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Loeys-Dietz syndrome 4(LDS4)

MedGen UID:
766676
Concept ID:
C3553762
Disease or Syndrome
Synonyms: ANEURYSM, AORTIC AND CEREBRAL, WITH ARTERIAL TORTUOSITY AND SKELETAL MANIFESTATIONS; LDS4; TGFB2-Related Loeys-Dietz Syndrome
 
Gene (location): TGFB2 (1q41)
 
Monarch Initiative: MONDO:0013897
OMIM®: 614816

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  |  Chapter Notes  |  References
Authors:
Bart L Loeys  |  Harry C Dietz   view full author information

Additional descriptions

From OMIM
Loeys-Dietz syndrome-4 (LDS4) is characterized by aortic aneurysm, with other variable features including arterial tortuosity, skeletal anomalies (e.g., pectus deformity, scoliosis, and arachnodactyly), and skin involvement (e.g., thin skin, easy bruising, striae). Mild craniofacial anomalies including retrognathia, high-arched palate, hypertelorism, and bifid uvula may be present. Tarlov cysts and dural ectasia have been reported (Lindsay et al., 2012, Boileau et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see 609192.  http://www.omim.org/entry/614816
From MedlinePlus Genetics
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.

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 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.

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).

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 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.  https://medlineplus.gov/genetics/condition/loeys-dietz-syndrome

Clinical features

From HPO
Chronic pain
MedGen UID:
57452
Concept ID:
C0150055
Finding
Persistent pain, usually defined as pain that has lasted longer than 3 to 6 months.
Arachnodactyly
MedGen UID:
2047
Concept ID:
C0003706
Congenital Abnormality
Abnormally long and slender fingers ("spider fingers").
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).
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.
Protrusio acetabuli
MedGen UID:
98369
Concept ID:
C0409495
Anatomical Abnormality
Intrapelvic bulging of the medial acetabular wall.
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
One or both of the leaflets (cusps) of the mitral valve bulges back into the left atrium upon contraction of the left ventricle.
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).
Aortic dissection
MedGen UID:
83315
Concept ID:
C0340643
Disease or Syndrome
Aortic dissection refers to a tear in the intimal layer of the aorta causing a separation between the intima and the medial layers of the aorta.
Ascending tubular aorta aneurysm
MedGen UID:
163631
Concept ID:
C0856747
Anatomical Abnormality
An abnormal localized widening (dilatation) of the tubular part of the ascending aorta.
Aortic root aneurysm
MedGen UID:
720712
Concept ID:
C1298820
Anatomical Abnormality
An abnormal localized widening (dilatation) of the aortic root.
Arterial tortuosity
MedGen UID:
480821
Concept ID:
C3279191
Finding
Abnormal tortuous (i.e., twisted) form of arteries.
Aortic tortuosity
MedGen UID:
870555
Concept ID:
C4025003
Anatomical Abnormality
Abnormal tortuous (i.e., twisted) form of the aorta.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
A height above that which is expected according to age and gender norms.
Eosinophilic infiltration of the esophagus
MedGen UID:
1637185
Concept ID:
C4703646
Finding
Infiltration of numerous eosinophils (usually greater than 15 per high power field) into the squamous epithelium of the esophagus, and layering of eosinophils on the surface layer of the esophagus.
Torticollis
MedGen UID:
11859
Concept ID:
C0040485
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
Dural ectasia
MedGen UID:
377094
Concept ID:
C1851712
Finding
A widening or ballooning of the dural sac surrounding the spinal cord usually at the lumbosacral level.
Recurrent thrombophlebitis
MedGen UID:
763064
Concept ID:
C3550150
Finding
Repeated episodes of inflammation of a vein associated with venous thrombosis (blood clot formation within the vein).
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Spondylolisthesis
MedGen UID:
52470
Concept ID:
C0038016
Disease or Syndrome
Spondylolisthesis is defined as forward slipping of a vertebral body on the one below it. Spondylolysis is defined as a defect in the pars interarticularis without vertebral slipping (summary by Wiltse et al., 1975).
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Abnormal sternum morphology
MedGen UID:
349830
Concept ID:
C1860493
Anatomical Abnormality
An anomaly of the sternum, also known as the breastbone.
Pneumothorax
MedGen UID:
19365
Concept ID:
C0032326
Disease or Syndrome
Accumulation of air in the pleural cavity leading to a partially or completely collapsed lung.
Emphysema
MedGen UID:
18764
Concept ID:
C0034067
Disease or Syndrome
A subcategory of chronic obstructive pulmonary disease (COPD). It occurs in people who smoke and suffer from chronic bronchitis. It is characterized by inflation of the alveoli, alveolar wall damage, and reduction in the number of alveoli, resulting in difficulty breathing.
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).
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
High, narrow palate
MedGen UID:
324787
Concept ID:
C1837404
Finding
The presence of a high and narrow palate.
Broad uvula
MedGen UID:
786050
Concept ID:
C3693299
Finding
Increased width of the uvula (subjective finding).
Bifid uvula
MedGen UID:
1646931
Concept ID:
C4551488
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.
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.
Hyperextensible skin
MedGen UID:
66023
Concept ID:
C0241074
Finding
A condition in which the skin can be stretched beyond normal, and then returns to its initial position.
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.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Cornea plana
MedGen UID:
576329
Concept ID:
C0344529
Congenital Abnormality
Cornea plana is an abnormally flat shape of the cornea such that the normal protrusion of the cornea from the sclera is missing. The reduced corneal curvature can lead to hyperopia, and a hazy corneal limbus and arcus lipoides may develop at an early age.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.

Professional guidelines

PubMed

Yamaguchi T, Hayashi S, Hayashi D, Matsuyama T, Koitabashi N, Ogiwara K, Noda M, Nakada C, Fujiki S, Furutachi A, Tanabe Y, Yamanaka M, Ishikawa A, Mizukami M, Mizuguchi A, Sugiura K, Sumi M, Yamazawa H, Izawa A, Wada Y, Fujikawa T, Takiguchi Y, Wakui K, Takano K, Nishio SY, Kosho T
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Diagnosis

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Ann Vasc Surg 2017 Jan;38:10-16. Epub 2016 Aug 10 doi: 10.1016/j.avsg.2016.06.007. PMID: 27521820
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Prognosis

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