Non-syndromic tooth agenesis associated with a nonsense mutation in ectodysplasin-A (EDA).

Mutations in the ectodysplasin-A (EDA) gene have been generally associated with X-linked hypohidrotic ectodermal dysplasia (XLHED). Recently, missense mutations in EDA have been reported to cause familial non-syndromic tooth agenesis. In this study, we report a novel EDA mutation in an Estonian family segregating non-syndromic tooth agenesis with variable expressivity. Affected individuals had no associated defects in other ectodermal organs. Using whole-exome sequencing, we identified a heterozygous nonsense mutation c.874G>T (p.Glu292X) in the TNF homology domain of EDA in all affected female patients. This protein-altering variant arose de novo, and the potentially causative allele was transmitted to affected offspring from the affected mother. We suggest that the dental phenotype variability described in heterozygous female carriers of EDA mutation may occur because of the differential pattern of X-chromosome inactivation, which retains reduced levels of EDA-receptor signaling in tissues involved in tooth morphogenesis. This results in selective tooth agenesis rather than XLHED phenotype. The present study broadens the mutation spectrum for this locus and demonstrates that EDA mutations may result in non-syndromic tooth agenesis in heterozygous females.

Inferomedially projecting pneumatised secondary middle turbinate.

Secondary middle turbinate (SMT), a rare variation of the nasal cavity, is a bony projection covered by soft tissue that arises from the lateral nasal wall. It is almost always bilateral and usually projects superomedially without any ostiomeatal unit obstruction. Herein, we report a case of bilateral inferomedially projecting secondary middle turbinates, one of which is pneumatised and hypertrophied, resembling a large ethmoid bulla extending into the middle meatus. The recognition of this variation is important since it may predispose to inflammatory sinus disease, by narrowing the ostiomeatal unit.

Human elastase 1: evidence for expression in the skin and the identification of a frequent frameshift polymorphism.

Human pancreatic elastase 1 is a serine protease which maps to the chromosomal region 12q13 close to a locus for an autosomal dominant skin disease, diffuse nonepidermolytic palmoplantar keratoderma, and was investigated as a possible candidate gene for this disorder. Expression of two elastase inhibitors, elafin and SLPI, has been related to several hyperproliferative skin conditions. elastase 1 is functionally silent in the human pancreas but elastase 1 expression at the mRNA level was detected in human cultured primary keratinocytes. Antibody staining localized the protein to the basal cell layer of the human epidermis at a number of sites including the palmoplanta. Sequencing of genomic DNA from individuals with/without the keratoderma revealed a sequence variant, which would result in a premature truncation of the protein. This sequence variant, however, did not segregate with the skin disease and, indeed, was found to occur at a relatively high frequency in the population. Individuals homozygous for the variant do not have any obvious skin abnormalities. Based on the analysis of the secondary structure of the translated putative protein, the truncation is unlikely to result in knock-out of the elastase, but may cause destabilization of the enzyme-inhibitor complex.

Fine genetic mapping of diffuse non-epidermolytic palmoplantar keratoderma to chromosome 12q11-q13: exclusion of the mapped type II keratins.

Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) belongs to the heterogeneous group of skin diseases characterized by thickening of the stratum corneum of the palms and soles (1). This autosomal dominant PPK is characterized by a diffuse pattern of palmar and plantar hyperkeratosis giving the affected areas a thickened yellowish appearance with a marked erythematous edge. Linkage of diffuse NEPPK to chromosome 12q11-q13 has been demonstrated in two independent reports (2, 3). In this study, we describe detailed haplotyping with microsatellite markers mapping to this chromosomal region in three diffuse NEPPK pedigrees from the south of England. Fine mapping of a previously identified recombination event and the identification of a common disease haplotype segregating in the three pedigrees places the diffuse NEPPK locus proximal to the type II keratin gene cluster.