ESPE Abstracts (2015) 84 P-2-466


Whole Exome Sequencing Identifies De Novo HRAS Mutation Underlying Primary IGF1 Deficiency (PIGFD)

Greta Grossea,e, Alina Hilgera, Markus Draakena, Michael Ludwigc, Heiko Reuttera,b, Franziska Lorenzend & Joachim Woelflee


aDepartment of Genomics Life and Brain Center, Institute of Human Genetics, Bonn, Germany; bDepartment of Neonatology, Children’s Hospital, Bonn, Germany; cDepartment of Clinical Chemistry and Pharmacology, Bonn, Germany; dPediatric Practice, Hannover, Germany; ePediatric Endocrinology Division, University of Bonn, Bonn, Germany

Background: Primary IGF1 deficiency (PIGFD) is a rare condition defined by low IGF1 levels, GH sufficiency and absence of secondary causes of growth failure. PIGFD is an approved indication for treatment with recombinant IGF1 (rIGF1). Its genetic causes remain largely unknown.

Objective and hypotheses: To elucidate genetic causes of PIGFD.

Method: Clinical phenotyping followed by trio-based whole-exome sequencing (WES) in 11 complete case-parent-trios.

Results: By WES we identified a HRAS mutation (G13C) in a boy with syndromic PIGFD. His phenotype included a history of infantile feeding problems, short stature, mild psychomotor delay, sparse hair and long eyelashes. Biochemically, at age 4 years serum IGF1 was 9 ng/ml (−4.1 SDS), IGFBP3 0.5 μg/l (−4.9 SDS) with sufficient stimulated GH secretion and slightly elevated prolactin concentration. Probatory GH treatment moderately improved his growth, but did not lead to a significant increase of circulating IGF1 concentration.

Conclusion: Our report of a patient with HRAS mutation enlarges the spectrum of genetic causes underlying syndromic PIGFD. With regard to rasopathies, GH insensitivity has been reported only in subjects with Noonan syndrome and PTPN11 mutations. Considering the increased risk for benign and malignant neoplasm in subjects with HRAS mutations, close clinical monitoring and a thoroughful discussion on the risk/benefit ratio of potential treatment with GH or rIGF1 is mandatory.

Conflict of interest: JW served as an advisor for Ipsen and Novo Nordisk.

Funding: This work was supported by the BONFOR reseach program of the University of Bonn, Germany and by an unrestricted research grant by Ipsen.

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