Abstract
Baller-Gerold (BGS, MIM#218600) and Roberts (RBS, MIM#268300) syndromes are rare autosomal recessive disorders caused, respectively, by biallelic alterations in RECQL4 (MIM*603780) and ESCO2 (MIM*609353) genes. Common features are severe growth retardation, limbs shortening and craniofacial abnormalities which may include craniosynostosis. We aimed at unveiling the genetic lesions underpinning the phenotype of two unrelated children with a presumptive BGS diagnosis: patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus. Patient 2 is an Iranian girl born to consanguineous parents with craniosynostosis, micrognathism, bilateral radial aplasia, thumbs, and foot deformity in the context of developmental delay. Upon negative RECQL4 test, whole exome sequencing (WES) analysis performed on the two trios led to the identification of two different ESCO2 homozygous inactivating variants: a previously described c.1131+1G>A transition in patient 1 and an unreported deletion, c.417del, in patient 2, thus turning the diagnosis into Roberts syndrome. The occurrence of a Baller-Gerold phenotype in two unrelated patients that were ultimately diagnosed with RBS demonstrates the strength of WES in redefining the nosological landscape of rare congenital malformation syndromes, a premise to yield optimized patients management and family counseling.
Highlights
Baller-Gerold syndrome (BGS, OMIM#218600) [1] and Roberts syndrome (RBS, OMIM#268300) [2] are two rare autosomal recessive congenital disorders with clinical overlap and a broad phenotypic variability.The major clinical findings of BGS involve the skeleton: all patients display craniosynostosis of any or all cranial sutures and pre-axial upper limb defects, mainly hypoplasia/aplasia of radii, ulnae, and/or thumbs and malformation or absence of some carpal and metacarpal bones
4 out of 5 BGS patients, who could be evaluated, present with poikiloderma, a chronic cutaneous alteration manifesting in the first years of life in most of the RECQL4-mutated patients [4, 10, 11]
We describe two affected patients of two unrelated families (1 and 2) with a syndromic phenotype suggestive of BGS referred to our laboratory by clinical geneticists and pediatricians
Summary
Baller-Gerold syndrome (BGS, OMIM#218600) [1] and Roberts syndrome (RBS, OMIM#268300) [2] are two rare autosomal recessive congenital disorders with clinical overlap and a broad phenotypic variability. Facial dysmorphisms included low anterior and posterior hairlines, arched eyebrows, telecanthus, epicanthal folds, eye proptosis, left exotropia, cutaneous hemangioma on the frontal region expanding to the nose which is small and flared, a short philtrum, wide mouth with downturned corners and high-arched palate (Figure 1B) Her upper limbs were extremely short, thumbs. Proband 2 is a 2-year-old Iranian girl born to consanguineous parents, presenting with a malformation syndrome comprising craniosynostosis, bilateral radial ray hypoplasia and absent thumbs (Figures 1N,O,R). A large frontal hemangioma and craniofacial dysmorphisms including large alae nasi, small nose with deep nasal bridge, arched palate, micrognathia, simple ears, and short neck were observed since birth (Figures 1O–Q) She had bilateral hypoplastic radius, oligodactyly, and knee joints stiffness. C-banding chromosome analysis of patient 1 showed the premature centromere separation and heterochromatin repulsion known to be pathognomonic for RBS (Figure 1M)
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