Paula and Bobby
Parents of Lillie
What is Rothmund-Thomson syndrome?
It is a rare genetic syndrome that affects multiple parts of the body. Many of the main symptoms affect the skin especially. The syndrome also presents with many unique physical features. Affected individuals are also at higher risk of cancer. There are around 300 reported cases of the syndrome worldwide currently.
This syndrome is also known as:
Poikiloderma Atrophicans And Cataract Poikiloderma congenita RTS
What gene changes cause Rothmund-Thomson syndrome?
Changes to the RECQL4 and ANAPC1 genes are responsible for causing the syndrome.
It is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
What are the main symptoms of Rothmund-Thomson syndrome?
The main symptoms of the syndrome affect the skin of an affected individual. A common sign is a red rash on the cheeks that develops in infants between the ages of 3 and 6 months. This rash spreads to the arms and legs, over time. Other skin issues include changes in the coloring of the skin, skin thinning and clusters of blood vessels under the skin. These skin issues are known as poikiloderma.
Unique facial features of the syndrome include sparse hair, sparse eyebrows and eyelashes. A clouding of the lens (cataracts) and consequent vision problems present in some affected individuals. Other characteristic physical features include growth delay and small stature, as well as teeth and nail abnormalities.
Gastrointestinal issues are also common with the syndrome. These can include chronic diarrhea and vomiting.
The syndrome has also been associated with skeletal abnormalities- usually absent or malformed bones, fused bones a low bone mineral density.
Affected individuals have a higher risk of developing cancer. They are most at risk of developing a type of bone cancer known as osteosarcoma as well as more at risk of developing different types of skin cancer such as basal cell carcinoma and squamous cell carcinoma.
Possible clinical traits/features:
Decreased corneal thickness, Microcornea, Arthrogryposis multiplex congenita, Cryptorchidism, Craniosynostosis, Cutis marmorata, Epicanthus, Deeply set eye, Dermal atrophy, Delayed eruption of teeth, Limitation of joint mobility, Anemia, Dry skin, External ear malformation, Congenital hip dislocation, Juvenile zonular cataracts, Joint dislocation, Joint hypermobility, Irregular hyperpigmentation, Kyphoscoliosis, Abnormal immunoglobulin level, Increased number of teeth, Myelodysplasia, Intellectual disability, Short nose, Nausea and vomiting, Nephropathy, Neoplasm of the skin, Neoplasm of the stomach, Microphthalmia, Micrognathia, Mandibular prognathia, Microdontia, Cataract, Carious teeth, Aplasia/Hypoplasia of the thumb, Aplasia/Hypoplasia of the skin, Aplasia/Hypoplasia of the radius, Aplasia/Hypoplasia of the eyebrow, Abnormal sacrum morphology, Abnormality of the nail, Abnormality of the ulna, Abnormal blistering of the skin, Basal cell carcinoma, Abnormality of the genital system, Abnormal fingernail
How does someone get tested for Rothmund-Thomson syndrome?
The initial testing for Rothmund-Thomson syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Medical information on Rothmund-Thomson syndrome
Rothmund-Thomson syndrome (RTS) is the association of poikiloderma congenita, alopecia, photosensitivity, dystrophic nails, abnormal teeth, cataracts, short stature and hypogonadism. The skin abnormalities appear before 6 months of age with reticular or diffuse erythema on the face, hands and extensor surfaces of the limbs. The trunk is relatively spared. Photosensitivity may manifest with bullae. Older children have dermal atrophy, telangiectasia, patchy increased pigmentation or depigmentation of the skin, hyperkeratosis and scaling. The hands may be short and stubby and absent thumbs occur in about 5% of cases. A case reported by Pasagadugula et al., (2016) had an absent little finger and a cleft foot (there were no molecular studies). Lin et al., (1995) reported a case with a persistent pupillary membrane and iris stromal hypoplasia as well as ""pseudodistichiasis"". They review the other ocular features of the condition including keratoconus, sclerocornea, and microcornea. Nathanson et al., (2004) reported a case with glaucoma. Mak et al., (2006) reported a patient with bilateral iris dysgenesis and porokeratosis (annular lesions with raised keratotic margins and an atrophic centre).
