Rothmund-Thomson syndrome is rare autosomal recessive disorder characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease (Simon et al., 2010).
- Genetic Heterogeneity of ... Rothmund-Thomson syndrome is rare autosomal recessive disorder characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease (Simon et al., 2010). - Genetic Heterogeneity of Rothmund-Thomson Syndrome 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.
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 ... 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. - Clinical Variability 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.' 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.
Kitao et al. (1999) identified compound heterozygous mutations in the helicase gene RECQL4 (603780) in 2 sibs with Rothmund-Thomson syndrome and in an isolated case. In 4 other patients, no mutation was found.
In 2 brothers ... Kitao et al. (1999) identified compound heterozygous mutations in the helicase gene RECQL4 (603780) in 2 sibs with Rothmund-Thomson syndrome and in an isolated case. In 4 other patients, no mutation was found. 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 (603780.0007 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 and 603780.0013). 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.
A diagnosis of Rothmund-Thomson syndrome (RTS) can be made in individuals in whom poikiloderma, the classic rash, shows the following pattern of onset, spread, and appearance:...
DiagnosisClinical DiagnosisA diagnosis of Rothmund-Thomson syndrome (RTS) can be made in individuals in whom poikiloderma, the classic rash, shows the following pattern of onset, spread, and appearance:Poikiloderma starts in infancy, usually between age three and six months, as erythema on the cheeks and face (acute phase), and spreads to involve the extensor surfaces of the extremities. The trunk and abdomen are usually spared; the buttocks may be involved. Gradually, over a period of months to years, the rash enters a more chronic phase with reticulated hyper- and hypopigmentation, telangiectases, and areas of punctate atrophy. These changes, described as poikiloderma, persist throughout life.A diagnosis of probable RTS can be made if the rash is atypical (either in appearance, distribution, or pattern of onset and spread) and two other features of RTS are present:Sparse scalp hair, eyelashes, and/or eyebrowsSmall size, usually symmetric for height and weightGastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubesRadial ray defectsRadiographic bone abnormalities that include dysplasias, absent or malformed bones, osteopenia, abnormal trabeculationDental abnormalities that include rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruptionNail abnormalities such as dysplastic or poorly formed nailsHyperkeratosis particularly of the soles of the feetCataracts, usually juvenile, bilateralCancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular bone cancer (osteosarcoma)TestingCytogenetic testing. Routine cytogenetic testing of lymphocytes or skin fibroblasts may reveal abnormalities of chromosome 8 (e.g., trisomy 8, partial 8q duplication, tetrasomy 8q) caused by the presence of an isochromosome 8q [Miozzo et al 1998]. The percentage of cytogenetically abnormal cells can vary. Note: (1) Many individuals with RTS have normal cytogenetic studies. (2) Routine cytogenetic testing is not a useful adjunct to clinical diagnosis.Molecular Genetic TestingGene. To date RECQL4 is the only gene in which mutations are known to cause RTS [Kitao et al 1999, Lindor et al 2000, Wang et al 2003a].Evidence for locus heterogeneity. Although evidence suggests genetic heterogeneity, no other locus for RTS has been identified. Clinical testingTable 1. Summary of Molecular Genetic Testing Used for Rothmund-Thomson SyndromeView in own windowGene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3Test AvailabilityRECQL4Sequence analysis / mutation scanning 4Sequence variants 566% 6ClinicalDeletion / duplication analysis 7Partial- or whole-gene deletionsUnknown, none reported 81. See Table A. Genes and Databases for chromosome locus and protein name.2. See Molecular Genetics for information on allelic variants. 3. The ability of the test method used to detect a mutation that is present in the indicated gene4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.6. Wang et al [2003b]7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 8. The sensitivity, specificity, and accuracy of such testing for RTS are not known.Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found online [Larizza et al 2012]. Testing StrategyConfirming the diagnosis in a proband. Sequence analysis identifies a disease-causing mutation in approximately 66% of individuals with RTS; the reduced detection frequency has been attributed to possible locus heterogeneity. Thus the inability to identify a RECQL4 mutation does not rule out a diagnosis of RTS. Sequence analysis should include sequencing of the entire gene, including introns, since deletions in the short introns of RECQL4 can be deleterious [Wang et al 2002].Deletion/duplication analysis. It is unknown whether a significant number of individuals with RTS harbor RECQL4 deletions. No deletions or duplications involving RECQL4 as causative of RTS have been reported. Deletion/duplication analysis may be most helpful in people with RTS when only one RECQL4 mutation is identified by sequence analysis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersTwo other phenotypes are associated with mutations in RECQL4:RAPADILINO, an autosomal recessive disorder described in the Finnish population, is characterized by irregular pigmentation with café au lait spots (but no poikiloderma), small stature, palate defects, radial ray defects, patellar hypoplasia, and GI abnormalities. Sequence analysis of RECQL4 in the initial cohort of Siitonen and colleagues revealed that the majority of those with RAPADILINO were homozygous for IVS7+2delT (NM_004260.3:c.1432+2delT) (termed Fin-major mutation), which destroys the 5' splice site of intron 7 causing in-frame deletion of exon 7 [Siitonen et al 2003]. The other mutations found in individuals who are compound heterozygotes include inactivating mutations of RECQL4 typical of RTS [Siitonen et al 2009]. Follow-up studies by this group of investigators revealed seven new RECQL4 mutations in individuals with RAPADILINO, and importantly, the development of osteosarcomas and lymphomas in some of these patients.Baller-Gerold syndrome (BGS) is characterized by radial ray defects, skeletal dysplasia, short stature, and craniosynostosis, a feature not usually associated with RTS. RECQL4 mutations have been reported in six individuals (4 unrelated and 2 sibs) with BGS [Van Maldergem et al 2006, Debeljak et al 2009, Siitonen et al 2009]. The first reported case of cancer in BGS was a midline NK/T cell lymphoma in a girl age 2.5 years.
