Laryngo-onycho-cutaneous (LOC) syndrome
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||LARYNGO ONYCHO CUTANEOUS (LOC) SYNDROME, LOGIC 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)1. 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.1-3
Laryngo-Onycho-Cutaneous syndrome is a subtype of junctional EB (JEB). characterized by dermal and submucosal hypergranulation.
LOC-symptoms develop in the first months of life and include skin ulcerations, over granulation of wounds with frequent bleeding, periungual hypergranulation, onychodystrophy and conjunctival scarring with symblepharon formation. Skin fragility is rather mild. Because of laryngeal hypergranulation many children with LOC require tracheostomy early on. Hoarse cry is usually the first sign of laryngeal involvement. Some of the affected persons have dental involvement with hypoplastic teeth and amelogenesis imperfecta as well as anemia starting early in life. Death in early childhood was previously common due to respiratory tract infection and/or obstruction.The disease has initially been reported in Muslim families of Punjabi origin. Several cases from other regions have shown a broad clinical (overlap with JEB) and genetical heteorgeneity.1,2, 4
Molecular pathogenesis of laryngo-onycho-cutaneous (LOC) syndrome 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.4 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 thus the only exon specific to the LAMA3A isoform. These are also non-founder mutations within and outside the Punjab, which can result in LOC (mutations in LAMB3 gene and LAMA3 gene).1,2, 5
Whenever possible, laboratory diagnosis should be performed in a specialized EB centre.
Clinical features are important for diagnosis as in contrast to other forms of JEB with LAMA3 mutations, the laminin-332 skin immunoreactivity is not reduced as the laminin-a3b polypeptide is not affected in LOC. Via genetic testing, the typical mutation for LOC syndrom, a frameshift mutation 151insG in LAMA3A, may be detected. An EB gene panel may further be used if no mutation can be found in the LAMA3A isoform and clinical signs indicative for LOC are present.1, 4, 6, 7
Chronic hypergranulating wounds pose a huge therapeutic challenge as topical antiinflammatory and antiseptic agents show only moderate benefit against hypergranulation. Treatment of ophahlmologic symptoms includes topical preservative-free lubricating agents, antibiotics (chloamphenicol 1%), dexamethason, mitomycin C and bevacizumab injections. Simple excision of granulation tissue leads frequently to rapid recurrence. Reapeated surgery and ocular surface reconstruction methods may be necessary as well as close monitoring by experienced ophthalmologists for prevention of blindness. Mitomycin C and topical as well as systemic corticosteroids are also used against laryngeal hypergranulation. Microlaryngobronchoscopy should be performed by expert otolaryngologists at the first signs of laryngeal stenosis (e.g. hoarseness, inspiratory stridor).1, 8, 9
1. Prodinger C, Chottianchaiwat S, Mellerio JE, McGrath JA, Ozoemena L, Liu L, Moore W, Laimer M, Petrof G, Martinez AE. The natural history of laryngo-onycho-cutaneous syndrome: A case series of six pediatric patients and literature review. Pediatr Dermatol. 2021 Sep;38(5):1094-1101.
2. Shabbir G, Hassan M, Kazmi A. Laryngo-onycho-cutaneous syndrome: a study of 22 cases. Biomedica. 1986; 2: 15- 25.
3. Fine JD, Johnson LB, Suchindran C, Carter M, Moshell A. The National Epidermolysis bullosa registry. In: Fine JD, Bauer EA, McGuire J, Moshell A (Eds). Epidermolysis bullosa. Clinical, epidemiologic, and laboratory findings of the National Epidermolysis Bullosa Registry. The Johns Hopkins University Press, Baltimore, Maryland, 1999, pp 79-100
4. McLean WH, Irvine AD, Hamill KJ, Whittock NV, Coleman-Campbell CM, Mellerio JE, Ashton GS, Dopping-Hepenstal PJ, Eady RA, Jamil T, Phillips RJ, Shabbir SG, Haroon TS, Khurshid K, Moore JE, Page B, Darling J, Atherton DJ, Van Steensel MA, Munro CS, Smith FJ, McGrath JA. An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Hum Mol Genet. 2003 Sep 15;12(18):2395-409. Epub 2003 Jul 15. Erratum in: Hum Mol Genet. 2004 Feb 1;13(3):36
5. Cohn HI, Murrell DF. Laryngo-onycho-cutaneous syndrome. Dermatol Clin. 2010 Jan;28(1):89-92
6.Murrell DF, Hamill KJ, Pfender E. Late onset herlitz junctional epidermolysis bullosa mimicking laryngo-onycho-cutaneous syndrome. Aust Soc Derm Research [abstract]. J Invest Dermtol. 2005; 125: A10.
7. Ranugha P, Shastry V. A novel mutation in LAMA3A gene in a child with laryngo-onycho-cutaneous syndrome from the Indian subcontinent. Indian J Dermatol Venereol Leprol. 2020; 86(5): 555- 559.
8. Moore JE, Dua HS, Page AB, Irvine AD, Archer DB. Ocular surface reconstruction in LOGIC syndrome by amniotic membrane transplantation. Cornea. 2001; 20(7): 753- 756.
9. Moore JE, Shah S, Kumar V, Ainsworth JR, Page AB, McLean WH. Follow up of patients with ocular scarring secondary to LOC syndrome treated by amniotic membrane transplantation. Br J Ophthalmol. 2005; 89(8): 939- 941.