What are the signs, symptoms, and diagnosis of Roberts syndrome?

Roberts Syndrome: Clinical Features and Diagnosis

Roberts syndrome (RBS) is a rare autosomal recessive disorder characterized by tetraphocomelia (symmetric limb reduction defects), distinctive craniofacial anomalies, pre- and postnatal growth retardation, and intellectual disability, diagnosed through clinical recognition of these cardinal features combined with characteristic cytogenetic findings of premature centromere separation and confirmed by molecular testing for ESCO2 gene mutations. 1, 2

Cardinal Clinical Features

Limb Abnormalities

• Symmetric reduction defects are the hallmark, with upper limbs typically more severely affected than lower limbs 3, 1
• Upper limb involvement ranges from thumb and radial defects to complete phocomelia (absence of long bones with hands attached directly to trunk) 3, 1
• Lower limb defects primarily involve absent or severely hypoplastic fibula 3
• Oligodactyly (reduced number of digits) is common, with symmetric presentation 1
• Flexion contractures of various joints may be present 2

Craniofacial Malformations

• Hypertelorism (widely spaced eyes) is a consistent finding 1
• Hypoplastic nasal alae (underdeveloped nasal wings) 1
• High incidence of cleft lip and/or cleft palate 1
• Prominent eyes with underdeveloped supraorbital ridges 1
• Micrognathia (small jaw) and low-set, posteriorly rotated ears 1
• Glabellar nevus flammeus (capillary malformation on forehead) may be present 1

Growth and Development

• Severe pre- and postnatal growth retardation is universal 1, 2
• Intellectual disability ranges from mild learning difficulties to severe mental retardation 1, 2
• Microcephaly is frequently observed 1

Additional Systemic Involvement

• Cardiac malformations occur and can be major 2
• Renal abnormalities may be present 2
• Complex cerebrovascular diseases including leukoencephalopathy, calcifications, cysts, and aneurysms have been reported 4
• Risk of ischemic stroke and cerebellar hemorrhage in adolescence 4

Diagnostic Approach

Clinical Recognition

• Suspect RBS in any infant presenting with symmetric limb reduction defects combined with characteristic facial features 1
• Assess severity of limb involvement: upper limbs (thumb/radius to phocomelia) and lower limbs (fibular hypoplasia/absence) 3
• Document specific craniofacial features: hypertelorism, hypoplastic alae nasi, cleft lip/palate 1
• Measure growth parameters: pre- and postnatal growth retardation is consistent 1

Cytogenetic Studies

• Karyotype analysis reveals premature centromere separation (PCS), also called heterochromatin repulsion or "puffing" - this is pathognomonic for RBS 1, 2
• PCS is most prominent in chromosomes 1,9,16, and the acrocentric chromosomes 1
• DAPI staining demonstrates heterochromatin repulsion consistently 3
• Metaphase cells show prolonged metaphase duration and abnormal anaphase progression 1
• Increased frequency of lagging chromosomes, micronucleation, and abnormal nuclear morphology 1
• Note: Obligate heterozygote parents show normal cytogenetic findings 3

Molecular Genetic Testing

• Whole exome sequencing (WES) or targeted ESCO2 gene sequencing confirms the diagnosis 4, 2
• ESCO2 gene is located at chromosome 8p21.1 2
• Look for biallelic mutations (compound heterozygous or homozygous) 4
• ESCO2 encodes a protein essential for establishing sister chromatid cohesion during S phase 2

Neuroimaging (When Indicated)

• Brain MRI may reveal leukoencephalopathy, calcifications, and cysts (characteristic triad) 4
• Cerebrovascular imaging should be considered given risk of aneurysms and stroke 4
• Histopathology may show angiomatous changes and perivascular cysts suggesting chronic small vessel disease 4

Severity Assessment

Apply the Roberts Syndrome Rating system to quantitate severity and guide prognosis 1:

• Rate limb reduction defects (upper and lower extremities separately)
• Assess craniofacial malformation severity
• Document growth retardation degree
• Evaluate intellectual disability level
• Note presence of cardiac, renal, or other organ involvement

Phenotypic Spectrum and Prognosis

• RBS exists on a severity spectrum, with SC phocomelia representing the milder end 2
• Severely affected infants may be stillborn or die in the postnatal period 2
• Patients surviving infancy can reach adulthood and benefit from corrective surgeries 5, 2
• Phenotypic variability occurs both within families and between different families 3
• Adults with milder presentations may have normal or near-normal limbs, mild facial anomalies, and only mild learning difficulties 2

Genetic Counseling Considerations

• Autosomal recessive inheritance pattern 1, 2
• 25% recurrence risk for subsequent pregnancies in carrier couples 1
• Consanguinity increases risk - high frequency reported in Egyptian populations 3
• Molecular diagnosis is essential for accurate prenatal diagnosis in future pregnancies 3
• Prenatal diagnosis should be performed by genetics healthcare professionals 3

Common Diagnostic Pitfalls

• Do not dismiss RBS based on less severe limb involvement - the spectrum ranges from mild to severe 2
• Facial features may fade over time in survivors, making diagnosis more challenging in older children and adults 2
• Normal cytogenetics in parents does not rule out RBS in offspring 3
• Phenotypic overlap with other limb reduction syndromes requires molecular confirmation 1