Table 3.

Genes of Interest in the Differential Diagnosis of MBTPS1-Related Spondyloepimetaphyseal Dysplasia with Elevated Lysosomal Enzymes

GeneDisorderMOISelected Features of Disorder
ClinicalRadiographic
Genetically heterogeneous 1 Silver-Russell syndrome See footnote 1.
  • Growth deficiency
  • Relative macrocephaly
  • Frontal bossing or prominent forehead
  • Body asymmetry
ARSE Chondrodysplasia punctata 1, X-linked XL
  • Brachytelephalangy
  • Nasomaxillary hypoplasia
  • Postnatal short stature
  • Stippled epiphyses
  • Calcifications
  • Vertebral abnormalities
COL2A1 Spondyloepiphyseal dysplasia congenita (SEDC), COL2A1-related (See Type II Collagen Disorders Overview.)AD
(AR) 2
  • Severe disproportionate short stature, short extremities
  • Hypertelorism, flat profile, Pierre Robin sequence
  • Myopia & hearing loss
  • Delayed/poor ossification of vertebrae & pubic bones
  • Short long bones w/hypoplastic epiphyses
  • ↑ risk for cervical instability & spinal cord compression
Spondyloperipheral dysplasia, COL2A1-related (See Type II Collagen Disorders Overview.)AD
  • Mild-to-moderate disproportionate short stature & short extremities
  • Brachydactyly type E, short ulnae, variable clubfeet, cleft palate
  • Myopia & hearing loss
  • Ovoid vertebra
  • Delayed ossification of pubic bones
  • Flattened & irregular epiphyses in long bones
  • Premature hip arthrosis causes joint pain.
Kniest dysplasia, COL2A1-related (See Type II Collagen Disorders Overview.)AD
  • Severe disproportionate short stature, short neck, short thorax, short extremities
  • Myopia, vitreous abnormalities, & retinal detachment
  • Platyspondyly w/anterior wedging & coronal clefting of lumbar vertebral bodies
  • Delayed ossification in distal femoral & proximal tibial epiphyseal ossification centers
  • Short long bones w/large metaphyses & epiphyses
Spondyloepimetaphyseal dysplasia, COL2A1-related (See Type II Collagen Disorders Overview.)ADInfants initially present w/same findings as those w/SEDC.Metaphyseal flaring becomes evident in 1st yr of life.
EBP Chondrodysplasia punctata 2, X-linked XL
  • Growth deficiency
  • Frontal bossing; depressed nasal bridge; sparse eyebrows & lashes, often asymmetric
  • Rhizomelia
  • Scoliosis
  • Abnormalities of skin, hair, & nails; ocular anomaly
Stippling involving epiphyses of long bones & vertebrae, trachea, & distal ends of ribs
GALNS Mucopolysaccharidosis type IVA AR
  • Marked disproportionate short stature w/short trunk
  • Ulnar deviation of wrists
  • Pectus carinatum & flaring of lower rib cage
  • Gibbus, kyphosis, & scoliosis
  • Genu valgum
  • Hypermobile joints
  • Waddling gait w/frequent falls
  • Odontoid hypoplasia w/subsequent cervical instability
  • Short ulnas & delayed bone maturation
  • Short metacarpals
  • Flared iliac wings, flattening of femoral epiphyses, & coxa valga
GLB1 Mucopolysaccharidosis type IVB (MPS IVB) (See GLB1-Related Disorders.)AR
  • Short stature (below 15th centile in adults)
  • Kyphoscoliosis
  • Joint laxity
  • Axial & appendicular dysostosis multiplex
  • Platyspondyly
  • Odontoid hypoplasia
  • Coxa/genu valga
GNPTAB Mucolipidosis II (See GNPTAB-Related Disorders.)ARIn neonatal period:
  • Small to low-normal anthropometric measurements for gestational age
  • Restricted range of passive motion in shoulders
  • Flat face, shallow orbits, depressed nasal bridge
  • Thick skin w/wax-like texture
  • Variable musculoskeletal findings
Note: Activity of multiple lysosomal hydrolases is ↑ in plasma, dried blood, & other body fluids.		Severe dysostosis multiplex
GNPTG Mucolipidosis III gamma AR
  • Growth rate deceleration
  • Joint stiffness of fingers, shoulders, & hips
  • Gradual mild coarsening of facial features
  • Genu valgum
  • Spinal deformities incl scoliosis & hyperlordosis
  • No organomegaly
Note: Activity of nearly all lysosomal hydrolases is up to 10x higher than normal in plasma, dried blood, & other body fluids.
  • Mild-to-moderate dysostosis multiplex
  • Hypoplastic iliac bones w/flared iliac wings
  • Shallow & irregular acetabula & moderate-to-severe dysplasia of proximal femoral epiphyses giving rise to coxa valga
TRAPPC2 X-linked spondyloepiphyseal dysplasia tarda (SED-XL), TRAPPC2-relatedXL
  • Disproportionate short stature in adolescence or adulthood w/short trunk & barrel-shaped chest.
  • Short neck, dorsal kyphosis, scoliosis, & lumbar hyperlordosis may be evident by puberty.
  • Early-onset osteoarthritis
  • Multiple epiphyseal abnormalities
  • Platyspondyly; characteristic superior & inferior "humping" on lateral radiograph
  • Hypoplastic odontoid process
  • Short femoral necks
  • Coxa vara

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; SEDC = spondyloepiphyseal dysplasia congenita; XL = X-linked

1.

Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes Silver-Russell syndrome (SRS) in 35%-50% of individuals; maternal uniparental disomy causes SRS in 7%-10% of individuals. A small number of affected individuals have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, SRS is caused by pathogenic variants in CDKN1C, IGF2, PLAG1, or HMGA2. Accurate assessment of SRS recurrence risk requires identification of the causative genetic mechanism in the proband.

2.

Type II collagen disorders are inherited in an autosomal dominant manner. However, rare instances of autosomal recessive inheritance in spondyloepiphyseal dysplasia congenita have been reported.

From: MBTPS1-Related Spondyloepimetaphyseal Dysplasia with Elevated Lysosomal Enzymes

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