A founder deletion in ECM1 of 1163 bp causes lipoid proteinosis in the southeast region of Turkiye.

Lipoid proteinosis (LP) is an inherited disorder characterized by the accumulation of hyaline-like material in the skin, oral cavity, and larynx. The primary symptoms include hoarseness, restricted tongue movements, and various skin lesions. LP is caused by biallelic pathogenic variants in the ECM1 gene. We studied 20 patients from nine different families with LP, 19 of whom are from Sanliurfa in the southeastern region of Turkiye. Overall, the clinical features of the patient cohort were consistent with those mentioned in the literature, except for one exhibited an atrophoderma vermiculatum-like lesion, which is atypical for LP. The clinical exome sequencing analysis revealed three different homozygous variants in the ECM1 gene (NM_004425). While c.1246C>T p.(Arg416*) on Exon 8 and c.806G>A p.(Cys269Tyr) on Exon 7 were detected in 1 patient each, an intragenic deletion of 1163 base-pairs including Exons 9 and 10 (c.1304 + 33_*300del) was identified in 18 patients from 7 unrelated families. The haplotype analysis of the deletion variant indicated a founder effect in the families from the Sanliurfa province of Turkiye. Based on all this information, copy number variation analysis is recommended for patients with LP. In addition to this rare observation, this study represents the largest examination of the molecular spectrum of LP patients in Turkiye, alongside the clinical spectrum.

Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data.

PURPOSE: Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists. METHODS: PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations. RESULTS: The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19 months of age (CI: 3.00-20.00), while the mean age at diagnosis was 15 years (CI: 10.00-30.00). Therefore, the diagnostic delay amounted to 13.42 years (CI: 8.00-23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion. CONCLUSION: Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked.

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.

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.

Pulmonary storage.

Interstitial lung diseases (ILDs) are not just a matter of scarring or inflammation in the lung tissue. The lungs can also serve as a repository for products that can be produced in excessive amounts in the human body as a result of disease. Geneticaly based dysfunctions of lysosomal enzymes, which leads to an unefficient degradation and transport of various macromolecules from lysosomes, are considered to be storage diseases sensu stricto. ILDs were described in patients with Gaucher disease, Niemann-Pick disease and Fabry disease. In a broader context, however, the accumulation of various substances in the lung tissue is also encountered in cases of pediatric pulmonary interstitial glycogenosis (PIG), alveolar lipoproteinosis or pulmonary amyloidosis. The cause of PIG is not clear. The disease was first described in 2002 and a lung tissue sample is required to establish this diagnosis. Even though PIG usually goes well in childhood and the patients difficulties spontaneously subside over time, the long-term prognosis of the patients is unknown. Alveolar lipoproteinoses can be acquired (e.g. after massive exposure to silica dust), autoimmune, but also genetically determined. Unlike lysosomal storage diseases, in the case of pulmonary alveolar lipoproteinosis, accumulation of abnormal macromolecules occurs only in the lungs of affected individuals. Similarly, amyloidosis is not a single disease, but a group of diseases with different etiopathogenesis, as a result of which amyloid - a group of different proteins with a distinctvive conformation, which can be deposited in various organs, including the lungs - is formed. The diagnosis of pulmonary alveolar lipoproteinosis is based on the typical appearance and biochemical composition of the fluid obtained by bronchoalveolar lavage, the diagnosis of amyloidosis is histological.

Assessment of dynamic thiol-disulfide homeostasis in patients with lipoid proteinosis (Urbach-Wiethe syndrome).

OBJECTIVE: Lipoid proteinosis is a rare autosomal recessive genetic dermatological disease that occurs due to the accumulation of hyaline material in the skin and mucous membranes. This study aimed to investigate whether dynamic thiol-disulfide homeostasis is a new marker of oxidative stress in patients suffering from lipoid proteinosis. METHODS: The study group involved 17 patients with lipoid proteinosis and 17 healthy controls with same gender and age. Native thiol, total thiol, disulfide levels, and thiol-disulfide indexes were measured with the fully automated spectrophotometric method described by Erel and Neselioglu, and the results of the two groups were statistically analyzed. RESULTS: Serum total thiol and native thiol levels were significantly lower in lipoid proteinosis group compared to the control group (p=0.020 and p=0.014, respectively). The disulfide levels were found to be higher in lipoid proteinosis group, but there was no significant difference between two groups. CONCLUSIONS: Impaired dynamic thiol-disulfide homeostasis was observed in lipoid proteinosis patients, suggesting that thiol-disulfide homeostasis may have a role in the pathogenesis of this disease.

