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Vertebral, cardiac, renal, and limb defects syndrome 2(VCRL2)

MedGen UID:
1624065
Concept ID:
C4540014
Disease or Syndrome
Synonyms: CONGENITAL NAD DEFICIENCY DISORDER 2; KYNURENINASE DEFICIENCY, COMPLETE
 
Gene (location): KYNU (2q22.2)
 
Monarch Initiative: MONDO:0060555
OMIM®: 617661

Definition

Vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2) is an autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal defects, and mild distal limb defects. Additional features are variable (summary by Shi et al., 2017). 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.
Renal hypoplasia
MedGen UID:
120571
Concept ID:
C0266295
Congenital Abnormality
Hypoplasia of the kidney.
Chronic kidney disease
MedGen UID:
473458
Concept ID:
C1561643
Disease or Syndrome
Functional anomaly of the kidney persisting for at least three months.
Talipes
MedGen UID:
220976
Concept ID:
C1301937
Congenital Abnormality
A deformity of foot and ankle that has different subtypes that are talipes equinovarus, talipes equinovalgus, talipes calcaneovarus and talipes calcaneovalgus.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
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.
Hypoplastic left heart syndrome
MedGen UID:
57746
Concept ID:
C0152101
Disease or Syndrome
Each 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.\n\nCritical 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.
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).
Anteriorly placed anus
MedGen UID:
333160
Concept ID:
C1838705
Finding
Anterior malposition of the anus.
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.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Hemivertebrae
MedGen UID:
82720
Concept ID:
C0265677
Congenital Abnormality
Absence of one half of the vertebral body.
Narrow chest
MedGen UID:
96528
Concept ID:
C0426790
Finding
Reduced width of the chest from side to side, associated with a reduced distance from the sternal notch to the tip of the shoulder.
Vertebral segmentation defect
MedGen UID:
96577
Concept ID:
C0432163
Congenital Abnormality
An abnormality related to a defect of vertebral separation during development.
11 pairs of ribs
MedGen UID:
326950
Concept ID:
C1839731
Finding
Presence of only 11 pairs of ribs.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.

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
Forman M, Canizares MF, Bohn D, James MA, Samora J, Steinman S, Wall LB, Bauer AS; CoULD Study Group
J Bone Joint Surg Am 2020 Oct 21;102(20):1815-1822. doi: 10.2106/JBJS.20.00281. PMID: 33086350
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
Halverson SJ, Takayama S, Ochi K, Seki A, Wall LB, Goldfarb CA
J Hand Surg Am 2020 Mar;45(3):196-202.e2. Epub 2020 Jan 17 doi: 10.1016/j.jhsa.2019.12.004. PMID: 31959377

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
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
Solomon BD
Orphanet J Rare Dis 2011 Aug 16;6:56. doi: 10.1186/1750-1172-6-56. PMID: 21846383Free PMC Article
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

Brosens E, de Jong EM, Barakat TS, Eussen BH, D'haene B, De Baere E, Verdin H, Poddighe PJ, Galjaard RJ, Gribnau J, Brooks AS, Tibboel D, de Klein A
Eur J Hum Genet 2014 Sep;22(9):1077-84. Epub 2014 Jan 8 doi: 10.1038/ejhg.2013.295. PMID: 24398799Free 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
Schramm C, Draaken M, Bartels E, Boemers TM, Aretz S, Brockschmidt FF, Nöthen MM, Ludwig M, Reutter H
Eur J Med Genet 2011 Jan-Feb;54(1):9-13. Epub 2010 Sep 16 doi: 10.1016/j.ejmg.2010.09.001. PMID: 20849991
Lammer EJ, Cordero JF, Khoury MJ
Teratology 1986 Oct;34(2):165-9. doi: 10.1002/tera.1420340205. PMID: 3775669

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
Amelot A, Cretolle C, de Saint Denis T, Sarnacki S, Catala M, Zerah M
Eur J Pediatr 2020 Jul;179(7):1121-1129. Epub 2020 Feb 13 doi: 10.1007/s00431-020-03609-4. PMID: 32055959
Salinas-Torres VM, Rivera H
Genet Couns 2014;25(1):29-33. PMID: 24783652
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
Solomon BD
Orphanet J Rare Dis 2011 Aug 16;6:56. doi: 10.1186/1750-1172-6-56. PMID: 21846383Free PMC Article

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
Slagle CL, Schulz EV, Annibale DJ
Neonatal Netw 2019 Mar 1;38(2):98-106. Epub 2019 Mar 6 doi: 10.1891/0730-0832.38.2.98. PMID: 31470372
Castori M, Rinaldi R, Capocaccia P, Roggini M, Grammatico P
Birth Defects Res A Clin Mol Teratol 2008 Mar;82(3):169-72. doi: 10.1002/bdra.20432. PMID: 18181216

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