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Loeys-Dietz syndrome 1(LDS1)

MedGen UID:
395828
Concept ID:
C2697933
Disease or Syndrome
Synonyms: Aortic aneurysm syndrome, Loeys-Dietz type; Aortic aneurysm, familial thoracic 5; Furlong syndrome; LDS1; Loeys-Dietz syndrome type 1A; Loeys-Dietz syndrome type 2A; TGFBR1-Related Loeys-Dietz Syndrome; TGFBR1-Related Thoracic Aortic Aneurysms and Aortic Dissections
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
OMIM®: 609192

Disease characteristics

Excerpted from the GeneReview: Loeys-Dietz Syndrome
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]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Bart L Loeys  |  Harry C Dietz   view full author information

Additional descriptions

From OMIM
The Loeys-Dietz syndrome (LDS) is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement. As defined by Loeys et al. (2006), the disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Some patients have craniofacial involvement consisting of cleft palate, craniosynostosis, or hypertelorism. Bifid uvula may also be present. The natural history is characterized by aggressive arterial aneurysms and a high rate of pregnancy-related complications. LDS is also associated with immunologic-related disorders: approximately one-third of affected individuals exhibit food allergies, in contrast to a prevalence of 6 to 8% in the general population, and LDS patients have an increased prevalence of asthma, rhinitis, and eczema (summary by MacCarrick et al., 2014). Nomenclature In initial reports, LDS patients, defined as those with mutations in TGFBR1 or TGFBR2, were stratified into 2 types, depending on severity of craniofacial features (type 1) or cutaneous features (type 2) (MacCarrick et al., 2014). Given that vascular disease is the major concern in LDS irrespective of the severity of systemic features, a revised nosology was proposed with sequential numbering corresponding to the gene mutant in each group (see below). Genetic Heterogeneity of Loeys-Dietz Syndrome LDS1 is caused by mutation in the TGFBR1 gene. LDS2 (610168) is caused by mutation in the TGFBR2 gene (190182). LDS3 (613795), which is associated with early-onset osteoarthritis, is caused by mutation in the SMAD3 gene (603109). LDS4 (614816) is caused by mutation in the TGFB2 gene (190220). LDS5 (615582) is caused by mutation in the TGFB3 gene (190230). Reviews MacCarrick et al. (2014) provided a review of LDS, stating that there are no specific clinical criteria for the diagnosis, which is confirmed by molecular testing. They proposed that mutation in any of the 4 genes, TGFBR1, TGFBR2, SMAD3, or TGFB2, in combination with arterial aneurysm or dissection or a family history of documented LDS, should be sufficient to establish the diagnosis. The authors noted that rapidly progressive aortic aneurysmal disease is a distinct feature of LDS, and they discussed management strategies for cardiovascular issues as well as other complications of LDS.  http://www.omim.org/entry/609192
From GHR
Loeys-Dietz syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, and blood vessels.There are five types of Loeys-Dietz syndrome, labelled types I through V, which are distinguished by their genetic cause. Regardless of the type, signs and symptoms of Loeys-Dietz syndrome can become apparent anytime from childhood through adulthood, and the severity is variable.Loeys-Dietz syndrome is characterized by enlargement of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). People with Loeys-Dietz syndrome can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns (arterial tortuosity).Individuals with Loeys-Dietz syndrome often have skeletal problems including premature fusion of the skull bones (craniosynostosis), an abnormal side-to-side curvature of the spine (scoliosis), either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum), an inward- and upward-turning foot (clubfoot), flat feet (pes planus), or elongated limbs with joint deformities called contractures that restrict the movement of certain joints. A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia). In individuals with Loeys-Dietz syndrome, dural ectasia typically does not cause health problems. Malformation or instability of the spinal bones (vertebrae) in the neck is a common feature of Loeys-Dietz syndrome and can lead to injuries to the spinal cord. Some affected individuals have joint inflammation (osteoarthritis) that commonly affects the knees and the joints of the hands, wrists, and spine.People with Loeys-Dietz syndrome may bruise easily and develop abnormal scars after wound healing. The skin is frequently described as translucent, often with stretch marks (striae) and visible underlying veins. Some individuals with Loeys-Dietz syndrome develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax) or a protrusion of organs through gaps in muscles (hernias). Other characteristic features include widely spaced eyes (hypertelorism), eyes that do not point in the same direction (strabismus), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and an opening in the roof of the mouth (cleft palate).Individuals with Loeys-Dietz syndrome frequently develop immune system-related problems such as food allergies, asthma, or inflammatory disorders such as eczema or inflammatory bowel disease.  https://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome

