Advances in treatment for lipoid proteinosis (Urbach-Wiethe disease): a case report and systematic review.

BACKGROUND: Lipoid proteinosis (LP), also known as Urbach-Wiethe disease, is a rare autosomal recessive genodermatosis, caused by mutations in the ECM1 gene. This results in the deposition of periodic acid-Schiff (PAS)-positive, hyaline-like material on the skin, mucosae and internal organs. OBJECTIVES: To present a case report of LP and a systematic review to synthesize the scientific literature on the management of this uncommon and frequently missed diagnosis. METHODS: We present a case report of a 48-year-old man with LP who exhibited significant improvement after oral acitretin therapy. To address the lack of large case-control studies on LP treatment, we performed a systematic review of the literature following the PRISMA 2020 criteria. The search was conducted in PubMed, Web of Science, Cochrane and Scopus databases from inception until June 2023. To assess the methodological quality of case reports and case series, we used the Joanna Briggs Collaboration critical appraisal tool. RESULTS: We included 25 studies that met eligibility criteria. Data from 44 patients with a histopathologically confirmed diagnosis were analysed. Treatment ranged from systemic therapies (acitretin, etretinate, dimethyl sulfoxide, corticosteroids, penicillamine) to surgical or laser procedures. Regarding methodological quality, the main discrepancies arose in the reporting of participant characteristics and treatment interventions. CONCLUSIONS: Low-dose oral acitretin could have potential in managing LP, exhibiting fewer side-effects compared with other therapeutic agents. Further research is needed to establish more comprehensive and evidence-based treatment guidelines.

Urbach-Wiethe disease in a young patient without apparent amygdala calcification.

Urbach-Wiethe disease is an extremely rare genetically-based syndrome which usually leads to dermatological and neurological changes. Neurologically, the amygdaloid region is primarily bilaterally affected. Therefore, several functions modulated by the amygdala are changed in patients with Urbach-Wiethe disease. As the neurological alterations evolve only gradually, it is particularly important to determine the cognitive and brain status of a juvenile. The patient described here was seen briefly at age 9 and tested neuropsychologically at age 19; furthermore, computer tomography and magnetic resonance imaging of his head was done. There were no important abnormalities in the brain, which is unusual in the light of previous data from other patients. On the cognitive level, the patient was generally within normal limits. However, he had mild problems in attention and concentration, and more prominent problems in emotional processing domain, and in personality dimensions. It is concluded that amygdala calcifications in Urbach-Wiethe disease take place progressively-possibly underpinned by genetic and gender variables; this can subsequently allow psychosocial-social factors (such a proper education and socialization) and biological factors (compensatory neuroplasticity) to retard and diminish the development of socio-emotional and cognitive deteriorations, though the outcome of questionnaires indicates that such patients may develop substantial concerns as to their future life and well-being.

Lipoid proteinosis: Novel ECM1 pathogenic variants and intrafamilial variability in four unrelated Arab families.

BACKGROUND/OBJECTIVES: Lipoid proteinosis (LP) is a rare autosomal recessive multisystem disorder that is caused by loss-of-function pathogenic variants in the extracellular matrix protein-1 (ECM1) gene. The typical clinical manifestations of LP include hoarseness of voice, beaded papules on the eyelids, infiltration and scarring of the skin and mucosa, as well as neuropsychological abnormalities. Currently, more than 70 pathogenic variants have been reported, including nonsense, missense, splice site, deletion and insertion pathogenic variants, and more than half of them occurred in exons 6 and 7. METHODS: Clinical evaluation and Sanger sequencing were performed on eight patients from four unrelated Arab families. RESULTS: We identified two novel ECM1 variants, one nonsense pathogenic variant in exon 6 (c.579G>A, p.Trp193*) and a deletion of three nucleotides (c.1390_1392del, p.Glu464del) in exon 9, and two previously reported frameshift variants; c.692_693delAG, in exon 6 and c.11dupC in exon 1. CONCLUSIONS: Although all patients had characteristic manifestations of lipoid proteinosis, we observed intrafamilial phenotypic variability. Our data expand the pathogenic variant spectrum of ECM1 and also supports the fact that exon 6 is one of the most common hot spots of pathological variants in ECM1.

Lipoid Proteinosis presenting as beaded papules of the eyelid: report of three cases.

