Cowden's disease--a report on the first case in Korea and literature review

Cowden's disease, or multiple hamartoma syndrome, is an uncommon condition with characteristic mucocutaneous lesions associated with abnormalities of the breast, thyroid, and gastrointestinal tract. We describe a 32-year-old man with oral mucosal papillomatosis and plantar hyperkeratosis as a definite case of Cowden's disease according to the criteria proposed by Salem and Steck. The patient also had a thyroid mass and numerous gastrointestinal polyps endoscopically. Histologically the polyps were hamartomatous or hyperplastic polyps. The oral papillary lesions were fibroepithelial polyps and the thyroid mass was a follicular adenoma. We review the literature on this entity and summarize the pertinent findings. To the best of our knowledge, this is the first documented case of Cowden's disease in a Korean.     

Diffuse esophageal glycogenic acanthosis: an endoscopic marker of Cowden's disease

Cowden's disease is a rare autosomal dominant condition characterized by multiple hamartomas of ectodermal, endodermal, and mesodermal origin affecting many organ systems. Gastrointestinal manifestation includes the formation of multiple polyps of various benign histopathological types throughout the alimentary tract. Recent literature suggests that the frequency of gastrointestinal involvement is approximately 70-85%. The diagnosis of Cowden's disease, however, relies mainly on subtle dermatologic findings, which may not be obvious to the gastroenterologist. We describe a patient with Cowden's disease and review the English literature on the topic of gastrointestinal polyposis and Cowden's disease. These studies suggest that gastrointestinal polyposis is commonly found in this disease, and that diffuse esophageal glycogenic acanthosis is a characteristic feature of Cowden's disease. We propose that the finding of extensive glycogenic acanthosis in the presence of other benign gastrointestinal polyposis should be considered pathognomonic for the diagnosis of Cowden's disease.     

The high rate of antibodies to hepatitis E virus in young, intravenous drug-abusers with acute hepatitis B-virus infection in a Swedish community: a study of hepatitis markers in individuals with intravenously or sexually acquired hepatitis B-virus infection

Sclerotic fibroma is an uncommon fibrotic neoplasm that occurs both sporadically as well as in patients affected by Cowden's disease. We present an additional case of solitary sclerotic fibroma not associated with Cowden's disease. Although most of the lesion was sclerotic, there was a cellular area with some multinuclear cells. We conclude that sclerotic fibroma is a mesenchymal neoplasm whose clinical and histopathologic features are not only different but opposite to those of dermatofibroma.     

Inherited syndromes of colon polyps

Recognition of the mendelian dominant inherited syndrome of familial polyposis coli in the 1930s has been followed by the recognition of many inherited colonic polyposis syndromes. The recognition of different histological types of colon polyps was associated by the gradual recognition that some, such as the hamartomatous polyps, do not progress into adenocarcinoma, and others, such as various adenomas have a greater or lesser propensity to eventually give rise to invasive cancer. As the host of inherited syndromes expanded and were more widely recognized, additional inherited characteristics became apparent: such tumors as breast and thyroid associated with Cowden's syndrome, ovarian cysts and sex cord tumors with Peutz-Jeghers syndrome, and, of course, the soft tissue, bony tumors, ampullary cancers, and fibroadenomas associated with Gardner's syndrome. In recent years, genetic markers for the various syndromes have been studied, and in some cases confirmed. This whole field is rapidly developing and is briefly covered. All the steps and influencing factors in cancer development are shown in one phase or another of the polyp-cancer sequence in these inherited syndromes.     

Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome)

BACKGROUND: Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, a storage-pool deficiency, and lysosomal accumulation of ceroid lipofuscin, which causes pulmonary fibrosis and granulomatous colitis in some cases. All identified affected patients in northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of a recently cloned gene, HPS. We compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. METHODS: Forty-nine patients -- 27 Puerto Ricans and 22 patients from the mainland United States who were not of Puerto Rican descent -- were given a diagnosis on the basis of albinism and the absence of platelet dense bodies. We used the polymerase chain reaction to determine which patients carried the 16-bp duplication. RESULTS: Twenty-five of the Puerto Rican patients were homozygous for the 16-bp duplication, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80 percent of the predicted value. High-resolution computed tomography in 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in eight patients without the duplication revealed minimal fibrosis in three and no fibrosis in the rest. Inflammatory bowel disease developed in eight patients (four in each group) between 3 and 25 years of age. CONCLUSIONS: The 16-bp duplication in exon 15 of HPS, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.     

