Rothmund–Thomson Syndrome (poikiloderma congenitale)

Rothmund-Thomson Syndrome (poikiloderma congenitale)

Are You Confident of the Diagnosis?

• What you should be alert for in the history

The clinical presentation of Rothmund-Thomson Syndrome (RTS) patients is extremely heterogeneous, making the molecular diagnosis the only tool to subgroup them correctly.

• Characteristic findings on physical examination

The clinical diagnostic hallmark is the cutaneous rash appearing within the first year of life on the face and subsequently spreading to the extremities. The rash develops over time from the acute phase of swelling and blistering to the chronic phase of poikiloderma (telangiectasic lesions, reticulated areas of depigmentation, hyperpigmentation and punctate atrophy) (Figure 1, Figure 2).

Figure 1.

Figure 2.

Dermatological examination should take into account the differential diagnosis with other genodermatoses with poikiloderma or prominent telangiectasias, such as, in order of the number of shared phenotypic signs: Poikiloderma with Neutropenia (PN); Dyskeratosis Congenita (DC); Werner syndrome (WS); Bloom’s syndrome (BS) and Hereditary Fibrosing Poikiloderma with Tendon Contractures; Myopathy and Pulmonary Fibrosis (POIKTMP).

Delayed growth and proportionately small stature are common features.

Additional characteristic findings at physical examination include: sparse scalp hair, eyelashes and eyebrows, dental and nail abnormalities, and palmo-plantar hyperkeratosis (in one third of the patients).

Skeletal anomalies such as congenital radial ray defects (thumb aplasia or hypoplasia, delayed bone formation) are suggestive of RTS type II associated with defects of the RECQL4 helicase gene, accounting for about two-thirds of RTS clinically diagnosed patients.

The RECQL4-positive patients may develop cancers, in particular osteosarcoma at pediatric age and skin cancer later in life. Immunological impairment has been observed in a few cases. Reduced fertility is common in males and females. Several clinical features of aging, such as atrophic skin, osteoporosis and frequent fractures are often displayed.

Intellectual development is usually normal.

Bilateral juvenile cataracts are never present in RTS type II and when associated to poikiloderma, small stature and ectodermal dysplasia represent another RTS subset, indicated as RTS type I, to be molecularly defined.

Poikiloderma starting on the limbs and spreading centrally, dystrophic nails, pachyonychia, palms/soles hyperkeratosis, persistent moderate to severe neutropenia and recurrent infections are associated with defects of the C16orf57/USB1 gene and allow for the definite diagnosis of Poikiloderma with neutropenia (PN).

• Expected results of diagnostic studies

For RTS II patients without overt skeletal defects, radiographic scan may evidence abnormal metaphyseal trabeculation, osteopenia, brachymesophalangy and destructive bone lesions.

For patients with clinical diagnosis mimicking PN, hematological tests including neutrophil count, LDH and CPK dosage are helpful.

• Diagnosis confirmation

Identification of biallelic pathogenic RECQL4 mutations, either in homozygous or in compound heterozygous condition, confirms or excludes the clinical diagnosis. The genetic test of RECQL4 gene should also include transcript analysis in order to detect deep intronic mutations which may lead to missplicing and would be overlooked by the standard DNA analysis.

More than 70 different RECQL4 mutations, many of which affect the highly conserved helicase domain of the protein, have been reported including inactivating (nonsense, frameshift), splicing and missense mutations. Out of these, >50 mutations have been characterized in RTS patients, while the remaining have been associated with two additional autosomal recessive disorders; Rapadilino, which is prevalent in Finland, and Baller-Gerold syndrome (BGS) which is characterized by radial hypoplasia and craniosynostosis.

A few mutations are shared by RTS, Rapadilino and BGS patients, making hard to address mutation(s)-phenotype correlations. RTS is viewed as the “core” syndrome, while the rarer Rapadilino and BG syndromes are considered endophenotypes; overall the three conditions are part of the RECQL4 spectrum of disorders (Figure 3).

Figure 3.

Besides targeted gene testing by conventional Sanger sequencing, next generation DNA sequencing using a multi-gene panel including RECQL4 and genes underlying disorders which, due to partial clinical overlap enter in differential diagnosis with RTS, are increasingly used. The gene panel is customized by laboratory and can be expanded over time. Whole exome sequencing (WES) may be considered when the targeted and the multi-gene panel testing fail to confirm the clinical RTS diagnosis.

Who is at Risk for Developing this Disease?

RTS is a very rare monogenic autosomal recessive disease and data on its prevalence are not available. To date approximately 400 patients have been recorded in the medical literature belonging to all ethnic groups.

Consanguinity, also geographic (both partners from the same small isolate), should be inquired about, along with autosomal recessive transmission. A couple with an affected sibling has a 25% recurrence risk, based on the predicted status of healthy carriers.

