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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