Lipoid proteinosis: A systematic presentation of an unusual disease.

BACKGROUND: Lipoid proteinosis (LP) or Hyalinosis Cutis et Mucosae or Urbach-Wiethe disease is a rare autosomal recessive genodermatosis characterized by an amorphous hyaline material deposition in the skin mucosa and viscera. The clinical symptoms of this disease often begin in childhood, which persist throughout life. Skin manifestations include inflammation, scaling, acne, and eventually ulceration, and hyaline amorphous deposits in these areas of the wound cause a waxy and thick appearance on the skin. In addition, wounds leave atrophic scars like chickenpox. AIM: Herein, we present the first case of LP in the north of Iran; although LP is a sporadic disease, it occurs all around the world, with about 400 cases worldwide having been reported thus far. PATIENT: We report the case of a 28-year-old female patient with a history of skin lesions on her face, scalp, extremities, and buttock, as well as hoarse cry, respiratory problems, dysphagia, and migraine since childhood. There was no evidence of other clinical presentations. A biopsy was taken from the lesions, and the patient was diagnosed with LP. A laryngeal laser was performed for the patient, and peeling creams were used for her skin lesions. RESULT: According to previous findings, there has been no case report of LP with systemic symptoms in the north of Iran.

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.

Is it always blepharitis? Urbach-Wiethe syndrome (lipoid proteinosis) / É sempre blefarite? Síndrome de Urbach-Wiethe (proteinose lipóide)

ABSTRACT A 12-year-old girl presented with recurrent crusty debris and dandruff at the base of both eyelashes despite having completed different medical treatments. She had had a hoarse voice since her early childhood. Upon anterior segment examination of the eyes, we found yellow-white, bead-like papules on the margins of the eyelids. An otolaryngologist detected multiple nodules on the vocal cords and buccal mucosa. Ultrasonography revealed salivary stones in the main parotid ducts. And a dermatological examination revealed thickened skin lesions on the elbows and knees with a biopsy showing histopathological findings of lipoid proteinosis. We diagnosed the patients as having Urbach-Wiethe syndrome or lipoid proteinosis, a rare autosomal recessive multisystem disorder with variable manifestations vary that difficult the diagnosis. The ocular manifestations are not well known among ophthalmologists, but the typical lid lesions are pathognomonic and ophthalmologists should be aware of this presentation to identify patients with Urbach-Wiethe syndrome.

RESUMO Uma menina de 12 anos apresentava restos crostosos e caspa recorrente na base de ambos os cílios, apesar de ter completado diferentes tratamentos médicos. Ela tinha uma voz rouca desde a infância. No exame do segmento anterior dos olhos, encontramos pápulas amarelo-esbranquiçadas nas margens das pálpebras. Um otorrinolaringologista detectou múltiplos nódulos nas cordas vocais e na mucosa bucal. A ultrassonografia revelou cálculos salivares nos principais ductos parotídeos. Um exame dermatológico revelou lesões cutâneas espessas nos cotovelos e joelhos com uma biópsia mostrando os achados histopatológicos de proteinose lipoide. Diagnosticamos os pacientes da síndrome de Urbach-Wiethe ou proteinose lipoide, um distúrbio multissistêmico autossômico recessivo raro, com manifestações variáveis, que dificultam o diagnóstico. Manifestações oculares não são bem conhecidas entre oftalmologistas, mas as lesões típicas da pálpebra são patognomônicas e os oftalmologistas devem estar atentos a essa apresentação para identificar pacientes com síndrome de Urbach-Wiethe.

Is it always blepharitis? Urbach-Wiethe syndrome (lipoid proteinosis).

A 12-year-old girl presented with recurrent crusty debris and dandruff at the base of both eyelashes despite having completed different medical treatments. She had had a hoarse voice since her early childhood. Upon anterior segment examination of the eyes, we found yellow-white, bead-like papules on the margins of the eyelids. An otolaryngologist detected multiple nodules on the vocal cords and buccal mucosa. Ultrasonography revealed salivary stones in the main parotid ducts. And a dermatological examination revealed thickened skin lesions on the elbows and knees with a biopsy showing histopathological findings of lipoid proteinosis. We diagnosed the patients as having Urbach-Wiethe syndrome or lipoid proteinosis, a rare autosomal recessive multisystem disorder with variable manifestations vary that difficult the diagnosis. The ocular manifestations are not well known among ophthalmologists, but the typical lid lesions are pathognomonic and ophthalmologists should be aware of this presentation to identify patients with Urbach-Wiethe syndrome.

