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Silver-Russell syndrome 3(SRS3)

MedGen UID:
894912
Concept ID:
C4225307
Disease or Syndrome
Synonyms: Growth restriction, severe, with distinctive facies; SRS3
 
Gene (location): IGF2 (11p15.5)
 
Monarch Initiative: MONDO:0014663
OMIM®: 616489

Definition

Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay (Begemann et al., 2015; Yamoto et al., 2017). For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860). [from OMIM]

Clinical features

From HPO
Ambiguous genitalia
MedGen UID:
78596
Concept ID:
C0266362
Congenital Abnormality
A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale
Unilateral cryptorchidism
MedGen UID:
98467
Concept ID:
C0431664
Congenital Abnormality
Absence of a testis from the scrotum on one side owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.
Penoscrotal hypospadias
MedGen UID:
105291
Concept ID:
C0452147
Congenital Abnormality
A severe form of hypospadias in which the urethral opening is located at the junction of the penis and scrotum.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Small hand
MedGen UID:
108279
Concept ID:
C0575802
Finding
Disproportionately small hand.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Decreased body weight
MedGen UID:
1806755
Concept ID:
C5574742
Finding
Abnormally low body weight.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Elbow contracture
MedGen UID:
331445
Concept ID:
C1833142
Anatomical Abnormality
A limitation in the passive range of motion of the elbow resulting from loss of elasticity in the periarticular tissues owing to structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules or skin.
Relative macrocephaly
MedGen UID:
338607
Concept ID:
C1849075
Congenital Abnormality
A relatively mild degree of macrocephaly in which the head circumference is not above two standard deviations from the mean, but appears dysproportionately large when other factors such as body stature are taken into account.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Melanocytic nevus
MedGen UID:
14364
Concept ID:
C0027962
Neoplastic Process
A oval and round, colored (usually medium-to dark brown, reddish brown, or flesh colored) lesion. Typically, a melanocytic nevus is less than 6 mm in diameter, but may be much smaller or larger.
Antecubital pterygium syndrome
MedGen UID:
401231
Concept ID:
C1867439
Disease or Syndrome
Antecubital pterygium syndrome is an autosomal dominant disorder characterized by a fleshy web extending across the anterior aspect of the cubital fossa, absence of the long head of the triceps, limitation of full elbow extension, and missing skin creases over the terminal interphalangeal joints of the fingers (summary by Wallis et al., 1988).
Oligohydramnios
MedGen UID:
86974
Concept ID:
C0079924
Pathologic Function
Diminished amniotic fluid volume in pregnancy.

Professional guidelines

PubMed

Świąder-Leśniak A, Jurkiewicz D, Kołodziejczyk H, Kozłowska A, Korpysz A, Szalecki M, Chrzanowska K
Endokrynol Pol 2023;74(3):285-293. Epub 2023 Jun 19 doi: 10.5603/EP.a2023.0042. PMID: 37335065
Smeets CC, Renes JS, van der Steen M, Hokken-Koelega AC
J Clin Endocrinol Metab 2017 Mar 1;102(3):983-991. doi: 10.1210/jc.2016-3388. PMID: 28001454
Marsaud C, Rossignol S, Tounian P, Netchine I, Dubern B
Arch Dis Child 2015 Apr;100(4):353-8. Epub 2014 Nov 18 doi: 10.1136/archdischild-2013-305864. PMID: 25700540

Recent clinical studies

Etiology

Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group
N Engl J Med 2021 Feb 4;384(5):403-416. Epub 2020 Dec 30 doi: 10.1056/NEJMoa2035389. PMID: 33378609Free PMC Article
INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD
N Engl J Med 2015 Aug 27;373(9):795-807. Epub 2015 Jul 20 doi: 10.1056/NEJMoa1506816. PMID: 26192873Free PMC Article
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators
N Engl J Med 2015 Jun 18;372(25):2387-97. Epub 2015 Jun 3 doi: 10.1056/NEJMoa1410489. PMID: 26039521
Eggermann T
Am J Med Genet C Semin Med Genet 2010 Aug 15;154C(3):355-64. doi: 10.1002/ajmg.c.30274. PMID: 20803658
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M
N Engl J Med 2009 Sep 10;361(11):1045-57. Epub 2009 Aug 30 doi: 10.1056/NEJMoa0904327. PMID: 19717846

