PMC6546804_01
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').
fped-07-00210-g0001.jpg
PMC6546804_03_fped-07-00210-g0001.jpg
F1
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). Sanger sequencing confirmed the biallelic pathogenic alterations in the probands and the carrier status of their parents (Figures 1L,S) and of the elder brother of patient 1. Moreover, C-banding chromosome analysis of patient 1 showed the premature centromere separation and heterochromatin repulsion known to be pathognomonic for RBS (Figure 1M).
PMC6546804_02
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').
fped-07-00210-g0001.jpg
PMC6546804_03_fped-07-00210-g0001.jpg
F1
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). Sanger sequencing confirmed the biallelic pathogenic alterations in the probands and the carrier status of their parents (Figures 1L,S) and of the elder brother of patient 1. Moreover, C-banding chromosome analysis of patient 1 showed the premature centromere separation and heterochromatin repulsion known to be pathognomonic for RBS (Figure 1M).
PMC6546804_03
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').
fped-07-00210-g0001.jpg
PMC6546804_03_fped-07-00210-g0001.jpg
F1
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). Sanger sequencing confirmed the biallelic pathogenic alterations in the probands and the carrier status of their parents (Figures 1L,S) and of the elder brother of patient 1. Moreover, C-banding chromosome analysis of patient 1 showed the premature centromere separation and heterochromatin repulsion known to be pathognomonic for RBS (Figure 1M).