What is the Cause of the Disease?

• Pathophysiology

Type II RTS, characterized by poikiloderma and skeletal defects is caused by pathogenic homozygous or more often compound heterozygous mutations of the RECQL4 helicase gene leading to defective RECQL4 protein. Patients found to have at least one truncating mutation are at increased risk for developing osteosarcoma.

RECQL4 belongs to the RECQ DNA helicases family, which includes 5 members in humans. Genetic defects in three of the five human RecQ helicases give rise to defined syndromes associated with chromosomal instability and cancer predisposition and some features of premature ageing, namely Bloom’s syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS). RECQ helicases are designated the “caretakers” of the genome as they function at the interface of DNA replication, recombination and repair. Despite structural common features, RECQ helicases do not have redundant functions, accounting for the distinctive clinical signs of the three syndromes caused by defective RECQ2, RECQ3 and RECQL4 (Figure 4) and for the different hallmarks of chromosomal instability observed at the cellular level.

Figure 4.

RECQL4 is a multifunctional protein playing a role in initiation of DNA replication, in repair of double strands breaks, functioning both in homologous recombination and end-joining pathways, in oxidative stress and in repair of UV-induced DNA damage, as well as in telomere maintenance. Compared to other RECQ helicases it has the unique function to transport p53 to the mitochondria under unstressed condition and to regulate mitochondrial biogenesis.

Given the multiple roles of RECQL4, RTS II patients accumulate defects in DNA metabolism and repair which lead to sustained genomic instability, a strong driver of neoplastic transformation and cancer development.

At the karyotypic level cells from RTS II patients show an unusual frequency of mosaic numerical and structural abnormalities often including isochromosome formation with chromosome 8 as preferential target and display fragile telomeres.

The molecular defects leading to type I RTS are yet unknown.

Biallelic mutations in the USB1 gene underlie PN, a disorder which for the phenotypic overlap, has been often misdiagnosed as RTS before the identification of the causative gene.

Specific mutations of RECQL4 and USB1 are present within certain ethnic groups, highlighting a founder effect of the respective rare mutant alleles.

Systemic Implications and Complications

RTS type II patients show a significant correlation between the mutational status and the skeletal abnormalities and are highly predisposed to the development of osteosarcoma, even multicentric, with a mean age of onset of 14.03 years.

Epithelial tumors (most notably squamous cell carcinoma) of the skin are well represented in adult RTS patients (onset at a mean age of 34.4 years); however, the correlation with the molecular subclass is undefined.

Only a few cases of RTS type II patients were found develop myelodysplasia and/or acute myeloid leukemia, for which PN patients are at increased risk.

Treatment Options

A multidisciplinary team is needed to offer long-term follow up and treatment to RTS patients.

It includes a dermatologist, an orthopedic surgeon and an oncologist for RTS type II, a dermatologist, a hematologist and an oncologist for PN and a dermatologist, an ophthalmologist and an oncologist for RTS type I. Dental treatment is required in RTS I and II as well as in PN patients who suffer from carious lesions, microdontia, multiple decayed primary teeth and multiple congenitally missing permanent teeth.

Topical Medical Options

Pulsed dye laser photocoagulation to improve the telangiectatic component of the rash.

Systemic Medical Options

Due to increased photosensitivity observed in a few instances, patients should be advised to use sunscreens. Despite growth retardation most RTS patients have normal growth hormone (GH) levels. Routine treatment with GH is appropriate only for individuals with documented GH deficiency.

Surgical options

Removal of the cataracts (RTS I), excision of osteosarcoma (RTS II) or cutaneous tumors (RTS I, RTS II).

Optimal Therapeutic Approach for this Disease

Confirmation of the molecular diagnosis in the clinically diagnosed RTS patient is instrumental in determining the appropriate therapeutic ladder. Single-gene conventional sequencing or multi-gene panel massive DNA sequencing are available testing approaches.

Treatment of skin erythema and sun sensitivity and periodontitis in early infancy can be provided independently of the genetic test.

Conversely, the higher incidence of cancer at an earlier age than in the normal population is best monitored by assessing the presence/absence of the molecular lesion.

The potential risk of radiation exposure from radiologic screening for osteosarcoma in RTS II is under debate, given the modest sensitivity of RECQL4-mutated patients to DNA-damaging agents. Replacement of doxorubicin with cisplatinum as osteosarcoma chemotherapy agent is advised due to lesser sensitivity of RECQL-deficient fibroblasts to cisplatinum and avoidance of mucositis as a side effect.

The histological response of osteosarcoma to standard chemotherapy and the clinical outcome are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. After treatment a prolonged period of follow-up is recommended not only for metastasis, which is predominantly pulmonary, but also for the occurrence of a second malignancy that has been reported in a notable proportion of RTS tumor carriers. For this purpose patients should be screened periodically with use of chest radiographs, computed tomography or bone scanning.

