Bone and Soft-Tissue Disorders
= inherited lysosomal storage disorder from deficiency of specific lysosomal enzymes involved in degradation of mucopoly-saccharides (= inability to break down glycosaminoglycan)
Types:
- Type I = Hurler
- Type II = Hunter
- Type III = Sanfilippo
- Type IV = Morquio (most common)
- Type V = Scheie
- Type VI = Maroteaux-Lamy
- Type VII = Sly
◊All autosomal recessive except for Hunter (X-linked)!
Associated with: valvular heart disease
- corneal clouding; elevation of glycosaminoglycan in urine
- mental retardation (prominent in types I, II, III, VII)
- skeletal involvement dominates in types IV and VI
- scaphocephaly, macrocephaly; thick calvarium; hypertelorism
- platyspondyly with kyphosis + dwarfism
- irregularity at anterior aspect of vertebral bodies
- atlantoaxial subluxation + instability ← laxity of transverse ligament / hypoplasia or absence of odontoid
- limb contractures
- broad hands + brachydactyly
- hepatosplenomegaly
- Brain
- brain atrophy
- varying degrees of hydrocephalus
- dilated Virchow-Robin spaces (from accumulation of glycosaminoglycan) resulting in cribriform appearance of white matter, corpus callosum and basal ganglia
- increased SI of white matter surrounding Virchow-Robin spaces on T2WI + FLAIR ← edema, gliosis, de- / dysmyelination
- ± arachnoid cyst ← meningeal glycosaminoglycan deposition
Cx: cord compression at atlantoaxial joint (types IV + VI)
Dx: combination of clinical features, radiographic abnormalities correlated with genetic + biochemical studies
Prenatal Dx: occasionally successful analysis of fibroblasts cultured from amniotic fluid
DDx: Gaucher disease, Niemann-Pick disease
[Gertrud Hurler (1889–1965), pediatrician in München-Neuhausen, Germany]
= GARGOYLISM = PFAUNDLER-HURLER DISEASE = MPS I-H
[Meinhard von Pfaundler (1872–1947), Austrian pediatrician and director of the university children's hospital in München]
= autosomal recessive disease
Cause: homozygous for MPS III gene with excess chondroitin sulfate B ← deficient X-L iduronidase (= Hurler corrective factor)
Prevalence: 1÷10,000 births
Age: usually appears >1st year
- dwarfism; progressive mental deterioration after 1–3 years
- large head; sunken bridge of nose; hypertelorism
- early corneal clouding progressing to blindness
- “gargoyle” features = everted lips + protruding tongue
- teeth widely separated + poorly formed
- progressive narrowing of nasopharyngeal airway
- protuberant abdomen ← dorsolumbar kyphosis + hepatosplenomegaly
- urinary excretion of chondroitin sulfate B (dermatan sulfate) + heparan sulfate
- Reilly bodies (metachromic granules) in white blood cells or bone marrow cells
- Skull (earliest changes >6 months of age)
- frontal bossing
- calvarial thickening
- premature fusion of sagittal + lambdoid sutures
- deepening of optic chiasm
- enlarged J-shaped sella (undermining of anterior clinoid process)
- small facial bones
- wide mandibular angle + underdevelopment of condyles
- communicating hydrocephalus
- Extremities
- thick periosteal cloaking of long-bone diaphyses (early changes)
- swelling / enlargement of diaphyses + cortical thinning (← dilatation of medullary canal) + tapering of either end: distal humerus, radius, ulna, proximal ends of metacarpals
- deossification with heterogeneous bone density + course trabeculation ← deposition of accumulated precursor metabolites in bone marrow
- flexion deformities of knees + hips
- trident hands; clawing (occasionally)
- delayed maturation of irregular carpal bones
- Spine
- thoracolumbar kyphosis with lumbar gibbus
- oval centra with normal / increased height + anterior beak at T12/L1/L2
- long slender pedicles
- proximally long slender ribs at level of neck and wide distally = spatulate rib configuration
- Pelvis
- widely flared iliac wings with inferior tapering
- constriction of iliac bones
- coxa valga
Prognosis: death by age 10–15 years
= KERATOSULFATURIA = MPS IV (most common type)
= autosomal recessive; excess keratosulfate
