Growth Restriction, Severe, With Distinctive Facies

A number sign (#) is used with this entry because of evidence that severe growth restriction with distinctive facies (GRDF) is caused by heterozygosity for a paternally inherited mutation in the IGF2 gene (147470) on chromosome 11p15. One such family has been reported.

Silver-Russell syndrome (SRS; 180860), which has overlapping features, is caused by epigenetic alteration in the chromosome 11p15 region.

Begemann et al. (2015) reported a 4-generation family in which 4 affected individuals had severe prenatal and postnatal growth restriction and a distinctive triangular face with prominent forehead and low-set ears. The proband was a 26-year-old man born with hypotrophy and relative macrocephaly, who also exhibited right ulnar ray defect (missing digits 3-5) and contracture of the right elbow with pterygium. He had severe feeding problems that necessitated a nasogastric tube for the first 3 years of life. His 21-year-old affected sister was born by cesarean section due to progressive oligohydramnion and fetal growth restriction; she required feeding through a nasogastric tube for 6 months. Their 20-year-old male cousin was also born by cesarean section due to poor fetal growth, and had ambiguous genitalia with penoscrotal hypospadias and unilateral cryptorchidism. The proband and his sister had low to low-normal intelligence and attended special schools, whereas their cousin had intelligence scores at or above the 50th percentile and attended high school. The proband's daughter was small at birth and had severe feeding problems; at age 18 months, she had relative macrocephaly with severe frontal bossing, small hands and feet, hypotonia, and developmental delay. Endocrine analysis showed IGF2 deficiency in the 2 affected sibs and their cousin; all 3 had normal levels of IGF1 (147440) and IGFBP3 (146732), and spontaneous secretion of growth hormone (GH1; 139250) at night and after stimulation with arginine was normal to high-normal.

In a 4-generation family with GRDF, in which Silver-Russell syndrome-associated molecular alterations had been excluded, Begemann et al. (2015) performed exome sequencing and identified a heterozygous nonsense mutation in the IGF2 gene (S64X; 147470.0004) that segregated fully with the disorder. Affected individuals inherited the mutation from their healthy fathers, and it originated from the healthy paternal grandmother. Clinical features occurred only in those who inherited the variant allele through paternal transmission, consistent with maternal imprinting of IGF2.