The diagnosis of RTS can be difficult. Several cases have been identified only after they had developed cancer, especially osteosarcoma [50
]. The onset of osteosarcoma in a young patient should raise the suspicion of a cancer predisposition syndrome such as retinoblastoma, Li-Fraumeni, Werner (see below) and RTS syndrome. In the absence of cancer, especially when other clinical signs are missing, the differential diagnosis begins with a dermatological examination and, if a chronic phase is established, the following causes of childhood poikiloderma should be taken in account [8
• Acrogeria (Gottron syndrome), a premature skin aging syndrome, characterised by poikiloderma and lipoatrophy which affects mainly the distal extremities and manifests itself at birth or shortly afterwards. The skin becomes dry, thin, transparent and wrinkled, is easily bruised and exhibits telangiectasia. Hair and eyes are normal. Small stature has been reported in several patients.
• Hereditary sclerosing poikiloderma (AD), the main signs of which are a generalised poikiloderma appearing in childhood, with accentuation in flexural areas and on extensor surfaces and sclerodermatous plaques on palms and soles.
• Dyskeratosis congenita (XR, AD or AR) characterised by the triad: abnormal skin pigmentation (89% of patients), nail dystrophy (88%) and leukoplakia (78%). Skin changes are characterised by reticulated hyperpigmentation or hypopigmentation on the face, the neck, the trunk, and the thighs. The onset of poikiloderma and other clinical manifestations occurs generally during childhood, though later than in RTS. Severe nail involvement is the initial feature, which is followed by poikiloderma. Defective dentition and mental retardation are more commonly noted than in RTS. There is no photosensitivity. About 80-90% of patients develop bone marrow abnormalities by the age of 30.
• Kindler's syndrome (bullous acrokeratotic poikiloderma) (AR), is a hereditary bullous poikiloderma syndrome, where poikiloderma arises generally at the age of 2-3 years. Chronic trauma-induced blistering and photosensitivity, which usually start in early infancy, develop further. Indeed, the patients typically show acral bullae, which are present at birth or develop during the first few days of life, with an onset often resembling epidermolysis bullosa. The trauma-induced blistering and photosensitivity of early infancy improve with age giving place to poikiloderma, more prominent on the face and neck, and involving sun-exposed and non-sun-exposed skin, while skin atrophy is diffuse. Additional features include stenosis of the oesophagus, anus and urethra, webbing of digits, ectropion and chronic inflammation of oral mucosa, dental abnormalities and anhidrosis. A few of these signs may also be found in RTS patients.
• Xeroderma pigmentosum (AR), an accelerated photo-aging syndrome, with clinical signs limited to UV-exposed skin/tissue. Acute sun sensitivity from early infancy, characterised by severe sunburn with blistering or persistent erythema after minimal sun exposure, affects 50% of the patients. Numerous freckle-like hyperpigmented macules appear on sun-exposed skin in all individuals, and typically, when present on the face of a child before age two years, represent the hallmark of the disease. These abnormalities evolve into poikilodermatous changes in late childhood and give a greater than 1000-fold increased risk of cutaneous skin cancer. Ophthalmologic abnormalities are as frequent as cutaneous findings and are usually limited to the UV-exposed portion of the eyes: conjunctiva, cornea, and lids (no congenital cataract). Other signs include neurologic abnormalities (30% of patients).
• Clericuzio type Poikiloderma with Neutropaenia (PN)
(AR). Poikiloderma on the face and limbs (starting in infancy) and short stature are features in common with RTS. However, unlike in RTS, the poikiloderma spreads from a rash arising on the distal limbs to the rest of the body, without sparing the flexural areas and trunk. Other particular signs of Clericuzio Poikiloderma are neutropaenia causing recurrent, especially pulmonary, infections, and pronounced hyperkeratotic nails, especially of the toes. No photo or heat sensitivity has been reported [94
]. The gene for Clericuzio type Poikiloderma with Neutropenia (PN) has been recently identified [96
], confirming the distinct genetic control of PN and RTS.
• Exocrine pancreatic hypofunction and atrophy of the pancreas
have been recently described in a 20-year-old male with many clinical features of RTS, but no mutation in the RECQL4
]. Due to marked blister formation, the initial differential diagnosis included epidermolysis bullosa (EB) and Kindler syndrome (KS). The authors considered this case to be a peculiar variant of RTS.
Other rare genodermatoses, with prominent telangiectasias but not true poikiloderma, also need to be differentiated from RTS. They comprise a panel of DNA repair defects, in particular Bloom's syndrome and Werner syndrome, which are caused by defects in two other RECQ helicases and are also characterised by chromosomal instability.
• Bloom's syndrome (AR) is characterised by skin lesions (patchy areas of hypo- or hyperpigmentation) that are caused by chronic exposure to the sun. These develop from a red sun-sensitive telangiectatic erythema, which appears during the first or second year of life, into a "butterfly distribution" on the face (similar to lupus erythematosus) and sometimes on the dorsa of the hands and forearms. However, the hallmark of the syndrome is the consistent proportionate pre- and postnatal growth retardation accompanied by dolichocephaly, and predisposition to a wide variety of malignancies. Recurrent infections (otitis media and pneumonia), chronic pulmonary disease, diabetes mellitus and learning disabilities are common.
• Werner syndrome (AR) has a few clinical features of premature aging in common with RTS. Werner syndrome is also known as segmental progeria of the adult, as the cardinal signs (i.e. bilateral cataracts, short stature, premature greying, a "bird-like" facies and skin changes) appear after the age of ten. Skin changes include scleroderma-like lesions on acral areas, with mottled hyperpigmentation, telangiectasias, subcutaneous calcification and ulceration. Increased risk of mesenchymal cancer, OS included, has been recorded.
• Fanconi anemia
(AR) presents with skin pigmentary changes occurring in 55% of the patients, characterised by generalised, dusky, olive-brown pigmentation that is most intense on the lower part of the trunk, in the flexures, and on the neck (85% of patients) [17
]. Short stature (51%) and upper limb malformations (43%) are signs in common with RTS. Pancytopaenia typically presents in the first decade. Malformations of the eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system may be present. The patients may also suffer from hearing loss, hypogonadism and developmental delay.
• Ataxia-telangiectasia (AR) patients show a combination of progressive cerebellar ataxia, severe combined immunodeficiency (affecting mainly the humoral immune response) and oculocutaneous telangiectasia. Onset, related to ataxia, usually occurs first when the child begins to walk. Cutaneomucosal telangiectasias, which become apparent between the ages of 3 and 7 years, are first seen on the face. These then extend to the neck, the dorsa of the hands and feet, and to the antecubital and popliteal areas. Growth delay is also relatively frequent. Cancer predisposition, particularly to leukaemia and Hodgkin's lymphoma, has been noted.
• Cockayne syndrome patients develop a photodistributed erythema, atrophy, and hyperpigmentation. They may simulate RTS, but later develop typical facies, limb abnormalities, wasting and neurological manifestations between the ages of 1 and 2 years. Diagnosis is based on clinical findings: poikiloderma, dwarfism, mental retardation, pigmentary retinopathy, blindness and conduction hearing loss.