Alternative titles; symbols
SNOMEDCT: 722675000; ORPHA: 2407;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q11.2 | Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous | 245660 | Autosomal recessive | 3 | LAMA3 | 600805 |
A number sign (#) is used with this entry because of evidence that laryngoonychocutaneous junctional epidermolysis bullosa 2C (JEB2C), also known as laryngoonychocutaneous syndrome (LOCS), is caused by homozygous or compound heterozygous mutation in the LAMA3 gene (600805) on chromosome 18q11.
Junctional epidermolysis bullosa 2C (JEB2C), also known as laryngoonychocutaneous syndrome (LOCS), is an autosomal recessive disorder characterized by skin erosions, nail dystrophy, dental anomalies, and excessive vascular granulation tissue of the conjunctiva and larynx. Onset is characterized by a hoarse cry soon after birth. Beginning in infancy, chronic skin ulcers and conjunctival lesions appear. Patients may die in childhood secondary to acute or chronic respiratory obstruction. Long-term survivors have visual loss and often require tracheostomy (McLean et al., 2003).
For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (226650).
Reviews
Has et al. (2020) reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa.
Shabbir et al. (1986) described a novel autosomal recessive syndrome, which they called laryngoonychocutaneous syndrome, in 22 patients in 12 families living in Lahore, Pakistan. Beginning within 2 weeks of birth, the disorder presented with hoarseness (which was not associated with any obvious laryngeal lesion), dystrophic changes in the nails, and chronic bleeding, crusted lesions of the skin of the face. In addition, the teeth were deformed. The ulcers did not respond to any drugs, including antibiotics, antituberculosis therapy, corticosteroids, and dapsone.
Ainsworth et al. (1991, 1992) expanded on the description of this progressive multisystem disorder manifested by dermal and submucosal granulation with vocal cord involvement. The manifestations were hoarse cry and dermal granuloma formation. The disorder had been reported only in Muslim families of Punjabi origin. Manifestations appeared during the first months of life and included skin ulceration, recurrent loss of toenails and fingernails, and conjunctival scarring. Other epithelial surfaces were later involved. The voice was sometimes affected because of vocal cord thickening and/or nodules; in some children a weak cry was noted at birth. Some of the affected persons had amelogenesis imperfecta. No impairment of immune function was detected. Death in childhood was common, although among those who survived, remission occurred during the second decade. Ainsworth et al. (1992) examined 27 affected children in 18 families. (Phillips (2005) noted that this series included the 22 patients reported by Shabbir et al. (1986) and 5 English children of Punjabi Muslim ancestry.) In all but 3 families, the parents were consanguineous. In 10 of the families, 2 sibs were affected. The male-to-female ratio was 18:9; this was thought to be due to greater readiness of poor families to refer males for treatment. Ainsworth et al. (1991, 1992) proposed the designation LOGIC syndrome for 'laryngeal and ocular granulation in children from the Indian subcontinent.'
From Melbourne, Australia, Phillips et al. (1994) described 3 unrelated children of Pakistani ancestry. The parents were known to be consanguineous in 2 of the 3 cases and a pedigree with 6 affected individuals in 3 sibships connected through consanguineous marriages was presented. All developed laryngeal abnormalities, chronic skin ulceration, nail dystrophy, and conjunctival disease in infancy. In each case, dental enamel was hypoplastic and both skin and mucosal surfaces demonstrated increased susceptibility to trauma. The disease progressed to life-threatening respiratory obstruction in 2 patients and to virtual blindness and fatal respiratory obstruction in the third child. Laser therapy was partially successful in alleviating laryngeal manifestations. The 2 children with the severest clinical disease showed abnormal hemidesmosomes on ultrastructural examination. Phillips et al. (1994) interpreted this and the abnormally weak immunoreactivity with antibodies directed against basal cell proteins as consistent with the LOGIC syndrome being caused by an inherited defect affecting the lamina lucida of the skin basement membrane zone. Thus, the syndrome may represent a distinctive form of junctional epidermolysis bullosa (226700). Phillips (2005) stated that the children they described were 3 of the English children reported by Ainsworth et al. (1992).
Figueira et al. (2007) described a 7-year-old Caucasian boy with JEB2C and mutation in the LAMA3 gene. He developed periungual blisters, oral mucosal erosions, and hoarseness due to laryngeal blisters and ulcerations at 9 months of age. Eyelid involvement was first noticed at 15 months with bilateral bulbous lesions of the eyelids followed by small ulcerations and crust formation. Biopsy of the eyelid lesions revealed exuberant granulation tissue with overlying mucosal and cutaneous ulceration. The eyelid granulation tissue resembled granulomas seen in LOCS. The eyelid lesions were surgically excised and healed well. He was treated for recurrent corneal ulcerations at age 6. Other complications included an emergency permanent tracheostomy placed due to stridor caused by laryngotracheal involvement and a gastrostomy tube placement at 4 years to manage feeding problems causing failure to thrive.
