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Roberts syndrome (RBS) is characterized by pre- and postnatal growth retardation, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit. SC phocomelia is a milder form of RBS.
ORPHA:3103Classification level: Disorder
The prevalence and incidence are not known. Less than 150 cases have been described in the literature.
Upper limbs are more frequently and severely affected than lower limbs. The defect is mostly mesomelic with the radius being the most affected in the upper limbs, and the fibula in the lower limbs. The most severe defects result in phocomelia. Aplastic or hypoplastic thumbs, oligodactyly, clinodactyly or syndactyly can also occur. Craniofacial anomalies include microcephaly (more severe in males than in females), hypoplastic nasal alae, malar hypoplasia, hypertelorism, micrognathia, capillary hemangioma, exophthalmos, downslanting palpebral fissures, dysplastic or small ears, cloudy cornea or cataracts, and cleft lip and palate. There is a correlation between the degree of limb and facial malformations. Other malformations such as congenital heart defects, cystic kidney and large genitalia (enlarged phallus or clitoris), may occur. Severe intellectual deficit is observed in patients surviving the newborn period.
The disease is caused by mutations in the ESCO2 gene (8p21.1), which encodes a protein belonging to the Eco1/Ctf7 family of acetyltransferases, involved in the establishment of sister chromatid cohesion during S phase. ESCO2 mutations lead to delayed cell division, increased cell death and impaired cell proliferation. The loss of progenitor cells during embryogenesis is likely responsible for the developmental defects observed in RBS.
The diagnosis is based on clinical features and karyotyping (with a characteristic ``railroad track'' appearance of chromosomes due to repulsion of heterochromatic regions and premature centromere separation). Direct sequencing of the ESCO2 gene can confirm the diagnosis.
Differential diagnoses include thalidomide embryopathy, and the Baller-Gerold, Cornelia de Lange and TAR syndromes (see these terms).
When a previous child in the family is diagnosed with RBS and carries ESCO2 mutations, prenatal diagnosis can be performed through DNA analysis of chorionic villus samples. Otherwise, RBS may be suspected by observation of characteristic RBS anomalies at ultrasonography and can be confirmed by karyotyping.
The mode of transmission is autosomal recessive.
Management and treatment
Management includes surgical correction of facial malformations, surgical and/or orthopedic treatment of limb defects and management of the cognitive disabilities.
Prognosis is relatively unfavorable. High mortality in the newborn period or early childhood is due to cardiac or renal malformations.