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Vertebral, cardiac, renal, and limb defects syndrome 3(VCRL3)

MedGen UID:
1709064
Concept ID:
C5394250
Disease or Syndrome
Synonym: CONGENITAL NAD DEFICIENCY DISORDER 3
 
Gene (location): NADSYN1 (11q13.4)
 
Monarch Initiative: MONDO:0030077
OMIM®: 618845

Definition

Vertebral, cardiac, renal, and limb defects syndrome-3 (VCRL3) is an autosomal recessive disorder characterized by severe cardiac and renal anomalies that are lethal in infancy, including hypoplastic or absent left ventricle, transposition of the great arteries, absent pulmonary trunk, and hypoplastic or absent kidneys. Patients also exhibit vertebral segmentation defects and shortening of the proximal long bones or micromelia (Szot et al., 2020). For a discussion of genetic heterogeneity of VCRL, see VCRL1 (617660). [from OMIM]

Clinical features

From HPO
Unilateral renal agenesis
MedGen UID:
75607
Concept ID:
C0266294
Congenital Abnormality
A unilateral form of agenesis of the kidney.
Ureteral atresia
MedGen UID:
120572
Concept ID:
C0266320
Congenital Abnormality
A developmental defect defined by the failure of the formation of the lumen (tube) of the ureter.
Bilateral renal agenesis
MedGen UID:
296299
Concept ID:
C1609433
Disease or Syndrome
A bilateral form of agenesis of the kidney.
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Double outlet right ventricle
MedGen UID:
41649
Concept ID:
C0013069
Congenital Abnormality
Double outlet right ventricle (DORV) is a type of ventriculoarterial connection in which both great vessels arise entirely or predominantly from the right ventricle.
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.
Bicuspid aortic valve
MedGen UID:
57436
Concept ID:
C0149630
Congenital Abnormality
Aortic valve disease-2 (AOVD2) is characterized by bicuspid aortic valve (BAV) and dilation of the ascending aorta. Calcification of the valve and the aorta has been observed, and some patients exhibit coarctation of the aorta (Tan et al., 2012; Luyckx et al., 2019; Park et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of aortic valve disease, see AOVD1 (109730).
Hypoplastic left heart syndrome
MedGen UID:
57746
Concept ID:
C0152101
Disease or Syndrome
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.\n\nAlthough babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.\n\nSome people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.\n\nEach of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.\n\nPeople with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Anomalous origin of left coronary artery from the pulmonary artery
MedGen UID:
760471
Concept ID:
C1735886
Disease or Syndrome
Left main coronary artery begins (branches off from) the pulmonary artery rather than as normal from the root of the aorta, above the left cusp of the aortic valve.
Short thorax
MedGen UID:
140876
Concept ID:
C0426789
Finding
Reduced inferior to superior extent of the thorax.
Vertebral segmentation defect
MedGen UID:
96577
Concept ID:
C0432163
Congenital Abnormality
An abnormality related to a defect of vertebral separation during development.
Short long bone
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Vertebral fusion
MedGen UID:
480139
Concept ID:
C3278509
Anatomical Abnormality
A developmental defect leading to the union of two adjacent vertebrae.
Sacral dimple
MedGen UID:
98428
Concept ID:
C0426848
Finding
A cutaneous indentation resulting from tethering of the skin to underlying structures (bone) of the intergluteal cleft.

Recent clinical studies

Etiology

Lim JX, Fong E, Goh C, Ng LP, Merchant K, Low DCY, Seow WT, Low SYY
J Neurosurg Pediatr 2023 Mar 1;31(3):197-205. Epub 2022 Dec 2 doi: 10.3171/2022.8.PEDS22103. PMID: 36461829
Schierz IAM, Piro E, Giuffrè M, Pinello G, Angelini A, Antona V, Cimador M, Corsello G
J Matern Fetal Neonatal Med 2022 Dec;35(23):4513-4520. Epub 2020 Dec 1 doi: 10.1080/14767058.2020.1854213. PMID: 36062518
Nguyen JL, Ho CA
JBJS Rev 2022 Mar 1;10(3) doi: 10.2106/JBJS.RVW.21.00147. PMID: 35230999
Tan Tanny SP, Beck C, King SK, Hawley A, Brooks JA, McLeod E, Hutson JM, Teague WJ
Pediatrics 2021 May;147(5) doi: 10.1542/peds.2020-029884. PMID: 33911029
van de Putte R, van Rooij IALM, Haanappel CP, Marcelis CLM, Brunner HG, Addor MC, Cavero-Carbonell C, Dias CM, Draper ES, Etxebarriarteun L, Gatt M, Khoshnood B, Kinsner-Ovaskainen A, Klungsoyr K, Kurinczuk JJ, Latos-Bielenska A, Luyt K, O'Mahony MT, Miller N, Mullaney C, Nelen V, Neville AJ, Perthus I, Pierini A, Randrianaivo H, Rankin J, Rissmann A, Rouget F, Schaub B, Tucker D, Wellesley D, Wiesel A, Zymak-Zakutnia N, Loane M, Barisic I, de Walle HEK, Bergman JEH, Roeleveld N
Birth Defects Res 2020 May 15;112(9):688-698. Epub 2020 Apr 22 doi: 10.1002/bdr2.1686. PMID: 32319733Free PMC Article