Diagnosis

Dunkle LM, Kotloff KL, Gay CL, Áñez G, Adelglass JM, Barrat Hernández AQ, Harper WL, Duncanson DM, McArthur MA, Florescu DF, McClelland RS, Garcia-Fragoso V, Riesenberg RA, Musante DB, Fried DL, Safirstein BE, McKenzie M, Jeanfreau RJ, Kingsley JK, Henderson JA, Lane DC, Ruíz-Palacios GM, Corey L, Neuzil KM, Coombs RW, Greninger AL, Hutter J, Ake JA, Smith K, Woo W, Cho I, Glenn GM, Dubovsky F; 2019nCoV-301 Study Group
N Engl J Med 2022 Feb 10;386(6):531-543. Epub 2021 Dec 15 doi: 10.1056/NEJMoa2116185. PMID: 34910859Free PMC Article
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group
N Engl J Med 2021 Feb 4;384(5):403-416. Epub 2020 Dec 30 doi: 10.1056/NEJMoa2035389. PMID: 33378609Free PMC Article
Hübner CT, Meyer R, Kenawy A, Ambrozaityte L, Matuleviciene A, Kraft F, Begemann M, Elbracht M, Eggermann T
J Clin Endocrinol Metab 2020 Jul 1;105(7) doi: 10.1210/clinem/dgaa273. PMID: 32421827
Aygun D, Bjornsson HT
Dev Med Child Neurol 2020 Feb;62(2):192-200. Epub 2019 Nov 20 doi: 10.1111/dmcn.14398. PMID: 31749156
Eggermann T
Am J Med Genet C Semin Med Genet 2010 Aug 15;154C(3):355-64. doi: 10.1002/ajmg.c.30274. PMID: 20803658

Therapy

Dunkle LM, Kotloff KL, Gay CL, Áñez G, Adelglass JM, Barrat Hernández AQ, Harper WL, Duncanson DM, McArthur MA, Florescu DF, McClelland RS, Garcia-Fragoso V, Riesenberg RA, Musante DB, Fried DL, Safirstein BE, McKenzie M, Jeanfreau RJ, Kingsley JK, Henderson JA, Lane DC, Ruíz-Palacios GM, Corey L, Neuzil KM, Coombs RW, Greninger AL, Hutter J, Ake JA, Smith K, Woo W, Cho I, Glenn GM, Dubovsky F; 2019nCoV-301 Study Group
N Engl J Med 2022 Feb 10;386(6):531-543. Epub 2021 Dec 15 doi: 10.1056/NEJMoa2116185. PMID: 34910859Free PMC Article
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group
N Engl J Med 2021 Feb 4;384(5):403-416. Epub 2020 Dec 30 doi: 10.1056/NEJMoa2035389. PMID: 33378609Free PMC Article
INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD
N Engl J Med 2015 Aug 27;373(9):795-807. Epub 2015 Jul 20 doi: 10.1056/NEJMoa1506816. PMID: 26192873Free PMC Article
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators
N Engl J Med 2015 Jun 18;372(25):2387-97. Epub 2015 Jun 3 doi: 10.1056/NEJMoa1410489. PMID: 26039521
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M
N Engl J Med 2009 Sep 10;361(11):1045-57. Epub 2009 Aug 30 doi: 10.1056/NEJMoa0904327. PMID: 19717846

