Alternative titles; symbols
SNOMEDCT: 1003923009, 69093006; ICD10CM: Q82.8; ORPHA: 221008, 221016, 2909; DO: 2732;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.3 | Rothmund-Thomson syndrome, type 2 | 268400 | Autosomal recessive | 3 | RECQL4 | 603780 |
A number sign (#) is used with this entry because of evidence that Rothmund-Thomson syndrome type 2 (RTS2) is caused by homozygous or compound heterozygous mutation in the DNA helicase gene RECQL4 (603780) on chromosome 8q24.
Rothmund-Thomson syndrome type 2 (RTS2) is an autosomal recessive disorder characterized by poikiloderma, congenital bone defects, and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose, and congenital radial ray defects) and/or subtle (visible only by radiographic analysis) (summary by Larizza et al., 2010).
Genetic Heterogeneity of Rothmund-Thomson Syndrome
Rothmund-Thomson syndrome type 1 (618625) is caused by mutation in the ANAPC1 gene (608473) on chromosome 2q13.
Rothmund-Thomson syndrome type 3 (RTS3; 615789) is caused by mutation in the CRIPT gene (604594) on chromosome 2p21.
On the basis of their analysis of the clinical and molecular spectra of RTS, Wang et al. (2003) suggested that there may be at least 2 forms of the disorder: a form as originally described by Rothmund (1868), associated with the characteristic poikiloderma but not with osteosarcoma, which they designated 'type 1;' and a form characterized by poikiloderma with an increased risk of osteosarcoma and deleterious mutations in the RECQL4 gene (603780), which they designated 'type 2.'
Rothmund (1868) described 2 related consanguineous families in the small Walser valley in Austria in which 4 girls and 1 boy had lenticular opacities with skin disease. According to Waardenburg et al. (1961), this family was further investigated by Siemens. Waardenburg et al. (1961) described the disorder as a hereditary dermatosis characterized by atrophy, pigmentation, and telangiectasia and frequently accompanied by juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, and hypogonadism. Prognosis for survival is fairly good. In the disorder described by Thomson (1936), saddle nose was not present and cataract did not occur. An excellent color illustration was provided by Thomson (1936).
Greaves and Inman (1969) described a brother and sister, born of healthy unrelated parents, as having Morquio syndrome (253000, 253010) with previously unrecognized cutaneous manifestations. However, specific enzyme assays later excluded this diagnosis. Spellacy et al. (1981) reported extensive investigations which appeared to delineate the condition as a 'new' disorder. In addition to having severe skeletal dysplasia, the sibs had cutaneous atrophy with striking telangiectases and shallow indolent cutaneous ulcers, mesodermal dysgenesis of the iris, and joint abnormalities. The 15-year-old brother had severe kyphoscoliosis and hypermobility of some joints, with a restricted range of motion in other joints. His 17-year-old sister, who had bilateral congenitally dislocated hips, was less severely affected. The telangiectasia in both patients was generalized and associated with sensitivity to the sun. The odontoid process was normal and there was no corneal clouding. Moss (1990) reviewed the 2 patients when they were aged 25 and 27 years and concluded it was 'now clear that their disorder is the Rothmund-Thomson syndrome.' At 25 years of age, the brother was 97 cm tall, and photographs demonstrated saddle-nose. The telangiectasia on the face and extensor surfaces of the limbs, most marked on the hands and with wrinkling of the affected skin, was striking. In addition to the previously described changes in the iris, there were bilateral nuclear and posterior cortical lens opacities precluding a clear view of the fundus. The sister had iris atrophy but no cataracts.
Starr et al. (1985) reported 2 cases and emphasized the less well-known nondermatologic features, namely, hypodontia, soft tissue contractures, proportionate short stature, hypogonadism, anemia, and osteogenic sarcoma. Birth weight in the 2 cases was 3 kg and 2.83 kg.
Drouin et al. (1993) described osteosarcoma of the distal femoral metaphysis in an 11-year-old French Canadian boy with RTS. Several such cases had previously been reported.