BACKGROUND: Lipoid proteinosis (LP) is a rare multisystem inherited disease. We report here in three LP cases with beaded papules of the eyelid. Their clinical presentations, histological characteristics, and genetic findings are described and discussed. CASE PRESENTATION: A 12-year-old boy reported to our hospital with a complaint of ocular irritation, redness, and tearing for two years. He had a history of hoarseness since childhood. His younger brother (5 years old) also complained of hoarseness. Another patient, a 26-year-old woman, described many beaded papules on the edge of her eyelids since age 11 years. She additionally reported hoarseness since 4 years of age. Careful slit-lamp examination in these cases revealed waxy beaded papules on the margins of both eyelids and mild conjunctival congestion. Physical examination showed irregular, rugged scars on their facial skin. Genetic analysis showed the mutation located in exon 6 of the ECM1 gene. CONCLUSIONS: Three LP cases first diagnosed by ophthalmologists are presented. The presence of eyelid papules should prompt the ophthalmologist to pay close attention to the patient's voice. If there is a definite history of hoarseness, these patients should undergo gene sequence analysis. If necessary, otorhinolaryngology and dermatology consults may help confirm the diagnosis. Treatment is primarily symptomatic to improve patients' quality of life.

Identification of a novel three-nucleotide duplication in ECM1 in Chinese siblings affected with lipoid proteinosis.

Lipoid proteinosis (LP) is a rare autosomal recessive disorder caused by pathological mutations in the glycoprotein extracellular matrix protein 1 gene (ECM1). In this study, we examined two sibling patients who were suspected of LP in a consanguineous Chinese family for clinical manifestations and sequenced the all coding exonic regions of ECM1 in the proband. Both siblings were detected a homozygous three-nucleotide duplication, c.506_508dupCTG in the exon 6 of ECM1. This mutation introduces an alanine addition between two highly conserved amino acids (Pro169 and Gly170), designated as p.169_170insA, within one of the two tandem repeat domains which are functional important for protein-protein interactions. Their parents were unaffected and heterozygous for this mutation. This mutation wasn't found in one hundred normal Chinese individuals screened and wasn't previously reported elsewhere, excluding it as a common neutral polymorphism. These evidences supported this duplication as the causative mutation of LP. Our finding expanded the spectrum of disease-causing mutations in LP and provides further evidence for the importance of ECM1 gene in the development of this rare genodermatosis.

Intracranial calcifications associated with epilepsy: A case report of lipoid proteinosis.

Lipoid proteinosis (LP) is a very rare autosomal-recessive disease characterized by multisystem involvement due to intracellular deposition of amorphous hyaline material. Clinical manifestations include hoarness, acne-like facial scarring and neurological manifestation including seizures. We describe the clinical, genetics and radiological features of LP in a refractory epileptic patient with genetic confirmation.

Intravascular cardiac lipoproteinosis: extrarenal manifestation of lipoprotein glomerulopathy.

Intracapillary lipoprotein thrombi are a distinct histopathologic finding described in the setting of lipoprotein glomerulopathy. The disease is associated with mutations in the apolipoprotein E gene and responds well to lipid-lowering treatments. Lipoprotein glomerulopathy is thought to primarily affect the kidneys, and lipoprotein thrombi have never been described in any other organ. Herein we present the first recognized case with extrarenal manifestations in the form of intravascular cardiac lipoprotein deposition.

Lipoid Proteinosis: A Rare Cause of Hoarseness.

Lipoid proteinosis is a rare cause of voice problems. Hoarseness is often the first clinical manifestation of this disorder and can present years before any other symptom. Therefore, it is very important as an otorhinolaryngologist to be familiar with the main characteristics of this disease. We present a case report and a review of current literature to provide a concise overview of this frequently missed diagnosis.

Pathogenetic mechanism of lipoid proteinosis caused by mutation of the extracellular matrix protein 1 gene.

