Connective Tissue/Skeletal Dysplasia/Collagenopathies

Question 1

List the disorders of fibrillin-TGFbeta pathway.

Answer 1

Marfan Syndrome

Loeys-Deitz Syndrome

Question 2

List the disorders of collagen production and assembly.

Answer 2

Ehlers Danlos Syndrome
Osteogenesis Imperfecta
Stickler Syndrome

Question 3

What is Marfan Syndrome?

Answer 3

AD
mutations in FBN1 gene with complete penetrance (though normally age related)
25% spontaneous mutations

Question 4

What is the 2010 Ghent criteria?

Answer 4

used to diagnose Marfan Syndrome
without family history
Ao (Z>2) + Ectopia Lentis
Ao (Z>2) + FBN1 mutation
Ao (Z>2) + Systemic score (>7 points)
Ectopia Lents + FBN1 known Ao
with family history
one of (Ectopia lentis, systemic score >7 points, Ao (Z>2 above 20, >3 below 20yo)

Question 5

What contributes to the Marfan Syndrome systemic score?

Answer 5

pectus excavotum/pigeon (1-2 points)
wrist/thumb signs (1-3 points)
pneumothorax (2 points)
armspan/height or US/LS (1)
scoliosis/kyphosis (1)
myopia (>3 dpts)
facial features (1 each)
dural ectasia (2)
food deformity/pes planus (1-2)
elbow extension decreased (1)
skin striae (1)
protrusio acetabulae (2)

Question 6

What are the most common phenotypes associated with Marfan syndrome?

Answer 6

ectopia lentis (bilateral, symmetrical, and superotemporal/upsloping)
other ocular abnormalities (myopia, retinal detachment, glaucoma)
progressive aortic dilation
other cardiac (MVP, MR, TR, enlarged pulmonary artery)
dural ectasia
dolichostenomelia
arachnodactyly

Question 7

What is Neonatal Marfan Syndrome?

Answer 7

severe early presentation of symptoms
50% mortality by 1st year (due to severe mitral valve regulation and heart failure)
most de novo mutations (exons 24-32)

Question 8

What fetal US findings are associated with Neonatal Marfan Syndrome?

Answer 8

arachnodactyly
joint contractures
AV valve insufficiency
worsening cardiomegally
dilated pulmonary and aortic roots

Question 9

What other conditions have FBN1 mutations but do not meet the Ghent criteria?

Answer 9

MASS phenotype
Mitral valve prolapse
Familial ectopia lentis
Thoracic aortic aneurysm

Question 10

How is Marfan Syndrome managed?

Answer 10

restriction of contact/competitive sports and isometric exercise
surveillance (annual or more frequent CT/MRA in adults for cardiology to assess aorta size)
medications (beta blockers; losartan)
surgical repair
avoide LASIK and SCUBA procedures

Question 11

How is Marfan Syndrome managed in females who are or are planning to become pregnant?

Answer 11

pre-pregnancy ECHO with monitoring every 2-3 months
aortic diameter <40mm and minimal cardiac disease do well
1% risk of endocarditis, dissection, heart failure
10% risk if aortic diameter is >40mm (>47 repair recommended)
beta blockers
consult with anesthesiology (dural ectasia could complicate epidural)
15% prematurity (20-32 weeks)due to PRM, cervical insufficiency, or maternal cardiac status
no increased fetal morbidity

Question 12

What conditions would be included on a DDx for symptoms of Marfan syndrome?

Answer 12

Loeys-Deitz
Congenital Contractural Arachnodactyly
Familial or Hereditary Thoracic Artery Aneurysms and Disection (FTAAD or HTAD)
Shprintzen-Goldberg
Homocystenuria

Question 13

What symptoms over lap between Marfan Syndrome and Homocystenuria?

Answer 13

ectopia lentis (homocystenuria is downslanting)
myopia
tendency to thrombosis
failure to thrive in newborns and/or developmental delay
tall stature with long, thin limbs and fingers
chest deformaties
scoliosis

Question 14

What symptoms are associated with Loeys-Dietz Syndrome 1?

Answer 14

facial dysmporphism
cleft palate
bifid uvula
cranisynostosis
micrognathia

Question 15

What symptoms are associated with Loeys-Deitz Syndrome?