Barzegar et al. (2013) described 2 Iranian sibs with LOCS born to consanguineous parents. The older sib was a 27-year-old man who manifested periungual erosions followed by erosions on the face, elbows, hands, and knees after minor trauma in the neonatal period. Excessive granulation tissue under fingers and toenails led to detachment of the nails. At around age 5 years, erosions developed around the corners of his mouth and nostrils. The eroded alae nasi took 2 years to heal, with scarring and occlusion of the nares bilaterally. Scarring of the left eye with extensive symblepharon led to visual impairment. Hoarseness developed at puberty, without stridor or respiratory difficulty. The 9-year-old sister had a similar presentation in the neonatal period, with erosions at minor trauma or pressure sites. Ocular granulation tissue required surgery, but subsequent regrowth led to significant visual loss. Both sibs were noted to have small, yellow teeth with enamel hypoplasia.
Prodinger et al. (2021) identified 6 LOCS patients, all female. Periungual hypergranulation and skin fragility were the earliest presenting signs (0 to 3 months of age) followed by laryngeal stenosis (onset 10.7 months of age), temporally advancing symblepharon (onset 11.8 months of age), and dental abnormalities including delayed eruption, microdontia, and enamel defects. Five children developed microcytic, hypochromic anemia, (onset 19.2 months of age) requiring repeated blood transfusions or iron infusions. Recurrent corneal erosions and scarring occurred in 5 of the 6 patients. Prodinger et al. (2021) described the principal clinical features of LOCS: (1) hypergranulating wounds or slow-healing skin ulcerations with only mild skin fragility, (2) hypergranulation tissue on distal fingers/toes or nail dystrophy, (3) temporally advancing symblepharon, and (4) laryngeal stenosis secondary to hypergranulation. Prodinger et al. (2021) reviewed 31 LOCS published cases plus their 6 patients and determined that the 4 principal clinical features were present in 94.6% (35) of all cases.
Wang et al. (2022) described 2 Chinese brothers with epidermolysis bullosa. The 42-year-old proband had extensive mutilating erosions and scars of the extremities and orofacial region with hypertrophic scarring in the armpit. He also had severe fingernail onychodystrophy and severe enamel hypoplasia manifesting as discolored, pitted teeth, hypodontia, and dental caries. His brother had extremity and eyelid scarring as well as symblepharon. Granulation tissue or hoarse voice were not mentioned. Wang et al. (2022) concluded that the patients most closely resembled LOCS, particularly the symblepharon that led to visual impairment in the proband's brother.
The transmission pattern of JEB2C in the families studied by McLean et al. (2003) was consistent with autosomal recessive inheritance.
McLean et al. (2003) localized the gene for LOCS to a 2-Mb region on chromosome 18q11.2 (lod = 19.8 at theta = 0) using genomewide homozygosity mapping.
Prodinger et al. (2021) provided recommendations on management of LOCS. Although generalized skin fragility is mild in comparison to other subtypes of JEB, wounds heal poorly, bleed frequently, and are covered with exuberant granulation tissue. Topical treatment includes a combination of antiinflammatory (medium to high potency corticosteroids) and antiseptic agents. Bleeding from wounds can lead to early-onset microcytic hypochromic anemia. Early laboratory screening for anemia by 1 year of age is recommended in all infants with LOCS. Laryngeal stenosis is common. Microlaryngobronchoscopy (MLB) should be performed early on with the first symptoms of airway disease (hoarseness, inspiratory stridor, increased work of breathing). Development of conjunctival granulation tissue with symblepharon is rare in other forms of JEB but highly characteristic in LOCS. Treatment is extremely challenging as simple excision of granulation tissue leads to rapid recurrence. Close monitoring by experienced pediatric ophthalmologists and early intervention to avoid or delay total palpebral occlusion and blindness is necessary.
McLean et al. (2003) noted that mutations in a candidate gene on chromosome 18q11.2, laminin alpha-3 (LAMA3; 600805), cause the lethal skin blistering disorder Herlitz-Pearson junctional epidermolysis bullosa. The gene encodes 3 distinct proteins, designated laminin alpha-3a, alpha-3b1 and alpha-3b2, which are produced by alternative splicing. In affected members of 15 consanguineous Punjabi families with LOCS, McLean et al. (2003) identified homozygosity for a frameshift mutation in the LAMA3 gene (151insG; 600805.0004), predicting a stop codon in an exon that is specific to laminin alpha-3a. This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOCS may be caused by dysfunction of keratinocyte-mesenchymal communication. McLean et al. (2003) hypothesized that the laminin alpha-3a N-terminal domain may be a key regulator of the granulation tissue response.
