ABGC Skeletal and Connective Tissue Disorders

Osteogenesis Imperfecta (Classic Non-Deforming; Type 1) - 3 Key Features

Most common type. Bone fractures w/o deformity (none at birth); blue sclerae; 1A: normal teeth, 1B: dentinogenesis imperfecta (fragile pearly teeth)

Osteogenesis Imperfecta (Perinatal Lethal; Type 2) - 3 Key Features

Most severe type. Prenatal fractures (beaded ribs, accordion limb bones, short/bowed extremities); blue sclerae; thin/translucent skin

Osteogenesis Imperfecta (Progressive Deforming; Type 3) - 3 Key Features

Prenatal fractures (severe deformity +growth restriction +kyphosis); white sclerae; sometimes dentinogenesis imperfecta (fragile pearly teeth) or hearing loss

Osteogenesis Imperfecta (Common Variable; Type 4) - 3 Key Features

Childhood fractures +kyphosis; infancy blue sclerae -> white sclerae; common dentinogenesis imperfecta (fragile pearly teeth)

Osteogenesis Imperfecta (Type 5) - 3 Key Features

Bone fractures w/ hyperplastic callus (bone healing bumps); white sclerae; no other features

Osteogenesis Imperfecta (Type 6) - 3 Key Features

Childhood fractures +kyphosis; only white sclerae; no dentinogenesis imperfecta (fragile pearly teeth)

Osteogenesis Imperfecta (Type 7 and 8) - 3 Key Features

Prenatal fractures (severe deformity +growth restriction +kyphosis); white sclerae; Popcorn Epiphyses (irregular density at ends of long bones)

Achondroplasia - 3 Key Features

Most common skeletal dysplasia; Leg bowing (femur overgrowth); short stature; Spine Abns. +macrocephaly/hydrocephalus

Thanatophoric Dysplasia - 3 Key Features

2 Types: Type 1: Telephone-reciever femurs, Micromelia (short limbs), rare/no craniosynostosis (clover-leaf skull) +macrocephaly/hydrocephaly; Type 2: straight femurs, micromelia (short limbs), common craniosynostosis (clover-leaf skull) +macrocephaly/hydrocephaly

Marfan Syndrome - 3 Key Features

Skeletal abns. (tall stature, arachnodactyly, scoliosis); Chest involvement (aortic root dilation, pneumothorax, pectus excavatus/carinatum); Eye involvement (upward ectopic lentis (dislocation of the lens), glaucoma, early cataracts)

Loeys-Dietz Syndrome - 3 Key Features

Abn. Head Formation (Bifid Uvula, Cleft Palate, Hypertelorism, Craniosynostosis); Skeletal abns. (tall stature, arachnodactyly, scoliosis); Vascular abns. (head/trunk arterial aneurysms, twisting blood vessels (tortuosity))

Hypermobile Ehlers-Danlos Syndrome - 3 Key Features

joint hypermobility +pain +joint dislocations; Skin abns. (hyperflexible skin, easy bruising, atrophic scarring); has MANY comorbidities (POTS, MCAS, IBS, autoimmune conditions, migraines)

Classic Ehlers-Danlos Syndrome - 3 Key Features

joint hypermobility +pain +joint dislocations; Skin abns. (hyperflexible skin, poor wound healing, easy bruising, atrophic/hemisiderotic/"cigarette-paper" scarring); muscle hypotonia

Cardiovascular Ehlers-Danlos Syndrome

Connective tissue fragility (arteries, lungs, intestines, and uterus) = frequent GI bleeding/aneurysm/pneumothorax; Skin involvement (thin/translucent skin, easy bruising); Club foot

Thanatophoric Dysplasia - Imaging

Bowed femurs/telephone-shaped femurs and no cloverleaf skull (type 1), straight femurs and cloverleaf skull (type 2); flat vertebrae (platyspondyly); Rhizomelic (upper limb bone) shortening; Small foramen magnum (skull base opening) w/ brain stem compression (hydrocephaly/macrocephaly)

Thanatophoric Dysplasia - Genetics and Inheritance

AD (majority de novo); FGFR3 (Type 1 90% p.Arg248Cys and p.Tyr373Cys; Type 2 99% p.Lys650Glu variant)

Thanatophoric Dysplasia - Onset and Progression

At birth; Not compatible with life, death by respiratory failure (only 5 people reported living past 1y)

Thanatophoric Dysplasia - Treatment

Comfort Care; long-term monitoring

Thanatophoric Dysplasia - Prenatal Findings

Shortening of long bones and Large NT visible by Tri1; Polyhydramnios, Macrocephaly, Narrow Chest, Growth Deficiency; Bowed/Telephone Femurs or Cloverleaf Skull by Tri2

Achondroplasia - Imaging

Bowed femurs; Rhizomelic (upper limb bone) shortening; Trident-shaped hands; Small foramen magnum (skull base opening) w/ brain stem compression (hydrocephaly/macrocephaly); Spine Abns. (Kyphosis (round upper back))

Achondroplasia - Genetics and Inheritance

AD (majority de novo); FGFR3 (98% c.1138G>A variant)

Achondroplasia - Onset and Progression

At birth; 60y lifespan

Achondroplasia - Treatment

Several drugs to help with height velocity if taken from birth; shunting for hydrocephalus; spine surgery if needed; lifestyle modifications or surgical limb lengthening available; lifetime surveillance

