ORPHA: 397590;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q14.3 | Silver-Russell syndrome 5 | 618908 | Autosomal dominant | 3 | HMGA2 | 600698 |
A number sign (#) is used with this entry because of evidence that Silver-Russell syndrome-5 (SRS5) is caused by heterozygous mutation in the HMGA2 gene (600698) on chromosome 12q14.
Silver-Russell syndrome-5 (SRS5) is characterized by intrauterine growth retardation, with feeding difficulties in early childhood and postnatal growth failure. Relative macrocephaly may be present at birth. Other dysmorphic features include triangular face with prominent forehead (De Crescenzo et al., 2015).
For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860).
De Crescenzo et al. (2015) reported a 4-year-old Italian girl who had intrauterine growth retardation (IUGR) and relative macrocephaly at birth, with feeding difficulties during early childhood resulting in postnatal growth retardation. Examination at 20 months of age showed triangular face with broad and prominent forehead, hypertelorism, epicanthus, thin upper lip, micrognathia, fifth-finger brachydactyly and clinodactyly, and 2-3 syndactyly of the toes. Other features included gastroesophageal reflux, reduced musculature, cafe au lait spot, and clitoral hypertrophy. The proband's mother also exhibited short stature (-3.87 SD), with triangular face, prominent forehead, and fifth-finger brachydactyly; she reported a history of feeding difficulties in early childhood with postnatal growth retardation. A maternal aunt and the maternal grandfather were also said to show growth retardation.
Costain et al. (2018) described a 10.5-year-old boy (case 1096) who was born with IUGR and had difficulties with feedings during infancy. He did not show catch-up growth postnatally, with heights consistently -3 SD below the median. Skeletal x-rays showed delayed bone age and metaphyseal irregularity at the base of the metacarpals and metatarsals. Other features included triangular face, reactive airway disease, and gastroesophageal reflux. In addition, he had delays in gross and fine motor development, learning disability, attention-deficit/hyperactivity disorder, and obsessive-compulsive disorder. He did not show relative macrocephaly or body asymmetry. His mother also had IUGR and short stature; other features included neonatal teeth, hydrocephalus, and bicuspid aortic valve. She was diagnosed with hypothyroidism at age 10 years, rheumatoid arthritis at age 11, and also had Crohn disease. The maternal grandfather and maternal great-uncle both had short stature and mild learning difficulties.
Leszinski et al. (2018) reported a 4-year-old girl with IUGR, postnatal feeding difficulties, and postnatal growth failure. She also showed triangular face and protruding forehead, but did not have relative macrocephaly or body asymmetry. Psychomotor development was normal.
The transmission pattern of SRS5 in the family reported by Costain et al. (2018) was consistent with autosomal dominant inheritance.
In a 4-year-old Romanian boy with severe pre- and postnatal growth restriction, Mari et al. (2009) identified heterozygosity for a de novo 1.8-Mb deletion on chromosome 12q14.3 that encompassed 6 genes, including HMGA2. Other features in the proband consistent with SRS included microcephaly, triangular face with prominent forehead, downturned corners of the mouth, high-arched palate, and slight micrognathia; body asymmetry was not present. He also had patent ductus arteriosus and ventricular septal defect, and exhibited significant developmental delay: at age 3 years, he was unable to walk completely unaided, and did not speak. The deletion was not found in either of his healthy first-cousin parents, and HMGA2 analysis did not reveal any sequence change in the remaining allele. The authors stated that the phenotype was similar to that of primordial dwarfism or severe Silver-Russell syndrome (SRS).
Heldt et al. (2018) reported a mother and her son and daughter with IUGR, postnatal feeding difficulties, and short stature, in whom they identified heterozygosity for a 1.67-MB deletion on chromosome 12q14.3 (chr12:65,863,186_67,528,640, GRCh37) encompassing 7 genes, including HMGA2. The mother and daughter exhibited prominent forehead and eyes as well as mild facial asymmetry, but these features were not noted in the affected brother. Other features included arthrosis in the mother; increased sweating in the daughter, although blood sugar level were always within normal limits; and cardiac arrhythmias in the brother. None of the affected individuals showed relative macrocephaly.
In a cohort of 45 patients with syndromic or isolated pre- and postnatal growth retardation, who were negative for epimutation at chromosome 11p15 and maternal uniparental disomy of chromosome 7, De Crescenzo et al. (2015) searched for chromosome 12q14 imbalances and mutations in the HMGA2 gene, and identified an Italian mother and daughter with SRS who were heterozygous for a 7-bp deletion in HMGA2 (600698.0001). Functional analysis indicated that the mutation severely affected splicing efficiency of HMGA2.
