Skeletal Dysplasias

• A heterogenous group of disorders that include disorders of Bone Growth (eg, achondroplasia).

Limb Malformations

• Of the digit (suffix: -dactly)
• Of the limbs (suffix: -melia)

BONE GROWTH: REVIEW

Typical long bone in a mature stage of endochondral ossification

• We see the hyaline cartilaginous model (its template) and periosteal bone collar.
  -In the center, we draw the medullary cavity, which forms as the primary ossification center degenerates and remodels. It’s filled with hematopoetic marrow (which comprises red and white blood cell precursors) from vasculature that invades the cavity.
  -Secondary ossification centers lie in the epiphyses.
  -We include the epiphyseal growth plates and specify the direction of growth.

Epiphyseal growth plate zones

• The reserve zone is filled with fetal hyaline cartilaginous cells.
• The proliferative zone is filled with chrondrocytes that proliferate but do NOT hypertrophy.
• The hypertrophic zone is filled with hypertrophic chondrocytes.
• We show the zone of vascular invasion.

BONE REMODELING: REVIEW

Osteoprogenitor cells and Osteoblasts

• We see an osteoprogenitor cell and an osteoblast on a slab of bone matrix (the inorganic component is hydroxyapatite and the organic component is osteoid).
• Members of the (bone morphogenetic protein) BMP family and Transforming growth factor stimulate these cells to become osteoblasts.
• Within a lacuna, lies an osteocyte.
• Vitamin D and Parathyroid hormone (PTH) stimulate osteoblasts to secrete factors that promote osteoclastogenesis – the formation of osteoclasts.
• Osteoblasts produce M-CSF (macrophage colony stimulating factor), which stimulates proliferation of monocytes, which later fuse into multinucleated PREosteoclasts (we’ll see that these nuclei can be as robust as 30 nuclei in a single osteoclast).
• RANKL (an osteoprotegerin ligand) binds to the RANK receptor on the multinucleated osteoclast to stimulate differentiation from pre-osteoclast to osteoclast.
• To regulate osteoclast differentiation, osteoblasts release osteoprotegerin, which binds RANKL and inhibits its binding to the RANK receptor.

Osteoclasts

• Osteoclasts resorb bone.
• They are dome-shaped with a ruffled border, and have a site of active bone resorption, the subosteoclast/Howship lacuna.
• Actin fibers attach the edge of the cell to the bony surface, which forms the sealing (aka clear) zone of the osteoclast.
• Cytoplasm contains:
  -Numerous nuclei.
  -Acidophilic vesicles, which are key to the osteoclasts ability to degrade bone – these vesicles release hydrogen ions into the subosteoclastic zone that can reduce the pH to as low as ~4.5 to solubilize mineralized bone.
• The cytoplasm is also rich in mitochondria.

THE SKELETAL DYSPLASIAS

ACHONDROPLASIA

• This is an ossification anomaly that manifests with short limbs.
• Patients have short stature, pronounced lordosis, and bowed legs.
• This is a more severe form of hypochondroplasia.

Systemic complications

• Obstructive sleep apnea (OSA)
• Recurrent otitis media

Neurologic manifestations

• Macrocephaly
• Spinal stenosis
• Hydrocephalus

Genetics

• Autosomal Dominant (80%) of patients have denovo mutations
• FGRFR3 gene Mutation

Achondrogenesis

• Think Achondroplasia but as a Lethal Skeletal Dysplasia — prenatally morbid or stillbirth.

MARFAN SYNDROME

• Patients have abnormally long bones.

Systemic complications

• Dislocated lens (ectopia lentis)
• Aortic aneurysm and dissection
• Mitral valve prolapse
• Long, narrow face, with crowded teeth
• Scoliosis or kyphosis

Neurologic manifestations

• Dural ectasia
• Spinal stenosis
• Hydrocephalus

Genetics

• Autosomal Dominant
• FBN1 gene
• Fibrillin-1 protein with mycrofibril abnormalities with decreased elasticity

HEREDITARY MULTIPLE OSTEOCHONDROMAS (AKA HEREDITARY MULTIPLE EXOSTOSES)

• Bone tumors (osteochondromas) form at the end of long bones and cause shortening of growth.