Answer 15

EDS-like with bruising, poor scaring, joint laxity, and visceral rupture
newer phenotypic findings include facial milia, IBD, eosinophilic esophagitis

Question 16

What symptoms are associated with Loeys-Deitz Syndrome in general?

Answer 16

aortic root aneurysm (common, early rupture at small diameters- 50% will have at other locations)
bicuspid aortic valve
arterial tortuosity (head and neck vessels)
dissection of vessels in thoracic region
average age at first surgery:13 y/o
average age at death: 26 y/o
increased risk of uterine rupture in pregnancy

Question 17

What is Loeys-Deitz syndrome?

Answer 17

AD
75% new mutations
TGFBR1 and TGFBR2 (55-60%)
SMAD3 (osteoarthritis)
TGFB2 and TGFB3 (milder)

Question 18

What other conditions result from mutations in FBN1?

Answer 18

Weill Marchesani
Geleophysical dysplasia
Acrommicric dysplasia

Question 19

List the disorders of collagen production and assembly and which type of collagen the affect.

Answer 19

Type I: Osteogenesis Imperfecta
Type II, IX, and XI: Stickler Syndrome
Type III: Vascular Ehler’s Danlose Syndrome
Type V: Classic Ehler’s Danlose Syndrome

Question 20

What is Ehler’s Danlose Syndrome?

Answer 20

mostly AD
heterogenous group of disorders
best known subtypes include classic, hypermobile, adn vascular

Question 21

What are the symptoms consistent across all subtypes of Ehler’s Danlose Syndrome?

Answer 21

skin hyperextensibility
joint hypermobility
connective tissue fragility

Question 22

Describe the vascular subtype of EDS.

Answer 22

COL3A1 gene (encodes type III procollagen homotrimer in skin, blood vessels, and organs)
accounts for 4% of all EDS
most severe with high mortality
hard to diagnose without a genetic test
mean age of death is 48y/o presenting with to acute abdomen, retroperitoneal hemorrhage, and sudden collapse/shock

Question 23

What are the major clinical diagnostic criteria for vascular EDS?

Answer 23

arterial rupture (young age)
intestinal rupture
uterine rupture
family history of vascular EDS with documented mutation
AV fistula (carotid-cavernous sinus)

Question 24

What are the minor clinical diagnostic criteria for vascular EDS?

Answer 24

skin bruising/translucency
facial appearance
acrogeria
hypermobility of small joints
tendon/muscle rupture
pneumothorax
joint subluxation/dislocations
CHD/club foot
varicose veins
gingival recession
keratoconus

Question 25

What other symptoms are present with vascular EDS?

Answer 25

mitral valve prolapse strokes and progressively dilating aneurysms (less common) GI issues (sigmoid perforations) uterine rupture in perinatal period pregnancy related complications inguinal hernias, pneumothorax, and/or joint dislocations in childhood

Question 26

How is vascular EDS managed?

Answer 26

avoid contact/competitive sports and isomeric exercise anticoagulation contraindicated DON'T stick needles in arteries elective surgery increases complication rates beta blockers or celiprolol questionable possible surveillance with MRA/MRI medical alert bracelets 11.5% maternal mortality (due to uterine rupture)

Question 27

Describe classic EDS.

Answer 27

COL5A1/COL5A2 mutants resulting in type V collagen defect (90% of patients) complete lack of Tenascin XB (TNX gene)

Question 28

How is classic EDS diagnosed?

Answer 28

``` skin hyperextensibility and atrophic scarring with joint hypermobility and/or at least three of the following (minor criteria): family history bruising soft skin fragility hernia ```

Question 29

Describe the hypermobile form of EDS.

Answer 29

clinical diagnosis ONLY because basically no genes criteria is the Beighton scale which requires >5.. plus two of the following: 5+ symmetric feature positive family history musculoskeletal (pain and medically confirmed dislocations/instability) EXCLUDES: unusual fragility/rheumatological or other alternative diagnosis such as neuromuscular, etc

Question 30

What disorders other than EDS affect the ascending aorta?

Answer 30

FTAAD (Familial aortic aneurysm and dissection)

Question 31

What kinds of testing is available for EDS?

Answer 31

biochemical/genetic testing with skin fibroblasts (secrete connective tissue proteins so you can quantitatively and qualitatively assay for abnormal collagen or fibrillin by electrophoresis- this is rare) or NGS (COL5A1/COL5A2, COL3A1, COL1A1/COL1A2 or single gene testing with del/dup)

Question 32

What is Osteogenesis Imperfecta?

Answer 32

AD (collagen-related subtypes) AR (non-collagen subtypes- only 10-15%) COL1A1 or COL1A2 abnormal collagen microfibril assembly 4 common subtypes

Question 33

List the most common collagen-related subtypes of Osteogenesis Imperfecta.

Answer 33

