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

Abstract

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. K E Y W O R D S ECM1, extracellular matrix protein 1, lipoid proteinosis, pathogenic variant 1 | INTRODUCTION Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis (OMIM 247100), characterized by deposition of an amorphous hyaline-like material in the skin, mucosa, and internal organs. 1 Since its first description by Urbach and Wiethe in 1929 2 about 500 cases have been reported worldwide. 3Clinically, LP is characterized by a wide range of manifestations with variable severity and a slowly progressive course. 1 In most cases, the first clinical sign is a hoarse cry or voice, which develops soon after birth or during infancy, and is caused by laryngeal infiltration. 4 Subsequently, skin and mucous membrane changes develop during the first few years of life, or even later. During childhood, the skin may be easily damaged by minor trauma or friction, resulting in

Multiple facial atrophic scars in childhood

“…Stiff sublingual frenulum, restricted tongue movement, macroglossia, oral mucosal erosions, ulcerations of the tongue and oral mucosa, dysphonia, dry eye syndrome and visual disturbances may occur later in life. 2,3 Other systems may also be involved, including the gastrointestinal (dysphagia, yellowish nodules, gastrointestinal bleeding), genitourinary (renal cysts), respiratory (airway obstruction), endocrine (insulin resistance, short stature), neuropsychological (migraine, seizures, intracranial mesiotemporal calcifications), and psychiatric (cognitive dysfunction, memory impairment, schizophrenia, depression, anxiety disorder) systems. [1][2][3][4] In early childhood, multiple facial atrophic scars are an important clue to lipoid proteinosis and should prompt careful examination for other diagnostic features such as hoarse voice and moniliform blepharosis, which in our patient were clinically subtle and appeared more distinctive on dermoscopy.…”

“…2,3 Other systems may also be involved, including the gastrointestinal (dysphagia, yellowish nodules, gastrointestinal bleeding), genitourinary (renal cysts), respiratory (airway obstruction), endocrine (insulin resistance, short stature), neuropsychological (migraine, seizures, intracranial mesiotemporal calcifications), and psychiatric (cognitive dysfunction, memory impairment, schizophrenia, depression, anxiety disorder) systems. [1][2][3][4] In early childhood, multiple facial atrophic scars are an important clue to lipoid proteinosis and should prompt careful examination for other diagnostic features such as hoarse voice and moniliform blepharosis, which in our patient were clinically subtle and appeared more distinctive on dermoscopy. As our patient lacked the rough keratotic plaques or waxy infiltration that typically appear later in life, 1,2 and eyelid biopsy was deemed too traumatic, histopathology was not…”

“…are frameshift or nonsense mutations in exons 6 or 7, and a very few mutations are found in exon 1. 2,3 Homozygous mutations are more common. 1 Clinically, patients with exon 7 mutations display milder clinical features, while mutations in exon 6 result in a more severe phenotype.…”