although an autosomal recessive disorder, the severity of mucocutaneous findings and the presence of neurological and neuropsychiatric symptoms can vary among individuals affected by this syndrome. There is a need for further research to explore the relationship between neurological findings, which have a significant impact on patients’ quality of life, and the identified genetic variants. Since genotype-phenotype relationships cannot be established, genetic counseling, particularly in prenatal settings or at an early age, remains difficult.
Acknowledgments
The authors thank the patients and their families for their cooperation in this study. The authors also thank all referring physicians.
Statement of Ethics
The protocols used in this study were in compliance with the Declaration of Helsinki. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images. Informed consent for genetic analysis was obtained from the family in compliance with national ethics regulations. This study was approved by the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (dated January 07, 2015, and number 10).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was funded by the Scientific Research Projects Unit of Istanbul University (Project No. 52427).
Author Contributions
All authors read, reviewed, edited, and approved the manuscript. F.D.B., Z.O.U., B.K., and H.K. designed and coordinated the study. C.B., N.B., B.T., A.G., B.U., and B.K. referred the patients to our clinic. F.D.B. and Z.O.U. performed molecular analysis.
Funding Statement
This study was funded by the Scientific Research Projects Unit of Istanbul University (Project No. 52427).
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.