Clinical features

Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of ocular misalignment where the visual axes diverge inappropriately. For example, medial rectus muscle weakness may produce this condition as the affected eye will deviate laterally upon attempted forward gaze. An exotropia occurs due to the relatively unopposed force exerted on the eye by the lateral rectus muscle, which pulls the eye in an outward direction.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
A congenital abnormality of the jaws (particularly the mandible) in which they are unusually small. This condition is not always pathological and may correct itself as the patient matures; however, it may also present as a birth defect in multiple syndromes.
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
A fairly common and often benign valvular heart disorder characterized by redundancy or hooding of mitral valve leaflets so that they prolapse into the left atrium, often causing mitral regurgitation. It is often a symptomless condition but may be marked by varied symptoms (e.g. chest pain, fatigue, dizziness, dyspnea, or palpitations) leading in some cases to endocarditis or ventricular tachycardia.
Joint laxity
MedGen UID:
39439
Concept ID:
C0086437
Pathologic Function
Lack of stability of a joint.
Bicuspid aortic valve
MedGen UID:
57436
Concept ID:
C0149630
Congenital Abnormality
A congenital anomaly in which the aortic valve has two leaflets. It is associated with mutations in the NOTCH1 gene or the SMAD6 gene, encoding neurogenic locus notch homolog protein 1 and mothers against decapentaplegic homolog 6, respectively. It is a clinically heterogeneous condition, with a high incidence of aortic valve and ascending aortic complications requiring surgery.
Pulmonary artery aneurysm
MedGen UID:
57839
Concept ID:
C0155676
Finding
An aneurysm (severe localized balloon-like outward bulging) in the pulmonary artery.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Postaxial hand polydactyly
MedGen UID:
609221
Concept ID:
C0431904
Congenital Abnormality
Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).
Camptodactyly
MedGen UID:
195780
Concept ID:
C0685409
Congenital Abnormality
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers or toes cannot be extended to 180 degrees by either active or passive extension.
Dilatation of ascending aorta
MedGen UID:
163631
Concept ID:
C0856747
Disease or Syndrome
A bulging, weakened area in the wall of the ascending thoracic aorta.
Dermal translucency
MedGen UID:
373141
Concept ID:
C1836646
Finding
An abnormally increased ability of the skin to permit light to pass through (translucency) such that subcutaneous structures such as veins display an increased degree of visibility.
Generalized arterial tortuosity
MedGen UID:
322965
Concept ID:
C1836651
Finding
Abnormal tortuous (i.e., twisted) form of arteries affecting most or all arteries.
Ascending aortic dissection
MedGen UID:
322966
Concept ID:
C1836653
Pathologic Function
A separation of the layers within the wall of the ascending aorta. Tears in the intimal layer result in the propagation of dissection (proximally or distally) secondary to blood entering the intima-media space.
Soft skin
MedGen UID:
336730
Concept ID:
C1844592
Finding
Subjective impression of increased softness upon palpitation of the skin.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
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.
Dilatation of the descending aortic
MedGen UID:
1393606
Concept ID:
C4476542
Anatomical Abnormality
A bulging, weakened area in the wall of the descending thoracic aorta.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwöger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ; ESC Committee for Practice Guidelines.
Eur Heart J 2014 Nov 1;35(41):2873-926. Epub 2014 Aug 29 doi: 10.1093/eurheartj/ehu281. PMID: 25173340
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article
Pyeritz RE; American College of Medical Genetics and Genomics.
Genet Med 2012 Jan;14(1):171-7. Epub 2012 Jan 5 doi: 10.1038/gim.2011.48. PMID: 22237449
Arslan-Kirchner M, Epplen JT, Faivre L, Jondeau G, Schmidtke J, De Paepe A, Loeys B
Eur J Hum Genet 2011 Oct;19(10) Epub 2011 Apr 27 doi: 10.1038/ejhg.2011.68. PMID: 21522183Free PMC Article