All roads lead to Rome? The multiple pathways of protein folding

A family was cytogenetically studied because of the birth of a male child with a multiple congenital anomaly pattern, in whom a dup (4q) recombinant was found. His phenotypically normal mother's karyotype showed an apparently balanced pericentric inversion in a chromosome 4. So as to analyze the occurrence of recombinants, the cytogenetic data from this family are compared with those of the 18 previously reported familial cases of pericentric inversions (PIs) of chromosome 4. The congenital anomalies observed in the child strongly suggest Wolf-Hirschhorn syndrome but some of his clinical features seem to be pathogenetically related to the presence of lymphedema during the intrauterine period. In the multiple congenital anomaly pattern observed in this patient, the lymphedema could be the consequence of the large 4q duplication. The review of chromosome 4 PIs with 4q duplication suggests that the q3 region should be examined when edema is detected prenatally.     

Clinical and research issues in breast cancer genetics

Breast cancer is the most common form of cancer in women in the U.S. The risk factors for developing breast cancer include increasing age, a family history of breast cancer, and the lack of a child by age 30. A substantial fraction of breast cancer, however, occurs in women who have no identifiable risk factors. The diagnosis, pathology, treatment, and presymptomatic testing of cancer susceptibility genes are reviewed. Syndromes with an associated risk of breast cancer are described, such as hereditary breast-ovarian cancer syndrome, Li-Fraumeni syndrome, ataxia telangiectasia, and Cowden's disease. With the localization of the BRCA1 gene to chromosome 17q21 and the BRCA2 gene to chromosome 13q12, issues surrounding breast cancer susceptibility genetic testing are assuming an ever greater measure of importance. The sensitivity and specificity for molecular testing of cancer susceptibility genes, however, have not been well defined. The progress in presymptomatic genetic testing is further hampered by various factors such as the technical difficulty in distinguishing mutations from polymorphisms, the number of different mutations identified thus far and the possibility of false positive and false negative results. Laboratory quality assurance/quality control issues are of paramount importance to avoid misleading interpretations. Many issues surrounding genetic screening and testing, such as insurance and employment discrimination, privacy, and informed consent, are under active debate, and guidelines and standards are under active development. It is therefore important to proceed with caution, so that irreversible harm resulting from data misinterpretation can be avoided.     

Non-thyroid illness" or changed thyroid hormone parameter syndrome with non-thyroid illnesses

BACKGROUND: The multiple effects of systemic illness on thyroid economy are commonly referred to "non-thyroidal illness" (NTI) or "sick euthyroid syndrome". The various aspects of this common syndrome are summarized in this article. STUDIES: Results of the relevant studies published during the past 25 years were evaluated. The influence of the underlying illness and of drug administration was especially emphasized. RESULTS: The most common abnormalities in NTI are 1. the "low-T3 syndrome" due to a decreased T3 generation from T4 by a reduced activity of 5'-deiodinase (a selenoprotein); 2. the "low-T3 low-T4 state", which is associated with a poor prognosis. The low T4-levels are related to a binding inhibitor that displaces T4 from its binding proteins. However, there exists some controversy regarding the character of this binding inhibitor. 3. The high-T4 state is often found in acute psychiatric and liver diseases. The nutritional status of the patients and drugs known to influence thyroid hormone parameters have to be considered when patients with NTI are evaluated. Some difficulties may arise, when there is evidence of coexisting thyroid disease. Here aside from further biochemical evaluation such as thyroid antibodies, thyroid ultrasound and a thyroid scan have to be performed. CONCLUSION: NTI is associated with various alterations in thyroid hormone parameters when no intrinsic thyroid hormone disease exists. The severity of NTI reflects clinical outcome and clinical amelioration is associated with normalization of thyroid hormone parameters. There is no need for specific therapeutic intervention such as the administration of thyroid hormones in patients with the various forms of the NTI-syndrome.     

Antenatal diagnosis of congenital heart disease and Down's syndrome: the potential effect on the practice of paediatric cardiology

OBJECTIVE: To predict the effect of antenatal ultrasound screening for congenital heart disease and maternal serum screening of Down's syndrome on the practice of paediatric cardiology and paediatric cardiac surgery. DESIGN: A retrospective and prospective ascertainment of all congenital heart disease diagnosed in infancy in 1985-1991. SETTING: One English health region. PATIENTS: All congenital heart disease diagnosed in infancy by echocardiography, cardiac catheterisation, surgery, or necropsy was classified as "complex", "significant", or "minor" and as "detectable" or "not detectable" on a routine antenatal ultrasound scan. RESULTS: 1347 infants had congenital heart disease which was "complex" in 13%, "significant" in 55%, and "minor" in 32%. 15% of cases were "detectable" on routine antenatal ultrasound. Assuming 20% detection and termination of 67% of affected pregnancies, liveborn congenital heart disease would be reduced by 2%, infant mortality from congenital heart disease by 5%, and paediatric cardiac surgical activity by 3%. Maternal screening for Down's syndrome, assuming 75% uptake, 60% detection, and termination of all affected pregnancies, would reduce liveborn cases of Down's syndrome by 45%, liveborn cases of congenital heart disease by 3.5%, and cardiac surgery by 2.6%. CONCLUSIONS: Screening for congenital heart disease using the four chamber view in routine obstetric examinations and maternal serum screening for Down's syndrome is likely to have only a small effect on the requirements for paediatric cardiology services and paediatric cardiac surgery.     

