Roberts syndrome (SC phocomelia)

AR; ESCO2 (establishment of sister chromatid cohesion N-acetyltransferase 2). Roberts syndrome is a cohesinopathy: ESCO2 acetylates the SMC3 subunit of the cohesin complex during S phase, an essential step for sister chromatid cohesion. Loss of function → cohesin fails to hold sister chromatids together properly → the cytogenetic hallmark of premature centromere separation (PCS) and heterochromatin repulsion.

The historical clinical split, "Roberts syndrome" (severe) vs. "SC phocomelia" (milder), turned out to be allelic: both are caused by biallelic ESCO2 variants, with severity correlating with residual function.

• Limb anomalies (hallmark):
  • Symmetric reduction defects, often tetraphocomelia (severe shortening or absence of long bones in all four limbs)
  • Severity is variable, from mild bilateral radial defects to all four limbs absent
  • Upper limbs more severely affected than lower limbs
  • Oligodactyly, syndactyly, ectrodactyly
• Craniofacial:
  • Cleft lip ± palate (often bilateral)
  • Midfacial capillary hemangioma
  • Micrognathia, microcephaly
  • Hypertelorism, downslanting palpebral fissures, widely spaced exophthalmic eyes
  • Sparse silvery-blond hair
• Growth: severe pre- and postnatal growth retardation
• Neurodevelopmental: intellectual disability is common but variable; correlates with severity
• Cardiac, renal, genital anomalies in subset
• Diagnostic cytogenetic finding: PCS / heterochromatin "puffing" on metaphase preparations, best seen at centromeres and on the Y chromosome long arm

• Cytogenetic test for PCS: pathognomonic; standard karyotype with Giemsa staining shows the railroad-track centromeres and puffed heterochromatin. Always order this when Roberts is suspected
• ESCO2 sequencing (and del/dup analysis) confirms
• Prenatal: severe limb defects on ultrasound + parents known to be carriers → fetal molecular testing on CVS

• Supportive and multidisciplinary; no disease-specific therapy
• Orthopedic and prosthetic/rehabilitative care for limb reduction defects to maximize function
• Surgical repair of cleft lip and palate; feeding support in infancy
• Evaluate and manage associated cardiac, renal, and genital anomalies; developmental support and surveillance

• Thalidomide embryopathy: phenocopy with phocomelia; obtain medication history
• Cornelia de Lange syndrome: different cohesinopathy (NIPBL, SMC1A, SMC3, RAD21, HDAC8); shares limb anomalies and growth restriction but no PCS on karyotype
• TAR syndrome (thrombocytopenia-absent radius): bilateral radial aplasia with thumbs present, plus thrombocytopenia
• Holt-Oram syndrome: radial-ray + cardiac, AD (TBX5); see holt-oram-syndrome
• Fanconi anemia: radial-ray defects, growth restriction, marrow failure; chromosome breakage with mitomycin C/DEB

• AR; recurrence risk 25% per pregnancy for known carrier couples
• Prenatal molecular diagnosis available; severity prediction limited
• Founder ESCO2 variants exist in some populations