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 Rômulo Mombach,6 Rita de Cássia M. Pavanello,1
Paulo A. Otto,1 and Angela M. Vianna-Morgante1*
1
Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências,
Universidade de São Paulo, São Paulo, Brazil
2
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
3
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
4
Hospital Infantil Darcy Vargas, São Paulo, Brazil
5
Departamento de Genética Médica, Univille, Joinville, Brazil
6
Centrinho Prefeito Luiz Gomes, Secretaria Municipal de Saúde, 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 characterized by fetal facies, mesomelic dwarfism, and hypoplastic genitalia. An autosomal recessive (RRS) and
an autosomal dominant form (DRS) of the syndrome
have been described, the former presenting with
more severe skeletal anomalies. The gene mutated in
RRS has been identified as ROR2 at 9q22 [Afzal et al.,
2000; Van Bokhoven et al., 2000], and encodes a
tyrosine–kinase receptor involved in cell growth and
differentiation. The gene associated with DRS has not
been identified. We describe two unrelated patients
with clinical pictures of DRS and chromosome
1 abnormalities. In one patient, a duplication of
chromosome 1p [46,XX,dir dup(1)(p13p31)] was
identified by G-banding, and the breakpoints were
mapped by fluorescent in situ hybridization (FISH).
In the other patient, array–CGH analysis revealed a
microdeletion of chromosome 1q (1q41 ! q42.1).
The finding of different chromosome rearrangements in DRS patients points to genetic heterogeneity in the phenotype, and genes mapped to
rearranged segments appear as candidates for the
syndrome.
This study has been approved by the institutional
ethics committee, and the families provided written
informed consent.
At age 3 4/12 years the girl was diagnosed as
affected by DRS (Fig. 1A). Detailed clinical examination at age 9 4/12 years showed short stature (117 cm;
<3rd centile), frontal bossing, hypertelorism (ICD:
4.0 cm > 97th centile, OCD: 11.5 cm > 97th centile),
down-slanted palpebral fissures, facial nevus, strabismus, short nose with mildly anteverted nares,
depressed nasal bridge, long philtrum, microretrognathia, large downturned mouth with thin upper lips,
highly arched palate, and posteriorly rotated ears.
Her teeth were hypoplastic and malaligned. She had
pectus excavatum. Both hands showed a single
palmar crease and fifth finger clinodactyly. Webbing
of the first and second toes was present bilaterally.
Radiographs showed rhizomesomelic dysplasia; no
vertebral anomalies were observed. Examination of
the genitalia showed hypoplastic labia majora and
Grant sponsor: FAPESP, CAPES, CNPq.
*Correspondence to: Angela M. Vianna-Morgante, Departamento de
Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de
São Paulo; C.P.11461; 05422-970-São Paulo, SP, Brazil.
E-mail: [email protected]
DOI 10.1002/ajmg.a.31661
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
ROBINOW SYNDROME
FIG. 1. A: Patient 1 at age 3 4/12 years; B: Patient 2 at age 6 months.
minora, but normal sized clitoris. The patient was
developmentally delayed and could not speak. She
sat at 7 months of age and walked at 4 8/12 years.
Audiometry was normal. There were recurrent ear
infections. Bone length measures on radiographs
at age 9 4/12 years confirmed the presence of
rhizomesomelic upper limb shortening, as revealed
by ratios radius/humerus (0.72 at left, 0.71 at right;
5th centile, indicating preponderant mesomelic
shortening), radius/tibia (0.58 at both sides; <5th
centile, indicating upper limb shortening), and tibia/
femur (0.90 at left, 0.84 at right; 50th–95th centile,
indicating no marked length difference between the
two lower limb segments).
