Chromosome Abnormalities in Two Patients with Features of Autosomal Dominant Robinow Syndrome

ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1790–1795 (2007) Research Letter Chromosome Abnormalities in Two Patients With Features of Autosomal Dominant Robinow Syndrome Juliana F. Mazzeu,1 Ana Cristina Krepischi-Santos,1 Carla Rosenberg,1 Karoly Szuhai,2 Jeroen Knijnenburg,2 Janneke M.M. Weiss,3 Irina Kerkis,1 Zan Mustacchi,4 Guilherme Colin,5 Roˆmulo Mombach,6 Rita de Ca´ssia M. Pavanello,1 Paulo A. Otto,1 and Angela M. Vianna-Morgante1* 1Centro de Estudos do Genoma Humano, Departamento de Gene´tica e Biologia Evolutiva, Instituto de Biocieˆncias, Universidade de Saõ Paulo, Saõ Paulo, Brazil 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands 3Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands 4Hospital Infantil Darcy Vargas, Saõ Paulo, Brazil 5Departamento de Gene´tica Me´dica, Univille, Joinville, Brazil 6Centrinho Prefeito Luiz Gomes, Secretaria Municipal de Sau´de, Joinville, Brazil Received 13 April 2006; Accepted 13 December 2006 How to cite this article: Mazzeu JF, Krepischi-Santos AC, Rosenberg C, Szuhai K, Knijnenburg J, Weiss JMM, Kerkis I, Mustacchi Z, Colin G, Mombach R, Pavanello RM, Otto PA, Vianna-Morgante AM. 2007. Chromosome abnormalities in two patients with features of autosomal dominant Robinow syndrome. Am J Med Genet Part A 143A:1790–1795. To the Editor: Patient 1 Robinow syndrome [OMIM 180700] is characteriz- At age 3 4/12 years the girl was diagnosed as ed by fetal facies, mesomelic dwarfism, and hypo- affected by DRS (Fig. 1A). Detailed clinical examina- plastic genitalia. An autosomal recessive (RRS) and tion at age 9 4/12 years showed short stature (117 cm; an autosomal dominant form (DRS) of the syndrome <3rd centile), frontal bossing, hypertelorism (ICD: have been described, the former presenting with 4.0 cm > 97th centile, OCD: 11.5 cm > 97th centile), more severe skeletal anomalies. The gene mutated in down-slanted palpebral fissures, facial nevus, stra- RRS has been identified as ROR2 at 9q22 [Afzal et al., bismus, short nose with mildly anteverted nares, 2000; Van Bokhoven et al., 2000], and encodes a depressed nasal bridge, long philtrum, microretrog- tyrosine–kinase receptor involved in cell growth and nathia, large downturned mouth with thin upper lips, differentiation. The gene associated with DRS has not highly arched palate, and posteriorly rotated ears. been identified. We describe two unrelated patients Her teeth were hypoplastic and malaligned. She had with clinical pictures of DRS and chromosome pectus excavatum. Both hands showed a single 1 abnormalities. In one patient, a duplication of palmar crease and fifth finger clinodactyly. Webbing chromosome 1p [46,XX,dir dup(1)(p13p31)] was of the first and second toes was present bilaterally. identified by G-banding, and the breakpoints were Radiographs showed rhizomesomelic dysplasia; no mapped by fluorescent in situ hybridization (FISH). vertebral anomalies were observed. Examination of In the other patient, array–CGH analysis revealed a the genitalia showed hypoplastic labia majora and microdeletion of chromosome 1q (1q41 ! q42.1). The finding of different chromosome rearrangements in DRS patients points to genetic hetero- geneity in the phenotype, and genes mapped to rearranged segments appear as candidates for the Grant sponsor: FAPESP, CAPES, CNPq. syndrome. *Correspondence to: Angela M. Vianna-Morgante, Departamento de This study has been approved by the institutional Gene´tica e Biologia Evolutiva, Instituto de Biocieˆncias, Universidade de Saõ Paulo; C.P.11461; 05422-970-Saõ Paulo, SP, Brazil. ethics committee, and the families provided written E-mail: [email protected] informed consent. DOI 10.1002/ajmg.a.31661 American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ROBINOW SYNDROME 1791 showing that the maternally inherited chromosome had the duplicated segment (data not shown). Both parents had normal chromosomes. Probes cloned in YACs (CEPH, Paris) and BACs (CHORI, Oakland) mapping to the short arm of chromosome 1 (The GDB Human Genome Database (GDB), www.gdb.org; and National Center for Biotechnol- ogy Information (NCBI), www.ncbi.nih.gov) were used to delimit the duplicated segment and map the breakpoints by FISH (Fig. 2A). Conditions for probe hybridization and detection were as previously described [Rosenberg et al., 1994]. Double- FIG.1. A: Patient 1 at age 3 4/12 years; B: Patient 2 at age 6 months. color hybridization confirmed that the duplication was direct (Fig. 2D). BAC RP11-585M16 contained the distal breakpoint at 1p31.1 (Fig. 2C), and the minora, but normal sized clitoris. The patient was partially overlapping BACs RP11-155D24 and RP11- developmentally delayed and could not speak. She 140L8 contained the proximal breakpoint at 1p13.3 sat at 7 months of age and walked at 4 8/12 years. (Fig. 2B). Audiometry was normal. There were recurrent ear To determine the parental origin of the duplicated infections. Bone length measures on radiographs segment, genotyping of six microssatelite loci at age 9 4/12 