DOI:10.2214/AJR.07.3619
AJR 2008; 191:W62-W66
© American Roentgen Ray Society
Radiographic Abnormalities in Rothmund-Thomson Syndrome and Genotype–Phenotype Correlation with RECQL4 Mutation Status
Amy R. Mehollin-Ray1,
Claudia A. Kozinetz2,
Alan E. Schlesinger1,
R. Paul Guillerman1 and
Lisa L. Wang3
1 Department of Radiology, Baylor College of Medicine, The Edward B. Singleton
Department of Diagnostic Imaging, Texas Children's Hospital, Houston,
TX.
2 Department of Pediatrics, Baylor College of Medicine, Houston, TX.
3 Texas Children's Cancer Center, Department of Pediatrics, Baylor College of
Medicine, 6621 Fannin St., MC 3-3320, Houston, TX 77030.
Received January 6, 2008;
accepted after revision February 20, 2008.
Supported by National Institutes of Health grant NICHD NIH-K08HD42136, a
Doris Duke Charitable Foundation Clinical Scientist Development Award,
National Institutes of Health grant NIH-RR000188-42 (BCM–General
Clinical Research Center), National Institutes of Health grant NIH-HD024064
(BCM–Mental Retardation Developmental Disabilities Research Center,
Tissue Culture Core), the Curtis Hankamer Basic Research Fund, The Bone
Disease Program of Texas Rolanette, and a Berdon Lawrence Bone Research
Award.
Address correspondence to L. L. Wang
(llwang{at}bcm.edu).
WEB
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Abstract
OBJECTIVE. The purpose of this study was to summarize the
radiographic skeletal findings in patients with Rothmund-Thomson syndrome
(RTS) and to determine whether there is an association between the presence of
skeletal abnormalities and the mutational status of the RECQL4
gene.
SUBJECTS AND METHODS. Twenty-eight subjects with RTS underwent
skeletal surveys and RECQL4 DNA mutation testing. Radiographs were
reviewed by two radiologists. RECQL4 mutation testing by DNA
sequencing of the gene was performed by a diagnostic laboratory.
Genotype–phenotype analysis by Fisher's exact test was performed to
investigate whether there was a correlation between mutation status and
skeletal abnormalities.
RESULTS. Twenty-one (75%) of the subjects had at least one
significant skeletal abnormality, the more common being abnormal metaphyseal
trabeculation, brachymesophalangy, thumb aplasia or hypoplasia, osteopenia,
dislocation of the radial head, radial aplasia or hypoplasia, and patellar
ossification defects. Three subjects had a history of destructive bone lesion
(osteosarcoma). Genotype–phenotype analysis showed a significant
correlation between RECQL4 mutational status and the presence of
skeletal abnormalities (p < 0.0001).
CONCLUSION. Skeletal abnormalities are frequent in persons with RTS.
Many of these abnormalities are not clinically apparent but are detectable on
radiographs. The presence of skeletal abnormalities correlates with
RECQL4 mutation status, which has been found to correlate with risk
of osteosarcoma. Skeletal surveys aid in both diagnosis and management of
RTS.
Keywords: bone abnormality • RECQL4 mutation • Rothmund-Thomson syndrome • skeletal dysplasia
Introduction
Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder with
heterogeneous clinical features, including a characteristic rash
(poikiloderma), small stature, sparse hair, juvenile cataracts, skeletal
abnormalities including radial ray defects, and a predisposition to
osteosarcoma, a malignant tumor originating in bone
[1]. Rothmund
[2] described patients who had
a rash and juvenile cataracts, but unlike those patients, the patients
described by Thomson [3] had
osseous abnormalities, including bilateral thumb aplasia and hypoplastic radii
and ulnae. Subsequent case reports of RTS mentioned variable skeletal
abnormalities.
In a review of the world literature by Vennos et al.
[4] in 1992, 68% of patients
were found to have skeletal abnormalities, including frontal bossing, saddle
nose, small hands and feet, and long-bone abnormalities, including radial ray
defects. Later publications focused on the occurrence of osteosarcoma in RTS
patients
[5–9].
Most of these case reports described clinically overt skeletal abnormalities
but did not thoroughly discuss the entire skeletal system. In a review
[1] of the cases of 41 patients
with RTS, 75% of the 20 patients who underwent radiographic skeletal surveys
were found to have had skeletal abnormalities, whereas only 20% had skeletal
abnormalities appreciable at clinical examination alone. Limitations of that
study were that the skeletal surveys were performed at various institutions
and interpreted by different radiologists and that the analysis was based on
the official diagnostic imaging report, which may or may not have been issued
by a radiologist familiar with RTS.