Chromosome analysis after G-banding, in peripheral blood lymphocytes, showed a direct interstitial duplication of the short arm of chromosome
1,46,XX,dir dup(1)(p13p31). C-banding showed an
increased polymorphic pericentromeric heterochromatic region on the duplicated chromosome 1. This
variant was also present in the patient’s mother
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 Biotechnology 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]. Doublecolor hybridization confirmed that the duplication
was direct (Fig. 2D). BAC RP11-585M16 contained
the distal breakpoint at 1p31.1 (Fig. 2C), and the
partially overlapping BACs RP11-155D24 and RP11140L8 contained the proximal breakpoint at 1p13.3
(Fig. 2B).
To determine the parental origin of the duplicated
segment, genotyping of six microssatelite loci
(D1S2792, D1S2778, D1S248, D1S1623, D1S1163,
D1S406) mapped to the duplicated segment was
performed by standard radioactive (32P) PCR, using
the patient’s and their parent’s genomic DNA
extracted from peripheral blood lymphocytes.
Primer sequences were obtained from GDB. The
patient was heterozygous for four loci mapped
within the duplicated segment (D1S2778, D1S248,
D1S1623, D1S1163), but three different alleles were
not identified in any of these loci. We performed
dosage analysis for loci D1S1623, D1S1163 based on
the ratios of band optical densities (OD) in autoradiograms [Antonini et al., 2002] in the patient and
her mother. The maternally inherited alleles were the
more amplified ones, thus pointing to the maternal
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
At birth the boy’s length was 48 cm (< 10th centile)
and weight, 3780 g (75th centile). At clinical examination at age 2 years he presented with delayed
neuropsychomotor development, generalized hypotonia, and hemiparesis at right. He had short stature
(84 cm, 3rd centile), coarse facies, midface hypoplasia, hypertelorism (ICD: 3.1 mm; OCD: 9.4 mm both >
98th centile), upslanted palpebral fissures, long eyelashes, blue sclerae, convergent strabismus, wide flat
nasal bridge, bulbous nose with anteverted nares,
long well marked philtrum, triangular mouth, downslanted mouth corners, thin upper lip, cleft palate,
gum hyperplasia, micrognathia, thick ear lobes with
hyperfolded helix, and short neck (Fig. 1B). Examination of the genitalia showed micropenis and right
cryptorchidism. Upper arms presented with mesomelic shortening with limited elbow supination. Hands
showed metacarpal shortening, wide thumbs, and
nail dysplasia. He had congenital club foot, large first
toes, and widely spaced first and second toes. He had
skin laxity and well marked palmar and plantar
creases. Ophthalmologic examination revealed
hypermetropia, glaucoma, nystagmus, and alternating strabismus. An ECG performed at 9 months of age
revealed reflux of tricuspid valve and thickening of
pulmonary valve. X-rays documented enlarged
femoral epiphysis, a higher distance between femoral
heads and iliac bones, and kyphosis. Brain MRI
showed left-brain hemiatrophy with cortical dysplasia, and possible frontal microgyria at right.
The presence of glaucoma (that may represent a
manifestation of an anterior eye-chamber anomaly),
short stature, and developmental delay raised the
possibility of the child having the Peters Plus
syndrome, which has recently been associated with
mutations in the B3GALTL gene [Lesnik et al., 2006].
The sequencing of exon 8, the described hotspot
for the causative mutations, and exon 5, in which
a pathogenic mutation has also been identified,
revealed no pathogenic mutations.
No chromosome abnormalities were identified
after G-banding. Array–CGH analysis was performed using DNA from peripheral blood lymphocytes, as previously described Rosenberg et al. [2006].
The slides containing triplicates of 3,500 large
insert clones spaced at 1.0 Mb density over the full
genome were produced at the Leiden University
Medical Center. Information regarding the full set of
clones is available at the Wellcome Trust Sanger
Institute mapping database site, Ensembl [http://
www.ensembl.org/]. Probes RP11-308113 (1q41),
RP11-239e10 (1q41-q42.1), and RP11-105I12
(1q42.1) were found to be deleted (Fig. 3A). We
confirmed the deletion by FISH of corresponding
probes (Fig. 3B) to patient metaphases. Neither
parent carried the deletion as shown by FISH (data
not shown).
