Multiple synostoses syndrome

Multiple synostoses syndrome (SYNS), proximal symphalangism (SYM), tarsal-carpal coalition (TCC) syndrome, stapes ankylosis with broad thumbs and toes (SABTT), and brachydactyly B2 (BDB2) are overlapping autosomal dominant conditions united by typically displaying ankylosis of the proximal interphalangeal (PIP) joints, and carpal and tarsal bones

Pathology

They all typically display ankylosis of the PIP joints, carpal and tarsal bones. More specifically:

  • SYM displays variable fusion of the PIP joints and occasionally metacarpophalangeal joints
  • SYNS is distinguished from SYM by more severe joint involvement which may include the hips and vertebrae; affected individuals may have characteristic facial features and at times conductive hearing loss
  • TCC has a focus on carpal and tarsal fusion in addition to brachydactyly, varus/valgus foot anomalies
  • SABTT is known for its broad thumbs and toes in addition to conductive hearing loss
  • brachydactyly is as the name describes
Genetics

Mutations in specific genes have been found to be responsible for more than one syndrome type. For example, different mutations within the NOGGIN locus can result in all five overlapping syndromes 1 and the same specific mutations in NOGGIN, in different families, has resulted in the separate diagnoses of SYM1, SABTT and BDB2 1, and TCC and SYM 2. Similarly an allele of GDF5 results in both SYNS and BDA1 in different families 3. This has led to the suggestion, that these syndromes are part of a spectrum with variable penetrance 1,4.

Whilst these syndromes overlap with respect to causative genes, four SYNS subtypes have been described. Each SYNS subtype is associated with a specific genetic mutation. This may suggest that the above described syndromes (SYNS, SYM, TCC, SABTT and BDB2) could be better classified as variable penetrance of the four subtypes of SYNS.

All four subtypes of SYNS have variable carpal and tarsal fusion 5. In addition, all multiple synostoses syndromes with the exception of SYN4 display symphalangism in the hands and humeroradial synostoses. Other differentiating features include 5:

  • SYNS1
    • hands and feet: brachydactyly
    • elbow: elbow joint dysplasia
    • spine: cervical vertebral fusions
    • hearing: early conductive hearing loss
    • facial: long face, broad tubular nose, short philtrum, thin upper vermilion, strabismus
    • other: pectus carinatum
  • SYNS2
    • hands and feet: brachydactyly
    • spine: vertebral fusions
    • facial: broad hemicylindrical nose
  • SYNS3
    • elbow: semidislocation or cubital valgus
    • spine: lumbar vertebral fusions
  • SYNS4
    •  feet: Symphalangism
    •  hearing: late onset (after 40 years) conductive hearing loss

The four genes and the various mutations relating to the SYNS subtypes are listed below.

  • SYNS1
    • NOGGIN
    • NOGGIN W205C 6
    • NOGGIN W217G 7
    • NOGGIN g58delC (Frameshift) 8
    • NOGGIN C232W 9
  • SYNS2
    • GDF5
    • GDF5 (R438L) 10
      • initially described as representing SYNS1 10 but the phenotype is more suggestive of SYNS2 and has thus been categorised as an SYNS2 phenotype mutation 3,6
    • GDF5 (N445K, N445T) 11
      • initially described as representing SYNS1 11 but the phenotype is more suggestive of SYNS2 and has thus been categorised as an SYNS2 phenotype mutation ref required
    • GDF5 (W414R) 3
  • SYNS3
    • FGF9
    • FGF9 (S99N) 12
  • SYNS4
    • GDF6
    • GDF6 (Y444N) 5

Additionally, some patients with features of SYNS additionally have craniosynostosis13. Unfortunately, the genetic mutation(s) in these patients were not characterised.

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Article information

rID: 50073
Section: Pathology
Tag: cases
Synonyms or Alternate Spellings:
  • Proximal symphalangism (SYM)
  • Tarsal-carpal coalition (TCC) syndrome
  • Stapes ankylosis with broad thumbs and toes (SABTT)
  • Brachydactyly B2 (BDB2)

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    Case 1: multiple synostoses syndrome
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