Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder characterized by deficient development of ectoderm-derived structures including sweat glands, hair and teeth, leading to the medical triad of hypo- or anhidrosis, hypotrichosis and hypo- or anodontia. X-linked HED (XLHED), the most frequent subtype, is caused by a broad spectrum of mutations in the gene EDA.
The aim of this study was to assess the impact of individual EDA mutations on the number and function of sweat glands. For this purpose we investigated the mutational spectrum in a large cohort of pediatric XLHED patients by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA), determined the palmar and/or plantar sweat pore density by confocal laser scanning microscopy and quantified pilocarpine-induced sweating. 
Most of our patients had small EDA mutations like missense, indel, splice site and stop mutations, but we also detected some rare genomic rearrangements. The variations were distributed over the gene regions encoding the furin cleavage site, the collagen-like domain (COL) and the TNF homology domain of ectodysplasin A, confirming the known mutational hot spots. All male subjects with in-frame deletions in the first part of the COL region showed significant residual sweating ability indicating some biological activity of the mutant protein, while the remaining male patients carrying deletions or mutations of different type in other EDA regions were – with two exceptions – unable to sweat. As expected, female carriers displayed milder phenotypes with higher sweat duct densities and sweating ability.
Thus, more than the type of EDA mutation, its location in the gene may be considered as major determinant of the disease phenotype, allowing some prediction of the severity of disease already perinatally. The assessment of genotype-phenotype correlations also represents an important prerequisite for the evaluation of future medical treatments.

Residual sweating ability of children with hypohidrotic ectodermal dysplasia – is it predictable?