EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features

Abstract

The epidermal growth factor receptor (EGFR) is part of a large family of receptors required for communicating extracellular signals through internal tyrosine kinases. Epidermal growth factor (EGF) signaling is required for tissue development, whereas constitutive activation of this signaling pathway is associated with oncogenic transformation. We identified homozygous c.1283G>A (p.Gly428Asp) mutations in the extracellular domain of EGFR in two siblings. The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perforation. EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. Cells from the affected patient undergo early senescence with accelerated expression of β-galactosidase and shortened telomeres at all passages when compared to controls. A comparison of homozygous inherited regions from a separate report of a patient from the same ethnic background and EGFR genotype confirms the pathogenicity of EGFR mutations in congenital disease.

Fatal neonatal nephrocutaneous syndrome in 18 Roma children with EGFR deficiency

“…All children in our study were of Roma origin and most of their families are from Eastern Slovakia, strongly supporting a “founder effect” as suggested by Ganetzky et al. …”

“…In conclusion, the results of our study of 18 children together with three published cases suggest that EGFR deficiency due to the homozygous mutation p.Gly428Asp in EGFR results in a devastating neonatal nephrocutaneous syndrome. The disease is almost always fatal in the neonatal or early infantile period due to skin lesions and severe secondary infections, but as seen in the one surviving boy, extremely demanding skin care with proper management of infections, ion and water imbalances may improve the unfavorable outcome of patients.…”

“…In contrast, germ line loss‐of‐function mutations in EGFR have been described in four infants with severe neonatal skin disorders. Three of these infants were from Roma families and had the homozygous missense mutation c.1283G˃A (p.Gly428Asp) in EGFR , resulting in a misfolding of the extracellular protein domain with impaired stability . The other was a Japanese boy who was a compound heterozygote for the mutations c.292C˃T (p.Arg98*) and c.1094T˃A (p.Ile365Asn) .…”

Biallelic mutations of EGFR in a compound heterozygous state cause ectodermal dysplasia with severe skin defects and gastrointestinal dysfunction

“…Epidermal growth factor receptor (EGFR), a receptor that recognizes EGF, is a very important regulator of cell proliferation and differentiation 2 , 3 . Campbell et al 4 and Ganetzky et al 5 reported on patients with ED who possessed homozygous loss-of-function (LoF) mutations of EGFR . These patients had common biallelic homozygous mutations.…”

The Molecular Revolution in Cutaneous Biology: Era of Molecular Diagnostics for Inherited Skin Diseases

“…From perhaps the earliest report of a homozygous missense mutation in SLC26A3 (Choi et al, 2009) in a patient with Bartter syndrome, a renal saltwasting disease, more than 20 novel and previously uncharacterized genodermatoses, germline and mosaic, have been identified through WES, and many further discoveries are anticipated. Selected recent examples include the discovery of somatic mutations in HRAS and KRAS in nevus sebaceus (Levinsohn et al, 2013) and a new autosomal recessive epithelial inflammatory disease resulting from germline mutations in EGFR (Campbell et al, 2014;Ganetzky et al, 2015). For diagnostic applications, however, there are some limitations to WES, mainly centered on the management and analysis of the large-scale data that are generated.…”