Patient Management

Patients with a consistent diagnosis of RTS should have their diagnosis confirmed or excluded by the gene-targeted, multi-gene panel or WES analyses. The genetic test should be accompanied by appropriate genetic counseling to ensure timely identification and treatment of syndrome-associated manifestations.

As RTS is an autosomal recessive genetic disease, the patient’s parents and siblings should also have the genetic test to confirm the carrier status (parents) and the risk of being a carrier (siblings). Once an at-risk sibling is known to be unaffected, his/her risk of being a carrier is 2/3.

Prenatal diagnosis can be offered once both disease-causing alleles have been identified in an affected family member.

Annual physical examination of patients should include:

• thorough examination of the skin to follow the onset and the features of poikiloderma

• eye examination because of increased incidence of cataracts (RTS I)

• oral examination for increased incidence of caries, malocclusion and early-onset periodontitis and dental radiographic screening for dental abnormalities (RTS I, RTS II, PN)

• baseline skeletal radiographs by age five years to define underlying skeletal dysplasias (RTS II)

• baseline complete blood count to detect isolated neutropenia, plasmatic increase of enzymes such as LDH and CPK

• pulmonary function tests and computed tomography to monitor respiratory infections

• abdominal ultrasonography to check increased size of spleen and liver (PN)

Specific attention is needed for cancer surveillance which should be provided at follow-up of :

• RTS II patients to monitor bone pain, swelling or an enlarging lesion on a limb suggestive of a bone tumor

• PN patients with clinical evidence of anemia or cytopenia: bone marrow biopsy should be performed to check the onset of myelodysplastic features and allogenic bone marrow transplantation may be planned

• RTS I and II patients for skin lesions with unusual color texture and color

Unusual Clinical Scenarios to Consider in Patient Management

Unusual clinical scenarios, including exocrine pancreatic hypofunction, calcinosis cutis, porokeratosis, iris dysgenesis and gastrointestinal system malformations are likely features of the RTS patients, and not yet molecularly defined.

What is the Evidence?

Wang, LL, Plon, SE, Pagon, RA, Adam, MP, Ardinger, HH, Wallace, SE, Amemiya, A, Bean, LJH, Bird, TD, Fong, CT, Mefford, HC, Smith, RJH, Stephens, K. “Rothmund-Thomson Syndrome”. 1999 Oct 6. pp. 1993-2016. (A comprehensive and updated review highlighting the clinical aspects and differential diagnoses of Rothmund-Thomson syndrome and the molecular diagnostic approaches.)

Larizza, L, Roversi, G, Volpi, L. “Rothmund-Thomson syndrome”. Orphanet J Rare Dis. vol. 29. 2010. pp. 5-2. (A review of the clinical findings and molecular basis of the syndrome.)

Larizza, L, Magnani, I, Roversi, G. “Rothmund-Thomson syndrome and RECQL4 defect: splitting and lumping”. Cancer Lett. vol. 232. 2006 Jan 28. pp. 107-20. (A review of RECQL4 associated disorders, focussed on the splitting of the RTS clinical phenotype and the lumping of the gene to three disorders. A summary of the findings on chromosomal instability in humans and in Recql4-deficient mice is provided.)

Croteau, DL, Singh, DK, Hoh Ferrarelli, L, Lu, H, Bohr, VA. “RECQL4 in genomic instability and aging”. Trends Genet. vol. 28. 2012 Dec. pp. 624-31. (A review on the role of RECQ DNA helicases as caretakers of the genome, placing RECQL4 at the crossroads of genomic instability and ageing processes.)

Siitonen, HA, Sotkasiira, J, Biervliet, M, Benmansour, A, Capri, Y, Cormier-Daire, V. “The mutation spectrum in RECQL4 diseases”. Eur J Hum Genet. vol. 17. 2009. pp. 151-8. (A comprehensive overview of the mutations within the RECQL4 gene, from the founder variant of the Finnish population leading to RAPADILINO syndrome, the few mutations causing Baller-Gerold syndrome to the large spectrum of mutations responsible for RTS syndrome.)

Colombo, EA, Fontana, L, Roversi, G, Negri, G, Castiglia, D, Paradisi, M, Zambruno, G, Larizza, L. “Novel physiological RECQL4 alternative transcript disclosed by molecular characterization of Rothmund-Thomson Syndrome sibs with mild phenotype”. Eur J Hum Genet. vol. 22. 2014. pp. 1298-304. (Paper disclosing a novel physiological RECQL4 alternative transcript with a partially skipped exon 14 which is increased in the described RTS sibs – and interestingly may account for their mild phenotype.)

