Silver-Russell Syndrome

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Silver-Russell syndrome (SRS) originally was described by Silver and colleagues in 1953 and, soon afterwards, by Russell in 1954. [1, 2]  Silver-Russell syndrome is characterized by intrauterine and postnatal growth retardation leading to a small-for-gestational-age (SGA) infant at birth, feeding difficulties during infancy, short stature, body asymmetry, characteristic triangular facies with prominent forehead, and several other anomalies.

Over the past several years, more than 400 patients have been described, with phenotypes ranging from mild to classic. Most patients are found to have hypomethylation in the chromosome 11p15 imprinting center 1 (IC1); some patients have maternal uniparental disomy of chromosome 7, with the possibility of imprinting (eg, inheriting two copies of maternal chromosome 7, with no paternal contribution). [3, 4, 5, 6]

Growth failure is the primary abnormality. The American of Radiology has established guidelines regarding growth disturbances. [7]

Patients typically present with intrauterine growth retardation, difficulty feeding, failure to thrive, or postnatal growth retardation. Adequate catch-up growth often does not occur, and final adult height still is less than normal (≤ -3.6 standard deviations [SD]). See the image below.

Older children and adults do not manifest clinical features as clearly as infants or young children. Growth hormone insufficiency may be present. Abnormalities of spontaneous growth hormone (GH) secretion and subnormal responses to provocative growth hormone stimulation testing have been reported in a significant number of children with Silver-Russell syndrome. Facial dysmorphism is observed, with small triangular facies and normal head circumference. Because length usually is less than normal, the head appears disproportionately large. Intelligence may be normal, or the patient may have a learning disability. The limbs may be asymmetric, and camptodactyly (ie, fixed flexion of digits) or clinodactyly (ie, incurving) of one or more fingers may be present.

International

Estimates of incidence range from as high as 1 case in 3000 population to as low as 1 case in 100,000 population.

Infants have failure to thrive, feeding difficulties, and fasting hypoglycemia. A retrospective study by Marsaud et al found digestive problems and malnutrition to be common in children with Silver-Russell syndrome. The study, in which 75 patients (median age 24.3 mo) were assessed, found malnutrition in 70% of them and gastrointestinal signs in 77% of them. The latter included feeding difficulties (65%), severe (55%), severe vomiting before age 1 year (50%), persistent vomiting from age 1 year (29%), and constipation (20%). [8]

The male-to-female ratio is equal.

Clinical features are easier to identify in infants and younger children, particularly the small triangular facies. These findings are more difficult to recognize in adults.

Silver HK, Kiyasu W, George J. Syndrome of congenital hemihypertrophy, shortness of stature and elevated urinary gonadotropins. Pediatrics. 1953. 12:368-75.

Russell A. A syndrome of “intrauterine dwarfism” recognisable at birth with craniofacial dysostosis, disproportionately short arms and other abnormalities (5 examples). Proc Royal Soc Med. 1954. 47:1040-4.

Eggermann T, Spengler S, Gogiel M, Begemann M, Elbracht M. Epigenetic and genetic diagnosis of Silver-Russell syndrome. Expert Rev Mol Diagn. 2012 Jun. 12(5):459-71. [Medline].

Chiesa N, De Crescenzo A, Mishra K, Perone L, Carella M, Palumbo O, et al. The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases. Hum Mol Genet. 2012 Jan 1. 21(1):10-25. [Medline]. [Full Text].

Fuke T, Mizuno S, Nagai T, Hasegawa T, Horikawa R, Miyoshi Y, et al. Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome. PLoS One. . 8(3):e60105. [Medline]. [Full Text].

Pianka MA, McIntosh AT, Patel SD, Bakhshi PR, Jung M. Close yet so far away: a look into the management strategies of genetic imprinting disorders. Am J Stem Cells. 2018. 7 (4):72-81. [Medline].

[Guideline] Zelop C, Fleischer AC, Andreotti RF, et al. Growth disturbance–risk of intrauterine growth restriction. ACR Appropriateness Criteria. 2007. [Full Text].

Marsaud C, Rossignol S, Tounian P, et al. Prevalence and management of gastrointestinal manifestations in Silver-Russell syndrome. Arch Dis Child. 2015 Apr. 100(4):353-8. [Medline].

Lahiri A, Lester R. Hand anomalies in Russell Silver syndrome. J Plast Reconstr Aesthet Surg. 2009 Apr. 62(4):462-5. [Medline].

South ST, Whitby H, Maxwell T, Aston E, Brothman AR, Carey JC. Co-occurrence of 4p16.3 deletions with both paternal and maternal duplications of 11p15: modification of the Wolf-Hirschhorn syndrome phenotype by genetic alterations predicted to result in either a Beckwith-Wiedemann or Russell-Silver phenotype. Am J Med Genet A. 2008 Oct 15. 146A(20):2691-7. [Medline].

Amor DJ, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod. 2008 Dec. 23(12):2826-34. [Medline].

Hattori H, Hiura H, Kitamura A, et al. Association of four imprinting disorders and ART. Clin Epigenetics. 2019 Feb 7. 11 (1):21. [Medline]. [Full Text].

Cortessis VK, Azadian M, Buxbaum J, et al. Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology. J Assist Reprod Genet. 2018 Jun. 35 (6):943-52. [Medline].

[Guideline] Wakeling EL, Brioude F, Lokulo-Sodipe O, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017 Feb. 13 (2):105-24. [Medline]. [Full Text].

Azzi S, Salem J, Thibaud N, et al. A prospective study validating a clinical scoring and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet. 2015 Jul. 52 (7):446-53. [Medline]. [Full Text].

Wollmann HA, Kirchner T, Enders H, et al. Growth and symptoms in Silver-Russell syndrome: review on the basis of 386 patients. Eur J Pediatr. 1995 Dec. 154(12):958-68. [Medline].

Smeets CC, Zandwijken GR, Renes JS, Hokken-Koelega AC. Long-Term Results of GH in Silver-Russell Syndrome (SRS): Do They Benefit the Same as Non-SRS Short-SGA?. J Clin Endocrinol Metab. 2016 May. 101 (5):2105-12. [Medline]. [Full Text].

Sunil Kumar Sinha, MD 

Sunil Kumar Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Luis O Rohena, MD, FAAP, FACMG Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Elaine H Zackai, MD Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children’s Hospital of Philadelphia

Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate-Craniofacial Association, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University, New York

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Genzyme Grant/research funds PI

Ainu Prakash-Cheng, MD, PhD† Former Co-Director, Comprehensive Gaucher Disease Center, Department of Human Genetics, Mount Sinai School of Medicine

Lawrence A Wetterau, MD Assistant Professor, Section of Endocrinology, Children’s Hospital Central California.

Lawrence A Wetterau is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Silver-Russell Syndrome

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