Rothmund-Thomson syndrome

Abstract

Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised 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). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The...

Saccharomyces cerevisiae Hrq1 helicase activity is affected by the sequence but not the length of single-stranded DNA

“…This is largely due to technical challenges of working with RecQ4 both in vivo and in vitro. For instance, the presence of a Sld2-like domain (an essential replication initiation factor in yeast) at the N-terminus of RecQ4 makes mutational analysis difficult as mutations could disrupt DNA replication [2], which is independent of RecQ4-mediated DNA repair [3]. The Sld2-like domain also confounds biochemical analysis because Saccharomyces cerevisiae Sld2 is a known annealase [4], and the Sld2-like portion of RecQ4 plays a significant role in DNA annealing activity [5].…”

CUGC for hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP)

“…2,7 The identification of a molecular anomaly in FAM111B gives definitive proof of POIKTMP and enables its distinction from other types of hereditary poikiloderma, such as RTS (MIM#268400), hereditary sclerosing poikiloderma of Weary (MIM#173700), poikiloderma with neutropenia (PN; MIM#604173) or Kindler syndrome (MIM#173650). 6,[8][9][10][11] Above all, the main differential diagnosis of POIKTMP is RTS as all patients were initially misdiagnosed with RTS in childhood. These two entities share indeed common characteristics, such as early-onset poikiloderma, ectodermal dysplasia features, palmoplantar hyperkeratotic lesions, growth delay.…”

“…These two entities share indeed common characteristics, such as early-onset poikiloderma, ectodermal dysplasia features, palmoplantar hyperkeratotic lesions, growth delay. 10 Cataract observed in some of the POIKTMP cases is also characteristic of individuals negative for RECQL4-mutations presenting the sub-type I of RTS. 10 It is noteworthy that POIKTMP may also be misdiagnosed with other rare genodermatoses such as acrodermatitis enteropathica, more especially in the early infancy (Mercier et al, in review).…”

Clinical utility gene card for: Rothmund–Thomson syndrome

“…More than 60 disease-causing mutations have been reported, of which at least 40 have been detected in RTS patients. 1,2 The types of observed mutations are as follows, in order of decreasing prevalence: nonsense or frameshift mutations; splicing alterations, including substitutions at canonical splice junctions or at splice-site consensus sequences and subtle intronic deletions that reduce intron size below the threshold (o80 bp) required for correct splicing; 3,4 and missense mutations. There are a few recurrent mutations, among which the most common, exon 9 c.1573delT (p.Cys525AlafsX33), has been detected in patients with all three RECQL4-associated diseases.…”