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Loeys-Dietz syndrome 6(LDS6)

MedGen UID:
1794251
Concept ID:
C5562041
Disease or Syndrome
Synonyms: LDS6; LOEYS-DIETZ SYNDROME 6
 
Gene (location): SMAD2 (18q21.1)
 
Monarch Initiative: MONDO:0030500
OMIM®: 619656

Definition

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant. [from GeneReviews]

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Chronic fatigue
MedGen UID:
760077
Concept ID:
C0518656
Finding
Subjective feeling of tiredness characterized by a lack of energy and motivation that persists for six months or longer.
Arachnodactyly
MedGen UID:
2047
Concept ID:
C0003706
Congenital Abnormality
Abnormally long and slender fingers ("spider fingers").
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Osteoarthritis, knee
MedGen UID:
98371
Concept ID:
C0409959
Disease or Syndrome
Noninflammatory degenerative disease of the knee joint consisting of three large categories: conditions that block normal synchronous movement, conditions that produce abnormal pathways of motion, and conditions that cause stress concentration resulting in changes to articular cartilage. (Crenshaw, Campbell's Operative Orthopaedics, 8th ed, p2019)
Varicose disease
MedGen UID:
21827
Concept ID:
C0042345
Disease or Syndrome
Enlarged and tortuous veins.
Abdominal aortic aneurysm
MedGen UID:
56524
Concept ID:
C0162871
Anatomical Abnormality
An abnormal localized widening (dilatation) of the abdominal aorta.
Thoracic aortic aneurysm
MedGen UID:
56525
Concept ID:
C0162872
Anatomical Abnormality
An abnormal localized widening (dilatation) of the thoracic aorta.
Ventricular hypertrophy
MedGen UID:
87400
Concept ID:
C0340279
Disease or Syndrome
Enlargement of the cardiac ventricular muscle tissue with increase in the width of the wall of the ventricle and loss of elasticity. Ventricular hypertrophy is clinically differentiated into left and right ventricular hypertrophy.
Vertebral artery aneurysm
MedGen UID:
657756
Concept ID:
C0574027
Anatomical Abnormality
Abnormal outpouching or sac-like dilatation in the wall of the vertebral artery .
Dilatation of the cerebral artery
MedGen UID:
1386760
Concept ID:
C4476540
Anatomical Abnormality
The presence of a localized dilatation or ballooning of a cerebral artery.
Carotid artery dilatation
MedGen UID:
1393749
Concept ID:
C4476554
Anatomical Abnormality
A dilatation (balooning or bulging out of the vessel wall) of a carotid artery.
Disproportionate tall stature
MedGen UID:
323048
Concept ID:
C1836996
Finding
A tall and slim body build with increased arm span to height ratio (>1.05) and a reduced upper-to-lower segment ratio (<0.85), i.e., unusually long arms and legs. The extremities as well as the hands and feet are unusually slim.
Osteoarthritis, hip
MedGen UID:
14530
Concept ID:
C0029410
Disease or Syndrome
Osteoarthritis of the hip joint.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Intervertebral disk degeneration
MedGen UID:
102357
Concept ID:
C0158266
Disease or Syndrome
The presence of degenerative changes of intervertebral disk.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Striae distensae
MedGen UID:
57541
Concept ID:
C0152459
Acquired Abnormality
Thinned, erythematous, depressed bands of atrophic skin. Initially, striae appear as flattened and thinned, pinkish linear regions of the skin. Striae tend to enlarge in length and become reddish or purplish. Later, striae tend to appear as white, depressed bands that are parallel to the lines of skin tension. Striae distensae occur most often in areas that have been subject to distension such as the lower back, buttocks, thighs, breast, abdomen, and shoulders.

Professional guidelines

PubMed

Colombi M, Dordoni C, Chiarelli N, Ritelli M
Am J Med Genet C Semin Med Genet 2015 Mar;169C(1):6-22. doi: 10.1002/ajmg.c.31429. PMID: 25821090
Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC; Canadian Cardiovascular Society
Can J Cardiol 2014 Jun;30(6):577-89. Epub 2014 Feb 28 doi: 10.1016/j.cjca.2014.02.018. PMID: 24882528
Paterick TE, Humphries JA, Ammar KA, Jan MF, Loberg R, Bush M, Khandheria BK, Tajik AJ
Am J Med 2013 Aug;126(8):670-8. Epub 2013 Jun 22 doi: 10.1016/j.amjmed.2013.01.029. PMID: 23800581