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.

Seeing Fear: It's All in the Eyes?

Is an amygdala necessary to experience and perceive fear? Intriguing evidence comes from patient S.M. who lost her left and right amygdalae to disease. Initial testing suggested that S.M.'s most defining symptom was an inability to recognize fear in other people's facial expressions. A fascinating paper by Adolphs and colleagues in 2005 examined one potential mechanism for this impairment: a failure to spontaneously attend to widened eyes, the most distinctive physical feature portrayed in symbolic fear expressions. This study helped to invigorate debates about the brain basis of fear and paved the way for a more nuanced understanding of amygdalar function.

The management of laryngeal lipoid proteinosis.

BACKGROUND: Lipoid proteinosis is a rare autosomal recessive disorder caused by mutations in the extracellular matrix protein 1 gene. It is characterised by deposition of hyaline material in the skin and mucous membranes. This paper describes the management of two cases with laryngopharyngeal disease. METHODS: Two patients with a biopsy diagnosis of lipoid proteinosis were identified from the surgical pathology archive covering the period 2004-2016. Their notes were reviewed. RESULTS: An adult male and an adult female were identified. Both had dysphonia and laryngopharyngeal lesions. The patients underwent interval laser microlaryngoscopy to debulk disease but minimise mucosal injury and scarring, using a 'pepper pot' technique. Both had adequate symptom control. CONCLUSION: Lipoid proteinosis is a rare genetic condition, which typically presents in infancy with dysphonia and subsequent skin involvement. Two cases are presented to demonstrate that laryngotracheal symptoms can be controlled with interval laser debulking and the 'pepper pot' technique without causing stenosis.

Lipoid proteinosis: A case with distinct histopathological and radiological findings.

Lipoid proteinosis is a rare inherited genodermatosis characterized by hyaline deposits in various tissues. Clinically, it manifests with cutaneous as well as extracutaneous features. Periodic acid-Schiff (PAS)-reactive hyaline deposits in the upper dermis, with localization around blood vessels and eccrine sweat glands, in particular, is the histopathological hallmark finding. On brain imaging, bilateral symmetrical temporal lobe calcifications are considered to be pathognomonic of this disorder. We report a case of lipoid proteinosis in which hyaline deposits were present in the papillary and reticular dermis, without being seen at the periphery of eccrine sweat glands, along with dystrophic calcification. Magnetic resonance imaging (MRI) of brain revealed hydrocephalus, subependymal heterotropia and absent splenium of corpus callosum with no evidence of temporal lobe calcification. Thus, our case highlights the inherent diverse nature of lipoid proteinosis.

Extracellular matrix protein 1 gene (ECM1) mutations in nine Iranian families with lipoid proteinosis.

BACKGROUND & OBJECTIVES: Lipoid proteinosis (LP) is an autosomal recessive disease. Clinical characteristics of this disease are hoarse voice, scarring of the skin, brain calcifications, and eyelid papules (moniliform blepharosis). Mutations in the ECM1 gene on 1q21.2 are responsible for this disease. This study was conducted to investigate the mutation spectrum of ECM1 gene in nine Iranian families having at least one LP patient diagnosed clinically. METHODS: The entire ECM1 gene was screened using PCR and direct sequencing in nine Iranian families with 12 suspected LP patients who were referred to the clinic, along with their parents and siblings. Thirty healthy individuals were included as controls. RESULTS: In only one patient a homozygous G>A transition at nucleotide c.806 in exon 7 was detected. A G>A substitution at nucleotide 1243 in exon 8 that changes glycine (GGT) to serine (AGT) was observed in most of our patients. Furthermore, in one patient there was a change in the sequence of intron 8, the A>T transition in nucleotide 4307. In addition, in two cases (one patient and one healthy mother with affected child) there was a C (4249) deletion in intron 8. INTERPRETATION & CONCLUSIONS: Our results indicate that although mutation in ECM1gene is responsible for lipoid proteinosis, it is likely that this is not the only gene causing this disease and probably other genes may be involved in the pathogenesis of the LP disease.