SKELETAL DYSPLASIAS

Question 1

OSTEOGENESIS IMPERFECTA

Answer 1

Bone deformity and predisposition to fractures, “codfish vertebrae common in adults (spinal compression fractures), “wormian bones” ; Type 1 = Classic non-deforming + blue sclera, mildest form; Type 2 = Perinatal lethal, “beaded rib” is pathognomonic, severe micromelia in utero; Type 3 = Progressive deforming, severe and apparent at birth, hearing loss common, short stature; Type 4 = Common variable + nml sclera; Genetics: COL1A1, COL1A2 (combined make up 90% of cases); type 1 caused by COL1A1 mutations (reduce amount of collagen); frameshift/nonsense = haploinsufficiency, missense = dominant negative, alter structure of collagen molecules

Question 2

BEALS SYN (AKA CONGENITAL CONTRACTURAL ARACHNODACTYLY)

Answer 2

Multiple joint contractures, “crumpled ear”, arachnodactyly (think spider fingers), marfanoid habitus, severe CCA includes GI and cardiac anomalies, Genetics: FBN2 gene, A dominant but high de novo rate; Germline mosaicism has been reported therefore risk to sibs in “de novo” situation would be slightly higher than gen pop

Question 3

SHPRINTZEN-GOLDBERG SYN

Answer 3

ID/DD, Skeletal findings (craniosynostosis, C1/C2 spine abnormality), similar to Marfan and Loey Dietz; however ID, spine abnormalities, and Chiari malformation rare in Marfan and Loey Dietz; Genetics: SKI gene, mostly de novo

Question 4

ACHONDROPLASIA

Answer 4

Defect in conversion of cartilage to bone (ossification); Short stature, average trunk but short limbs, macrocephaly, prominent forehead, spinal stenosis, Genetics: FGFR3 gene (common mutations c.1138G>A and c.1138G>C), mostly de novo (de novo mutations inherited from father, and association with advanced paternal age); ultrasound findings are generally not apparent until about 24 weeks GA; Testing Strategy: Thorough physical eval recommended first, genetic testing helpful when uncertain, genetic testing of two mutations first

Question 5

CHONDRODYPLASIA PUNCTATA

Answer 5

Stippled epiphyses, Brachtelephalangy (shortening of distal phalanges), nasomaxillary hypoplasia; Genetics: ARSL gene, X-linked, Testing Strategy: Sequencing; consider microarray if other findings such as ID and autism (contiguous gene del of Xp including ARSL gene); Of note, teratogens can cause chondrodysplasia punctata phenotype, such as Warfarin and other vitamin K deficiencies

Question 6

CAMPOMELIC DYSPLASIA

Answer 6

Pierre Robin sequence w/ cleft palate, 11 pairs of ribs short bowed legs, clubfeet, ambiguous genitalia; Newborns often pass from repiratory insufficiency related to airway instability (tracheobronchomalacia) or cervical spine instability; Genetics: De novo SOX9 mutation, rarely, chromosome rearrangement

Question 7

ELLIS-VAN CREVELD SYN

Answer 7

Short forearms, lower legs, narrow chest w/short ribs, polydactyly, malformed fingers and toenails (ectodermal features), congenital heart defect, dental abnormalities; Genetics: EVC, EVC2, A recessive, Ancestry: Amish

Question 8

THANATOPHORIC DYSPLASIA

Answer 8

Type 1: Micromelia + bowed femurs vs. Type 2: Micromelia + straight femurs + cloverleaf skull deformity; Genetics: de novo FGFR3; Testing Strategy: If type 2 suspicious&raquo_space; one specific mutation >99% (p.Lys650Glu), if type 1&raquo_space; full sequencing of FGFR3; Advanced Paternal Age has been associated; Ultrasound shows severe rhizomelic shortening, 5th centile by 20 wk GA)

Question 9

HEREDITARY MULTIPLE OSTEOCHONDROMAS

Answer 9

Growths of multiple osteochondromas (benign cartilage capped bone tumors)&raquo_space; can lead to reduction in skeletal growth, shortened stature, characteristic finding is “uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma”; Genetics: EXT1 and EXT2, A Dominant, 90% have an affected parent; Testing Strategy: Sequencing. Clinical dx through xray identifying multiple osteochondromas

Question 10

CLEIDOCRANIAL DYSPLASIA (CCD)

Answer 10

Spectrum disorder: Classic triad&raquo_space; delayed closure of cranial sutures, hypoplastic clavicles, dental abnormalities (delayed tooth eruption) to mild CCD with isolated dental abnormalities, Genetics: High de novo rate of RUNX2 mutations; however if parents negative recurrence 1% due to possible germline mosacism, Testing Strategy: NGS of RUNX2, if DD and other congenita abnormalities, consider karyotype for chromosomal rearrangement

Question 11

DIASTROPHIC DYSPLASIA

Answer 11

Limb shortening, joint contractures, spine abnormalities, hitchhiker’s thumb; Genetics: SLC26A2 gene, A recessive, 4 common mutations make up 65% of cases, one being a Finnish founder mutation

Question 12

METATROPIC DYSPLASIA

Answer 12

A. dominant TRPV4 gene skeletal dysplasias spectrum&raquo_space; metatropic is on severe end: At birth»disporportionately short limbs compared to trunk then in childhood&raquo_space;trunk short compared to limbs (b/c of spine abnormalities), spine abnormalities (platyspondyly), dumbbell shaped long bones; Can be lethal in perinatal period due to narrow chest and lung compromise&raquo_space; infants that survive develop severe kyphoscoliosis which eventually affects lung function

Question 13

SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA (SEDC)

Answer 13

Collagen type 2 spectrum (SEDC in severe moderatly severe “middle” of spectrum) Severe disporportionate short stature/growth deficiency (occurs before birth), spine abnormalities, myopia, hearing loss; Genetics: COL2A1 gene, typically A dominant but A. recessive cases of SEDC have been reported

Question 14

KNIEST DYSPLASIA

Answer 14

Collagen type 2 spectrum (same range of severity as SEDC), Severe disporportionate short stature, High prevalence of eye abnormalities (myopia, retinal detachment, lens subluxation), dumbbell shaped long bones, most severe type 2 collagen disorder resulting in live birth