Alternative titles; symbols
SNOMEDCT: 1003922004, 69093006; ICD10CM: Q82.8; ORPHA: 221008;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q13 | Rothmund-Thomson syndrome, type 1 | 618625 | Autosomal recessive | 3 | ANAPC1 | 608473 |
A number sign (#) is used with this entry because of evidence that Rothmund-Thomson syndrome type 1 (RTS1) is caused by homozygous or compound heterozygous mutation in the ANAPC1 gene (608473) on chromosome 2q13.
Rothmund-Thomson syndrome type 1 (RTS1) is an autosomal recessive disorder characterized by poikiloderma, sparse hair, and bilateral juvenile cataracts. Patients may also have growth retardation and genital, skeletal, and dental abnormalities. The disorder is not associated with an increased risk of cancer (summary by Ajeawung et al., 2019).
For a discussion of genetic heterogeneity of Rothmund-Thomson syndrome, see RTS2 (268400).
On the basis of an analysis of the clinical and molecular spectra of Rothmund-Thomson syndrome, 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.
Ajeawung et al. (2019) studied 10 patients from 7 families with a clinical diagnosis of Rothmund-Thomson syndrome, but no mutations in the RECQL4 gene. All 10 affected individuals presented the classic RTS features of poikiloderma and juvenile cataract, and 9 had sparse or absent hair, eyebrows, and/or eyelashes. All 5 male patients had undescended testes. In addition, multiple skeletal, nail, and dental abnormalities were primarily observed in the 5 male patients, including growth retardation with short stature, for which they all received growth hormone (GH1; 139250) therapy. Other skeletal features were variable and included osteoporosis, bone fracture, delayed bone age, short metacarpals and phalanges, dysplastic phalanges, sclerotic metaphyseal foci, and genu varum. None of the 10 patients had osteosarcoma.
By whole-exome sequencing in 4 affected individuals from 3 Amish families with RTS (families 1, 2, and 3), who were negative for mutation in the RECQL4 gene, Ajeawung et al. (2019) identified a single region of homozygosity larger than 1 Mb on chromosome 2q13-q14.1 (chr2:112,484,446-118,589,953, GRCh37).
Rothmund-Thomson syndrome type 1 is inherited as an autosomal recessive disorder (Rothmund, 1868; Ajeawung et al., 2019).
Using fibroblasts from 2 Amish patients (families 2 and 3) with RTS mapping to chromosome 2q13-q14.1, Ajeawung et al. (2019) performed qRT-PCR for genes within this interval and found significantly lower expression levels of ANAPC1 in the RTS patients than in controls. Analysis of exome data in 10 patients from 7 families with RTS, but no mutations in the RECQL4 gene, revealed homozygosity for an intronic variant in the ANAPC1 gene (608473.0001) in 4 Amish patients (families 1-3) and 1 unrelated patient (family 4), and compound heterozygosity for the intronic mutation and another ANAPC1 mutation in the remaining 5 patients (see, e.g., 608473.0002 and 608473.0003). Exome sequencing as well as screening for the intronic ANAPC1 mutation in 3 additional patients with RTS without juvenile cataract did not reveal any mutations, suggesting that ANAPC1 mutations are specific to patients with RTS and juvenile cataract. Noting that the 5 compound heterozygous male patients exhibited a more complex phenotype than the 5 female patients, who were all homozygous for the same intronic variant, the authors suggested that this might represent a genotype-phenotype correlation.
Ajeawung, N. F., Nguyen, T. T. M., Lu, L., Kucharski, T. J., Rousseau, J., Molidperee, S., Atienza, J., Gamache, I., Jin, W., Plon, S. E., Lee, B. H., Teodoro, J. G., Wang, L. L., Campeau, P. M. Mutations in ANAPC1, encoding a scaffold subunit of the anaphase-promoting complex, cause Rothmund-Thomson syndrome type 1. Am. J. Hum. Genet. 105: 625-630, 2019. [PubMed: 31303264] [Full Text: https://doi.org/10.1016/j.ajhg.2019.06.011]
Rothmund, A. Ueber Cataracte in Verbindung mit einer eigenthuemlichen Hautdegeneration. Albrecht von Graefes Arch. Klin. Exp. Ophthal. 14: 159-182, 1868.
Thomson, M. S. Poikiloderma congenitale. Brit. J. Derm. 48: 221-234, 1936.
Waardenburg, P. J., Franceschetti, A., Klein, D. Genetics and Ophthalmology. Vol. 1 Springfield, Ill.: Charles C Thomas (pub.) 1961. Pp. 895-897.
Wang, L. L., Gannavarapu, A., Kozinetz, C. A., Levy, M. L., Lewis, R. A., Chintagumpala, M. M., Ruiz-Maldanado, R., Contreras-Ruiz, J., Cunniff, C., Erickson, R. P., Lev, D., Rogers, M., Zackai, E. H., Plon, S. E. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J. Nat. Cancer Inst. 95: 669-674, 2003. [PubMed: 12734318] [Full Text: https://doi.org/10.1093/jnci/95.9.669]