Systemic complications

• Transformation from benign tumor to malignancy (sarcoma)

Neurologic manifestations

• Direct nerve pressure

Genetics

• EXT1 and EXT2 gene
• Heparan sulfate is nonfunctional
• Autosomal Dominant

ENCHONDROMATOSIS (AKA OLLIER’S SYNDROME)

• Bone tumors form at the ends of long bones, near the growth plates, thus these patients generally have short stature.

Systemic complications

• Transformation from benign tumor to malignancy (chondrosarcoma)

Genetics

• Somatic (non-heritable)
• IDH1 & IDH2 genes for isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2

POLYOSTOTIC FIBROUS DYSPLASIA

• Fibrous scar tissue develops in bones.

Mccune-Albright Syndrome

A genetic disorder that occurs in females, involves of polyostotic fibrous dysplasia and also multiple endocrinopathies that notably manifest with precocious puberty and café-au-lait spots.

Endocrinopathies in Mccune-Albright Syndrome

• Precocious Puberty
• Hyperthyroidism
• Goiter
• Acromegaly
• Cushing’s syndrome (rare)

Dermatologic Manifestations

• Café-au-lait spots

Genetics

• GNAS gene for guanine nucleotide-binding protein (G-protein)

FIBROUS DYSPLASIA OSSIFICANS (AKA PROGRESSIVE MYOSITIS OSSIFICANS)

• Musculoskeletal structures (muscles, tendons, ligaments) are replaced with bone (ossified). * This extra-skeletal ossification causes immobility, manifesting with difficulty even opening one’s mouth to eat or ability to breath.

Genetics

• AVCR1 gene for BMP type 1 receptor
• Autosomal Dominant

HEREDITARY HYPOPHOSPHATEMIC RICKETS

• Patients suffer from a bowing of bones due to chronic hypophosphatemia (in adults, this causes osteomalacia – bone softening).

Pathophysiology

• Hypophosphatemia

Genetics

• PHEX gene
• Most common: X-linked dominant

OSTEOPETROSIS

• Bones are abnormally dense (thick).

Systemic complications

• Anemia
• Hepatosplenomegaly
• Immunodeficiency

Neurologic manifestations

• Cranial neuropathies

OSTEOPOIKILOSIS

• Bones are spotted with round areas of increased bone density.

OSTEOGENESIS IMPERFECTA

• Bones are abnormally fragile: fractures occur commonly.
• Mild forms of the disease are associated with blue-appearing sclera.
• Severe forms are lethal just after birth due to inability to adequately breathe.

Genetics

• COL1A1 and COL1A2 genes (mostly)
• Autosomal Dominant (mostly)

EHLERS-DANLOS

• Causes hypermobile joints.

Systemic complications

• Hypermobile joints
• Elastic skin
• Kyphoscoliosis
• Respiratory changes from severe scoliotic abnormalities

Genetics

• Autosomal recessive

CLEIDOCRANIAL DYSPLASIA

• Manifests with abnormalities in the clavicles and skull [delayed closure of the fontanelles], most notably (hence its name).
• These bones develop from intramembranous ossification, thus we can remember the disorder as one of pathologic intramembranous ossification.

Bony abnormalities

• Clavicles
• Skull
• Teeth

Genetics

• RUNX2 gene
• Autosomal Dominant

Additional notable causes of skeletal dysplasia include:

Neurofibromatosis

Storage Disorders: Gaucher Disease and the Mucopolysaccharidoses.

LIMB AND DIGIT DEVELOPMENT

• The upper limb bud forms at ~ day 24, followed shortly thereafter by the lower limb bud (at ~ day 28).
• The limb bud comprises a core of mesenchyme, surrounded by ectoderm.
• The AER (apical ectodermal ridge) forms a thickening at the distal end of the limb bud.
• The distal upper limb bud forms a digital plate, distally (for the fingers) and a carpal plate (for the hand). Then, via programmed cell death, digital rays form.

COMMON LIMB DISORDERS: TERMINOLOGY

• Amelia is absence of a limb.
• Meromelia is absence of a part of a limb.

DIGIT DISORDERS

• Syndactyly is webbing (fusion) of digits.
• Polydactyly is presence of extra digits.
• Brachydactyly is shortening of digits.

Known Teratogens that cause limb and digit malformations, include

Pharmaceuticals

• Valproate
• Phenytoin
• Warfarin

Toxins

• Cocaine
• Alcohol (fetal alcohol syndrome)

Metabolic conditions

• Hyperglycemia (gestational diabetes)

Infections

• Varicella Zoster