Lipoid proteinosis: case report and review of the literature

Abstract

Lipoid proteinosis is a rare autosomal recessive disorder, characterized histologically by infiltration of periodic acid Schiff-positive hyaline material into the skin, upper aerodigestive tract, and internal organs. Classical clinical features include skin scarring, beaded eyelid papules, and laryngeal infiltration leading to hoarseness. Moreover, the infiltrates in the tongue and its frenulum limit lingual movements and cause speech difficulties. Usually, the hoarse voice is present at birth or in early infancy, as the first manifestation. In more severe cases, diffuse infiltration of the pharynx and larynx might cause respiratory distress, at times requiring tracheostomy. The disorder has recently been shown to result from loss-of-function mutations in the extracellular matrix protein 1 gene on chromosome 1q21. The function of the protein extracellular matrix protein 1 gene is still unclear, although an important role in skin physiology and homeostasis has been hypothesized. In this report, the case is described of a 6-year-old girl with lipoid proteinosis. Histopathological examination of a laryngeal biopsy specimen showed massive deposits of eosinophilic, periodic acid Schiff-positive, and diastase resistant material in the lamina propria corroborating the clinical diagnosis of lipoid proteinosis. Molecular analyses in this patient also confirmed the clinical diagnosis. The proposita was a compound heterozygote for a new small rearrangement (543de1TG/ins15) in exon 6, and a nonsense mutation (Arg243Stop) in exon 7. Together with previously documented mutations in the extracellular matrix protein 1 gene, this study supports the hypothesis that exons 6 and 7 are the most common sites for extracellular matrix protein 1 gene mutations in lipoid proteinosis.

Fig. 1

Morbidity map of ECM1 gene. Illustration of position of new frameshift mutation (543delTG/ins15) (grey arrow) and previously identified mutations. Missense or nonsense mutations are depicted above and frameshift mutations below gene structure. Most mutations are nonsense or frameshift changes that occur within exon 6 or within differentially spliced exon 7.

Fig. 2

A). Deposits of homogeneous, proteinaceous material in vocal cords before surgery. B). Light microscopy examination of laryngeal biopsy from child with lipoid proteinosis showed massive deposits of homogeneous, eosinophilic, hyaline-like material in lamina propria, without inflammation. Material was strongly PAS positive, diastase resistant, revealing glycoproteic nature of the substance.

Fig. 3

Segregation analysis of 543delTG/ins15 in family of child with LP. PCR products spanning exon 6 and its flanking introns were resolved by 12% bisacrylamide-polyacrylamide gel electrophoresis and stained with ethidium bromide. A single PCR fragment sized 671-bp is obtained in wild-type individuals (F and Ctrl). By contrast, in individuals bearing heterozygous rearrangement (→) two PCR bands sized 684 and 671-bp are obtained (P and M). Ctrl, genomic DNA from normal control; M, mother; P, patient; F, father. MW is an 100-bp molecular marker size.

Fig. 4

Primer extension technique using ABI PRISM SnaPshot Multiplex kit (Applied Biosystems, Foster City, CA,USA) showed that 726C>T mutation (Arg243Stop) in ECM1 was present on paternal allele in child with LP. Family pedigree is depicted and chromatograms of normal (c) and mutant (t) alleles are shown below. Ctrl, genomic DNA from normal control.