In a 7-year-old boy with overlapping features of junctional EB and laryngoonychocutaneous syndrome (LOCS), Figueira et al. (2007) identified compound heterozygosity for mutations in the LAMA3A gene: a paternally inherited splice site mutation at the donor site of intron 35 in LAMA3 (c.4651+1G-A; 600805.0006), and a maternally inherited missense mutation (I17N; 600805.0009) in the laminin alpha-3a isoform. Figueira et al. (2007) noted that the case was unique in having several features of LOCS (eyelid and laryngeal granulation tissue) and mutations in both the laminin alpha-3 and laminin alpha-3a isoforms, providing evidence that LOC is a variant of JEB.
In 2 Iranian sibs with LOCS, Barzegar et al. (2013) identified homozygosity for a nonsense mutation (G57X; 600805.0007) in the LAMA3 gene. The variation affects only the laminin alpha-3a transcript. Two unaffected sibs as well as both parents were heterozygous for this mutation. The mutation occurred 18 basepairs downstream from the 151insG mutation (600805.0004) described by McLean et al. (2003) in the original Punjab families.
In a proband and brother with a phenotype consistent with LOCS, Wang et al. (2022) identified a homozygous nonsense mutation in LAMA3 gene (W16X; 600805.0008). The W16X variant is located in exon 1 of the laminin alpha-3a (LAMA3A) transcript, specific to LAMA3A and corresponding to exon 39 of the full-length LAMA3 gene.
Ainsworth, J. R., Shabbir, G., Spencer, A. F., Cockburn, F. Multisystem disorder of Punjabi children exhibiting spontaneous dermal and submucosal granulation tissue formation: LOGIC syndrome. Clin. Dysmorph. 1: 3-14, 1992. [PubMed: 1342856]
Ainsworth, J. R., Spencer, A. F., Dudgeon, J., Geddes, N. K., Lee, W. R. Laryngeal and ocular granulation tissue formation in two Punjabi children: LOGIC syndrome. Eye 5: 717-722, 1991. [PubMed: 1800173] [Full Text: https://doi.org/10.1038/eye.1991.132]
Barzegar, M., Mozafari, N., Kariminejad, A., Asadikani, Z., Ozoemena, L., McGrath, J. A. A new homozygous nonsense mutation in LAMA3A underlying laryngo-onycho-cutaneous syndrome. Brit. J. Derm. 169: 1353-1356, 2013. [PubMed: 23869449] [Full Text: https://doi.org/10.1111/bjd.12522]
Figueira, E. C., Crotty, A., Challinor, C. J., Coroneo, M. T., Murrell, D. F. Granulation tissue in the eyelid margin and conjunctiva in junctional epidermolysis bullosa with features of laryngo-onycho-cutaneous syndrome. Clin. Exp. Ophthal. 35: 163-166, 2007. [PubMed: 17362460] [Full Text: https://doi.org/10.1111/j.1442-9071.2006.01436.x]
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
McLean, W. H. I., Irvine, A. D., Hamill, K. J., Whittock, N. V., Coleman-Campbell, C. M., Mellerio, J. E., Ashton, G. S., Dopping-Hepenstal, P. J. H., Eady, R. A. J., Jamil, T., Phillips, R. J., Shabbir, S. G., Haroon, T. S., Khurshid, K., Moore, J. E., Page, B., Darling, J., Atherton, D. J., van Steensel, M. A. M., Munro, C. S., Smith, F. J. D., McGrath, J. A. An unusual N-terminal deletion of the laminin alpha-3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Hum. Molec. Genet. 12: 2395-2409, 2003. Note: Erratum: Hum. Molec. Genet. 13: 365 only, 2004. [PubMed: 12915477] [Full Text: https://doi.org/10.1093/hmg/ddg234]
Phillips, R. J., Atherton, D. J., Gibbs, M. L., Strobel, S., Lake, B. D. Laryngo-onycho-cutaneous syndrome: an inherited epithelial defect. Arch. Dis. Child. 70: 319-326, 1994. [PubMed: 8185366] [Full Text: https://doi.org/10.1136/adc.70.4.319]
Phillips, R. Personal Communication. Melbourne, Australia 9/21/2005.
Prodinger, C., Chottianchaiwat, S., Mellerio, J. E., McGrath, J. A., Ozoemena, L., Liu, L., Moore, W., Laimer, M., Petrof, G., Martinez, A. E. The natural history of laryngo-onycho-cutaneous syndrome: A case series of six pediatric patients and literature review. Pediat. Derm. 38: 1094-1101, 2021. [PubMed: 34514630] [Full Text: https://doi.org/10.1111/pde.14790]
Shabbir, G., Hassan, M., Kazmi, A. Laryngo-onycho-cutaneous syndrome: a study of 22 cases. Biomedica 2: 15-25, 1986.
Wang, R., Sun, L., Habulieti, X., Liu, J., Guo, K., Yang, X., Ma, D., Zhang, X. Novel variants in LAMA3 and COL7A1 and recurrent variant in KRT5 underlying epidermolysis bullosa in five Chinese families. Front. Med. 16: 808-814, 2022. [PubMed: 35314946] [Full Text: https://doi.org/10.1007/s11684-021-0878-x]