External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Recent clinical studies

Etiology

Molina-Sánchez T, Calderón-Colmenero J, Sandoval JP
Cardiol Young 2017 Aug;27(6):1219-1220. Epub 2017 Jun 13 doi: 10.1017/S1047951117001056. PMID: 28606209
Frise CJ, Pitcher A, Mackillop L
Int J Cardiol 2017 Jan 1;226:21-25. Epub 2016 Oct 11 doi: 10.1016/j.ijcard.2016.10.024. PMID: 27780078
Braverman AC, Moon MR, Geraghty P, Willing M, Bach C, Kouchoukos NT
Am J Med Genet A 2016 Aug;170(8):2177-80. Epub 2016 Apr 29 doi: 10.1002/ajmg.a.37694. PMID: 27125181
Luo M, Yang H, Yin K, Chen Q, Zhang J, Fan Y, Zhou Z, Chang Q
Clin Chim Acta 2016 May 1;456:144-148. Epub 2016 Feb 11 doi: 10.1016/j.cca.2016.02.005. PMID: 26877057
Yu B, Liu L, Sun H, Chen Y
Int J Clin Exp Pathol 2015;8(9):10768-75. Epub 2015 Sep 1 PMID: 26617788Free PMC Article

Diagnosis

Molina-Sánchez T, Calderón-Colmenero J, Sandoval JP
Cardiol Young 2017 Aug;27(6):1219-1220. Epub 2017 Jun 13 doi: 10.1017/S1047951117001056. PMID: 28606209
Valenzuela I, Fernández-Alvarez P, Munell F, Sanchez-Montanez A, Giralt G, Vendrell T, Tizzano EF
Eur J Med Genet 2017 Jun;60(6):303-307. Epub 2017 Mar 24 doi: 10.1016/j.ejmg.2017.03.010. PMID: 28344185
Byard RW
J Forensic Sci 2017 Nov;62(6):1512-1515. Epub 2017 Feb 23 doi: 10.1111/1556-4029.13466. PMID: 28230898
Yamana K, Sakurai H, Nonaka T, Sakurai T
Eur J Cardiothorac Surg 2017 Apr 1;51(4):797-798. doi: 10.1093/ejcts/ezw376. PMID: 28082467
Braverman AC, Moon MR, Geraghty P, Willing M, Bach C, Kouchoukos NT
Am J Med Genet A 2016 Aug;170(8):2177-80. Epub 2016 Apr 29 doi: 10.1002/ajmg.a.37694. PMID: 27125181