We compared the clinical findings between Patient
1 and 4 previously described carriers of similar 1p
duplications [Mohammed et al., 1989; Hoechstetter
et al., 1995; Dhellemmes et al., 1998; Garcia-Heras
et al., 1999]. The localization of breakpoints was
based on G-banding, and therefore different breakpoints might be involved in these rearrangements.
None of the literature cases had a clinical picture
suggestive of DRS, although some DRS signs were
present in most of them, such as hypertelorism (DRS100%), brachydactyly (DRS-81%), clinodactyly (DRS70%), and micrognathia (DRS-56.7%). The only male
patient had cryptorchidism (DRS-71.6%), and one
patient [Dhellemmes et al., 1998] had rhizomelic
shortening (DRS-35.4%), also present in our patient
[frequencies in DRS according to Mazzeu et al.
(2007)].
All previous reports of deletions of chromosome 1q
encompassing 1q41 and/or 1q42 were based on Gbanding analysis without precise mapping of breakpoints, and are much larger than that described in
Patient 2; therefore, their precise overlapping with
the deletion in our patient could not be established
[Andrle et al., 1978; Kessel et al., 1978; Molina et al.,
1978; Dignan and Soukup, 1979; Neu et al., 1982;
Turleau et al., 1983; Beemer et al., 1985; Johnson
et al., 1985; Al-Awadi et al., 1986; Tolkendorf et al.,
1989]. The most common signs observed in the
described patients were low birth weight, delayed
neuropsychomotor development/ mental retardation, short stature, microcephaly, slanted palpebral
fissures, epicanthal folds, hypertelorism, short and
wide nose, long and smooth philtrum, downturned
mouth corners, and microretrognatia. Heart problems were observed in 4/11 cases. Our patient did
not present with low birth weight, microcephaly,
epicanthal folds, or smooth philtrum. However, he
had gum hyperplasia, mesomelic limb shortening,
nail dysplasia, clubfoot, hypermetropia, brain hemiatrophy, and cortical dysplasia, clinical signs not
described previously in association with chromosome 1q41 and/or 1q42 deletions. The patient
reported by Johnson et al. [1985] had skin laxity
and deep palmar and plantar creases also present in
our patient.
It is noteworthy that both patients here described
present with clinical signs frequent in autosomal DRS
(Table I). Patient 1 presents with 18 out of 21
pertinent signs present in more than 50% of DRS
patients, and Patient 2, 19 out of 22 signs. These
findings are suggestive of candidate regions for the
syndrome on chromosome 1.
Chromosome abnormalities have been previously
described in two girls with the diagnosis of Robinow
syndrome. In one girl, a deletion of chromosome 7,
del(7)(q32qter), was detected [Wang et al., 1997].
The other patient carried a chromosome 1p deletion,
del(1)(p22p32) [Sivasankaran et al., 1997]. Clinical
signs of Robinow syndrome are not typically found in
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
ROBINOW SYNDROME
1793
FIG. 3. Patient 2—A: Array–CGH profile of chromosome 1 shows deletion of clones RP11-308I13, RP11-239E10, and RP11-105I12 (red spots); the position of the
deletion is depicted on chromosome 1 idiogram. Underneath, enlargement of the deleted segment, including clones and genes. B: FISH of clone RP11-239E10
confirming the chromosome 1 deletion (arrow). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
patients with similar 1p [Mircher et al., 2003] or 7q
deletions [Verma et al., 1992]. The 1p duplication
here described and the deletion present in the RS
patient of Sivasankaran et al. [1997] include common
segments, thus pointing to a candidate region for
the syndrome on the short arm of chromosome 1. A
gene damaged by the duplication breakpoint could
be deleted in the other case. Alternatively, overexpression could occur due to gene duplication or
otherwise, to the deregulation of genes outside the
deleted segment. Approximately 140 known genes
map within the 34 Mb duplicated segment in
Patient 1 (NCBI). We looked for candidate genes for
DRS on 1p based on their location, function, and
similarity to genes known to be mutated in syndromes sharing clinical signs with RS. BAC RP11585M16, which contains the distal breakpoint, spans
gene TNNI3K. Although this gene may be disrupted
by the duplication breakpoint, TNNI3K is a kinase
expressed specifically in cardiac myocytes [Zhao
et al., 2003], and therefore does not appear as a
candidate for DRS. The proximal breakpoint, contained in partially overlapped BACs RP11-140L8 and
RP11-155D24, do not span any known gene. Another
candidate gene is VAV3 mapped at 1p13, within the
duplicated segment in our patient. VAV3 belongs to a
family of GEFs for Rho GTPases, acting on the actin
cytoskeleton rearrangement [Hornstein et al., 2004].