Prevalence: 1÷40,000 births
Etiology: N-acetyl-galactosamine-6-sulfatase deficiency resulting in defective degradation of keratin sulfate (mainly in cartilage, nucleus pulposus, cornea)
Age: normal at birth; skeletal changes manifest within first 18 months; M÷F = 1÷1
- excessive urinary excretion of keratan sulfate
- normal intelligence; muscular weakness + hypotonia
- ligamentous laxity, but joint stiffness; progressive deafness
- short-trunk dwarfism (<4 feet tall)
- semicrouching stance + knock knees ← flexion deformities of knees + hips
- head thrust forward + sunken between high shoulders
- corneal clouding evident around age 10
- coarse face with short nose, broad mouth, widely spaced teeth with thin enamel
- Skull
- mild dolichocephaly
- hypertelorism
- poor mastoid air cell development
- short nose + depression of bridge of nose
- prominent maxilla
- Chest
- increased AP diameter + marked pectus carinatum (horizontal protuberant sternum)
- slight lordosis with wide short ribs
- bulbous costochondral junctions
- failure of fusion of sternal segments
- Spine
- hypoplasia / absence of odontoid process of C2
- C1-C2 instability with anterior (life-threatening) atlanto-axial subluxation + progressive disabling myelopathy
- thick C2-body with narrowing of vertebral canal
- atlas close to occiput / posterior arch of C1 within foramen magnum
- platyspondyly = universal vertebra plana esp. affecting lumbar spine by age 2–3 years (DDx: normal height in Hurler syndrome)
- ovoid vertebral bodies with central anterior beak / tongue at lower thoracic / upper lumbar vertebrae
- mild gibbus at thoracolumbar transition = low dorsal kyphosis
- exaggerated lumbar lordosis
- widened intervertebral disk spaces
Mucopolysaccharidoses
Type Eponym Inheritance Enzyme Deficiency Urinary Glycosaminoglycan Neurologic Signs I-H Hurler autosomal recessive alpha-L-iduronidase dermatan sulfate marked II Hunter X-linked recessive iduronate sulfatase dermatan / heparan sulfate mild to moderate III Sanfilippo autosomal recessive heparan sulfate mental deterioration A heparan sulfate sulfatase B N-acetyl-alpha-D-glucosaminidase C alpha-glucosamine-N-acetyl-transferase D N-acetylglucosamine-6-sulfate sulfatase IV Morquio autosomal recessive N-acetylgalactosamine-6-sulfate sulfatase keratan sulfate none A–D beta-galactosidase I-S(V) Scheie autosomal recessive alpha-L-iduronidase heparan sulfate none VI Maroteaux-Lamy autosomal recessive arylsulfatase B dermatan sulfate none VII Sly autosomal recessive beta-glucuronidase dermatan / heparan sulfate variable - Pelvis
- “goblet-shaped” / “wineglass” pelvis = constricted iliac bodies + elongated pelvic inlet + broad flat “flared” iliac wings
- oblique hypoplastic acetabular roofs
- Femur
- initially well-formed femoral head epiphysis, then involution + fragmentation by age 3–6 years
- lateral subluxation of femoral heads; later hip dislocation
- wide femoral neck + coxa valga deformity
- Tibia
- delayed ossification of lateral proximal tibial epiphysis
- sloping of superior margin of tibial plateau laterally + severe genu valgum
- Hand & foot
- short bones of forearm with widening of proximal ends
- delayed appearance + irregularity of carpal centers
- small irregular carpal bones
- proximally pointed short metacarpals 2–5
- enlarged joints; hand + foot deformities (flat feet)
- ulnar deviation of hand
Cx: cervical myelopathy (traumatic quadriplegia / leg pains / subtle neurologic abnormality) most common cause of death ← C2 abnormality; frequent respiratory infections (from respiratory paralysis)
Rx: early fusion of C1–C2
Prognosis: may live to adulthood (3rd–4th decade)
DDx:
- Hurler syndrome (normal / increased vertebral height; vertebral beak inferior)
- Spondyloepiphyseal dysplasia (autosomal dominant, present at birth, absent flared ilia / deficient acetabular ossification, small acetabular angle, deficient ossification of pubic bones, varus deformity of femoral neck, minimal involvement of hand + foot, myopia)