Rothmund-Thomson syndrome (RTS) is a rare genetic disease that affects many parts of the body, particularly the skin which is typically normal at birth. The first sign of this disease is a rash that starts on the cheeks between ages three months and six months as erthema, swelling, and blistering on the face and subsequently spreads to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectases. These skin problems persist for life, and are collectively known as poikiloderma. This disease is also characterized by sparse hair, eyebrows, and eyelashes, slow growth and small stature, abnormalities of the teeth and nails, juvenile cataract, skeletal abnormalities (mainly osteopenia and defects of the radial ray: thumb appendages, hypoplasia or aplasia of the thumbs, or radial aplasia), gastrointestinal problems in infancy such as chronic diarrhea and vomiting, premature aging and predisposition to malignant tumors, especially osteosarcomas. Additional findings include saddle nose and hypogonadism. 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. Most individuals with RTS appear to have normal intelligence.
The diagnosis of RTS is established by clinical findings, particularly the characteristic rash. Skin biopsy may show poikilodermatous changes, which are nonspecific, but consistent with RTS. The only available treatment of this disease is treatment of manifestations by pulsed dye laser to treat the telangiectatic component of the rash, surgical removal of cataracts, and standard treatment for cancer. Avoidance of excessive sun exposure and use of sunscreens with both UVA and UVB protection are recommended to prevent skin cancer due to the sensitivity of RTS cells to ionizing radiation and oxidative stress and damage. Prognosis for survival is fairly good because life span, in the absence of malignancy, is probably normal.
RTS is a rare disease; its incidence is unknown. Despite its long history, only about 300 cases with this disease have been reported worldwide in scientific studies.
RTS is inherited in an autosomal recessive pattern and caused by mutations in the helicase gene, RECQL4, which is the only gene associated with RTS to date. RECQL4 gene normally encodes ATP-dependent DNA helicase Q4 that has homology to a family of proteins known as RecQ helicases. Helicases are enzymes that bind to DNA and temporarily unwind the double helix of the DNA molecule, allowing many basic cellular processes to occur such as replication of the DNA in preparation for cell division, and for repairing damaged DNA. The exact role of this gene is not known, but it has recently shown that it may play a role in the initiation of DNA replication. Thus, the shortage or production of nonfunctional version of the RECQL4 protein caused by mutation in its gene may prevent normal DNA replication and repair, causing widespread damage to a person's genetic information over time. It is unclear how a loss of this protein's activity leads to the specific features of RTS. Interestingly, mutations in the RECQL4 gene cause only 60% of all RTS causes. Accordingly, RTS seems to be a heterogeneous disease and mutations in other, yet unidentified, gene(s) seem to be responsible for the phenotype of the remaining 40% of RTS patients. Furthermore, mosaic abnormalities of chromosome 8; such trisomy 8, partial 8q duplication, and tetrasomy 8q, have been identified in some RTS cases. It is believed that these chromosomal abnormalities cause overall genomic instability.
El-Khoury et al. (1997) described a case of a female child with multicentric osteosarcoma associated with Rothmund-Thomson syndrome (RTS).
Bugrein et al. (1995) described the first RTS case in Libya. The case is a 7-year-old Libyan female referred for the first time at the age of one year from the pediatrician as a case of atopic infantile eczema that started at the age of three months. The baby was born after uneventful full term pregnancy. There was no family history of a similar illness. However, the patient had a sister who died at the age of eight months because of congenital anomalies in the heart. Patient's parents are first degree cousin. At the age of seven years, she had mottled hypopigmented and telangiectatic lesions over the face, arms, legs, and buttocks. In addition, she developed popular warty lesions over dorsa of hands and feet. She was short statured with very short thumbs. The hair was sparse, short, and thin. Both eye brows and lashes were absent. There was no cataract or other extracutaneous features. Her motor and mental developments were normal. Skin biopsy showed thinned epidermis with hydropic degeneration of the basal layer with histiocytic lymphocytic infiltration in the upper dermis.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing (WES) in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism (IEM) and other genetic disorders. Among the cohort with non-IEM related genetic disorders in whom mutational pathogenicity was confirmed, 1 patient harboring a mutation in RECQL4 was diagnosed with Rothmund-Thomson syndrome. The patient had presented with intrauterine growth retardation and was born prematurely; clinical presentations include dry skin and suspicion of Microcephalic Osteodysplastic Primordial Dwarfism type II.
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