Connective tissue disorders

Question 1

Congenital Contractural Arachnodactyly (Beals Syndrome)

Answer 1

Inheritance: Autsomal dominant
Gene: FBN2
Major features:
●Marfanoid habitus
●Flexion contractures of the elbows, hips, knees, and/or fingers
●Kyphoscoliosis
●Muscular hypoplasia
●Crumpled ear outer helices
Rare severe/lethal form exists (above features, plus):
●Cardiovascular anomalies
oASD, VSD, interrupted aortic arch, aortic root dilatation
oDuodenal and/or esophageal atresia, intestinal malrotation

Question 2

Cutis Laxa

Answer 2

Inheritance: Autosomal dominant, autosomal recessive, X-linked
Genes: ELN!!!!!!, ATP6V0A2, ATP7A, FBLN4, FBLN5, PYCR1
Major features:
●Loose, inelastic skin that hangs/looks wrinkled
Joint hypermobility
●Hernia
●Blue sclera
●Cardiopulmonary complications

Question 3

Classic EDS

Answer 3

Inheritance: Autosomal Dominant
Genes: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, TNXB, others
EDS I and II:
●“Classic” EDS
●Hyperelastic skin
●Atrophic scarring
●Joint hypermobility
●Smooth, velvety skin
●Pseudotumors over elbows and knees
●Dislocations, sprains, flat feet
●Joint pain
●Easy bruising
●Increased risk for postoperative hernia
●More skin involvement and more severe joint issues than hypermobile type

Question 4

Vascular EDS

Answer 4

Most severe/life-threatening form
●Cardiovascular concerns are major cause of mortality
     oVascular/arterial dissection or rupture, GI rupture, bowel rupture, organ rupture, retroperitoneal bleeding, uterine rupture can occur in pregnancy
●Club foot
●Spontaneous pneumothorax
●Congenital dislocation of the hips
●Inguinal hernia
●Average lifespan 48 years

Question 5

Loeys-Dietz Syndrome

Answer 5

Inheritance: Autosomal dominant
Genes: TGFBR1, TGFBR2, SMAD3, TGFB2
Major features:
●Aortic dilation/dissection
●Bicuspid aortic valve
●Arterial aneurysms
●Vessel tortuosity
●Pectus deformity
●Scoliosis
●Joint laxity or contracture
●Arachnodactyly
●Cervical spine instability
●Dural ectasia
●Bifid uvula/cleft palate
●Craniosynostosis/characteristic facies
●Translucent skin
●Dystrophic scars
●Type II has no craniofacial findings

Question 6

Marfan syndrome

Answer 6

●Increased armspan to height ratio
●Dolichostenomelia (long limbs)
●Arachnodactyly
●Joint laxity
●Pectus deformity
●Dental malocclusion
●Ectopia lentis
●Aortic root dilation/dissection
●Mitral valve prolapse
●Stretch marks (striae)
●Tall stature relative to familial height
●Flat feet
●Spontaneous pneumothorax
●Genu recurvatum
●Scoliosis
●Dural ectasia
●Increased risk for uterine prolapse
●Cardiac concerns are major source of mortality, but lifespan can be normal with proper management

Question 7

OI type 1

Answer 7

Inheritance: Autosomal dominant
Genes: COL1A1, COL1A2
OI Type I
●	Mild presentation
●	Normal quality of collagen, but insufficient quantity
●	Bones fracture easily
●	Blue sclera
●	Loose joints
●	Hypotonia
●	Scoliosis
●	Early hearing loss
●	Life expectancy is slightly reduced primarily due to the possibility of fatal bone fractures

Question 8

Sphrintzen-Goldberg Syndrome

Answer 8

Inheritance: Autosomal dominant
Gene: SKI
Major features:
●Clinically very similar to LDS (including dysmorphic features/craniosynostosis) with additional features
●Multiple abdominal hernias
●Intellectual disability
●Brain anomalies

Question 9

Stickler syndrome

Answer 9

Inheritance: Autosomal dominant
Genes: COL2A1, COL11A1, COL11A2, COL9A1
Major features:
●Type 1 is “Membranous” (most common type)
oPersistent vestigial vitreous gel in the retrolental space of the eye
●Type 2 is “beaded”
oSparse and irregularly thickened bundles throughout the vitreous cavity of the eye
●Midface hypoplasia
●Telecanthus and epicanthal folds
●Micrognathia w/ Pierre-Robin sequence
●Progressive sensorineural hearing loss (more severe in type II)
●High myopia
●Short stature
●Early-onset arthritis
●Kyphoscoliosis
●Platyspondylia (flattened vertebrae in spine)
●Mitral valve prolapse

Question 10

OI, Type 2

Answer 10

OI Type II
●Severe perinatal lethal
●Insufficient quantity and quality of collagen
●Death within the first year of life due to respiratory failure and intracerebral hemorrhage
●Underdeveloped lungs
●Severe bone deformity

Question 11

OT, Type 3

Answer 11

OI Type III
●Progressive and deforming
●Normal quantity of collagen, but poor quality
●Bones fracture easily, sometimes prenatally
●Severe bone deformity
●Respiratory problems
●Short stature
●Barrel-shaped rib cage
●Scoliosis
●Triangular face
●Loose joints
●Hypotonia
●Blue sclera
●Early hearing loss

Question 12

OI, Type 4

Answer 12

OI Type IV
●Deforming with normal sclera
●Normal quantity of collagen, but poor quality
●Bones fracture easily, especially before puberty
●Mild-to-moderate bone deformity
●Short stature
●Barrel-shaped rib cage
●Scoliosis
●Early hearing loss

Question 13

OI, type 5

Answer 13

OI Type V–>mutations in IFITM5
●Same features as type IV
●Distinguished by “mesh-like” bone appearance histologically
●Leads to calcification of the membrane between the two forearm bones
oLimited wrist mobility

Question 14

OI,Type 6-8

Answer 14

OI Type VI–>Due to mutations in SERPINF1
●Same features as type IV
●Distinguished by “fish scale” bone appearance histologically

OI Type VII–>Due to mutations in CRTAP, AR
●Limited to people of First Nations descent in Quebec

OI Type VIII, Caused by mutations in LEPRE1