Individuals with Rothmund-Thomson syndrome (RTS) can exhibit few or many of the associated clinical features. The severity of the features (e.g., rash) can also vary....
Natural HistoryIndividuals with Rothmund-Thomson syndrome (RTS) can exhibit few or many of the associated clinical features. The severity of the features (e.g., rash) can also vary.Skin. Children with RTS typically develop a rash between age three and six months but occasionally as late as age two years. The skin changes begin as erythema, swelling, and occasionally blistering on the face, then spread to the buttocks and extremities. Gradually, over a period of months to years, the skin changes become chronic with reticulated hypo- and hyperpigmentation, telangiectases, and punctate atrophy, which persist throughout life.Hyperkeratotic lesions occur in approximately one third of individuals.Uncommon but reported findings [Mak et al 2006] include the following: Calcinosis, the formation of calcium deposits in the skin usually at the site of an injury Note: Calcinosis cutis differs from osteoma cutis, which is true bone formation. Porokeratosis, a sign of disordered keratinization. This has been reported in one person with RTS, and thus may or may not be a related finding. Teeth. Many individuals with RTS also have dental abnormalities including rudimentary or hypoplastic teeth, microdontia, delayed eruption, supernumerary and congenitally missing teeth, ectopic eruption, and increased incidence of caries [Kraus et al 1970, Haytaç et al 2002]. Hair. Children with RTS may have sparse scalp hair or even total alopecia. Eyelashes and/or eyebrows may also be sparse or absent.Growth. Most individuals with RTS are the result of a full-term pregnancy but tend to have low birth weight and length for gestational age. They remain small throughout their lives, usually below the fifth percentile for both weight and height. Growth hormone levels appear to be normal.Skeleton. A study of 28 individuals with RTS examined by skeletal survey found that 75% had at least one major skeletal abnormality [Mehollin-Ray et al 2008].Findings can include generalized skeletal dysplasia (as visualized on x-ray) and can take the form of abnormal trabeculation with longitudinal metaphyseal striations, multiple transverse metaphyseal growth arrest lines, and dysplastic changes in the phalanges. They may have absent or malformed bones (e.g., aplastic radii, hypoplastic thumbs), delayed bone formation, osteopenia, and hypoplasia or absent patella [Green & Rickett 1998]. Gastrointestinal. Some infants or young children with RTS have feeding difficulties or other gastrointestinal problems including chronic emesis or diarrhea. Although feeding tubes are occasionally required, most of these problems resolve spontaneously during childhood [Wang et al 2001].Hematologic. Benign and malignant hematologic abnormalities, including isolated anemia and neutropenia, myelodysplasia, aplastic anemia, and leukemia, have been reported in individuals with RTS [Knoell et al 1999, Porter et al 1999, Narayan et al 2001, Pianigiani et al 2001].Cataract. The prevalence of juvenile cataracts has been reported in some series to be as high as 50%, with onset usually between age three and seven years. Earlier onset (as early as the first few months of life) and later onset (teens or adulthood) have also been reported. Most of the reports of early-onset, bilateral juvenile cataracts come from descriptions from Europe. More recently, in an international cohort of 41 individuals with RTS (age range 9 months to 42 years), the prevalence of cataracts was found to be much lower (<10%), and no cases were bilateral [Wang et al 2001].Cancer. The overall prevalence of cancers in adults with RTS is unknown.Osteosarcoma is the most commonly reported malignancy [Green & Rickett 1998, Wang et al 2003b]. In a contemporary cohort of those with RTS, the prevalence of osteosarcoma was 30% [Wang et al 2001]. The median age at diagnosis, 11 years, was slightly younger than that seen in the general population. Families in which more than one sib had RTS and osteosarcoma have been identified [Lindor et al 2000, Wang et al 2001]. Individuals with RTS are also at increased risk of developing skin cancer, including basal cell carcinoma and squamous cell carcinoma [Borg et al 1998], and more recently melanoma [Howell & Bray 2008]. The prevalence of skin cancers in individuals with RTS is estimated from the literature to be 5%. Skin cancer can occur at any age, although it often occurs earlier than in the general population. The mean age for epithelial tumors has been estimated at 34.4 years [Stinco