Prognosis

Dunkle LM, Kotloff KL, Gay CL, Áñez G, Adelglass JM, Barrat Hernández AQ, Harper WL, Duncanson DM, McArthur MA, Florescu DF, McClelland RS, Garcia-Fragoso V, Riesenberg RA, Musante DB, Fried DL, Safirstein BE, McKenzie M, Jeanfreau RJ, Kingsley JK, Henderson JA, Lane DC, Ruíz-Palacios GM, Corey L, Neuzil KM, Coombs RW, Greninger AL, Hutter J, Ake JA, Smith K, Woo W, Cho I, Glenn GM, Dubovsky F; 2019nCoV-301 Study Group
N Engl J Med 2022 Feb 10;386(6):531-543. Epub 2021 Dec 15 doi: 10.1056/NEJMoa2116185. PMID: 34910859Free PMC Article
El Sahly HM, Baden LR, Essink B, Doblecki-Lewis S, Martin JM, Anderson EJ, Campbell TB, Clark J, Jackson LA, Fichtenbaum CJ, Zervos M, Rankin B, Eder F, Feldman G, Kennelly C, Han-Conrad L, Levin M, Neuzil KM, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Polakowski L, Mascola JR, Ledgerwood JE, Graham BS, August A, Clouting H, Deng W, Han S, Leav B, Manzo D, Pajon R, Schödel F, Tomassini JE, Zhou H, Miller J; COVE Study Group
N Engl J Med 2021 Nov 4;385(19):1774-1785. Epub 2021 Sep 22 doi: 10.1056/NEJMoa2113017. PMID: 34551225Free PMC Article
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group
N Engl J Med 2021 Feb 4;384(5):403-416. Epub 2020 Dec 30 doi: 10.1056/NEJMoa2035389. PMID: 33378609Free PMC Article
Binder G, Schweizer R, Blumenstock G, Ferrand N
J Clin Endocrinol Metab 2017 Nov 1;102(11):4100-4108. doi: 10.1210/jc.2017-00874. PMID: 28945864
INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD
N Engl J Med 2015 Aug 27;373(9):795-807. Epub 2015 Jul 20 doi: 10.1056/NEJMoa1506816. PMID: 26192873Free PMC Article

Clinical prediction guides

Dunkle LM, Kotloff KL, Gay CL, Áñez G, Adelglass JM, Barrat Hernández AQ, Harper WL, Duncanson DM, McArthur MA, Florescu DF, McClelland RS, Garcia-Fragoso V, Riesenberg RA, Musante DB, Fried DL, Safirstein BE, McKenzie M, Jeanfreau RJ, Kingsley JK, Henderson JA, Lane DC, Ruíz-Palacios GM, Corey L, Neuzil KM, Coombs RW, Greninger AL, Hutter J, Ake JA, Smith K, Woo W, Cho I, Glenn GM, Dubovsky F; 2019nCoV-301 Study Group
N Engl J Med 2022 Feb 10;386(6):531-543. Epub 2021 Dec 15 doi: 10.1056/NEJMoa2116185. PMID: 34910859Free PMC Article
El Sahly HM, Baden LR, Essink B, Doblecki-Lewis S, Martin JM, Anderson EJ, Campbell TB, Clark J, Jackson LA, Fichtenbaum CJ, Zervos M, Rankin B, Eder F, Feldman G, Kennelly C, Han-Conrad L, Levin M, Neuzil KM, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Polakowski L, Mascola JR, Ledgerwood JE, Graham BS, August A, Clouting H, Deng W, Han S, Leav B, Manzo D, Pajon R, Schödel F, Tomassini JE, Zhou H, Miller J; COVE Study Group
N Engl J Med 2021 Nov 4;385(19):1774-1785. Epub 2021 Sep 22 doi: 10.1056/NEJMoa2113017. PMID: 34551225Free PMC Article
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group
N Engl J Med 2021 Feb 4;384(5):403-416. Epub 2020 Dec 30 doi: 10.1056/NEJMoa2035389. PMID: 33378609Free PMC Article
Hübner CT, Meyer R, Kenawy A, Ambrozaityte L, Matuleviciene A, Kraft F, Begemann M, Elbracht M, Eggermann T
J Clin Endocrinol Metab 2020 Jul 1;105(7) doi: 10.1210/clinem/dgaa273. PMID: 32421827
Eggermann T
Am J Med Genet C Semin Med Genet 2010 Aug 15;154C(3):355-64. doi: 10.1002/ajmg.c.30274. PMID: 20803658

Recent systematic reviews

Cortessis VK, Azadian M, Buxbaum J, Sanogo F, Song AY, Sriprasert I, Wei PC, Yu J, Chung K, Siegmund KD
J Assist Reprod Genet 2018 Jun;35(6):943-952. Epub 2018 Apr 25 doi: 10.1007/s10815-018-1173-x. PMID: 29696471Free PMC Article
Wheeler PG, Bresnahan K, Shephard BA, Lau J, Balk EM
Arch Pediatr Adolesc Med 2004 Mar;158(3):236-43. doi: 10.1001/archpedi.158.3.236. PMID: 14993082

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