Laryngoonychocutaneous Syndrome

A number sign (#) is used with this entry because of evidence that laryngoonychocutaneous syndrome (LOCS) is caused by homozygous mutation in the LAMA3 gene (600805) on chromosome 18q11.

Clinical Features

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).

Mapping

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.

Molecular Genetics

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.