et al 2008]. Piquero-Casals et al [2002] report on a consanguineous Brazilian family with classic features of RTS including poikiloderma and bilateral cataracts. All three affected sibs developed cutaneous squamous cell carcinoma in adulthood (age 35-48 years). The cancers occurred on non-sun-exposed surfaces. A few individuals with RTS have been reported to have a second malignancy. One developed non-Hodgkin lymphoma nine years after chemotherapy for osteosarcoma [Spurney et al 1998] and another developed Hodgkin lymphoma eight years after therapy for osteosarcoma [Wang et al 2001]. In general, follow-up time for individuals with RTS and osteosarcoma has been too short to draw conclusions about the risk of secondary malignancy.Multiple primary cancers have also been reported in individuals with RTS. For example, one affected individual developed anaplastic large-cell lymphoma at age nine years, diffuse large cell B lymphoma and osteosarcoma at age 14 years, followed by acute lymphoblastic leukemia at age 21 years. Whether the latter cancers represent secondary malignancies is not known [Simon et al 2010].Because RTS is felt to be a chromosome instability syndrome, those treated for malignancy may, in theory, be more sensitive to the effects of chemotherapy and have a higher risk for second malignancy. However, from the limited number of cases reported, it appears that most individuals with RTS and cancer treated with chemotherapy have not had significantly increased toxicities, although some individuals may experience increased mucositis with doxorubicin treatment [Hicks et al 2007, Simon et al 2010]. Other. Infertility has been described in affected males and females; however, a few affected females have had normal pregnancies, and a few males have produced offspring. Immunologic function appears to be intact. However there are several isolated case reports of individuals with RTS who have concomitant immune dysfunction. These include an individual who had humoral immune deficiency associated with granulomatous skin lesions [De Somer et al 2010], an affected individual with IgG4 deficiency and recurrent sinopulmonary infections [Kubota et al 1993], and another affected individual with low serum immunoglobulin (IgG and IgA) levels who presented with herpes encephalitis [Ito et al 1999]. One individual with RTS and severe combined immunodeficiency (T-B+NK- phenotype with agammaglobulinemia) underwent successful hematopoietic stem cell transplantation [Broom et al 2006].Most individuals with RTS appear to have normal intelligence.Life span, in the absence of malignancy, is probably normal, although follow-up data in the published literature are limited. Death from metastatic osteosarcoma and other cancers has been reported in a number of children and adults with RTS.
The correlation between presence of mutations in RECQL4 and presence of osteosarcoma in RTS has been evaluated [Wang et al 2003b]. Thirty-three individuals with RTS were screened for mutations in RECQL4. Twenty-three of these individuals were found to have at least one truncating mutation. All 11 of those with osteosarcoma had truncating mutations. Using Kaplan-Meier analysis, it was found that those with truncating mutations were at increased risk for developing osteosarcoma. The incidence of osteosarcoma was 0.05 per year in subjects with one or two truncating mutations (230 person-years of observation) and 0.00 per year in individuals with no RECQL4 mutations (100 person-years of observation) (p<0.04)....
Genotype-Phenotype CorrelationsThe correlation between presence of mutations in RECQL4 and presence of osteosarcoma in RTS has been evaluated [Wang et al 2003b]. Thirty-three individuals with RTS were screened for mutations in RECQL4. Twenty-three of these individuals were found to have at least one truncating mutation. All 11 of those with osteosarcoma had truncating mutations. Using Kaplan-Meier analysis, it was found that those with truncating mutations were at increased risk for developing osteosarcoma. The incidence of osteosarcoma was 0.05 per year in subjects with one or two truncating mutations (230 person-years of observation) and 0.00 per year in individuals with no RECQL4 mutations (100 person-years of observation) (p<0.04).The correlation between presence of mutations in RECQL4 and the presence of skeletal abnormalities has also been evaluated in 28 individuals with RTS [Mehollin-Ray et al 2008]. Genotype-phenotype analysis using Fisher’s exact test showed a significant positive correlation between those individuals with confirmed RECQL4 mutations and the presence of skeletal abnormalities (p < 0.0001).