Pujol et al. (2000) reported 2 patients with variable presentations of Rothmund-Thomson syndrome. Initial presenting symptoms included growth deficiency and absent thumbs in 1 patient and osteogenic sarcoma and poikiloderma in the other. The growth-deficient patient was found to have growth hormone deficiency and a subnormal response to growth hormone supplementation. Neither malformations nor growth deficiency was present in the patient with osteogenic sarcoma and her only other manifestation of RTS was poikiloderma. Pujol et al. (2000) suggested that RTS should be considered in all patients with osteogenic sarcoma, particularly if associated with skin changes. The authors pointed out that Lindor et al. (1996) had reported a brother and sister of Mexican descent with marked short stature, poikiloderma, absent or hypoplastic thumbs, osteogenic sarcoma, and no cataracts. They stated that these were the sibs in whom Kitao et al. (1999) had found mutations in the RECQL4 gene.
Wang et al. (2001) identified a cohort of 41 patients with RTS to better define the clinical profile, diagnostic criteria, and management of the disorder. Patients diagnosed with RTS were ascertained by referrals from dermatology, ophthalmology, genetics, and oncology or through direct contact with the patient's family. Medical information was obtained from interviews with physicians, patients, and their parents and a review of medical records. Age at ascertainment ranged from 9 months to 42 years. There were 28 males and 13 females. All subjects displayed a characteristic rash. Thirteen subjects had osteosarcoma (32%), 8 had radial defects (20%), 7 had gastrointestinal findings (17%), 2 had cataracts (6%), and 1 had skin cancer (2%). The gastrointestinal findings were feeding problems as infants, including chronic emesis or diarrhea, with some patients requiring tube feeding. One had documented duodenal stenosis, but the others had no clear explanation for the symptoms. Of the patients without osteosarcoma, 22 of 28 were less than 15 years old and thus remained at significant risk for this tumor. Compared with historical reports, this study showed a clinical profile of RTS that included a higher prevalence of osteosarcoma and fewer cataracts.
In 12 patients with RTS2 in whom Suter et al. (2016) identified homozygous or compound heterozygous mutations in the RECQL4 gene, the most common features were poikiloderma or other skin lesions (100%), growth retardation (83%), and skeletal manifestations (75%).
Clinical Variability
Hilhorst-Hofstee et al. (2000) described a syndrome observed in 3 isolated patients, the features of which included bilateral radial aplasia, short stature, an inflammatory based 'elastic' pyloric stenosis, a panenteric inflammatory gut disorder that appears to be due to an autoimmune process, and poikiloderma. Other features in individual cases included cleft palate, micrognathia, anal atresia, patellar aplasia/hypoplasia, and sensorineural deafness. Hilhorst-Hofstee et al. (2000) suggested that the combination may represent a severe form of Rothmund-Thomson syndrome or possibly a previously unrecognized condition.
Rothmund-Thomson syndrome type 2 is inherited as an autosomal recessive disorder (Kitao et al., 1999).
Wang et al. (2001) recommended baseline skeletal radiographs of the long bones by age 5 years for all patients with RTS, since patients often have underlying skeletal dysplasias and subsequent films based on clinical suspicion of osteosarcoma can be interpreted more easily in comparison to baseline findings. They stated that it is unclear whether RTS patients are more sensitive to the effects of chemotherapy and radiation. There had been no reports of increased toxicity to treatment comparable to that experienced by ataxia-telangiectasia (208900) patients treated for cancer.
Ying et al. (1990) described trisomy 8 mosaicism in association with Rothmund-Thomson syndrome. Der Kaloustian et al. (1990) found mosaic trisomy 8 and mosaic supernumerary i(2q) in fibroblasts from normal skin; lymphocytes, however, had a normal karyotype. Orstavik et al. (1994) likewise found instability of lymphocyte chromosomes in a young girl who had severe skeletal abnormalities of the upper limbs with absence of both radii, short dysmorphic ulnae, a rudimentary right thumb, and aplasia of the left thumb. She also had anal atresia with a rectovaginal fistula. Poikiloderma developed on the face and extensor surfaces of the limbs beginning at the age of 3 months. Mental development was normal.