Diagnosis

Schierz IAM, Piro E, Giuffrè M, Pinello G, Angelini A, Antona V, Cimador M, Corsello G
J Matern Fetal Neonatal Med 2022 Dec;35(23):4513-4520. Epub 2020 Dec 1 doi: 10.1080/14767058.2020.1854213. PMID: 36062518
Warner T, Scullen TA, Iwanaga J, Loukas M, Bui CJ, Dumont AS, Tubbs RS
World Neurosurg 2020 Jun;138:461-467. Epub 2020 Mar 19 doi: 10.1016/j.wneu.2020.03.057. PMID: 32200015
Stoll C, Dott B, Alembik Y, Roth MP
Am J Med Genet A 2018 Dec;176(12):2646-2660. Epub 2018 Dec 12 doi: 10.1002/ajmg.a.40530. PMID: 30548801
Aucourt J, Budzik JF, Manouvrier-Hanu S, Mézel A, Cotten A, Boutry N
Semin Musculoskelet Radiol 2012 Apr;16(2):146-58. Epub 2012 May 30 doi: 10.1055/s-0032-1311766. PMID: 22648430
Morcel K, Camborieux L; Programme de Recherches sur les Aplasies Müllériennes, Guerrier D
Orphanet J Rare Dis 2007 Mar 14;2:13. doi: 10.1186/1750-1172-2-13. PMID: 17359527Free PMC Article

Therapy

Kumar M, Ray L, Vemuri S, Simon TA
Semin Arthritis Rheum 2015 Dec;45(3):351-6. Epub 2015 Jun 26 doi: 10.1016/j.semarthrit.2015.06.016. PMID: 26210783
La Placa S, Giuffrè M, Gangemi A, Di Noto S, Matina F, Nociforo F, Antona V, Di Pace MR, Piccione M, Corsello G
Ital J Pediatr 2013 Jul 10;39:45. doi: 10.1186/1824-7288-39-45. PMID: 23842449Free PMC Article
Wijers CH, van Rooij IA, Bakker MK, Marcelis CL, Addor MC, Barisic I, Béres J, Bianca S, Bianchi F, Calzolari E, Greenlees R, Lelong N, Latos-Bielenska A, Dias CM, McDonnell R, Mullaney C, Nelen V, O'Mahony M, Queisser-Luft A, Rankin J, Zymak-Zakutnia N, de Blaauw I, Roeleveld N, de Walle HE
BJOG 2013 Aug;120(9):1066-74. Epub 2013 Apr 10 doi: 10.1111/1471-0528.12235. PMID: 23574029
Nora JJ, Nora AH
N Engl J Med 1974 Oct 3;291(14):731-2. doi: 10.1056/NEJM197410032911410. PMID: 4851496

Prognosis

Esposito G, Totonelli G, Iacobelli BD, Longo D, Caldaro T, Blasetti G, Bevilacqua F, Santato F, Lucignani G, Sollini ML, Marras CE, Bagolan P, Mosiello G
Pediatr Surg Int 2022 Oct;38(10):1461-1472. Epub 2022 Aug 9 doi: 10.1007/s00383-022-05168-1. PMID: 35943565
Tan Tanny SP, Beck C, King SK, Hawley A, Brooks JA, McLeod E, Hutson JM, Teague WJ
Pediatrics 2021 May;147(5) doi: 10.1542/peds.2020-029884. PMID: 33911029
Babaoğlu K, Altun G, Binnetoğlu K, Dönmez M, Kayabey Ö, Anık Y
Pediatr Cardiol 2013;34(8):1785-90. Epub 2013 May 10 doi: 10.1007/s00246-013-0714-4. PMID: 23660850
Aucourt J, Budzik JF, Manouvrier-Hanu S, Mézel A, Cotten A, Boutry N
Semin Musculoskelet Radiol 2012 Apr;16(2):146-58. Epub 2012 May 30 doi: 10.1055/s-0032-1311766. PMID: 22648430
Michielon G, Marino B, Formigari R, Gargiulo G, Picchio F, Digilio MC, Anaclerio S, Oricchio G, Sanders SP, Di Donato RM
Ann Thorac Surg 2006 Mar;81(3):968-75. doi: 10.1016/j.athoracsur.2005.09.033. PMID: 16488703

Clinical prediction guides

Lim JX, Fong E, Goh C, Ng LP, Merchant K, Low DCY, Seow WT, Low SYY
J Neurosurg Pediatr 2023 Mar 1;31(3):197-205. Epub 2022 Dec 2 doi: 10.3171/2022.8.PEDS22103. PMID: 36461829
Schierz IAM, Piro E, Giuffrè M, Pinello G, Angelini A, Antona V, Cimador M, Corsello G
J Matern Fetal Neonatal Med 2022 Dec;35(23):4513-4520. Epub 2020 Dec 1 doi: 10.1080/14767058.2020.1854213. PMID: 36062518
Esposito G, Totonelli G, Iacobelli BD, Longo D, Caldaro T, Blasetti G, Bevilacqua F, Santato F, Lucignani G, Sollini ML, Marras CE, Bagolan P, Mosiello G
Pediatr Surg Int 2022 Oct;38(10):1461-1472. Epub 2022 Aug 9 doi: 10.1007/s00383-022-05168-1. PMID: 35943565
Tan Tanny SP, Beck C, King SK, Hawley A, Brooks JA, McLeod E, Hutson JM, Teague WJ
Pediatrics 2021 May;147(5) doi: 10.1542/peds.2020-029884. PMID: 33911029
Schüler L, Salzano FM
Am J Med Genet 1994 Jan 1;49(1):29-35. doi: 10.1002/ajmg.1320490108. PMID: 8172248

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