Lipoid proteinosis (LP) is a rare form of dermatosis with autosomal recessive inheritance. The present study hypothesized that an extracellular matrix protein 1 (ECM1) gene mutation forms the pathological basis of LP. The association between ECM1 mutation and LP; however, requires further investigation and was thus investigated in the present study. Injury skin tissue samples from patients with LP were collected, along with venous blood samples for genomic DNA extraction. Immunohistochemical staining was performed. Polymerase chain reaction (PCR) was then used to obtain an ECM1 gene fragment, which was sequenced and compared with healthy individuals. Histopathological examination revealed that all included patients fitted the features of LP and PCR amplification of the ECM1 gene in all patients obtained positive results. Patients with LP in the present study exhibited point mutations in the ECM1 gene, including one homozygous mutation (C220G) as previously reported, and one novel homozygous mutation c.508insCTG and two heterozygous mutations (C220G/P.R481X and c507delT/c.l473delT). LP is correlated with ECM1 gene mutation.

[An atypical case of lipoid proteinosis]. / Un cas atypique de protéinose lipoïde.

The lipoid proteinosis is a rare autosomic recessive genodermatosis characterized histologically by deposits of hyaline-like eosinophilic material of characteristic distribution. We herein report the case of a 56-year-old man admitted for progressive aggravated dementia associated with a late-onset dysphonia. Histologic examination of cutaneous and laryngeal biopsies showed deposits of an amorphous and eosinophilic material arranged around vessels, and adnexal structures, stained by PAS and congo red negative. The detection of a mutation in the ECM1 gene confirmed the diagnosis of lipoid proteinosis of atypical clinical presentation.

Lipoid proteinosis: A clinical and molecular study in Egyptian patients.

Lipoid proteinosis (LP) is an autosomal recessive disorder caused by the loss of function of ECM1 gene. Clinical features include varying degrees of skin thickening, hoarseness of voice and less frequently neuropsychiatric abnormalities. Twelve patients from ten unrelated families with a clinical diagnosis of lipoid proteinosis were enrolled in this study. Extraction of DNA samples of the 12 patients and their parents from peripheral blood by standard methods was performed. Polymerase chain reaction (PCR) amplification of the ECM1 gene was conducted using eight pairs of primers spanning over the 10 exons and splice junctions. Patients exhibited a variety of clinical manifestations with skin affection and hoarseness of voice being the consistent feature. We identified five novel homozygous insertion, small deletion, missense, and splice site mutations as well as two homozygous previously published splice site mutation c.70+1G>C in intron 1 and c.1305-2A>G in intron 8. The specific mutations were: c.10_11insC in exon 1, c.690_691delAG in exon 6, c.734G>A in exon 7, c.1286_1287delAA in exon 8 and c.1393-1G>T in intron 9. The novel mutations c.1393-1G>T and c.10_11insC occurred in three (30%) and two (20%) unrelated patients of the studied families, respectively. Further studies may designate an increased frequency of these mutations among Egyptian LP patients. Identification of pathogenic ECM1 mutations is important for accurate diagnosis and proper genetic counseling.

Lipoid proteinosis unveiled by oral mucosal lesions: a comprehensive analysis of 137 cases.

OBJECTIVES: Lipoid proteinosis (LP) is a rare autosomal recessive disorder characterized by deposits of hyaline material within skin and mucous membranes of the upper aerodigestive tract, especially the vocal cords. We aimed to investigate possible associations between oral LP (oLP) manifestations and demographic data and extra-oral lesions. MATERIAL AND METHODS: Cases of oLP were collected following a systematic search of Medline's PubMed and Google Scholar (1948-2014). We added four new cases. Demographic data, consanguineous marriage status, oral lesion site(s), and related symptoms were analyzed for potential associations. RESULTS: A total of 137 patients with oLP lesions were analyzed. Parental consanguinity status was known for 52 patients, and the parents were not related in 38 (73%) of them. The tongue was the most commonly affected oral site (68%), and it was associated with significantly more affected family members (P = 0.002). The palate and gingiva were the least involved sites (25 and 6%, respectively): the former had a tendency to be affected in younger patients and the latter in older ones. Patients with palatal and labial lesions had significantly less skin scarring (P < 0.001 and P = 0.002, respectively). CONCLUSIONS: Extra-oral manifestations are easily recognizable and they can lead to early and accurate diagnosis of LP. In spite of early voice manifestations, diagnosis of LP might be obvious only later in life and usually sought due to presence of oral lesions. CLINICAL RELEVANCE: The diagnosis of oLP with obscure extra-oral signs is challenging, with dental surgeons playing a key role in its establishment.