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Case Reports
. 2019 May 28:7:210.
doi: 10.3389/fped.2019.00210. eCollection 2019.

Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations

Elisa Adele Colombo  1 , Hatice Mutlu-Albayrak  2 , Yousef Shafeghati  3 , Mine Balasar  4 , Juliette Piard  5 , Davide Gentilini  6   7 , Anna Maria Di Blasio  6 , Cristina Gervasini  1 , Lionel Van Maldergem  5 , Lidia Larizza  8
Affiliations
Case Reports

Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations

VSports注册入口 - Elisa Adele Colombo et al. Front Pediatr. .

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 VSports手机版. 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. .

Keywords: Baller-Gerold syndrome; ESCO2; RECQL4; Roberts syndrome; differential diagnosis; genetic counseling; patient management V体育安卓版. .

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Figures

Figure 1
Figure 1
Clinical and molecular features of patients 1 and 2. (A) Pedigree of family 1: the arrow indicates the proband. (B) Face of patient 1 at 12 years showing arched eyebrows, telecanthus, epicanthal folds, hemangioma on the frontal region, small and flared nose, short philtrum, and a wide mouth with downturned corners. (C) Forearm aplasia, manus varus deformity, and thumb aplasia. (D) Close-up of the left leg showing short cruris, flexion deformity on knees, and pes equinovarus. (E) Overall photo of patient 1 showing dysmorphisms of the face and malformations of arms and legs. (F) Coronal cross-sectional areas obtained with cranial MR T2 showing asymmetric colpocephalic expansion of lateral ventricles occipital horns. (G,H) X-rays images of arms showing bilaterally aplasia of radius, ulna and thumb, hypoplasia of middle phalanx, fusion of 4–5 metacarpals and carpal bones. (I) Sagittal cross-sectional areas obtained with cranial MR T2 showing partial corpus callosum agenesis. (J,K) X-rays images of the legs evidencing bilaterally fibular aplasia, femoral-tibial synostosis, fusion of tarsal bones, short and bowed tibias. (L) Chromatograms of ESCO2 sequence around c.1131+1G>A in intron 6 of the affected girl (top) and her obligate carriers parents (middle and bottom). Fex6 (5′-gaggaccaggatttgagtgtt-3′) and Rex6 (5′-accacctacaactcccattct-3′) primers were used to amplify this region. (M) C-banded metaphase spread showing premature centromere separation with puffing at the centromere and heterochromatic regions (arrowed). (N) Pedigree of family 2 with RBS-affected patient arrowed. (O) Photograph of patient 2, showing forearm aplasia, varus deformity of hands, thumb aplasia, extended capillary malformation, and sparse hair. Magnifications showing the protruding cupped ear (P) and the short nose with underdeveloped alae nasi and narrow and sharp nasal ridge (Q). (R) Coronal craniosynostosis and brachycephaly profile view of head X-rays. (S) Chromatograms of ESCO2 sequence around c.417del alteration in exon 3 in the affected girl (top) and her obligate carriers parents. The exon 3-specific amplicons were obtained using primers Fex3 (5′-gcaaatcaaggctcacca-3′) and Rex3 (5′-ttttggctcagaacccga-3′).
Figure 2
Figure 2
ESCO2 pathogenic alterations. Schematic diagram of full-length ESCO2 gene: exons are depicted as boxes while introns as thin bars. Exons encoding the acetyltransferase domain are in dark gray. The two mutations carried by the patients herein described are over the gene schematic while all the 32 known pathogenic alterations found in RBS-SC Phocomelia patients are listed below. The only 3 “non-inactivating” mutations (2 missense mutations and a three-nucleotide deletion) are bolded. The horizontal dashed lines indicate intronic mutations leading to miss-splicing.
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