Cerebral lesions of mature newborn due to perinatal hypoxia. I. Placental and umbilical cord pathology

We report the case of a patient with multiple endocrine neoplasia type three, which was first diagnosed by members of the department of Ophthalmology. He was found to have multiple mucosal neuromata and medullary thyroid carcinoma. The ocular components of this syndrome include visible corneal nerves, conjunctival neuromas, thickened lids, anterior displacement of the cilia and a "dry eye" syndrome. The major systemic components are medullary thyroid carcinoma and pheochromocytoma. It is important that the Ophthalmologist recognize the ophthalmic manifestations of this syndrome so that early diagnosis and treatment may be possible.     

Direct detection of multiple point mutations in mitochondrial DNA

Mitochondrial defects can be caused by mutations in nuclear or mitochondrial DNA. Large deletion/duplication and point mutations are the two major types of mitochondrial DNA (mtDNA) mutations. Comprehensive molecular diagnosis requires the analysis of multiple point mutations. We developed an effective multiplex PCR/allele-specific oligonucleotide (ASO) method to simultaneously screen multiple point mutations in mtDNA. The system involved three pairs of primers to amplify mutation "hot spots" at tRNA(leu(UUR)), tRNA(lys)/ATPase, and ND4 regions, followed by detection of point mutations with ASO probes. Over 2000 specimens were analyzed and the results were compared with those from previous studies with the PCR/restriction fragment length polymorphism method. Our data demonstrate that the multiplex PCR/ASO method is much more sensitive in the detection of low mutant heteroplasmy. It is simple and cost effective, especially if a large number of samples are to be screened for multiple point mutations.     

Alteration of the LIS1 gene in Japanese patients with isolated lissencephaly sequence or Miller-Dieker syndrome

Maffucci's syndrome is a rare, congenital disease due to neuro-ectodermal dysplasia and is characterized by enchondromatosis and multiple soft tissue haemangiomata. A case of Maffucci's syndrome with haemangiomata along the upper airways requiring laser surgery is described. The literature on Maffucci's syndrome is reviewed.     

Chondrosarcoma in nasal fossae and Maffucci's syndrome

INTRODUCTION: Maffucci's syndrome is a congenital non-hereditary disease very similar to Ollier's disease and associates multiple cutaneous hemangiomas, dyschondroplasia and often enchondromas. EXEGESIS: We report a unique case involving synchronous localization of chondrosarcoma in nasal fossae and anterior chest wall, disclosing Maffucci's syndrome. CONCLUSION: Atypical chondrosarcoma localization must lead to further investigation of potential multiple enchondromatosis.     

The usefulness of intra-operative endoscopy in Peutz-Jeghers syndrome: a case report

The Peutz-Jeghers syndrome is an autosomal dominant inherited disease manifested by a combination of mucocutaneous pigmentation and gastrointestinal hamartomatous polyps that usually cause intussusception and intestinal hemorrhage. We report a case in which the patient has been followed-up on for 14 years and who underwent surgical and endoscopic polyp removal several times as well as one intestinal resection. This time, with the use of combined surgery and perioperative endoscopy, 27 polyps were removed, performing only 3 enterotomies. This is the highest number in one session to be reported in the literature. The usefulness of this technique is providing a "clean small intestine" that allows the patient a longer time interval between laparotomies and reduces the complications associated with multiple laparotomies and resections.     

