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Introduction
Rothmund-Thomson syndrome (RTS), also known as congenital poikiloderma, is a rare autosomal recessive genodermatosis affecting multiple systems. RTS usually begins in infancy and is characterized by the presence of predominantly facial poikiloderma (telangiectasias, dermal atrophy, hyperpigmented and hypopigmented patches), short stature, sparse hair, dystrophic nails, juvenile cataracts, psychomotor retardation, skeletal abnormalities, premature aging, and predisposition to tumor development, mainly bone. Up to 2001, 300 cases have been published worldwide1.
We present the following case series from the Hospital Infantil de México Federico Gómez.
Clinical cases
Case 1
We report the case of a 4-year-old male patient, a native of Tlaxcala, with the following important antecedents: consanguineous parents, 26-year-old brother with a probable diagnosis of RTS. Since birth, the presence of right thumb adactyly, hypoplasia of the left thumb, delayed growth and psychomotor development were reported.
The condition was identified at 3 months of age with the presence of coarse, dry, sparse hair and erythematous lesions on the face, which left hyperpigmented and hypopigmented patches with a reticulated pattern. The patient attended the pediatrics department with impaired hearing, skeletal alterations, narrow chin, short stature, severe malnutrition, and hypodontia.
The dermatology department evaluated the patient for presenting a disseminated dermatosis, including palms and soles, consisting of multiple areas of poikiloderma, telangiectasias, dermal atrophy, hyperpigmented and hypopigmented patches, moderate xerosis of chronic and asymptomatic evolution (Figure 1).
Figure 1 A, B. Facies characteristic of Rothmund-Thomson syndrome, with areas of poikiloderma and telangiectasias on the cheeks. C, D, E. Poikilodermal lesions on the trunk. F. Absence of the thumb.
A skin biopsy of one poikiloderma lesion was performed, which reported vacuolar interface dermatitis with epidermal atrophy, pigment detachment, and vascular dilatation (Figure 2). Genetic sequencing of the RECQL4 gene was requested, where the variant was identified in the homozygous state, confirming the diagnosis of RTS.
Figure 2 A, B. Histologic section of skin stained with hematoxylin and eosin showing the epidermis with lamellar hyperkeratosis and areas of hypergranulosis. C, D. Areas of atrophy, with vacuolization of the basal layer, individual basal necrotic keratinocytes.
Photoprotection was indicated every 4 hours and follow-up every 6 months to detect future neoplasms. The patient has no ocular involvement or development of bone tumors or malignant skin lesions and continues in multidisciplinary follow-up by the Genetics, Gastroenterology, Nutrition, Endocrinology, Stomatology, Audiology, Orthopedics, Rehabilitation, Ophthalmology, and Oncology services.
Case 2
We report the case of a 2-year-old female, a native of Mexico City, with no medical history of importance, who started with facial erythema at 3 months of age, which spread to the arms and legs. The parents took her to a private physician, who referred her to our institution to initiate the diagnostic approach.
The dermatology department evaluated the patient for presenting with a disseminated dermatosis on the head, trunk, and extremities, affecting the cheeks, arms, thighs, and legs, characterized by plaques of poikiloderma (telangiectasias, dermal atrophy, hyperpigmented and hypopigmented patches) with a chronic and asymptomatic evolution (Figure 3). A biopsy of one of the representative lesions showed lamellar hyperkeratosis, areas of hypogranulosis and atrophy, vacuolization of the basal layer, and necrotic keratinocytes. A perivascular inflammatory infiltrates of lymphocytes and histiocytes was found in the papillary and reticular dermis, with proliferation and dilatation of blood vessels, pigment deposition, and melanophages. Histological changes were compatible with a poikiloderma lesion (Figure 4). The Orthopedics service evaluated the patient for presenting a spontaneous fracture in the distal metaphysis of the left tibia, which was managed conventionally; the Endocrinology service followed her up for short stature and hypogonadism. To date, the patient does not present cataracts. Unfortunately, a genetic study has not been performed yet. She is currently under strict photoprotection every 4 hours and multidisciplinary follow-up every 6 months.
Discussion
RTS, also known as congenital poikiloderma, is a rare autosomal recessive atrophic dermatosis with few cases reported in the literature. In more than 90% of patients, symptomatology develops between the third and sixth months of life. It presents with erythematous plaques of reticulated appearance, mild hyperkeratosis, which leave residual hypo- and hyperpigmented patches as they progress, giving the affected area the characteristic appearance of poikiloderma1.
This dermatosis was first described by Auguste Rothmund in 1868 and later by Sydney Thomson, a British dermatologist, in 1923. In 1957, William Taylor proposed the eponym RTS, which is how the disease is known today. This disease predominates in males, with a ratio of 2:1. The incidence of RTS in our country is unknown; currently, about 300 cases have been reported worldwide1,2.
This syndrome has described two clinical subtypes: type I is characterized by poikiloderma-like lesions, ectodermal dysplasia, and juvenile cataracts; type II is characterized by poikiloderma, congenital bone alterations, and an increased risk of developing osteosarcoma and skin cancer3. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: subtype I is associated with a mutation in the ANAPC1 gene, and subtype II is caused by homozygous or compound heterozygous mutations in the RECQ-like helicase type 4 (RECQL4) gene, located on chromosome 8q24.3, detectable in approximately 65% of patients. This gene encodes a DNA helicase involved in DNA repair and replication4. In subtype I, the mutations are unknown. This type of mutation increases the risk of developing neoplasms5. The reduced DNA repair capacity could be related to the photosensitivity of these patients in early childhood. Although RTS is considered a genodermatosis with multisystem involvement, it is referred to as a chromosomal instability syndrome when mentioning the clinical subtypes3,6.
