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Early blistering, poikiloderma, hypohidrosis, alopecia and exocrine pancreatic hypofunction: A peculiar variant of Rothmund-Thomson syndrome?

European Journal of Dermatology. Volume 18, Number 6, 632-4, Novembre-Décembre 2008, Genes and skin

DOI : 10.1684/ejd.2008.0509

Summary

Author(s) : Utako Otsu, Shinichi Moriwaki, Mariko Iki, Kenichi Nozaki, Yuji Horiguchi, Kimihiro Kiyokane , Department of Dermatology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki-city, Osaka 569-8686, Japan, Department of Dermatology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennouji-ku, Osaka-city, Osaka 543-8555, Japan.

Summary : A 20-year-old male developed early blistering, poikiloderma, hypohidrosis, alopecia and exocrine pancreatic hypofunction caused by atrophy and fatty replacement of the pancreas. At 5 months of age, he initially presented at the hospital with numerous blisters on his extremities, inguinal and genital area. A biopsy specimen from a vesicular lesion showed a subepidermal bulla. Electron microscopic examinations of a vesicular lesion revealed vacuolar changes of the basal cells without hemidesmosomes. Subsequently, the blisters gradually resolved and healed without scars. At the age of 11, he was admitted for the treatment of cellulitis on his foot and at that time, laboratory examinations detected a decreased level of pancreatic enzymes due to exocrine pancreatic hypofunction. Abdominal ultrasonography and computed tomography (CT) showed the pancreas to be atrophic with fatty replacement. A genetic analysis revealed no mutation in his RECQL4 gene, which is responsible for the pathogenesis of Rothmund-Thomson syndrome (RTS). Although marked blister formation and exocrine pancreatic hypofunction are unusual complications of RTS, this case showed many typical clinical features of RTS. Therefore, this case was considered to be a peculiar variant of RTS.

Keywords : Rothmund-Thomson syndrome, blister formation, exocrine pancreatic hypofunction, fatty replacement of pancreas

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ARTICLE

Auteur(s) : Utako Otsu¹, Shinichi Moriwaki¹, Mariko Iki¹, Kenichi Nozaki¹, Yuji Horiguchi², Kimihiro Kiyokane¹

¹Department of Dermatology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki-city, Osaka 569-8686, Japan
²Department of Dermatology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennouji-ku, Osaka-city, Osaka 543-8555, Japan

accepté le 22 Juin 2008

Rothmund-Thomson syndrome (RTS) was first described by Rothmund, a German ophthalmologist, in 1868, in a report of 10 related persons with early-onset poikiloderma and juvenile cataracts, in an isolated Bavarian village [1]. Several decades later, Thomson, a British dermatologist, reported three additional patients with similar skin findings, two of whom also had bony abnormalities [2, 3]. Now RTS is known to be a rare autosomal recessive genodermatosis characterized by poikiloderma appearing from infancy. In addition, patients exhibit variable clinical features including alopecia, dystrophic teeth and nails, juvenile cataracts, retarded physical development, hypogonadism, bony malformation and a high incidence of cutaneous and noncutaneous malignancies [4, 5]. This report describes a 20-year-old man thought to have a peculiar variant of RTS with unusual complications, including marked blister formation and exocrine pancreatic hypofunction as well as the typical clinical features of RTS.