The differential diagnosis of Rothmund-Thomson syndrome (RTS) includes the following disorders, which can exhibit features of poikiloderma but are otherwise clinically distinct from RTS. ...
Differential DiagnosisThe differential diagnosis of Rothmund-Thomson syndrome (RTS) includes the following disorders, which can exhibit features of poikiloderma but are otherwise clinically distinct from RTS. Bloom syndrome is characterized by severe pre- and postnatal growth retardation. The rash in Bloom syndrome is characterized by neonatal blistering, distinctive facial erythema, and telangiectases and develops in sun-exposed areas of the skin; it is not a true poikiloderma. Individuals with Bloom syndrome may also have café au lait spots or paired hypopigmented and hyperpigmented spots. Recurrent infections (otitis media and pneumonia), chronic pulmonary disease, and diabetes mellitus are common. Many have learning disabilities. The most common cause of death is cancer (epithelial, hematopoietic, lymphoid, connective tissue, germ cell, nervous system, or kidney), which occurs at younger-than-usual ages. A greatly increased frequency of sister chromatid exchanges (SCEs) in cells exposed to bromodeoxyuridine (BrdU) is diagnostic. Bloom syndrome is the only disorder in which such evidence of hyper-recombination is known to occur. Mutations in BLM are causative. Inheritance is autosomal recessive.Werner syndrome is characterized by the premature appearance of features associated with normal aging and by cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom is the lack of a growth spurt during the early teen years. Initial findings (usually observed in the 20s) include loss and graying of hair, alopecia, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death, typically at approximately age 48 years. Mutations in WRN are causative. Inheritance is autosomal recessive.Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between age one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Mutations in ATM are causative. Inheritance is autosomal recessive.Fanconi anemia (FA) is characterized by a range of physical abnormalities, bone marrow failure in the first decade, and myelodysplasia (~5%) or acute myelogenous leukemia (~10%). Physical abnormalities include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eye, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Individuals with FA are also at increased risk of developing solid tumors, particularly of the head and neck, skin, GI tract, and genital tract. Mutations in one of at least 15 genes are causative. Inheritance is autosomal recessive. Xeroderma pigmentosum (XP) is characterized by sun sensitivity, ocular involvement, and greater than 1000-fold increased risk for cutaneous and ocular neoplasms. Half of affected individuals demonstrate acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) from early infancy. Marked freckling of the face of a child under age two years is typical of XP and rarely seen in normal children. Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). Ophthalmologic abnormalities include keratitis, loss of lashes, and atrophy of the skin of the lids. The median age of onset of non-melanoma skin cancer is before ten years. Approximately 30% have neurologic manifestations. Xeroderma pigmentosum is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1 (XPH), and POLH. Inheritance is autosomal recessive.Kindler syndrome. Individuals with Kindler syndrome have acral bullae at birth and after minor trauma, diffuse poikiloderma with striate and reticulate atrophy, widespread eczematoid dermatitis, keratotic papules of the hands, feet, elbows, and knees, marked photosensitivity, esophageal and urethral strictures, webbing of fingers and toes, and no increased risk for cataract or malignancy. Mutations in FERMT1 (KIND1) are causative; both autosomal dominant and autosomal recessive inheritance are reported. Dyskeratosis congenita. The onset of poikiloderma and nail dystrophy occurs in late childhood. Individuals with dyskeratosis congenita do not have skeletal abnormalities or cataracts. They are at risk for aplastic anemia and skin cancers. Mutations in one of seven genes are causative and associated with different modes of inheritance: DKC1 (X-linked recessive); NHP2, NOP10, and WRAP53 (autosomal recessive); TERC (autosomal dominant), TERT (autosomal recessive or dominant), and TINF2 (autosomal dominant or sporadic) [Walne & Dokal 2009]. Poikiloderma with neutropenia (PN, Navajo poikiloderma) was first described in Navajo individuals and has now been described in individuals of other ethnicities as well. The onset of rash in individuals with PN differs from that seen in RTS in that it tends to be more eczematous and to start peripherally and spread centrally. The rash does not spare the trunk. Radial ray abnormalities and hair abnormalities are not seen. Individuals with PN have clinically significant neutropenia with recurrent sinopulmonary infections. Paronychias are commonly seen. Inheritance is autosomal recessive. Mutations in USB1 were first identified in individuals with PN in 2009 by Volpi et al [2010]. The encoded protein plays an important role in U6 small nuclear RNA biogenesis and cell viability [Mroczek et al 2012, Shchepachev et al 2012, Hilcenko et al 2013].