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

Ganetzky R, Finn E, Bagchi A, Zollo O, Conlin L, Deardorff M, Harr M, Simpson MA, McGrath JA, Zackai E, Lemmon MA, Sondheimer N - Mol Genet Genomic Med (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.

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.

No MeSH data available.


Related in: MedlinePlus

Physical features of the affected siblings. The sister (A) was photographed at 2 months of age and the brother (B) at 3 weeks of age.
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fig01: Physical features of the affected siblings. The sister (A) was photographed at 2 months of age and the brother (B) at 3 weeks of age.

Mentions: We evaluated two siblings from a consanguineous Roma family. Patient 1 was born at 34 weeks gestation. She had severe intrauterine growth restriction, nephromegaly, and renal tubulopathy. Weight, length, and head circumference were less than the first percentile (at 2 months weight and head circumference were 50th percentile for 33.5 weeks’ gestation; length was 50th percentile for 32 weeks’ gestation). She had craniofacial dysmorphism with pseudohydrocephalus, a progeroid appearance, striking desquamation with ichthyotic, hyperpigmented, translucent skin, absence of subcutaneous fat and sparse, stiff hair (Fig.1A). She had progressive abdominal distention and passed away after intestinal perforation at 3 months of age.


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

Ganetzky R, Finn E, Bagchi A, Zollo O, Conlin L, Deardorff M, Harr M, Simpson MA, McGrath JA, Zackai E, Lemmon MA, Sondheimer N - Mol Genet Genomic Med (2015)

Physical features of the affected siblings. The sister (A) was photographed at 2 months of age and the brother (B) at 3 weeks of age.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585453&req=5

fig01: Physical features of the affected siblings. The sister (A) was photographed at 2 months of age and the brother (B) at 3 weeks of age.
Mentions: We evaluated two siblings from a consanguineous Roma family. Patient 1 was born at 34 weeks gestation. She had severe intrauterine growth restriction, nephromegaly, and renal tubulopathy. Weight, length, and head circumference were less than the first percentile (at 2 months weight and head circumference were 50th percentile for 33.5 weeks’ gestation; length was 50th percentile for 32 weeks’ gestation). She had craniofacial dysmorphism with pseudohydrocephalus, a progeroid appearance, striking desquamation with ichthyotic, hyperpigmented, translucent skin, absence of subcutaneous fat and sparse, stiff hair (Fig.1A). She had progressive abdominal distention and passed away after intestinal perforation at 3 months of age.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.

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.

No MeSH data available.


Related in: MedlinePlus