Recent clinical studies

Etiology

Chmielewski P, Ponińska JK, Michalak E, Michałowska I, Kowalik I, Truszkowska G, Kugaudo M, Minota I, Stawiński P, Płoski R, Bilińska ZT
Kardiol Pol 2023;81(11):1096-1102. Epub 2023 Oct 12 doi: 10.33963/v.kp.97390. PMID: 37823753
Olsson KW, Mani K, Burdess A, Patterson S, Scali ST, Kölbel T, Panuccio G, Eleshra A, Bertoglio L, Ardita V, Melissano G, Acharya A, Bicknell C, Riga C, Gibbs R, Jenkins M, Bakthavatsalam A, Sweet MP, Kasprzak PM, Pfister K, Oikonomou K, Heloise T, Sobocinski J, Butt T, Dias N, Tang C, Cheng SWK, Vandenhaute S, Van Herzeele I, Sorber RA, Black JH 3rd, Tenorio ER, Oderich GS, Vincent Z, Khashram M, Eagleton MJ, Pedersen SF, Budtz-Lilly J, Lomazzi C, Bissacco D, Trimarchi S, Huerta A, Riambau V, Wanhainen A
JAMA Surg 2023 Aug 1;158(8):832-839. doi: 10.1001/jamasurg.2023.2128. PMID: 37314760Free PMC Article
Braverman AC, Mittauer E, Harris KM, Evangelista A, Pyeritz RE, Brinster D, Conklin L, Suzuki T, Fanola C, Ouzounian M, Chen E, Myrmel T, Bekeredjian R, Hutchison S, Coselli J, Gilon D, O'Gara P, Davis M, Isselbacher E, Eagle K
JAMA Cardiol 2021 Jan 1;6(1):58-66. doi: 10.1001/jamacardio.2020.4876. PMID: 33052376Free PMC Article
Marrache M, Byers PH, Sponseller PD
JBJS Rev 2020 Jun;8(6):e0122. doi: 10.2106/JBJS.RVW.19.00122. PMID: 33006458
Skeik N, Hyde JR, Olson SL, Thaler CM, Abuatiyeh W, Ahmed AK, Lyon DR, Witt DR, Garberich R, Sullivan T
Ann Vasc Surg 2019 Oct;60:128-146. Epub 2019 Jun 12 doi: 10.1016/j.avsg.2019.04.004. PMID: 31200053

Diagnosis

Chmielewski P, Ponińska JK, Michalak E, Michałowska I, Kowalik I, Truszkowska G, Kugaudo M, Minota I, Stawiński P, Płoski R, Bilińska ZT
Kardiol Pol 2023;81(11):1096-1102. Epub 2023 Oct 12 doi: 10.33963/v.kp.97390. PMID: 37823753
Braverman AC, Mittauer E, Harris KM, Evangelista A, Pyeritz RE, Brinster D, Conklin L, Suzuki T, Fanola C, Ouzounian M, Chen E, Myrmel T, Bekeredjian R, Hutchison S, Coselli J, Gilon D, O'Gara P, Davis M, Isselbacher E, Eagle K
JAMA Cardiol 2021 Jan 1;6(1):58-66. doi: 10.1001/jamacardio.2020.4876. PMID: 33052376Free PMC Article
Skeik N, Hyde JR, Olson SL, Thaler CM, Abuatiyeh W, Ahmed AK, Lyon DR, Witt DR, Garberich R, Sullivan T
Ann Vasc Surg 2019 Oct;60:128-146. Epub 2019 Jun 12 doi: 10.1016/j.avsg.2019.04.004. PMID: 31200053
Boone PM, Scott RM, Marciniak SJ, Henske EP, Raby BA
Am J Respir Crit Care Med 2019 Jun 1;199(11):1344-1357. doi: 10.1164/rccm.201807-1212CI. PMID: 30681372Free PMC Article
Colombi M, Dordoni C, Chiarelli N, Ritelli M
Am J Med Genet C Semin Med Genet 2015 Mar;169C(1):6-22. doi: 10.1002/ajmg.c.31429. PMID: 25821090