Larizza, L, Roversi, G, Verloes, A. “Clinical utility gene card for: Rothmund-Thomson syndrome”. Eur J Hum Genet. vol. 21. 2013 Jul. (Clinical utility gene card for RTS.)

Stinco, G, Governatori, G, Mattighello, P, Patrone, P. “Multiple cutaneous neoplasms in a patient Rothmund-Thomson syndrome: case report and published work review”. J Dermatol. vol. 35. 2008. pp. 154-61. (The authors, starting from a case who developed multiple cutaneous neoplasia, revise all the literature on the neoplasias associated with Rothmund Thomson showing that RTS patients are predisposed to bone tumors during childhood and adolescence and to skin tumors in adulthood.)

Jin, W, Liu, H, Zhang, Y, Otta, SK, Plon, SE, Wang, LL. “Sensitivity of RECQL4-deficient fibroblasts from Rothmund-Thomson syndrome patients to genotoxic agents”. Hum Genet. vol. 123. 2008. pp. 643-53. (This is the first systematic study on the sensitivity of RECQL4 deficient cells to DNA-damaging agents: results show increased sensitivity to HU, CPT and doxorubicin as compared to control fibroblasts, modest sensitivity to UV, ionizing radiation and cisplatinum and relative resistance to 4NQO.)

Hicks, MJ, Roth, JR, Kozinetz, CA, Wang, LL. “Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome”. J Clin Oncol. vol. 25. 2007. pp. 370-5. (Osteosarcoma associated with RTS has an earlier onset as compared to the sporadic OS cases, but the clinical behavior is overlapping. The authors suggest a conventional chemotherapeutic regimen according to current protocols, but cautious and careful clinical observation is recommended for the increased sensitivity to doxorubicin.)

Volpi, L, Roversi, G, Colombo, EA, Leijsten, N, Concolino, D, Calabria, A. “Targeted next-generation sequencing appoints C16orf57 as Clericuzio-type poikiloderma with neutropenia gene”. Am J Hum Genet. vol. 86. 2010. pp. 72-6. (This paper deals with the strategy leading to identify the gene responsible for poikiloderma with neutropenia starting from an inbred Italian pedigree with three affected sibs misdiagnosed as Rothmund-Thomson.)

Colombo, EA, Bazan, JF, Negri, G, Gervasini, C, Elcioglu, NH, Yucelten, D, Altunay, I, Cetincelik, U, Teti, A, Del Fattore, A, Luciani, M, Sullivan, SK, Yan, AC, Volpi, L, Larizza, L. “Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations”. Orphanet J Rare Dis. vol. 7. 2012 Jan 23. pp. 7(First clinical and molecular description of PN patients and bioinformatic prediction of the function of the C16orf56/USB1 protein.)

Larizza, L, Negri, G, Colombo, EA, Volpi, L, Sznajer, Y. “Clinical utility gene card for: poikiloderma with neutropenia”. Eur J Hum Genet. vol. 21. 2013 Oct. (Clinical utility gene card for PN.)

Mercier, S, Küry, S, Barbarot, S, Pagon, RA, Adam, MP, Ardinger, HH, Wallace, SE, Amemiya, A, Bean, LJH, Bird, TD, Ledbetter, N, Mefford, HC, Smith, RJH, Stephens, K. “Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis”. 2016 Oct 13. pp. 1993-2016. (A recent review on POIKMTP, useful for the differential diagnosis.)

Savage, SA, Pagon, RA, Adam, MP, Ardinger, HH, Wallace, SE, Amemiya, A, Bean, LJH, Bird, TD, Fong, CT, Mefford, HC, Smith, RJH, Stephens, K. “Dyskeratosis Congenita”. pp. 1993-2016. (An updated review on DC, useful for differential diagnosis.)

Oshima, J, Martin, GM, Hisama, FM, Pagon, RA, Adam, MP, Ardinger, HH, Wallace, SE, Amemiya, A, Bean, LJH, Bird, TD, Ledbetter, N, Mefford, HC, Smith, RJH, Stephens, K. “Werner Syndrome”. pp. 1993-2016. (An updated review on WS, useful for differential diagnosis.)

Sanz M, M, German, J, Cunniff, C, Pagon, RA, Adam, MP, Ardinger, HH, Wallace, SE, Amemiya, A, Bean, LJH, Bird, TD, Ledbetter, N, Mefford, HC, Smith, RJH, Stephens, K. “Bloom’s Syndrome”. pp. 2006-2016. (An updated review on BS, useful for differential diagnosis.)

Giordano, CN, Yew, YW, Spivak, G, Lim, HW. “Understanding photodermatoses associated with defective DNA repair: Syndromes with cancer predisposition”. J Am Acad Dermatol. vol. 75. 2016 Nov. pp. 855-870. (An excellent review of Rothmund-Thompson syndrome and other disorders associated with defective DNA repair.)

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