Ectodermal Dysplasia/short Stature Syndrome

A number sign (#) is used with this entry because of evidence that ectodermal dysplasia/short stature syndrome (ECTDS) is caused by homozygous mutation in the GRHL2 gene (608576) on chromosome 8q22.

Clinical Features

Petrof et al. (2014) reported 6 affected individuals from 2 unrelated consanguineous Kuwaiti families in which patients had short stature, nail dystrophy and/or loss, hyperpigmentation of the oral mucosa and/or tongue, abnormal dentition including delay, hypodontia, and enamel hypoplasia, keratoderma involving the margins of the palms and soles, and focal hyperkeratosis of the dorsal aspects of the hands and feet. None of the affected individuals had hair or sweating abnormalities, wound-healing defects, a blistering tendency, or other developmental anomalies. However, 3 of the 6 affected individuals developed sensorineural deafness in early infancy, and 3 had bronchial asthma. In addition, 2 affected sisters had dysphagia with apparent esophageal strictures. Light microscopy of lesional skin from 3 affected individuals showed mild acanthosis and hyperkeratosis, but electron microscopy was unremarkable as was skin immunolabeling. None of the parents had any skin, hair, teeth, nail, or hearing abnormalities.

Molecular Genetics

In affected individuals from 2 unrelated consanguineous Kuwaiti families with short stature and ectodermal defects, Petrof et al. (2014) performed whole-exome sequencing and identified homozygosity for 2 different missense mutations in the GRHL2 gene, Y398H (608576.0003) and I482K (608576.0004), respectively. Sanger sequencing confirmed the mutations and demonstrated segregation with disease in each family. Neither mutation was found in 260 ethnically matched controls, in approximately 1,200 control in-house exomes, or in the 1000 Genomes Project database. Examination of patient keratinocytes showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2 compared to controls; whole-skin transcriptomic analysis revealed changes in genes involved in networks of cell-cell and cell-matrix adhesion.