Table 5.

Other Genes of Interest in the Differential Diagnosis of Thanatophoric Dysplasia

Gene(s)DisorderMOIFeatures of Differential Diagnosis Disorder
Overlapping w/TDDistinguishing from TD
CFAP410
CEP120
DYNC2H1
DYNC2I1
DYNC2I2
DYNC2LI1
IFT52
IFT80
IFT81
IFT122
IFT140
IFT172
KIAA0586
KIAA0753
NEK1
TRAF3IP1
TCTEX1D2
TTC21B
WDR19
WDR35 		Skeletal ciliopathies: incl perinatal lethal short-rib polydactyly syndromes & Jeune asphyxiating thoracic dystrophy (See OMIM PS208500.)AR
Digenic 1
  • May be lethal in perinatal period or infancy
  • Narrow thorax & short ribs; short stature & short limbs noted in infancy (But survivors may manifest only mild-to-moderate short stature.)
  • Polydactyly & wide variety of multisystem features common; may involve cardiac, renal, liver, pancreatic, intestinal, genital, retinal, & ectodermal tissues 2
  • Improvement in respiratory status occurs in some survivors w/skeletal ciliopathies, & persons may manifest only mild-to-moderate short stature.
COL1A1
COL1A2 		Perinatally lethal osteogenesis imperfecta 3 (previously OI type II) (See COL1A1/2-OI.)AD
  • Typically lethal in perinatal period
  • Markedly shortened & bowed long bones; severe short stature
  • Absence of severe micromelia; craniosynostosis; small iliac bones, narrow sacroiliac notch, & platyspondyly; bowing more significant than in TD
  • Note: TD is not assoc w/undermineralization, fractures, wormian bones, dentinogenesis imperfecta, or dark blue sclera.
COL2A1
SLC26A2
TRIP11 		Achondrogenesis (ACG) type IA, type IB, & type II (OMIM PS200600)AR
AD
  • Typically lethal in perinatal period
  • Short stature w/micromelia, relative macrocephaly, short ribs, & brachydactyly
  • Minimal or absent ossification of vertebral bodies, iliac, & ischial bones in ACG
  • Rib fractures in type II ACG
  • Distinctive facial features, short neck w/excess soft tissue
COL2A1 Platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T) 4 (OMIM 151210)AD
  • Typically lethal in perinatal period
  • Short long bones w/ragged metaphyses, platyspondyly, & short ribs
  • Bowed radius/tibia may be present.
  • PLSD-T can be differentiated histologically by presence of dilated loops of endoplasmic reticulum in chondrocytes.
FGFR3 Homozygous achondroplasiaCodominantSee Allelic Disorders.See Allelic Disorders.
SADDANAD
GPX4 Spondylometaphyseal dysplasia, Sedaghatian type (OMIM 250220)AR
  • Typically lethal in perinatal period
  • Short long bones, metaphyseal abnormalities, cupped ribs, platyspondyly, brachydactyly
  • Cerebral ventriculomegaly, other CNS abnormalities
  • Irregular ("lacy") ossifications in iliac wings & calcaneus
  • Disproportionately long fibulae
  • Cardiac anomalies incl structural congenital heart disease
HSPG2 Dyssegmental dysplasia, Silverman-Handmaker type (OMIM 224410)AR
  • Typically lethal in perinatal period
  • Narrow thorax, short stature, bowed limbs
  • Spine anisospondyly is present.
  • Cleft palate & encephalocele may be present.
INPPL1 Opsismodysplasia (OMIM 258480)AR
  • May be lethal in perinatal period
  • Short long bones, platyspondyly, relative macrocephaly, small chest
Delayed bone maturation & poor bone quality
PAM16 Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type (OMIM 613320)AR
  • May be lethal in perinatal period
  • Short limbed short stature, narrow chest w/short ribs, narrowed cervical canal, platyspondyly
  • Frontal bossing, depressed nasal bridge
  • Developmental delay
  • Hearing impairment
  • Absence of epiphyseal ossification of the knees
  • Square iliac bones
  • Horizontal acetabulae w/medial & lateral spurs
  • Hypoplastic ischia
PEX7 Classic rhizomelic chondrodysplasia punctata type 1 (RCDP1)AR
  • Most affected children do not survive 1st decade of life; a proportion die in the neonatal period.
  • Rhizomelia, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities, coronal cleft or notch of vertebral bodies
  • Brain malformations
  • Punctate epiphyseal dysplasia evident as stippled epiphyses on radiography; coronal vertebral clefts may be present.
  • Rhizomelia prominent (compared to micromelia in TD)
  • Birth weight, length, & head circumference often at lower range of normal
  • Cataracts usually present at birth or in 1st few mos of life
SLC35D1 Schneckenbecken dysplasia (OMIM 269250)AR
  • Typically lethal in perinatal period
  • Short-limbed short stature
  • Platyspondyly
  • Hypoplastic iliac bones w/characteristic appearance resembling a snail
  • Broad long bones
  • Precocious ossification of the tarsus
  • Hydrops
SOX9 Campomelic dysplasia (CD)AD
  • Typically lethal in perinatal period
  • Variable stature (short to normal), w/short limbs & narrow thorax
  • Profound hypoplasia of the body of the scapulae (compared to globally small scapulae in TD)
  • Tibial & femoral bowing (w/longer femurs compared to TD)
  • Tubular bones are poorly developed & show immature ossification, w/nonossification of thoracic pedicles.
  • Many have 11 pairs of ribs.
  • Skin dimples are often present.
  • ≤75% of persons w/CD w/a 46,XY karyotype have either female external genitalia or ambiguous genitalia.

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; TD = thanatophoric dysplasia

1.

Biallelic inheritance of pathogenic variants in DYNC2H1 and NEK1 has been reported (see OMIM 613091).

2.
3.

Clinically, osteogenesis imperfecta (OI) was classified into four types; the type most reminiscent of TD is OI type II (perinatally lethal OI).

4.

The Luton type is considered to be a mild form of the Torrance type [Nishimura et al 2004].

From: Thanatophoric Dysplasia

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