Therapy

Sorber R, Bowen CJ, Hicks CW, Black JH 3rd
J Vasc Surg 2022 Jan;75(1):90-98. Epub 2021 Jun 26 doi: 10.1016/j.jvs.2021.05.062. PMID: 34186165Free PMC Article
van Dorst DCH, de Wagenaar NP, van der Pluijm I, Roos-Hesselink JW, Essers J, Danser AHJ
Cardiovasc Drugs Ther 2021 Dec;35(6):1233-1252. Epub 2020 Dec 7 doi: 10.1007/s10557-020-07116-4. PMID: 33283255Free PMC Article
David TE, David CM, Ouzounian M, Feindel CM, Lafreniere-Roula M
J Thorac Cardiovasc Surg 2021 Mar;161(3):890-899.e1. Epub 2020 Sep 5 doi: 10.1016/j.jtcvs.2020.07.121. PMID: 33008570
Skeik N, Hyde JR, Olson SL, Thaler CM, Abuatiyeh W, Ahmed AK, Lyon DR, Witt DR, Garberich R, Sullivan T
Ann Vasc Surg 2019 Oct;60:128-146. Epub 2019 Jun 12 doi: 10.1016/j.avsg.2019.04.004. PMID: 31200053
Verstraeten A, Alaerts M, Van Laer L, Loeys B
Hum Mutat 2016 Jun;37(6):524-31. Epub 2016 Mar 14 doi: 10.1002/humu.22977. PMID: 26919284

Prognosis

Chmielewski P, Ponińska JK, Michalak E, Michałowska I, Kowalik I, Truszkowska G, Kugaudo M, Minota I, Stawiński P, Płoski R, Bilińska ZT
Kardiol Pol 2023;81(11):1096-1102. Epub 2023 Oct 12 doi: 10.33963/v.kp.97390. PMID: 37823753
Braverman AC, Mittauer E, Harris KM, Evangelista A, Pyeritz RE, Brinster D, Conklin L, Suzuki T, Fanola C, Ouzounian M, Chen E, Myrmel T, Bekeredjian R, Hutchison S, Coselli J, Gilon D, O'Gara P, Davis M, Isselbacher E, Eagle K
JAMA Cardiol 2021 Jan 1;6(1):58-66. doi: 10.1001/jamacardio.2020.4876. PMID: 33052376Free PMC Article
Skeik N, Hyde JR, Olson SL, Thaler CM, Abuatiyeh W, Ahmed AK, Lyon DR, Witt DR, Garberich R, Sullivan T
Ann Vasc Surg 2019 Oct;60:128-146. Epub 2019 Jun 12 doi: 10.1016/j.avsg.2019.04.004. PMID: 31200053
Aftab M, Cikach FS, Zhu Y, Idrees JJ, Rigelsky CM, Kalahasti V, Roselli EE, Svensson LG
J Thorac Cardiovasc Surg 2019 Feb;157(2):439-450.e5. Epub 2018 Apr 30 doi: 10.1016/j.jtcvs.2018.03.172. PMID: 30669217
Van Hemelrijk C, Renard M, Loeys B
Curr Opin Cardiol 2010 Nov;25(6):546-51. doi: 10.1097/HCO.0b013e32833f0220. PMID: 20838339

Clinical prediction guides

Brunet-Garcia L, Prabaharan P, Bruyndonckx L, Field E, D'Arco F, Capelli C, Cervi E
Am J Med Genet A 2024 Mar;194(3):e63465. Epub 2023 Nov 2 doi: 10.1002/ajmg.a.63465. PMID: 37916856
Sanchez Tijmes F, Chan VSH, Murphy J, Hashem DAL, Hanneman K, Wald RM, Thavendiranathan P, Ouzounian M, Oechslin E, Karur GR
Int J Cardiol 2023 Dec 1;392:131276. Epub 2023 Aug 19 doi: 10.1016/j.ijcard.2023.131276. PMID: 37598908
Wang Y, Starovoytov A, Murad AM, Hunker KL, Brunham LR, Li JZ, Saw J, Ganesh SK
JAMA Cardiol 2022 Oct 1;7(10):1045-1055. doi: 10.1001/jamacardio.2022.2970. PMID: 36103205Free PMC Article
Kim ST, Brinjikji W, Lanzino G, Kallmes DF
Interv Neuroradiol 2016 Dec;22(6):624-637. Epub 2016 Aug 10 doi: 10.1177/1591019916659262. PMID: 27511817Free PMC Article
Morris SA
Curr Opin Cardiol 2015 Nov;30(6):587-93. doi: 10.1097/HCO.0000000000000218. PMID: 26398550Free PMC Article

Recent systematic reviews

Charoenngam N, Rittiphairoj T, Ponvilawan B, Jaroenlapnopparat A, Waitayangkoon P, Suppakitjanusant P, Prasitsumrit V, Pongchaiyakul C, Holick MF
Endocr Pract 2023 Jul;29(7):589-600. Epub 2023 Feb 17 doi: 10.1016/j.eprac.2023.02.003. PMID: 36804968
Velvin G, Wilhelmsen JE, Johansen H, Bathen T, Geirdal AØ
Clin Genet 2019 Jun;95(6):661-676. Epub 2019 Apr 2 doi: 10.1111/cge.13522. PMID: 30788842

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