Skin lesions manifest in up to 90% of patients as facial erythema and edema and vesicles on the cheeks that may extend to the pinnae, forehead, neck, and extremities during the first months of life. As the patient grows, the characteristic lesions of poikiloderma (telangiectasias, atrophic, hyperpigmented, or hypopigmented plaques) develop and persist for the rest of the patient's life; 30% may develop palmoplantar hyperkeratosis. Hair and nail manifestations are observed in 30% of cases, mainly with fine, thin, and sparse hair, development of premature graying, areas of alopecia, and dystrophic nails or anonychia7.
Photosensitivity occurs in 30% of patients and can trigger blistering lesions. Warty keratoses may develop in photo exposed areas, which in the long term may develop skin cancer (basal cell carcinoma being the most common), including melanoma by the age of 20-30 years. Other neoplasms associated with RTS are hematologic, gastrointestinal, and osteogenic sarcomas6,7. Some manifestations associated with RTS are short stature, dental hypoplasia, and hypogonadism; patients may present with cataracts, coloboma, or keratoconus at an early age. In most cases, mental development is normal8,9.
The skeletal malformations described in these patients are bone shortening, predisposition to fractures, metaphyseal growth arrest, dysplastic changes in the phalanges, hypoplasia of the bones of the forearm or thumb, and hypoplasia or absence of the patella. These manifestations taken together can guide the diagnosis. The most dramatic association is osteosarcoma, which only occurs in RTS patients with RECQL4 mutations10,11.
Table 1 describes the main manifestations of RTS and their frequency of presentation and Table 2 lists the manifestations found in our case series.
Table 1 Main manifestations of Rothmund-Thomson syndrome*
| Clinical manifestations | Percentage |
|---|---|
| Skin − Erythema and facial edema, in early ages, evolving to poikiloderma changes: atrophy, telangiectasias, hyperpigmentation, or hypopigmentation − Photosensitivity, blistering − Hyperkeratosis on hands, feet, knees − Calcinosis cutis, actinic keratosis |
90% |
| Hair − Fine, sparse, progressing to partial or total alopecia, absence of eyebrows and eyelashes |
30% |
| Nails − Nail dystrophy, anonychia |
30% |
| Dental disorders − Caries, microdontia, conical teeth |
40% |
| Skeletal alterations − Saddle nose, prognathism, agenesis of carpus and thumb, syndactyly, osteogenesis imperfecta, hyperostosis, osteoporosis |
70% |
| Ocular alterations − Cataracts, keratoconus, coloboma, strabismus, amblyopia, microphthalmia, optic nerve atrophy, exophthalmos, glaucoma, photophobia, hypertelorism |
50% |
| Neoplasms − Osteosarcomas, basal cell carcinoma, squamous cell carcinoma, melanoma, fibrosarcoma, lymphoma, gastric carcinoma, myelodysplastic syndrome, acute myelocytic leukemia. |
3-32% |
| Others − Low birth weight, growth retardation, short stature, hypogonadism |
20-50% |
*Based on the clinical description in references 1, 3, 6, 8, 15, 16 y 17.
Table 2 Clinical differences between patients with Rothmund Thomson syndrome
| Clinical manifestations | Case 1 | Case 2 |
|---|---|---|
| Facial erythema | Absent | Present |
| Poikiloderma | Present | Present |
| Photosensitivity | Present | Present |
| Hyperkeratosis | Absent | Absent |
| Actinic keratosis | Absent | Absent |
| Hair disorders | Present | Absent |
| Nail disorders | Present | Absent |
| Ocular alterations | Absent | Absent |
| Dental alterations | Present | Absent |
| Skeletal alterations | Present | Present |
| Neoplasms | Absent | Absent |
| Short stature | Present | Present |
| Hypogonadism | Absent | Present |
| Hearing loss | Present | Absent |
| Malnutrition | Present | Absent |
Diagnosis is clinical and is confirmed with a molecular study to detect the RECQL4 gene mutation; however, access to this study can be limiting12.
Histopathology analysis showed poikiloderma, hyperkeratosis, epidermal atrophy, basal vacuolar change, rare apoptotic keratinocytes in the basal layer, numerous telangiectatic vessels, scattered dermal melanophages, and a variable infiltrate of upper dermal inflammatory cells13,14.
The differential diagnosis should be conducted with other pathologies, such as Cockayne syndrome, trichothiodystrophy, congenital dyskeratosis, Fanconi anemia, Bloom syndrome, and poikiloderma with neutropenia. However, other diseases may present the same dermatologic features, as in systemic lupus erythematosus, which may obscure the diagnosis15-17.
The management of these patients focuses on multidisciplinary follow-up and genetic counseling for early identification of the manifestations associated with the syndrome, thus maintaining strict surveillance to detect the development of possible neoplasms18,19.
The management of dermatologic lesions consists of avoiding ultraviolet radiation and strict photoprotection. Currently, it has been shown that telangiectatic lesions in these patients respond favorably to pulsed dye laser treatment. When malignant tumors do not develop, life expectancy is normal20,21.
The prognosis is limited to the occurrence of malignant neoplasms; however, there are reports of patients over 50 years of age22.
In this report, we emphasize the clinical and dermatologic characteristics of RTS. We have identified two patients diagnosed with RTS in the Hospital Infantil de México Federico Gómez, making this series the first case series reported in our country. From the dermatological point of view, it is essential to maintain strict surveillance of these patients since they are at higher risk of developing cutaneous neoplasms, such as basal cell carcinoma, squamous cell carcinoma, and, less frequently, melanoma. It is, therefore, necessary to implement photoprotection measures and avoid ultraviolet radiation from the early stages of life, which will increase the life expectancy of these patients.
