Laryngo-onycho-cutaneous (LOC) syndrome
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||LARYNGO ONYCHO CUTANEOUS (LOC) SYNDROME|
|Gene (s)||LAMA3 (Laminin 332)|
Epidermolysis bullosa (EB) is the term applied to a clinically and genetically heterogeneous spectrum of rare inherited conditions that are characterized by a marked mechanical fragility of epithelial tissues with blistering and erosions following minor trauma. EB is based on mutations involving at least 14 structural genes expressed within the epidermis and mucocutaneous basement membrane zone (BMZ) . In addition to the skin involvement, many EB forms present as a multisystemic disease associated with numerous extracutaneous manifestations. The resulting morbidity and mortality makes it necessary to approach the patients by multidisciplinary management.
Molecular pathogenesis of EB
Causative mutations target intracellular, transmembrane and extracellular matrix proteins of the BMZ that is the adhesive interface between epithelial cells and the underlying matrix (Fig. 1). These components mantain the integrity of the dermal-epidermal anchoring complex and barrier function, control organizations, proliferation and differentiation of epithelial cells and extracellular matrix substitutes . The consequences of these mutations at mRNA and protein levels, epigenetically influenced by the individuals' genetic background and environmental trauma contribute to the pronounced phenotypic variability and severity within the broad spectrum of EB subtypes . The genetic heterogeneity also highlights the relevance of identification and characterization of specific mutation as a prerequisite for exact diagnosis and targeted molecular therapy.
Epidemiology of EB
Accuracy and comparability of epidemiological data regarding EB are limited by frequent misdiagnosis, misclassification and restricted access to experts . The first initiative to overcome these obstacles, the U.S. National EB registry (NEBR), was founded in 1986. It became the wolrd's largest cohort of well-characterized and systematically monitored EB patients that currently comprises more than 3200 individuals with long term follow-up and whose demographics have been shown to closely mirror that of the entire North American population, as well that of EB patient cohorts elsewhere in the world . Referring to evidence-based data on the NEBR study population, the overall prevalence and incidence rates of EB have been estimated to be 8.22 and 19.60 per million, respectively, by extrapolation (EBS: 4.60/10.75; JEB: 0.44/2.04; DDEB: 0.99/2.86; RDEB: 0.92/2.04).
Laryngo-onycho-cutaneous (LOC) syndrome
Laryngo-Onycho-Cutaneous syndrome is characterized by dermal and submucosal granulation with voice defects due to vocal cord thickening and/or nodules which clinically manifested as hoarse cry. In some children a weak cry was noted at birth. The first families had been reported only in Muslim families of Punjabi origin. Manifestations appeared in the early months of life and included skin ulcerations, loss of toenails and fingernails, and conjunctival scarring and pterygium formation. Other epithelial surfaces were later involved. Some of the affected persons had amelogenesis imperfecta. Death in early childhood was common due to respiratory tract infection, although among those who survived, remission occurred during the second decade.
Molecular pathogenesis of laryngo-onycho-cutaneous (LOC) syndrome, a distinct variant of JEB, indicates a founder effect as the majority of patients originate from the Punjabi region of Pakistan and India. These individuals are homozygous for the recessive frameshift mutation 151insG in LAMA3A on chromosome 18q11.2 , although also compund heterozygosity was rarely described. LAMA3A is an LAMA3 isoform that expresses one of at least three alternatively splices LAMA3 transcripts. It encodes the laminin α3a polypeptide, a component of the LM332 heterotrimer. The frameshift mutation leads to a premature termination codon (PTC) within exon 39. The exon is splices out of laminin α3b1 and α3b2 variants and htus the only exon specific to the LAMA3A isoform. These are also non-founder mutations within and outside the Punjab, which can result in LOC .
© graphic design by R. Hametner
Figure 1: Schematic of the basement membrane zone (BMZ).
Intermediate filaments composed of keratin 5 and 14 insert on the keratin (cytoskeletal) linker proteins plectin and BPAG1 (BP230) at the superior aspect of the BMZ. Plectin and BPAG1 interact with transmembrane a6b4 integrin and type XVII collagen (BP180/BPAG2), forming hemidesmosomes that attach basal keratinocytes to the underlying basement membrane. Anchoring filaments reach out below the hemidesmosome and include laminin-332 and laminin-311 that associate with type XVII collagen and a6b4 integrin, but also laminin-511, type IV collagen and nidogen, thereby forming the lamina densa. Anchoring fibrils extend as banded projections from the lamina densa and contain type VII collagen molecules. Type VII collagen triple helices attach the lamina densa to papillary dermis and are critical for the integrity of the epidermal-dermal junction through their ability to bind laminin-332.
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