Skeletal disorders Notes

NOTES NOTES SKELETAL DYSPLASIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Disorders affecting bone development CAUSES ▪ Inherited/sporadic (de novo) genetic mutation COMPLICATIONS ▪ Caused by bone malformations, depend upon affected bones SIGNS & SYMPTOMS ▪ Commonly involve growth impairment, bone malformation DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan/MRI ▪ Bone malformation, impaired ossification visualization ▪ Bone-age estimation Ultrasound ▪ Prenatal diagnosis TREATMENT SURGERY ▪ Bone malformation correction if warranted/ desired ACHONDROPLASIA osms.it/achondroplasia PATHOLOGY & CAUSES ▪ Genetic disorder, causes dwarfism with disproportionate short stature ▪ Relatively normal-sized torso, short limbs, normal–large head (macrocephaly) with prominent forehead (hence “disproportionate dwarfism”) ▪ Average height ▫ Biologically-male: 131cm/4’4’’ ▫ Biologically-female: 123 cm/4’ 692 OSMOSIS.ORG CAUSES ▪ Heterozygous “gain-of-function” mutation in fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4; individuals with homozygous mutation usually do not survive ▫ Mutated receptor displays “constitutive activity” (activated in ligand binding absence) → inhibits chondrocyte proliferation ▫ Endochondral ossification affected → inhibits long bone elongation (e.g. humerus, femur)

Chapter 118 Skeletal Dysplasia ▫ Intramembranous ossification less affected → relatively normal flat bone growth (e.g. skull, ribs) ▪ Autosomal dominant inheritance pattern (20%); sporadic mutation in most cases (80%) COMPLICATIONS ▪ Eustachian tube narrowing → recurrent middle ear infection ▪ Narrowing of ▫ Lumbar spinal canal → spinal stenosis ▫ Foramen magnum → cervical medullary compression ▪ Venous obstruction at sigmoid sinus → hydrocephalus ▪ Midface retrusion → obstructive sleep apnea ▪ Obesity ▪ Small flat squared iliac wings (“mickey mouse ear”) ▪ Fibular overgrowth ▪ Metaphyseal flaring: diaphysis narrowing, metaphysis widening LAB RESULTS ▪ DNA test ▫ FGFR3 mutation-positive TREATMENT SURGERY ▪ Bone malformation correction warranted/ desired SIGNS & SYMPTOMS ▪ Long bone malformations ▫ Rhizomelic (proximal) limb shortening ▫ Varus/valgus leg malformations ▫ Short metacarpals ▫ Short phalanges (brachydactyly) ▫ Trident hand (fingertips cannot touch) ▪ Flat bone malformations (less common) ▫ Enlarged head ▫ Frontal bossing (prominent forehead) ▫ Flattened nasal bridge (saddle nose malformation) ▫ Narrow foramen magnum ▫ Spinal kyphosis/lordosis DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Skull width to femur length ratio higher than normal Figure 118.1 An X-ray image of the knee of an individual with achondroplasia. There is flaring of the distal femoral metaphysis typical of the disease. X-ray/MRI/CT scan ▪ Large skull with small skull base ▪ Narrow foramen magnum, spinal canal ▪ Short, flattened vertebral bodies OSMOSIS.ORG 693

CLEIDOCRANIAL DYSPLASIA osms.it/cleidocranial-dysplasia PATHOLOGY & CAUSES ▪ AKA cleidocranial dysostosis ▪ Skeletal dysplasia ▫ Predominantly affects intramembranous ossification-derived bone development ▫ Clavicles (cleido-), skull bones (-cranial) ▪ Abnormal teeth development, delayed cranial fontanelle closure, clavicle underdevelopment/absence, distinctive craniofacial features CAUSES ▪ Heterozygous runt-related transcription factor 2 (RUNX2) gene mutation (transcription factor involved in osteoblast, chondrocytes differentiation → delayed ossification; 30% of cases are idiopathic) ▪ Autosomal dominant inheritance pattern, can be sporadic COMPLICATIONS ▪ Osteoporosis (adults) SIGNS & SYMPTOMS ▪ Dental abnormalities ▫ Supernumerary teeth (up to 13), delayed/failed permanent teeth eruption, abnormal deciduous dentition ▪ Delayed cranial fontanelle closure → soft skull areas ▪ Short stature ▪ Hypoplastic/aplastic clavicles → shoulder hypermobility ▪ Maxilla, mandibular prognathism hypoplasia ▪ Midface hypoplasia, flattened nasal bridge ▪ Frontal/parietal bossing ▪ Abnormal ear ossicles → hearing loss 694 OSMOSIS.ORG Figure 118.2 Retained deciduous teeth in the mouth of an individual with cleidocranial dysplasia. DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Hypoplastic/aplastic clavicles ▪ Widened fontanelles ▪ Wormian bones (multiple small bones between sutures) ▪ Frontal/parietal bossing ▪ Supernumerary teeth ▪ Supernumerary ribs ▪ Iliac bone hypoplasia ▪ Symphysis pubis widening (diastasis) ▪ Small, highly positioned scapulas LAB RESULTS ▪ Genetic testing (confirmation) TREATMENT SURGERY ▪ Bone malformation correction if warranted/ desired

Chapter 118 Skeletal Dysplasia Figure 118.3 A chest radiograph of a neonate with absent clavicles, consistent with a diagnosis of cleidocranial dysplasia. Figure 118.4 An X-ray image of the skull of a child with cleidocranial dysplasia. There is bitemporal bossing and a widened frontal fontanelle. The posterior lambdoid suture (not visible) contains multiple wormian bones. OSMOSIS.ORG 695