Case report

A 5-month-old Japanese male infant was referred to the hospital for the evaluation of numerous blisters and erosions on his extremities, inguinal and genital area (figure 1A). An examination showed that poikiloderma was present on the cheeks and nose (figure 1B). His eyebrows were sparse. He had no episodes of photosensitivity. His parents were not consanguineous. His physical and intellectual development was appropriate for his age. A biopsy specimen from a vesicular lesion showed a subepidermal bulla and some incontinentia pigmenti. The basal cells showed vacuolar alterations (figure 2). An electron microscopic examination of a vesicular lesion revealed that the basal cells showed vacuolar alterations and hemidesmosomes were absent. The keratin filaments which were dissociated from the hemidesmosomes remained in the lower portion of the basal cells (figure 3). Poikiloderma gradually spread to his neck and trunk. At one year of age, the number of blisters gradually decreased and he experienced recurrent episodes of high fever. He was admitted to the hospital for an evaluation of the fever. Since the fever usually occurred after exercise and crying and a starch iodine test showed a reduction in sweating, he was diagnosed to have hypohidrosis. A skin biopsy from his trunk showed few eccrine glands in the dermis. At two years of age, his hair was sparse and the blisters resolved completely and healed without scars. When he was three years old, he was diagnosed to have both footdrop and clawhand by an orthopedist. At 11 years of age, he was admitted to the hospital again for the treatment of cellulitis on his right foot and at that time laboratory examinations revealed a marked exocrine pancreatic hypofunction. His serum amylase level was 102 IU/L (normal 33-120), serum pancreatic isoamylase; 5 IU/L (normal 14-41), phospholipase A₂ was less than 50 ng/mL (normal 130-400), lipase; 3 IU/L (normal 16-44), elastase 1; 25.5 ng/mL (normal 94-334 and, para-aminobenzoic acid (PABA) excretion test; 58.5% (normal 73.4-90.4). The result of an oral glucose tolerance test was normal. Abdominal ultrasonography showed his pancreas to be hyperechoic, especially in the body and tail and the pancreas could not be detected by abdominal CT. These findings suggested that the pancreas was atrophic with fatty replacement. Pancreatic enzymes were administered orally. At the age of 16, he was hospitalized again for the examination of weight loss (from 42 to 36 kg, in half a year). No internal malignancy was detected by ultrasonography, CT, magnetic resonance imaging (MRI) and a bone marrow examination. The level of pituitary and thyroid hormones and his basal metabolic rate were normal. These findings showed the weight loss to be due to malabsorption caused by an exocrine pancreatic hypofunction. His bone mineral density (BMD), measured with a DEXA (dual-energy X-ray absorptiometry scan), was decreased to L3-L4 BMD 0.569 ± 0.02 g/cm². Osteoporosis was diagnosed and he began to undergo bisphosphonate treatment. Nutrition supplement and intravenous hyperalimentation stimulated his weight to increase to 42 kg and subsequently he underwent an operation for scoliosis. A genetic analysis was performed and no harmful mutations were found in the RECQL4 gene. He is now 20 years old and has normal growth, dentition and intelligence. No cataracts, saddle nose, prognathism and hypogonadism have been detected.

Discussion

The current case showed many typical clinical features of RTS, including poikiloderma, hypohidrosis, alopecia and skeletal abnormalities (scoliosis, footdrop, clawhand). However, marked blister formation and exocrine pancreatic hypofunction are unusual complications in RTS. The initial differential diagnosis of this case included epidermolysis bullosa (EB) and Kindler syndrome (KS) in addition to RTS because of the early marked blister formation. In RTS, poikiloderma is sometimes accompanied by blister formation [6-8]. In epidermolysis bullosa hereditaria, poikiloderma is not an essential characteristic cutaneous lesion. The clinical features of KS are nail dystrophy, webbing between the fingers and toes or hyperkeratotic lesions on the extremities, none of which were detected in this patient. In addition, patients with KS have neither hypohidrosis nor alopecia [9]. A vesicular lesion in this patient showed a subepidermal bulla. An electron microscopic examination of the vesicular lesion revealed that the basal cells showed vacuolar alterations. These vacuolar alterations of the basal cells might indicate early cytolysis and the subepidermal cleavage was a consequence of the degenerative cytolytic changes of the basal cells. This vacuolar change is similar to EB simplex. However, unlike EB, hemidesmosomes were absent in this patient. No reduplication of the lamina densa, characteristic of KS, was observed in this case.