Mutation of the RECQL4 gene was discovered as a cause of RTS in
1998 [10]. Since then it has
been shown that approximately two thirds of RTS patients have mutations in
RECQL4 [11]. The
presence of mutations correlates significantly with the development of
osteosarcoma. The exact function of the RECQL4 protein, particularly in
relation to skeletal development, is not currently understood, but the protein
is believed to be important in maintaining genomic stability and may play a
role in initiation of replication
[12].
Because RTS is rare and the radiologic skeletal findings have not been
clearly delineated, radiologists encountering radiographs of RTS patients
often rely on textbook descriptions based on early case reports. These
descriptions, however, may not accurately reflect the true spectrum of
radiologic findings in RTS. We undertook this study to define the spectrum and
prevalence of skeletal abnormalities in RTS by performing consistent skeletal
surveys at one institution and to determine whether these abnormalities are
associated with RECQL4 mutations. This study is, to our knowledge,
the largest and most comprehensive study of the skeletal abnormalities of RTS
patients. The data may help clinicians who are diagnosing and managing RTS.
Results of the genotype–phenotype analysis may provide information to
support a role of RECQL4 in bone development and lead to future
laboratory investigations.
Subjects and Methods
Twenty-eight persons with a clinical diagnosis of RTS were enrolled in a
study approved by the institutional review board at our institution. Written
informed consent was obtained, and all subjects underwent history interviews,
physical examinations, and skeletal surveys at our institution. All skeletal
surveys were reviewed independently by two radiologists. All subjects
underwent RECQL4 mutation testing through the medical genetics
laboratory at our institution. This testing involved a polymerase chain
reaction–based assay to amplify 6.5 kb of the genomic region of the
RECQL4 gene. Direct sequencing analysis of polymerase chain reaction
products corresponding to the entire RECQL4 genomic sequence was
performed in both the forward and reverse directions with automated
fluorescence dideoxy sequencing methods. Genotype–phenotype analysis was
performed with Fisher's exact test to determine whether the presence of
deleterious mutations correlated with the presence of skeletal
abnormalities.
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Fig. 1 —18-month-old girl with Rothmund-Thomson syndrome. Radiograph
shows aplasia of right thumb (arrow). Brachymesophalangy of second
and fifth fingers with associated clinodactyly also is present.
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Results
Skeletal Survey Results
We identified 11 major radiologic skeletal findings in 21 (75%) of the
subjects (Table 1). The more
common findings were abnormal metaphyseal trabeculation (64%),
brachymesophalangy (64%), first metacarpal or thumb agenesis or hypoplasia
(43%), osteopenia (25%), radial head dislocation (21%), radial agenesis or
hypoplasia (21%), radioulnar synostosis (18%), and ulnar hypoplasia or bowing
(18%). Examples of some of these findings are shown in Figures
1,
2, and
3. Other radiographic findings
encountered in the general population as normal variants, such as butterfly
vertebrae, rib anomalies, and genu valgum, were not included in this analysis.
In our cohort, only one subject had a single butterfly vertebra, one subject
had 13 rib pairs, and none had genu valgum. Also not included were findings
that could not be fully assessed with skeletal surveys; these findings
included scoliosis, frontal bossing, and patellar aplasia.
Two of the most striking skeletal features identified that have not to our
knowledge been systematically reported in RTS were brachymesophalangy
(Fig. 4) and an abnormal
metaphyseal trabecular pattern consisting of accentuated transverse and
longitudinal striations (Figs.
5A and
5B). In most (14 of 18) of the
cases of brachymesophalangy, patients had bilaterally symmetric
brachymesophalangy of the second and fifth fingers. In one case, the middle
phalanges of all digits were affected; in two cases, only both fifth middle
phalanges were affected; and in one case, only the right fifth middle phalanx
was affected.
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Fig. 4 —9-month-old boy with Rothmund-Thomson syndrome. Radiograph
shows brachymesophalangy of second and fifth fingers and associated
clinodactyly (arrows). Hypoplasia of radius, first metacarpal, and
first proximal phalanx also is present.
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Seven subjects had patellar findings that included hypoplasia or aplasia
and multicentric ossification. Many of the subjects, however, were too young
for evaluation of patellar ossification, and most of the subjects did not have
lateral patellar images as part of the skeletal survey for full assessment of
patellar development. None of the patellar findings was present in the absence
of other major skeletal defects. Therefore, patellar abnormalities were not
included in our table of major findings. Other findings that have been
described in RTS, such as phalangeal tuft resorption, flattened and elongated
vertebrae, soft-tissue calcifications, and knee subluxation
[13], were not detected among
the subjects in our cohort.