Blaustein et al., (1993) reported a case with annular pancreas and duodenal stenosis. Vennos et al., (1992) and Drouin et al., (1993) suggest that cutaneous malignancies (squamous and basal cell carcinomas) and osteogenic sarcomas may be more common in this condition (reviewed by Judge et al., 1993; Molina et al., 1995; Cumin et al., 1996; El-Khoury et al., 1997 and Anbari et al., 2000). Pianigiani reported a case with myelodysplasia at 14 years of age. It is difficult to assess the case with myelodysplasia reported by Narayan et al., (2001) as there are no convincing photographs of the skin lesions, and there were unusual features such as contractures of the hands, feet and hips. Lapunzina et al., (1995) reported an 18-year-old boy with the condition who had Addison's disease. Kerr et al., (1996) reported two cases where chromosomal radiosensitivity in lymphocytes was demonstrated. Both of these cases had intellectual handicap. From a review of the literature these authors suggest that 3-10% of cases have mental handicap (see also Berg et al., 1990 and Vennos et al., 1992). Wang et al., (2001) viewed 41 patients with Rothmund-Thomson syndrome and found that seven (17%) had feeding or gastrointestinal problems as infants including chronic emesis or diarrhoea. One case had duodenal stenosis and annular pancreas. Thirty-two patients were screened for cataracts. Two patients had unilateral cataracts, one diagnosed at the age of 12 years and the other at 27 years. Thirteen of the patient (32%) developed osteosarcoma with a median age of 11.5 years (range, 4-41 years). Two patients with bronchiectasis were reported by Reix et al., (2007) and another by Mahajan et al., (2015)
Shinya et al., (1993) reported a 5-year-old boy with the condition. Investigation of fibroblasts showed reduced unscheduled DNA synthesis after exposure to ultraviolet C.
GENETICS and MOLECULAR GENETICS
Der Kaloustian et al., (1990) and Ying et al., (1990) showed mosaicism for trisomy 8 in skin fibroblasts of affected patients. It is possible that acquired somatic mosaicism involving chromosome 8 is a feature of the condition, even though inheritance appears to be autosomal recessive. Lindor et al., (1996) reported two sibs with the condition where cells with either trisomy 8 or an isochromosome 8q were found in both. The authors point out that the gene for Werner syndrome is situated at 8p11 in the same region as the breakpoints in the isochromosome. Both of these sibs developed osteogenic sarcomas. Orstavik et al., (1994) also reported mosaicism for chromosome abnormalities in a case of Rothmund-Thomson syndrome. However, the aberrations involved were trisomy 7, isochromosome 7q or 7p, and translocations or rearrangements involving chromosomes 3 and 18. Anbari et al., (2000) reported a case with low-level mosaicism for trisomy 2 and trisomy 8 who developed two osteosarcomas.
Kitao et al., (1999) reported mutations in the RECQL4 gene situated at 8q24.3 in three patients with Rothmund-Thomson syndrome. This gene codes for a DNA helicase. Mohaghegh and Hickson (2001) review the role of DNA helicases in cancer predisposition and premature ageing disorder. A further mutation in three brothers was reported by Lindor et al., (2000). Megarbane et al., (2000) reported a case with convincing features of Rothmund-Thompson syndrome, but with craniosynostosis.
Wang et al., (2002) reported a case of Rothmund-Thomson syndrome with a 11-bp intronic deletion of the RECQL4 gene. This resulted in a 66-bp intron too small for proper splicing. The authors suggest that this might be quite a common mutational mechanism and monitoring of intron size may allow detection of mutations missed by exon-by-exon approaches.
Wang et al., (2003) studied 11 patients with Rothmund-Thompson syndrome and osteosarcoma. At least one truncating mutation in the RECQL4 gene was found in all the patients. RTS patients without a truncating mutation did not have a high risk of osteosarcoma (no cases in 100 patient years of observation). A patient with Rothmund-Thomson and an osteosarcoma reported by Gelaw et al., (2004), had in addition Klippel-Feil syndrome.
Note that some patients with the Rothmund-Thomson phenotype have mutations in C16orf57 (as seen in dyskeratosis congenita and poikiloderma - type clericuzio).
Van RIj et al. (2017) described two siblings with typical characteristics of Rothmund-Thomson syndrome including poikiloderma, hyperpigmentation/hypopigmentation, sparse hair, absent eyelashes, sparse/absent eyebrows, alopecia areata, dental abnormalities, low birth weight, short stature, metaphyseal changes, osteopenia/osteoporosis, small patellae, oesophageal or pyloric stenosis, feeding problems, and chronic emesis/diarrhea. One of the sibs had Hodgkin’s lymphoma, developmental delay, and calcinosis cutis; a previously undescribed feature was osteoma cutis. Karyotyping and FISH analysis on lymphocytes from both brothers showing a mosaicism for trisomy 8, isochromosome 8q and a normal karyotype. Both siblings had a compound heterozygous mutation in RECQL4. Previously, one of these patients was diagnosed with a novel entity designated as calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnormalities (COPS) syndrome.
* This information is courtesy of the L M D.
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