It is a protein functionally similar to FGD1, and
FGD1 gene mutations cause Aarskog syndrome, a
condition with several clinical signs in common with
RS. A third candidate gene on 1p is ROR1, which
codes for a member of the ROR family of tyrosine–
kinase receptors, sharing 58% identity with ROR2
protein. Mutations in ROR2 cause recessive Robinow
syndrome [Afzal et al., 2000; Van Bokhoven et al.
2000]. ROR1 maps to 1p31.3 and, although deleted in
the patient of Sivasankaran et al. [1997], it is not
duplicated in our patient, mapping approximately
10 Mb from the distal breakpoint. A positional effect
or the disruption of a long-distance regulatory region
should be considered in this case [Fritz et al., 2005;
Milot et al., 1996]. Studies in mice show that Ror1 and
Ror2 associate to different cytoskeletal structures,
Ror1 co-localizing with F actin and Ror2 with
microtubules [Paganoni et al., 2004]. Therefore, it is
reasonable to consider that dominant Robinow
syndrome may be caused by mutations in genes,
like ROR1 and VAV3, both involved in cytoskeletal
arrangement.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
1794
MAZZEU ET AL.
TABLE I. Clinical Signs Present in More than 50% of the Patients
With Autosomal Dominant Robinow Syndrome (DRS)* and Their
Presence in the Patients Herein Described
Clinical signs
Hypertelorism
Wide nasal bridge
Anteverted nares
Upturned nose
Micropenis
Short stature
Short nose
Brachydactyly
Midface hypoplasia
Mesomelic limb shortening
Prominent forehead
Depressed nasal bridge
Cryptorchidism
Clinodactyly
Triangular mouth
Long philtrum
Macrocephaly
Down-slanted mouth corners
Short hands
Micrognathia
Long eyelashes
Highly arched palate
Hypoplastic labia minora
Frequency
in DRS (%)*
Patient 1
Patient 2
100
100
100
86.7
84.1
81.2
81.2
81
80.6
80.1
79
77.9
71.6
70
64.9
64.7
64.2
62.9
61.5
56.7
54
51.5
50.4
þ
þ
þ
þ
Female
þ
þ
þ
þ
þ
þ
Female
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
Male
*Mazzeu et al. [2007]; (þ) present; () absent.
On the other hand, Patient 2 presented with a
deletion of chromosome 1q. Eight known genes,
which play essential roles during development, map
to the 5 Mb interval delimited by the two closest
BACs flanking the deletion (RP11-529d17 and RP11100e13): DUSP10 (dual specificity protein phosphatase 10), TAF1a (TBP-associated factor 1a), DISP1
(dispatched 1), CAPN2 (calpain 2, larger subunit),
TP53BP2 (tumor protein p53 binding protein 2), NVL
(nuclear valosin-containing protein-like), WDR26
(WD repeat domain 26), and DEGS1 (degenerative
spermatocyte homolog 1). These genes appear as
candidates for our patients’ phenotype and may be
considered as candidates for DRS.
The finding of different chromosome rearrangements in association with DRS points to genetic
heterogeneity in the syndrome.
ACKNOWLEDGMENTS
We thank Mrs. Dalva Marques and Mrs. Ligia S.
Vieira for technical assistance, and Maurı́cio S.
Galizia, MD and Luiz Antonio Nunes de Oliveira,
MD for radiograph analysis.
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