From a cohort of 192 patients with a suspected diagnosis of SRS, Abi Habib et al. (2018) identified 2 unrelated patients with heterozygous de novo mutations in the HMGA2 gene (600698.0002 and 600698.0003). In 6 more patients from 4 families in the SRS cohort, they identified mutations in the PLAG1 (603026) and IGF2 (147470) genes (see SRS4, 618907, and SRS3, 616489, respectively). Experiments in Hep3b cells demonstrated that HMGA2 and PLAG1 both positively regulate expression of the IGF2 promoter P3, independently and via an HMGA2-PLAG1-IGF2 pathway. The authors noted that disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus.
Costain et al. (2018) reanalyzed whole-genome sequencing data in 64 individuals from a previously studied cohort of pediatric patients (Stavropoulos et al., 2016), and identified heterozygosity for a 1-bp deletion in the HMGA2 gene (600698.0004) in a 10.5-year-old boy (case 1096) with IUGR, short stature, and learning difficulties. The mutation was inherited from his similarly affected mother.
In a 4-year-old girl with SRS, who was negative for hypomethylation at chromosome 11p15 and maternal uniparental disomy of chromosome 7, Leszinski et al. (2018) performed whole-exome sequencing and identified heterozygosity for a de novo 7.3-kb deletion on chromosome 12q14.3 that included exons 1 and 2 of the HMGA2 gene.
Abi Habib, W., Brioude, F., Edouard, T., Bennett, J. T., Lienhardt-Roussie, A., Tixier, F., Salem, J., Yuen, T., Azzi, S., Le Bouc, Y., Harbison, M. D., Netchine, I. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction. Genet. Med. 20: 250-258, 2018. [PubMed: 28796236] [Full Text: https://doi.org/10.1038/gim.2017.105]
Costain, G., Jobling, R., Walker, S., Reuter, M. S., Snell, M., Bowdin, S., Cohn, R. D., Dupuis, L., Hewson, S., Mercimek-Andrews, S., Shuman, C., Sondheimer, N., Weksberg, R., Yoon, G., Meyn, M. S., Stavropoulos, D. J., Scherer, S. W., Mendoza-Londono, R., Marshall, C. R. Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing. Europ. J. Hum. Genet. 26: 740-744, 2018. [PubMed: 29453418] [Full Text: https://doi.org/10.1038/s41431-018-0114-6]
De Crescenzo, A., Citro, V., Freschi, A., Sparago, A., Palumbo, O., Cubellis, M. V., Carella, M., Castelluccio, P., Cavaliere, M. L., Cerrato, F., Riccio, A. A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype. J. Hum. Genet. 60: 287-293, 2015. [PubMed: 25809938] [Full Text: https://doi.org/10.1038/jhg.2015.29]
Heldt, F., Wallaschek, H., Ripperger, T., Morlot, S., Illig, T., Eggermann, T., Schlegelberger, B., Scholz, C., Steineman, D. 12q14 microdeletion syndrome: a family with short stature and Silver-Russell syndrome (SRS)-like phenotype and review of the literature. Europ. J. Med. Genet. 61: 421-427, 2018. [PubMed: 29501611] [Full Text: https://doi.org/10.1016/j.ejmg.2018.02.010]
Leszinski, G. S., Warncke, K., Hoefele, J., Wagner, M. A case report and review of the literature indicate that HMGA2 should be added as a disease gene for Silver-Russell syndrome. Gene 663: 110-114, 2018. [PubMed: 29655892] [Full Text: https://doi.org/10.1016/j.gene.2018.04.027]
Mari, F., Hermanns, P., Giovannussi-Uzielli, M. L., Galluzzi, F., Scott, D., Lee, B., Renieri, A., Unger, S., Zabel, B., Superti-Furga, A. Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis. Europ. J. Hum. Genet. 17: 1141-1147, 2009. [PubMed: 19277063] [Full Text: https://doi.org/10.1038/ejhg.2009.27]
Stavropoulos, D. J., Merico, D., Jobling, R., Bowdin, S., Monfared, N., Thiruvahindrapuram, B., Nalpathamkalam, T., Pellecchia, G., Yuen, R. K. C., Szego, M. J., Hayeems, R. Z., Shaul, R. Z., and 51 others. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genomic Med. 1: 15012, 2016. Note: Electronic Article. [PubMed: 28567303] [Full Text: https://doi.org/10.1038/npjgenmed.2015.12]