ESPEYB17 4. Growth and Growth Factors Important for clinical practice (5 abstracts)
4.3. IGF2 Mutations
Masunaga Y , Inoue T , Yamoto K , Fujisawa Y , Sato Y , Kawashima-Sonoyama Y , Morisada N , Iijima K , Ohata Y , Namba N , Suzumura H , Kuribayashi R , Yamaguchi Y , Yoshihashi H , Fukami M , Saitsu H , Kagami M & Ogata T
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan kagami-ms@ncchd.go.jp
To read the full abstract: J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz034.
Using different genetic approaches, the authors identified 5 novel pathogenic or likely pathogenic IGF2 gene variants in Japanese patients who underwent genetic testing for the variable associations of multiple congenital anomalies such as mental retardation, Silver-Russell syndrome (SRS), disorders of sex development (DSD), ectrodactyly (split hand/foot malformation), fetal growth restriction (FGR) and extremely high serum insulin-like growth factor I (IGF-I). Four of the five patients had a Netchine-Harbison (N-H) score of 5+ out 6 for the clinical diagnosis of SRS. In comparison with H19/IGF2: IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemi-hypoplasia, high frequency of feeding difficulty and/or reduced body mass index, milder degree of relative macrocephaly, occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values.
The IGF2 gene is located on an imprinted paternally-expressed region on chromosome 11p15 and encodes for IGF-II which is actively involved in the regulation of placental and fetal growth. IGF2 up-regulating genetic and epigenetic mutations cause Beckwith-Wiedemann syndrome, characterized by overgrowth and increased risk of cancer, while down-regulating mutations cause Silver-Russell syndrome (SRS) characterized by intrauterine and postnatal growth retardation besides a wide range of dysmorphic features, severe feeding difficulties, body asymmetry, and neurodevelopmental delay (1)(2). The most frequent IGF2 alteration in SRS is hypomethylation of the paternally-inherited H19/IGF2 intergenic-DMR, although copy number variants of the 11p15.5 region have also been reported (1). So far, few heterozygous paternally-inherited IGF2 genetic mutations have been described in SRS patients (3)(4). A recent paper described a paternally-inherited IGF2 nonsense mutation in four members of one family with a clinical phenotype suggestive of SRS (2).
This study suggests that, although rare, DNA sequence analysis of IGF2 should be performed in patients with no demonstrable epigenetic cause of SRS. Furthermore, the results show a certain degree of phenotypic differences between patients with H19/IGF2: IG-DMR epimutations and those with IGF2 genetic mutations.
References:
1. Wakeling EL, Brioude F, Lokulo-Sodipe O, O’Connell SM, Salem J, Bliek J, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13(2):105–24.
2. Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Buttel HM, et al. Paternally Inherited IGF2 Mutation and Growth Restriction. N Engl J Med. 2015;373(4):349–56.
3. Liu D, Wang Y, Yang XA. De Novo Mutation of Paternal IGF2 Gene Causing Silver-Russell Syndrome in a Sporadic Patient. Front Genet. 2017;8:105.
4. Rockstroh D, Pfäffle H, Le Duc D, Rößler F, Schlensog-Schuster F, Heiker JT, et al. A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation. Eur J Endocrinol. 2019;180(1):K1–k13.
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ESPE Yearbook of Paediatric Endocrinology
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