Case Report Lipoid proteinosis: Rare case confirmed by ECM1 mutation detection Tatiana F. Almeida a,1 , Diogo C. Soares a,1, *, Caio R. Quaio a,1 , Rachel S. Honjo a,1 , De ´ bora R. Bertola a,1 , John A. McGrath b,2 , Chong A. Kim a,1 a Genetics Unit, Child’s Institute, University of Sa˜o Paulo, Sa˜o Paulo, Brazil b St John’s Institute of Dermatology, King’s College London, Guy’s Campus, London, UK 1. Introduction Lipoid proteinosis (LP; OMIM 247100), also known as Urbach– Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder with around 300 cases reported worldwide [1,2]. It is characterized by intercellular deposition of an amorphous hyaline material. It mainly involves skin and mucosal membranes of upper aerodigestive tract, central nervous system, lung, lymph nodes and striated muscles. However, etiology and pathogenesis are unknown. Laryngeal lesions resulting in hoarse- ness and a weak cry are a common symptom of the disease [3,4]. In two-thirds of the cases, voice changes are present at birth or in early infancy as the first manifestation [5]. This article reports a case of a 14-year-old female with clinical and molecular findings compatible with LP. 2. Case presentation A 14-year-old female has a history of a hoarse voice and an itchy blistering skin eruption. Her symptoms started at 1-year-old, including blisters that were widespread and typically ruptured spontaneously after 1–2 days. At the age of 4 years, the patient underwent a skin and trachea biopsy which histopathologic findings revealed homogeneous hyaline nodular areas in the dermis. At first medical evaluation by a geneticist, at 11-year-old, was observed multiple beaded papules on her eyelids (Fig. 1), desquamative lesions and hypotrophic scars on the neck, shoulders (Fig. 2), thorax, and lumbar region (Fig. 3), palmar hyperkeratosis and hair-loss affecting the parietal, occipital and temporal regions. However she had normal motor and cognitive development without any neurological or psychiatric symptoms. Brain CT scan performed at 11-year-old shows bilateral symmetric parasellar calcifications affecting parts of the hippocampus and parahippo- campal gyrus. The only treatment that the patient underwent was moisturizing cream. In order to obtain definitive molecular confirmation of LP in this patient, we analyzed the ECM1 (encoding extracellular matrix protein 1) gene. Following parents’ informed consent, genomic DNA was extracted from peripheral blood and the coding sequence of ECM1 (mRNA Genbank accession number NM_004425.2) was amplified by polymerase chain reaction (PCR) using intronic oligonucleotide primers, as previously reported [10]. The PCR products were gel purified and directly sequenced using BigDye Terminator chemistry on an ABI 377 automatic sequencer (Applied Biosystems, Foster City, CA, USA) which revealed frameshift mutations in exon 6 (c.541del3ins16), and exon 7 (c.735delTG). Both mutations are typical of the type of loss-of-function mutations in ECM1 that are found in patients with LP, thus providing a definitive diagnosis for her condition. 3. Discussion LP is a rare genodermatosis, inherited in an autosomal recessive fashion. The disease occurs worldwide but is more common in certain geographical areas such as the Northern Cape province of South Africa, including Namaqualand. It is caused by loss-of- function mutations in ECM1 [6] and approximately 50 different pathogenic mutations have been reported and there is no evidence for genetic heterogeneity [7]. The ECM1 protein is expressed by several cell types, including keratinocytes and fibroblasts. Within the epidermis, ECM1 has a role in epidermal differentiation although there is evidence for functional redundancy amongst other epidermal proteins [8]. Blistering is a common feature in LP and may be the earliest clinical abnormality in approximately half of all patients [8]. A more fundamental role for ECM1 is as a International Journal of Pediatric Otorhinolaryngology xxx (2014) xxx–xxx A R T I C L E I N F O Article history: Received 28 July 2014 Received in revised form 19 September 2014 Accepted 22 September 2014 Available online xxx * Corresponding author at: Av. Dr. Ene ´as de Carvalho Aguiar, 647, 7th floor, Cerqueira Ce ´ sar, Sa ˜o Paulo, SP 05403-000, Brazil. Tel.: +55 11 26618671. E-mail addresses: tatifalmeida@gmail.com (T.F. Almeida), diogo.soares@hc.fm.usp.br (D.C. Soares), caio.quaio@hc.fm.usp.br (C.R. Quaio), rachel.honjo@gmail.com (R.S. Honjo), debora.bertola@usp.br (D.R. Bertola), john.mcgrath@kcl.ac.uk (J.A. McGrath), chong.kim@hc.fm.usp.br (C.A. Kim). 1 Address: Av. Dr. Ene ´as de Carvalho Aguiar, 647, 7th floor, Cerqueira Ce ´ sar, Sa ˜o Paulo, SP 05403-000, Brazil. 2 Address: 9th Floor, Tower Wing, Great Maze Pond, London SE1 9RT, UK. Tel.: +44 20 7188 6409. G Model PEDOT-7299; No. of Pages 2 Please cite this article in press as: T.F. Almeida, et al., Lipoid proteinosis: Rare case confirmed by ECM1 mutation detection, Int. J. Pediatr. Otorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.09.025 Contents lists available at ScienceDirect International Journal of Pediatric Otorhinolaryngology jo ur n al ho m ep ag e: ww w.els evier .c om /lo cat e/ijp o r l http://dx.doi.org/10.1016/j.ijporl.2014.09.025 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.