Intralesionally implanted cisplatin plus systemic carmustine for the treatment of brain tumor in rats

Early alexia and higher visual impairments characterize Posterior cortical atrophy (PCA), a progressive dementing syndrome most often caused by Alzheimer disease. Posterior cortical atrophy is rare, and the nature of the visual impairments in PCA are unclear. The authors observed two patients who had an insidiously progressive reading difficulty characterized by letter-by-letter reading and otherwise intact cognitive functions. Over time, these patients developed "ventral simultanagnosia" with preserved detection of multiple stimuli but inability to interpret whole scenes. Subsequently, they progressed to Balint syndrome with "dorsal simultanagnosia," optic ataxia, and oculomotor apraxia. Structural imaging was normal, but functional imaging revealed posterior cortical dysfunction. On a letter reading task, both patients had a word superiority effect, and on a whole word reading task, they could not read most words with missing or crosshatched letters. An inability to assess whole scenes progressed to an inability to detect more than one stimulus in an array. These findings suggest an evolution of PCA with progressive difficulty in visual integration beginning with letters, progressing to whole scenes, and culminating in Balint syndrome. These changes may reflect an extension of the pathophysiology of PCA from the extrastriate visual cortex to its occipitotemporal and occipitoparietal connections.     

Variability of the clinical picture and the classification of progressive systemic scleroderma

Fiftythree patients with progressive systemic sclerosis were studied. Four of them (3 males) had the diffuse form of the disease. The skin manifestation of this clinical picture is characterized by diffuse progression of the cutaneous sclerosis over almost the whole body surface, except for the hands where it eventually may appear late. The prognosis for these patients it especially poor. Fortyfive patients (44 females) had acrosclerosis in the widest sence. Twentyseven of these ("acrosclerosis stricto sensu") had cutaneous sclerosis of the hands, face, and often other parts of the body, but not on the abdomen, arms or thighs. The remaining 18 patients had sclerotic alterations on these surfaces also. In this syndrome (which the authors call "the intermediary syndrome"), i.e. where the abdomen, arms, and thighs also are affected, certain internal organs and the joints are more involved than in "acrosclerosis stricto sensu". With rare exceptions, a symptomatic tetrade (REST-syndrome) occurred in acrosclerosis and all the intermediary syndromes. This consisted of Raynaud's syndrome (R), esophagopathy (E), cutaneous sclerosis (S), and telangectasia (T). Fifty % of the patients in addition had calcinosis (C), either subcutaneous or para-articular. The tetrade "REST syndrome" becomes in these cases the pentade "CREST syndrome". The addition of calcinosis to the other four phenomena of the REST syndrome does not alter the frequency of internal organ involvement or the prognosis of the disease. The term "REST syndrome" and its variant "CREST syndrome" should replace the conservative term "acrosclerosis" because they add to the purely cutaneous phenomena other characteristic manifestations of the disease. Two patients could neither be classified under the REST syndrome nor the progressive diffuse syndromes. Two other patients had no cutaneous phenomena ("scleroderma sine scleroderma").     

West's syndrome associated with inversion duplication of chromosome 15

We describe a five year old boy with inversion duplication of chromosome 15 (inv dup (15)) who, at the age of six months had started to develop West's syndrome. He later developed cryptogenic myoclonic epilepsy which was resistant to medication. On examination there was dysmorphia, overall hypotonia and diffuse pyramidalism. On starting ACTH the crises of flexion spasms were reduced but these were soon followed by myoclonic crises, both tonic and atonic, which did not respond to the various anticonvulsive treatments given. We comment on the changes in chromosome 15 linked to convulsions, and particularly the phenotypes of the inv dup (15) which depend on the size and genetic composition of the anomaly. This is the third case described in the literature of a patient with West's syndrome associated with supernumerary inversion duplication of chromosome 15. It is suggested that the karyotype be included when studying convulsive encephalopathies and cryptogenic refractory epilepsy, especially in infantile spasms.     

Zollinger-Ellison syndrome. Improved treatment options for this complex disorder

Zollinger-Ellison syndrome is a rare disorder characterized by severe peptic ulcer disease, gastric acid hypersecretion, and non-beta islet cell tumors of the pancreas. Most gastrinomas are found within an anatomic area known as the gastrinoma triangle. However, they commonly occur in extrapancreatic sites in multiple endocrine neoplasia type 1 syndrome. In patients in whom Zollinger-Ellison syndrome is suspected, laboratory evidence of hypergastrinemia and hyperacidity establishes the diagnosis. Until the advent of proton pump inhibitors, total gastrectomy was the treatment of choice. Therapy with these agents (eg, omeprazole, lansoprazole) can prevent ulcer disease. However, surgical removal of gastrinomas offers a chance for cure and can improve longevity by preventing the malignant spread of the tumors.     

Health care of adolescents

Partial trisomy 6p with duplications ranging from 6p21 to 6p25 is emerging as an established syndrome. A case of duplication of segment p22-p25 of the short arm of chromosome 6 as the result of a maternal t (1;6)(q44;p22.2) translocation in a mentally retarded girl with congenital anomalies is reported here. The associated phenotypic anomalies are compared with other reported cases of duplication 6p involving adjacent regions.