Therapy

Yamana K, Sakurai H, Nonaka T, Sakurai T
Eur J Cardiothorac Surg 2017 Apr 1;51(4):797-798. doi: 10.1093/ejcts/ezw376. PMID: 28082467
Beaulieu RJ, Lue J, Ehlert BA, Grimm JC, Hicks CW, Black JH 3rd
Ann Vasc Surg 2017 Jan;38:10-16. Epub 2016 Aug 10 doi: 10.1016/j.avsg.2016.06.007. PMID: 27521820
Akazawa Y, Motoki N, Tada A, Yamazaki S, Hachiya A, Matsuzaki S, Kamiya M, Nakamura T, Kosho T, Inaba Y
Circ J 2016 Oct 25;80(11):2369-2375. Epub 2016 Oct 13 doi: 10.1253/circj.CJ-16-0739. PMID: 27733734
Emmanuel Y, Gordon-Smith J, McKillop G, Duddy M, Clift P
J Vasc Interv Radiol 2015 Oct;26(10):1539-43. doi: 10.1016/j.jvir.2015.04.014. PMID: 26408217
Bunting AC, Bould MD
Paediatr Anaesth 2014 Dec;24(12):1302-4. Epub 2014 Sep 9 doi: 10.1111/pan.12511. PMID: 25203753

Prognosis

Molina-Sánchez T, Calderón-Colmenero J, Sandoval JP
Cardiol Young 2017 Aug;27(6):1219-1220. Epub 2017 Jun 13 doi: 10.1017/S1047951117001056. PMID: 28606209
Byard RW
J Forensic Sci 2017 Nov;62(6):1512-1515. Epub 2017 Feb 23 doi: 10.1111/1556-4029.13466. PMID: 28230898
Frise CJ, Pitcher A, Mackillop L
Int J Cardiol 2017 Jan 1;226:21-25. Epub 2016 Oct 11 doi: 10.1016/j.ijcard.2016.10.024. PMID: 27780078
Bennett CL, Aziz H, Sparks E, Shah T, Yoder M, MacCarrick G, Dietz HC
Am J Med Genet A 2016 Mar;170(3):725-7. Epub 2015 Nov 27 doi: 10.1002/ajmg.a.37487. PMID: 26614122
Yu B, Liu L, Sun H, Chen Y
Int J Clin Exp Pathol 2015;8(9):10768-75. Epub 2015 Sep 1 PMID: 26617788Free PMC Article

Clinical prediction guides

Frise CJ, Pitcher A, Mackillop L
Int J Cardiol 2017 Jan 1;226:21-25. Epub 2016 Oct 11 doi: 10.1016/j.ijcard.2016.10.024. PMID: 27780078
Braverman AC, Moon MR, Geraghty P, Willing M, Bach C, Kouchoukos NT
Am J Med Genet A 2016 Aug;170(8):2177-80. Epub 2016 Apr 29 doi: 10.1002/ajmg.a.37694. PMID: 27125181
Yu B, Liu L, Sun H, Chen Y
Int J Clin Exp Pathol 2015;8(9):10768-75. Epub 2015 Sep 1 PMID: 26617788Free PMC Article
Blinc A, Maver A, Rudolf G, Tasič J, Pretnar Oblak J, Berden P, Peterlin B
Eur J Vasc Endovasc Surg 2015 Dec;50(6):816-21. Epub 2015 Sep 26 doi: 10.1016/j.ejvs.2015.08.003. PMID: 26409702
Kuechler A, Altmüller J, Nürnberg P, Kotthoff S, Kubisch C, Borck G
Mol Cell Probes 2015 Oct;29(5):330-4. Epub 2015 Jul 13 doi: 10.1016/j.mcp.2015.07.003. PMID: 26184463

Recent systematic reviews

Halushka MK, Angelini A, Bartoloni G, Basso C, Batoroeva L, Bruneval P, Buja LM, Butany J, d'Amati G, Fallon JT, Gallagher PJ, Gittenberger-de Groot AC, Gouveia RH, Kholova I, Kelly KL, Leone O, Litovsky SH, Maleszewski JJ, Miller DV, Mitchell RN, Preston SD, Pucci A, Radio SJ, Rodriguez ER, Sheppard MN, Stone JR, Suvarna SK, Tan CD, Thiene G, Veinot JP, van der Wal AC
Cardiovasc Pathol 2016 May-Jun;25(3):247-257. Epub 2016 Mar 12 doi: 10.1016/j.carpath.2016.03.002. PMID: 27031798
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

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