RECQL4 Mutation Screening and Genotype–Phenotype Correlation
Deleterious mutations were detected in the RECQL4 genes of 18
(64%) of the 28 subjects (Table
1). These mutations included frameshift, nonsense, deletion, and
splice site mutations that have been predicted to result in a truncated or
absent protein as previously described
[11] (data not shown).
Subjects received a score of 0 if they had none of the major skeletal findings
and 1 if they had any of these findings. Osteosarcoma was not included in this
analysis because this finding has been previously correlated with
RECQL4 mutation status
[11]. Similarly, subjects
received a score of 0 if they carried no RECQL4 mutations and 1 if
they carried any mutations. All 18 subjects with mutations had skeletal
abnormalities, and only three of 10 subjects without mutations had skeletal
abnormalities. The average number of skeletal abnormalities among subjects
with mutations was 4 (median, 5), and the average number of skeletal
abnormalities among subjects without mutations was 1 (median, 0).
Genotype–phenotype anal ysis with Fisher's exact test showed a
significant correlation between RECQL4 mutation status and the
presence of skeletal abnormalities (p < 0.0001).
Discussion
Although it is well known that patients with RTS can have skeletal
dysplasia, to our knowledge no systematic or comprehensive study has been
conducted to define the spectrum and prevalence of skeletal abnormalities
associated with RTS. To our knowledge, our study included the largest number
of patients with RTS assembled thus far. The results of our analysis confirmed
several of the well-described features of RTS, such as radial ray anomalies
and hypoplasia and fusion of long bones. The study also revealed a substantial
number of subjects with findings not previously well described, such as
brachymesophalangy of the second and fifth digits, abnormal metaphyseal
trabeculation, and osteopenia.
A particularly high percentage of subjects had abnormal metaphyseal
trabeculation appreciable on radiographs. The nature of this abnormality is
unknown. It is possible that at least the transverse metaphyseal striations
represent growth arrest lines due to nutritional deficiencies. RTS patients
are known to have gastrointestinal disturbances that manifest as chronic
emesis and diarrhea, often necessitating nutritional supplementation through a
feeding tube [1,
14]. The nature of these
gastrointestinal problems is not understood, but in most cases they resolve in
early childhood. Another possibility is alteration of metaphyseal growth and
mineralization related to the administration of chemotherapy. However, only
three subjects received chemotherapy for osteosarcoma many years before
examination, and only one of these had transverse striations of a total of 15
subjects with this radiographic finding. The abnormality in metaphyseal
trabeculation is particularly intriguing because most osteosarcomas tend to
originate in the metaphyses, and patients with RTS are highly predisposed to
the development of osteosarcoma. The pathophysiologic basis of the disordered
trabecular pattern is not understood. Further clinical and laboratory
investigation may provide insight into the role of RECQL4 in bone
development and homeostasis.
A limitation of our study was the inability to fully assess certain
findings that have been previously described in RTS, such as scoliosis, knee
subluxation, frontal bossing, and microdontia. Because the skeletal surveys
were performed with patients supine, scoliosis was not adequately assessed.
Evaluation of the knees for delayed patellar ossification was limited in some
cases by the patient's age (many subjects underwent radiographic assessment
before the age of expected ossification of the patellae) and by the lack of
lateral extremity radiographs, which are not standard in skeletal surveys.
Several subjects were believed to have osteopenia on skeletal surveys, but the
presence of decreased bone mineral density necessitates confirmation by more
quantitative methods, such as dual-energy x-ray absorptiometry. Because
several subjects reported histories of frequent fractures, confirmation of
decreased bone mineral density may have therapeutic implications for patients
with RTS.
A large proportion of patients with a clinical diagnosis of RTS have
abnormal findings on skeletal radiographs that are not detectable with
physical examination alone. Therefore, skeletal surveys may aid in the
diagnosis of RTS, particularly when the rash is atypical and there are no
other clinically apparent findings. The presence of skeletal abnormalities
correlates with RECQL4 mutation status and may therefore also be
indicative of increased risk of osteosarcoma. Further study of the biologic
processes underlying the skeletal abnormalities seen on radiographs may
provide insight into the role of RECQL4 in bone development and
homeostasis.
Acknowledgments
We thank the patients and families for their participation in this
research. We thank Ta-Tara Rideau for data management and the following
ongoing collaborators in our research study: Moise Levy, Richard Lewis, and
Sharon Plon. We gratefully acknowledge critical reading of the manuscript and
helpful discussions by Alberto Pappo.
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Abstract
Introduction