``` Type I (50%): blue sclera, normal height, fractures, hearing loss, DI rare Type II (severe): perinatal lethality, limb defects, blue-grey sclera, soft calvarium, multiple fractures Type III (severe): fractures, deformities, early hearing loss, DI, progressive Type IV: normal sclera, DI common, adult hearing loss, milder than III ```

Question 34

How is Osteogenesis Imperfecta managed?

Answer 34

``` orthopedic PT psychosocial bisphosphinates (to improve mineralization) screenings for hearing loss dental screenings ```

Question 35

Describe the continuum of syndromes/phenotypes for Type II Collagenopathies.

Answer 35

skeletal dysplasia (severe disproportionate short stature) ocular (retinal and myopia) hearing loss (mixed) orofacial (flat facies, Pierre Robin sequence, cleft palate, laryngomalacia)

Question 36

List the Type II Collagenopathies.

Answer 36

Achondrogenesis type II (lethal) Kneist, SEDC (severe) SED, Stickler type I (intermediate) SED with arthritis (mild)

Question 37

What is Stickler Syndrome?

Answer 37

``` COL2A1 (80-90%) and COL11A1 (10-20%) results in ocular, mild hearing loss, joint involvement rare COL11A2 (non-ocular form) and COL9A1/COL9A2 (recessive forms) ```

Question 38

What symptoms are associated with Stickler Syndrome?

Answer 38

eye (early onset cataracts, vitreous anomaly, retinal detachment, myopia, >3D) craniofacial (depressed nasal bridge, bifid uvula or cleft palate, Robin sequence) hearing (sensorineural/conductive hearing loss) joint disease (hypermobility, osteoarthritis, spondyloepiphyseal dysplasia)

Question 39

List the perinatal lethal skeletal dysplasias.

Answer 39

FGFR3 (Thanatophoric dysplasia- AD) Type 2 Collagenopathy (Achondrogenesis II, hypochondrogenesis- AD) Sulfation disorder (achondrogenesis 1B- AR) Short Rib-Polydactyly syndromes (AR) Osteogenesis Imperfecta Type 2 (AD) Campomelia dysplasia (AD) or XY DSD

Question 40

What is Thanatophoric Dysplasia?

Answer 40

TD1 or TD2 | most common neonatal lethal dysplasia

Question 41

What phenotype is associated with Thanatophoric Dysplasia?

Answer 41

``` shortened and or bowed limbs platyspondyly narrow chest with protuberant abdomen short ribs macrocrania with frontal bossing +/- hydrocephalus cloverleaf skull polyhydramnios redundant, thickened soft tissues CNS abnormalities (mild ventriculomegaly, posterior fossa hypoplasia, temporal lobe abnormalities) ```

Question 42

What is Achondroplasia?

Answer 42

``` AD most common non-lethal dysplasia FGFR3 mutations fully penetrant 80% de novo paternal origin homozygous cases are lethal but can have compound hets with other genes ```

Question 43

What features at birth are indicative of Achondroplasia?

Answer 43

``` macrocephally sleep apnea frontal bossing cervical cranial junction rhizomelia and other segments trident hands (splaying of digits 3 and 4) lordosis, bowing hydrocephalus spinal stenosis abnormal radiological findings ```

Question 44

List the FGFR3 Related Disorders.

Answer 44

``` Hypochondroplasia Thanatopheric dysplasia Craniosynostosis SADDAN Homozygous Achondroplasia mutations ```

Question 45

What are common features of Skeletal Ciliopathies?

Answer 45

narrow chest short limbs short ribs polydactyly

Question 46

List examples of Skeletal Ciliopathies.

Answer 46

Cranioectodermal dysplasia | Ellis van Creveid

Question 47

What are Skeletal Ciliopathies?

Answer 47

AR | defects in non-motile cilia (primary cilia)