years confirmed the presence of (D1S2792, D1S2778, D1S248, D1S1623, D1S1163, rhizomesomelic upper limb shortening, as revealed D1S406) mapped to the duplicated segment was by ratios radius/humerus (0.72 at left, 0.71 at right; performed by standard radioactive (32P) PCR, using 5th centile, indicating preponderant mesomelic the patient’s and their parent’s genomic DNA shortening), radius/tibia (0.58 at both sides; <5th extracted from peripheral blood lymphocytes. centile, indicating upper limb shortening), and tibia/ Primer sequences were obtained from GDB. The femur (0.90 at left, 0.84 at right; 50th–95th centile, patient was heterozygous for four loci mapped indicating no marked length difference between the within the duplicated segment (D1S2778, D1S248, two lower limb segments). D1S1623, D1S1163), but three different alleles were Chromosome analysis after G-banding, in peri- not identified in any of these loci. We performed pheral blood lymphocytes, showed a direct inter- dosage analysis for loci D1S1623, D1S1163 based on stitial duplication of the short arm of chromosome the ratios of band optical densities (OD) in auto- 1,46,XX,dir dup(1)(p13p31). C-banding showed an radiograms [Antonini et al., 2002] in the patient and increased polymorphic pericentromeric heterochro- her mother. The maternally inherited alleles were the matic region on the duplicated chromosome 1. This more amplified ones, thus pointing to the maternal variant was also present in the patient’s mother origin of the duplicated segment (data not shown). FIG.2. Patient 1—Breakpoint mapping of 1p duplication by FISH: A: YAC (left) and BAC (right) clones hybridized. White boxes: nonduplicated clones; black boxes: duplicated clones; gray boxes: breakpoint-containing clones; B: At the proximal breakpoint, BAC RP11-155D24 mapped to 1p13.3 was duplicated, but the distal signal was less intense; C: at the distal breakpoint, BAC RP11-585M16 mapped to 1p31.1, also duplicated, produced a diminished proximal signal. D: Demonstration of the direct nature of the duplication by double-color hybridization of YACs 881f6 (green) and 963f5 (red). American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 1792 MAZZEU ET AL. Patient 2 We compared the clinical findings between Patient 1 and 4 previously described carriers of similar 1p At birth the boy’s length was 48 cm (< 10th centile) duplications [Mohammed et al., 1989; Hoechstetter and weight, 3780 g (75th centile). At clinical examina- et al., 1995; Dhellemmes et al., 1998; Garcia-Heras tion at age 2 years he presented with delayed et al., 1999]. The localization of breakpoints was neuropsychomotor development, generalized hypo- based on G-banding, and therefore different break- tonia, and hemiparesis at right. He had short stature points might be involved in these rearrangements. (84 cm, 3rd centile), coarse facies, midface hypopla- None of the literature cases had a clinical picture sia, hypertelorism (ICD: 3.1 mm; OCD: 9.4 mm both > suggestive of DRS, although some DRS signs were 98th centile), upslanted palpebral fissures, long eye- present in most of them, such as hypertelorism (DRS- lashes, blue sclerae, convergent strabismus, wide flat 100%), brachydactyly (DRS-81%), clinodactyly (DRS- nasal bridge, bulbous nose with anteverted nares, 70%), and micrognathia (DRS-56.7%). The only male long well marked philtrum, triangular mouth, down- patient had cryptorchidism (DRS-71.6%), and one slanted mouth corners, thin upper lip, cleft palate, patient [Dhellemmes et al., 1998] had rhizomelic gum hyperplasia, micrognathia, thick ear lobes with shortening (DRS-35.4%), also present in our patient hyperfolded helix, and short neck (Fig. 1B). Examina- [frequencies in DRS according to Mazzeu et al. tion of the genitalia showed micropenis and right (2007)]. cryptorchidism. Upper arms presented with mesome- All previous reports of deletions of chromosome 1q lic shortening with limited elbow supination. Hands encompassing 1q41 and/or 1q42 were based on G- showed metacarpal shortening, wide thumbs, and banding analysis without precise mapping of break- nail dysplasia. He had congenital club foot, large first points, and are much larger than that described in toes, and widely spaced first and second toes. He had Patient 2; therefore, their precise overlapping with skin laxity and well marked palmar and plantar the deletion in our patient could not be established creases. Ophthalmologic examination revealed [Andrle et al., 1978; Kessel et al., 1978; Molina et al., hypermetropia, glaucoma, nystagmus, and alternat- 1978; Dignan and Soukup, 1979; Neu et al., 1982; ing strabismus. An ECG performed at 9 months of age Turleau et al., 1983; Beemer et al., 1985; Johnson revealed reflux of tricuspid valve and thickening of et al., 1985; Al-Awadi et al., 1986; Tolkendorf et al., pulmonary valve. X-rays documented enlarged 1989]. The most common signs observed in the femoral epiphysis, a higher distance between femoral described patients were low birth weight, delayed heads and iliac bones, and kyphosis.

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