DISEASE CARD

Definition

Rothmund Thomson syndrome (RTS) is a rare autosomal recessive disorder first reported by Rothmund in 1868. The characteristic cutaneous feature is poikiloderma, comprising skin atrophy, hypo-/hyperpigmentation and telangiectasia. In addition, affected individuals present with abnormalities of the bones, eyes, nose, hair, teeth, gastrointestinal tract and reproductive organs. There are reports of an increased prevalence of osteosarcoma and skin cancer in affected individuals. The disease is caused by mutations in ANAPC1 (type 1 RTS) or RECQL4 (Type 2 RTS) genes.

Clinical Description

Patients present in infancy (between 3-6 months of age) with erythema on the cheeks and face, spreading to the extensor surfaces of the extremities. Over months to years, poikilodermatous (comprising skin atrophy, pigmentation, teleangiectasia) changes over the cheeks, limbs and buttocks develop. Photosensitivity and multiple developmental abnormalities are associated with RTS that include hypodontia, saddle-shaped nose, micrognathia, juvenile cataracts, sparse hair, short stature, anaemia and neutropenia, gastrointestinal tract (abnormalities may include chronic diarrhoea, vomiting, pyloric stenosis) and hypogonadism.^1-3

Skeletal pathologies are present in up to two-thirds of the patients and include congenital long bone defects, absent or malformed bones, osteopenia or dysplastic changes in the phalanges.⁴ Osteogenic sarcoma has been reported in up to one third of affected individuals (most commonly the tibia and fibula) at a median age of 11 years.¹ In absence of malignancy, lifespan is probably normal, although data are limited.

Clinical features⁵:

• Classic rash (acute erythematous phase | chronic poikilodermatous phase)
• Sparse scalp hair, eyelashes and/or eyebrows
• Short stature (height and weight)
• Gastrointestinal disturbance as young children (e.g. chronic vomiting, diarrhea)
• Dental abnormalities (e.g. rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruption)
• Nail abnormalities (e.g. dystrophic nails)
• Hyperkeratosis (typically plantar)
• Cataracts (typically juvenile, bilateral)
• Skeletal abnormalities (e.g. radial ray defects, ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation)
• Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular osteosarcoma

In case of an atypical rash (either in appearance, distribution or pattern of onset and spread), a diagnosis of probable RTS can be made, if two of the additional features of RTS mentioned above are present.

Pathogenesis

One defective gene in RTS was identified in 1999 as the helicase gene RECQL4 on 8q24.⁶ Mann et al. (2005) created a viable Recql4-mutant mouse model and suggested that RECQL4 may play a role chromosomal instability which may be the underlying cause of cancer predisposition and birth defects in affected mice.⁷

In 2019, the second gene ANAPC1 was identified as being causative for type 1 RTS.²

Osteosarcoma and skeletal defects are more often found in patients with RECQL4 mutations (type 2 RTS), while bilateral juvenile cataracts are more prevalent in patients with mutations in ANAPC1 (type 1 RTS).^{1, 2, 4, 8}

Diagnosis

Diagnosis is based on the clinical features and/or identification of biallelic pathogenic variants in ANAPC1 or RECQL4 via molecular genetic testing (by e.g. multigene panel, exome sequencing, singe-gene testing or genome sequencing). Individuals with distinctive findings (see clinical features) are more likely to be diagnosed using gene-targeted testing, whereas patients with atypical clinical findings are more likely to be diagnosed via genomic testing. ⁵

Treatment

The management of the RTS requires a multidisciplinary care.⁵

• Regular dermatologic evaluations are recommended, at least annually. Pulsed dye laser may reduce teleangiectasias. Patients require strict photoprotection with regular application of sunscreen with UVA and UVB coverage. Avoidance of sun exposure decreases the risk for skin cancer
• Baseline skeletal radiographs of the long bones should be performed by the age of 5 years for all patients for screening for skeletal abnormalities; A prompt X-ray is necessary if there is a clinical suspicion of osteosarcoma (e.g. bone pain, swelling, enlarging lesion on a limb)⁹
• DEXA scan should be performed for assessment of bone mineral density in case of suspected osteopenia (on skeletal survey ) or a history of fractures;
• Regular screening for hematologic changes (complete blood count, w/differential);
• Annually ophthalmological review is required for assessment of juvenile cataracts. Significant cataracts require surgical removal
• Oncologic therapy in case of cancer according to the guidelines

References

^{1. Wang LL, Levy ML, Lewis RA, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.Am J Med Genet. 2001;102(1):11-17.}

^{2. Ajeawung NF, Nguyen TTM, Lu L, et al. Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1. Am J Hum Genet. 2019;105(3):625-630.}

^{3. Pianigiani E, De Aloe G, Andreassi A, Rubegni P, Fimiani M. Rothmund-Thomson syndrome (Thomson-type) and myelodysplasia. Pediatr Dermatol. 2001;18(5):422-425.}

^{4. Mehollin-Ray AR, Kozinetz CA, Schlesinger AE, Guillerman RP, Wang LL. Radiographic abnormalities in Rothmund-Thomson syndrome and genotype-phenotype correlation with RECQL4 mutation status. AJR Am J Roentgenol. 2008;191(2):W62-66.}

^{5. Wang LL, Plon SE. Rothmund-Thomson Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle}

^{6. Kitao S, Shimamoto A, Goto M, et al. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet. 1999;22(1):82-84.}

^{7. Mann MB, Hodges CA, Barnes E, Vogel H, Hassold TJ, Luo G. Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome.Hum Mol Genet. 2005;14(6):813-825} 

^{8. Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003;95(9):669-674.}

^{9. Hicks MJ, Roth JR, Kozinetz CA, Wang LL. Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol. 2007;25(4):370-375.}