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the following evaluations are recommended:Baseline skeletal radiographs by age five years to define underlying skeletal dysplasiasOphthalmologic examination because of increased incidence of cataractsBaseline complete blood countMedical genetics consultationTreatment of ManifestationsDermatologic. Pulsed dye laser has been used to treat the telangiectatic component of the rash [Potozkin & Geronemus 1991]. Cataract. Visually significant cataracts require surgical removal.Hematologic. Individuals with clinical evidence of anemia or cytopenias should be evaluated by CBC and bone marrow biopsy if clinically indicated.Cancer. Affected individuals who develop cancer should be treated according to standard chemotherapy and/or radiation regimens. Doses should be modified only if the patient experiences significantly increased toxicities.Prevention of Secondary ComplicationsAvoidance of excessive sun exposure and use of sunscreens with both UVA and UVB protection are recommended to prevent skin cancer. Calcium and vitamin D supplements may also be warranted in individuals with osteopenia or a history of fractures.SurveillanceThe following are appropriate for affected individuals:Annual evaluation by a physician familiar with RTSFor individuals without cataracts, yearly eye examinations for screening purposesFor parents of an affected individual at the time of initial diagnosis, counseling with regard to risk for associated medical problems (e.g., cancer, cataract) and development of a surveillance planClose monitoring of the skin for lesions with unusual color or texture, as individuals with RTS are at risk for skin cancersSkeletal radiographs when clinical suspicion of osteosarcoma is presentCurrently, no specific guidelines exist with regard to screening for osteosarcoma. However, the high risk for this potentially lethal malignancy, particularly for those individuals with deleterious mutations in RECQL4, argues for prompt evaluation of any symptoms or signs (including bone pain, swelling, or an enlarging lesion on a limb) suggestive of osteosarcoma. Relatives at risk. Because of reports of more than one sib with osteosarcoma, particularly close attention for any evidence of malignancy should be paid to family members of an individual with RTS and osteosarcoma or individuals with documented RECQL4 mutations. Agents/Circumstances to AvoidExposure to heat or sunlight may exacerbate the rash in some individuals.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherGiven the theoretic potential for tumorigenesis, growth hormone (GH) therapy is not recommended for individuals who have normal GH levels. For individuals with documented GH deficiency, routine treatment with growth hormone is appropriate.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Rothmund-Thomson Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRECQL48q24.3ATP-dependent DNA helicase Q4Finnish Disease Database RECQL4 homepage - Mendelian genesRECQL4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Rothmund-Thomson Syndrome (View All in OMIM) View in own window 268400ROTHMUND-THOMSON SYNDROME; RTS 603780RECQ PROTEIN-LIKE 4; RECQL4Normal allelic variants. RECQL4 has 21 exons. The gene has a coding sequence consisting of 3,627 bases based on the open reading frame of the NM_004260.3 cDNA. Normal allelic variants have been identified.Pathologic allelic variants. Approximately 50 different mutations spanning exons 5 through 21 and introns 1 through 17 have been published [Siitonen et al 2009]. Normal gene product. The normal gene encodes ATP-dependent DNA helicase Q4, a protein [Kitao et al 1998] of 1,208 amino acids (NP_004251.3) that bears homology to a family of proteins known as RecQ helicases. RecQ helicases are DNA helicases (enzymes that promote DNA unwinding, allowing many basic cellular processes to occur) that probably play a role in maintaining chromosomal integrity [Chakraverty & Hickson 1999, van Brabant et al 2000, Mohaghegh & Hickson 2001]. They all share a conserved 350-amino acid helicase region consisting of seven consensus motifs, with 42%-44% identity in this region; they all have ATP- and Mg++-binding sites. RecQ helicases are found in many species, from worms to bacteria to yeast. In humans, five RecQ helicases have been identified; three are associated with diseases: Bloom syndrome, Werner syndrome, and RTS.The exact role of ATP-dependent DNA helicase Q4 is not known, but several lines of work show that it likely has diverse biologic functions [Larizza et al 2010]. These include roles in DNA replication [Sangrithi et al 2005, Matsuno et al 2006, Wu et al 2009], DNA repair [Kumata et al 2007, Schurman et al 2009, Singh et al 2010], and telomere maintenance [Ghosh et al 2012].Abnormal gene product. The majority of mutated alleles identified thus far in individuals with RECQL4-related disorders are predicted to encode absent or truncated proteins [Kitao et al 1999, Siitonen et al 2009].