Atypical presentation of laryngo‐onycho‐cutaneous syndrome resulting from novel mutations in LAMA3A

Abstract

Laryngo-onycho-cutaneous (LOC) syndrome (OMIM #245660), is a very rare subtype of junctional epidermolysis bullosa (JEB). It is caused by mutations in the LAMA3A gene, encoding laminin-a3, a subunit of the laminin 332 heterotrimer, which is a key component of the lamina lucida in the dermoepidermal junction and is associated with the pathogenesis of JEB. Unlike other subtypes of JEB, in which blistering is a predominant feature, LOC syndrome is characterized by minimal blistering and extensive granulation tissue formation in mucosal tissues, leading to hoarseness, upper airway obstruction, conjunctival granulation and scarring and severe nail dystrophy and teeth deformities. We report an atypical presentation of LOC syndrome associated with bi-allelic and unusual pathogenic variants in LAMA3A. A 17-year-old man of Russian origin reported having a high-pitched voice and hoarseness since birth, which had been shown to result from granulation tissue and scarring of his vocal cords. He also reported accumulation of granulation tissue under his fingernails and toenails, with complete shedding of the latter at 3 years of age. In addition, he reported gum swelling and tooth decay from a young age, with loss of most of his teeth by adulthood. He reported that there were no similar clinical symptoms among his family members, including his two healthy parents. Physical examination revealed missing teeth accompanied by severe tooth decay and clefting of the upper gingiva (Fig. 1a). The fingernails and toenails were dystrophic or absent (Fig. 1b). Additionally, the patient had patches of atrophic scars over his face (Fig. 1c) and extremities as well as mild conjunctival injection (not shown). Although part of the clinical presentation was compatible with LOC syndrome, the lack of conjunctival granulation tissue, a prominent and unique feature of LOC syndrome, was surprising. After obtaining ethics approval and informed consent, genetic study was performed to establish the diagnosis. Genomic DNA of the patient was subjected to Sanger sequencing and all coding exons and exon– intron boundaries of the LAMA3A isoform of LAMA3 were directly sequenced. The patient was found to be compound heterozygous for the LAMA3A mutations c.171 + 1G>C and c.221delG (Fig. 1d). The first mutation, c.171 + 1G>C, affects a splicing donor site located downstream of the unique LAMA3A exon (designated exon 39 of LAMA3, but exon 1 of LAMA3A). The Berkeley Drosophila Genome Project splice site prediction tool (http://www.fruitfly.org/seq_tools/ splice.html) predicted this mutation to abolish a donor splice site located in intron 1, resulting in a premature termination codon (PTC) (p.G58Vfs*5, reference sequence Ensembl accession number ENST00000269217.10). The second mutation, c.221delG, occurs in exon 2 of LAMA3A, which is common to all three isotypes of LAMA3, and is predicted to result in frameshift and PTC (p.C75Vfs*65). The healthy father of the patient was found to carry the second mutation in a heterozygous state. The c.221delG mutation is found in a heterozygous state in 4 out of 125 738 individuals in the gnomAD database, whereas the c.171 + 1G>C mutation was not found in any of the following databases: ESP, UCSC, NCBI, HGMD, Ensembl, gnomAD and 1000 genomes, which together comprise > 125 000 individuals. To date, three mutations in LAMA3A have been identified in patients with LOC syndrome, all of which Correspondence: Dr Ofer Sarig, Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel E-mail: [email protected]