The patient had exocrine pancreatic hypofunction caused by atrophy and fatty replacement of the pancreas, which has not been previously reported in RTS. The only pancreatic complication of RTS described previously was an annular pancreas with duodenal stenosis. However, in that case, the pancreatic function was normal and no fatty replacement of the pancreas was detected [10]. The most common disorder associated with fatty replacement of the pancreas in children is cystic fibrosis (CF), followed by Schwachman-Diamond syndrome (SDS). CF is an autosomal recessive disease caused by abnormalities in the gene that codes for cystic fibrosis transmembrane regulator (CFTR) , which functions as a chloride channel on the apical membranes of the epithelial cells lining the airways, pancreatic ducts, sweat ducts, intestines, biliary tree and vas deferens. The clinical characteristics of CF include elevated sweat chloride concentration, lung disease characterized by bacterial infection and bronchiectasis, pancreatic insufficiency, intestinal obstruction and biliary cirrhosis [11-13]. SDS is a rare autosomal recessive multisystem disorder associated with bone marrow failure, pancreatic insufficiency and skeletal abnormalities. Hematologically, SDS is characterized by various degrees of cytopenia. The clinical diagnosis of SDS requires evidence of exocrine pancreatic dysfunction and characteristic hematological abnormalities. A human gene responsible for SDS, SBDS, has recently been isolated, however the functions of the SBDS gene product has not yet been fully elucidated [14]. Other rare causes of fatty replacement in children are steroid therapy, Cushing syndrome, Johanson-Blizzard syndrome (pancreatic insufficiency, nasal alar hypoplasia, an absence of permanent teeth, short stature, congenital deafness) and obesity [15]. The current case showed no clinical or laboratory evidence of these disorders or conditions and the causes of pancreatic atrophy and fatty replacement in this case were not clarified.

Recently, one of the human DNA helicase genes, RECQL4, was identified to be a gene responsible for some cases of RTS. In 1999, Kitao et al. reported three RTS patients carrying two types of compound heterozygous mutations in RECQL4 gene [16]. The RECQL4 protein belongs to the RECQ family, which includes several helicases involved in the pathogenesis of Bloom syndrome and Werner syndrome, both of which are genetic diseases manifesting similar clinical features of immunodeficiency, premature aging and a high frequency of cancer [16, 17]. RECQL4 is involved in the pathogenesis of some RTS cases and not all patients with RTS have RECQL4 mutations. Therefore, the absence of mutations in the RECQL4 gene does not mean that a patient does not have RTS. Patients without RECQL4 mutations may have problems in genes other than RECQL4 [16]. Since no mutations were identified in the RECQL4 gene in the current case, another mutation in the genes coding for other DNA helicases or DNA repair related factors, may have caused the RTS phenotype with blister formation and a deficient pancreatic exocrine function. Although no mutations were observed in the RECQL4 gene in this case, it was thought to be a peculiar variant of RTS with uncommon complications, including severe blister formation and pancreatic hypofunction, since this patient showed many of the typical clinical features of RTS such as poikiloderma, hypohidrosis, alopecia and skeletal abnormalities. Further investigation is required to clarify the relationship between severe blister formation, pancreatic hypofunction and RTS.

In 2003 Wang et al. performed a DNA analysis of the RECQL4 gene and found 23 of 33 RTS patients carried at least one deleterious mutation in the RECQL4 gene. They also examined the incidence of osteosarcoma in those RTS patients with and without mutations in the RECQL4 gene and concluded that the patients with RECQL4 mutations were at a higher risk of osteosarcoma in comparison to those without the mutations [18]. From this point of view, the current case is not in a high risk group for osteosarcoma, because no genetic abnormalities were found in the RECQL4 gene. However, patients with RTS are at increased risk of other malignancies (squamous cell carcinoma, Bowen’s disease, basal cell carcinoma, spinocellular carcinoma, Hodgkin’s sarcoma, gastric carcinoma and acute myelogenous leukemia, etc.) [5]. Therefore, there is a possibility for these malignancies to occur in this patient.

Acknowledgements

The authors are grateful to Dr. Lisa L. Wang for the genetic analysis. We also thank Drs. Takashi Hashimoto and Naohiro Hamada for their invaluable comments. Financial support: none. Conflict of interest: none.

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