Achondroplasia - Prenatal Findings

Late Tri2: Rhizomelic (upper limb bone) shortening; Trident-shaped hands; Small foramen magnum (skull base opening) w/ brain stem compression (hydrocephaly/macrocephaly); Narrow Chest

Osteogenesis Imperfecta - Imaging

Type 1: Osteopenia (translucents bones), no deformity of bones; Type 2: Osteopenia (translucents bones), beaded ribcage, accordion pattern on long bones; Type 3: Osteopenia (translucents bones), long bone deformities (bowing/shortening), kyphosis; Type 4: Osteopenia (translucents bones), mild bone deformities (bowing); Type 5: Osteopenia (translucents bones), Hyperplastic callus formations (bone healing bumps); Type 6: Osteopenia (translucents bones), long bone deformities (bowing/shortening), Kyphosis; Type 7 and 8: Osteopenia (translucents bones), Rhizomelia (short upper bones), popcorn calcifications (patchy density in ends of long bones)

Osteogenesis Imperfecta - Genetics and Inheritance

AD for Type 1-4; 2 main genes: COL1A1 and COL1A2; 16 AR, 1 AD, 1 XL non-collagen genes. Type 5: AD, IFITM5; Type 6: AR, SERPINF1; Type 7: AR, CRTAP; Type 8: AR, P3H1 (LEPRE1)

Osteogenesis Imperfecta - Onset and Progression

Deaths usually due to respiratory failure from small ribcage/underdeveloped lungs. Type 1: childhood onset, normal lifespan; Type 2: at birth onset, survival < 1 week; Type 3: at birth onset, variable lifespan; Type 4: infancy onset, normal lifespan; Type 5: at birth onset, normal lifespan; Type 6: infancy onset, normal lifespan; Type 7: wide variability; Type 8: at birth onset, early infancy death

Osteogenesis Imperfecta - Treatment

Pain management, ambulatory devices, fracture prevention, vit/min/biphos medications to increase bone density, dental procedures

Osteogenesis Imperfecta - Prenatal Findings

some forms show prenatal fractures and deformities, narrow ribcage, growth restriction, and low birth weight around 16-20 weeks (Early Tri2), others show normal prenatal findings

Marfan Syndrome - Imaging

Long metacarpals, skeletal overgrowth of ribs and long bones, scoliosis/kyphosis, aortic root dilation

Marfan Syndrome - Genetics and Inheritance

AD; FBN1

Marfan Syndrome - Onset and Progression

Childhood; Live until 70's (death usually due to cardiovascular issues)

Marfan Syndrome - Treatment

Multidisciplinary team, intermittent chest CT to check aortic root dilation, surgical intervention when necessary, avoid contact sports and caffeine, take beta blockers to reduce aortic stress, no brass instruments of scuba diuving to avoid pneumothorax

Marfan Syndrome - Prenatal Findings

Late Tri2: cardiomegaly (big heart), skeletal overgrowth

Loeys-Dietz Syndrome - Imaging

Craniosynostosis, arterial abns. (aneurysms, tortuosity), aortic root dilation, scoliosis/kyphosis

Loeys-Dietz Syndrome - Genetics and Inheritance

AD: TGFBR2, TGFBR1, SMAD3, SMAD2, TGFR2, TGFB3; AR: IPO8

Loeys-Dietz Syndrome - Onset and Progression

At birth; 30y lifespan

Loeys-Dietz Syndrome - Treatment

Multidisciplinary team, intermittent chest CT to check aortic root dilation and aneurysm, surgical intervention when necessary, avoid contact sports and caffeine, take beta blockers to reduce aortic stress, no brass instruments of scuba diuving to avoid pneumothorax

Loeys-Dietz Syndrome - Prenatal Findings

Aortic root dilation on Late Tri2 echocardio; club foot, craniosynostosis, ventriculomegaly/hydrocephalus

Hypermobile Ehlers-Danlos Syndrome - Genetics and Inheritance

AD; No gene has been found

Hypermobile Ehlers-Danlos Syndrome - Onset and Progression

Childhood onset; normal lifespan (very low life quality, however)

Hypermobile Ehlers-Danlos Syndrome - Treatment

Multidisciplinary care, PT, OT, ambulatory devices, braces and pain management, avoid pain medication due to effect on GI

Classic Ehlers-Danlos Syndrome - Genetics and Inheritance

AD; COL1A1, COL5A1, COL5A2

Classic Ehlers-Danlos Syndrome - Onset and Progression

Childhood onset; normal lifespan +low life quality

Classic Ehlers-Danlos Syndrome - Treatment

Multidisciplinary care, PT, OT, ambulatory devices, braces and pain management, avoid unnecessary surgeries due to bleeding and slowed healing risk

Cardiovascular Ehlers-Danlos Syndrome - Treatment

Multidisciplinary care, periodic U/S screening of arteries and GI, BP monitor, avoid heavy lifting/contact sports

Cardiovascular Ehlers-Danlos Syndrome - Onset and Progression

Most not identified until major medical concern in adulthood; 50y lifespan

Cardiovascular Ehlers-Danlos Syndrome - Genetics and Inheritance

AD; COL3A1