Lindor et al. (1996) reported a brother and sister with typical clinical manifestations of RTS and tibial sarcoma. Three cell lines [46,XY; 47,XY,+8; 47,XY,+i(8q)] were found in lymphocyte cultures of the brother and 2 cell lines [46,XX; 47,XX,+i(8q)] were detected in the sister. FISH studies with a probe specific for the chromosome 8 centromere showed 3 chromosome 8 signals in 4 to 16% of uncultivated lymphocytes and buccal cells of these patients, suggesting the in vivo presence of abnormal cell lines. RTS may be associated with clonal rearrangements causing acquired somatic mosaicism.
In a Mexican brother and sister with Rothmund-Thomson syndrome and in an isolated case, Kitao et al. (1999) identified compound heterozygous mutations in the helicase gene RECQL4 (603780.0001-603780.0004). In 4 other patients, no mutation was found, suggesting genetic heterogeneity.
In 2 brothers with RTS, Lindor et al. (2000) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0005 and 603780.0006). One brother died at age 9 years from osteosarcoma of the right calcaneus and right iliac wing, whereas the other brother was diagnosed at age 21 years with osteoblastic osteosarcoma of the distal radius.
In a 19-year-old Caucasian male patient with RTS, Beghini et al. (2003) identified compound heterozygosity for mutations in the RECQL4 gene (603780.0005 and 603780.0008).
Wang et al. (2003) analyzed the RECQL4 gene in 33 RTS patients and identified 23 patients, including all 11 patients with osteosarcoma, who carried at least 1 of 19 truncating mutations (see, e.g., 603780.0002). The authors concluded that RECQL4 loss-of-function mutations occur in approximately two-thirds of RTS patients and are associated with the risk of osteosarcoma.
Simon et al. (2010) reported a 21-year-old male with RTS who was compound heterozygous for mutations in the RECQL4 gene (603780.0015 and 603780.0016) and who developed 4 malignant diseases: large-cell anaplastic T-cell lymphoma with histologic features of the syncytial variant of nodular sclerosing Hodgkin lymphoma at age 9.3 years; diffuse large B-cell lymphoma, centroblastic variant, at age 14.3 years; osteosarcoma at age 14.6; and acute leukemia at age 21.6 years. Despite achieving remission with the first 3 malignancies, including spontaneous remission of the diffuse large cell lymphoma, the patient died from leukemia progression at age 21.9 years.
By screening DNA samples from 43 index patients with RTS for variants in the 21 exons of the RECQL4 gene by PCR, SSCP-PAGE analysis, and/or Sanger sequencing, Suter et al. (2016) identified 23 different RECQL4 mutations, 10 of which were novel, in 18 patients. The novel mutations included 5 frameshift, 3 in-frame, 1 nonsense, and 1 missense. Twelve patients had homozygous or compound heterozygous mutations; in 5 patients, only 1 mutation was identified, and in 1 patient 3 mutations were identified.
Heterogeneity
Wang et al. (2003) analyzed the RECQL4 gene in 33 RTS patients and found an absence of RECQL4 mutations in 10 patients. Analysis of a family with an affected sib pair excluded RECQL4 as a recessive locus for RTS in the family, arguing strongly for genetic heterogeneity in RTS.
Simon et al. (2010) stated that only 40 to 66% of patients with RTS have been found to have mutation in the RECQL4 gene, indicating genetic heterogeneity.
Mann et al. (2005) created a viable Recql4-mutant mouse model. Mutant mice exhibited a distinctive skin abnormality, birth defects of the skeletal system, genomic instability, and increased cancer susceptibility in a sensitized genetic background. Cells from Recql4-mutant mice had high frequencies of premature centromere separation and aneuploidy. The authors proposed a role for Recql4 in sister-chromatid cohesion, and suggested that chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.
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