Cerebrotendinous xanthomatosis: case report with evidence of oxidative stress

Cerebrotendinous xanthomatosis is an autosomal recessive disorder of bile acid synthesis, characterized by mutation in the mitochondrial enzyme 27-hydroxylase that leads to an accumulation of cholestanol and cholesterol. Characterized clinically by premature bilateral cataracts, slowly progressive neurological deterioration with dementia, cerebellar and brainstem signs, peripheral neuropathy, and seizures, the disease presents pathologically with lipid granulomata with foamy histiocytes and cholesterol clefts. Replacement therapy with chenodeoxycholic acid slows progression of the disease but does not reverse neurological deficits. Here, we present the case of a 49-year-old woman diagnosed at autopsy with cerebrotendinous xanthomatosis, on the basis of bilateral Achilles tendon granulomas, and typical foamy histiocytic infiltration of the brain, most severe in the dentate nucleus, and a typical clinical presentation. To investigate the pathological manifestations of this disease further, we performed immunohistochemistry for N(epsilon)-(carboxymethyl)-lysine, an indicator of oxidative damage, and found strong labeling of cytoplasmic material within histiocytes. In summary, this case of undiagnosed cerebrotendinous xanthomatosis during life emphasizes the need for a greater awareness of the disease, and early diagnosis and treatment. Further, the involvement of oxidative stress in cerebrotendinous xanthomatosis indicates that combined therapy with chenodeoxycholic acid and antioxidants may improve clinical outcome.     

Cerebrotendinous xanthomatosis: case report with evidence of oxidative stress

Abstract

Cerebrotendinous xanthomatosis is an autosomal recessive disorder of bile acid synthesis, characterized by mutation in the mitochondrial enzyme 27-hydroxylase that leads to an accumulation of cholestanol and cholesterol. Characterized clinically by premature bilateral cataracts, slowly progressive neurological deterioration with dementia, cerebellar and brainstem signs, peripheral neuropathy, and seizures, the disease presents pathologically with lipid granulomata with foamy histiocytes and cholesterol clefts. Replacement therapy with chenodeoxycholic acid slows progression of the disease but does not reverse neurological deficits. Here, we present the case of a 49-year-old woman diagnosed at autopsy with cerebrotendinous xanthomatosis, on the basis of bilateral Achilles tendon granulomas, and typical foamy histiocytic infiltration of the brain, most severe in the dentate nucleus, and a typical clinical presentation. To investigate the pathological manifestations of this disease further, we performed immunohistochemistry for N^?-(carboxymethyl)-lysine, an indicator of oxidative damage, and found strong labeling of cytoplasmic material within histiocytes. In summary, this case of undiagnosed cerebrotendinous xanthomatosis during life emphasizes the need for a greater awareness of the disease, and early diagnosis and treatment. Further, the involvement of oxidative stress in cerebrotendinous xanthomatosis indicates that combined therapy with chenodeoxycholic acid and antioxidants may improve clinical outcome.     

Cerebrotendinous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27 hydroxylase gene (CYP27). Clinically, a multitude of neurological, skeletal, and vascular manifestations are usually present. Premature atherosclerosis has been reported in CTX and may be related to the metabolic derangement caused by the deficiency of the enzyme. A CYP27 nonsense mutation created by the deletion of cytosine376 has been identified in four Israeli Druze CTX patients residing in the same village. Molecular screening for this mutation in families of two probands revealed a total of 10 homozygotes and 28 heterozygotes whose clinical and biochemical characteristics are described. Overall, except for tendon xanthomas, most of the clinical manifestations progress with age. The CYP27 mutation was associated with modest differences in the levels of plasma total cholesterol (TC) and LDL cholesterol (LDL-C). The distribution of plasma concentrations of TC and LDL-C in the CTX families was consistent with a polygenic model. A similar model that includes also the effects of the CYP27 genotypes was not better supported by the data. It may be concluded that, in CTX, the presence of a CYP27 mutation does not significantly affect the plasma concentrations of lipids and lipoproteins. Therefore, the reported increased prevalence of atherosclerosis in this disease must be related to other factors.     

Cerebrotendinous xanthomatosis: An inborn error in bile acid synthesis with defined mutations but still a challenge

Cerebrotendinous xanthomatosis [CTX] is a rare disease characterized by the accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene [CYP27A1] involved in bile acid synthesis. Disruption of this gene in mice does not give rise to xanthomas. The gene defect leads to reduced bile acid synthesis with a compensatory increase in the activity of the rate-limiting enzyme in bile acid synthesis, cholesterol 7α-hydroxylase. This leads to a marked accumulation of 7α-hydroxylated bile acid precursors, in particular 7α-hydroxy-4-cholesten-3-one. The latter oxysterol passes the blood-brain barrier and is an efficient precursor to cholestanol. The activity of cholesterol 7α-hydroxylase is normalized by treatment with bile acids. Such treatment reduces the xanthomas in CTX patients in parallel with decreased cholestanol levels. The relationship between the accumulation of cholestanol and the development of cholesterol-rich xanthomas has however not been clarified and a suitable animal model is still lacking.     

骨髓中检出组织胞浆菌1例

组织胞浆菌（Histoplasma capsulatum）是一种深部真菌,可引起人体深部组织胞浆菌病。最近我们从1例患者骨髓涂片瑞氏染色、PAS染色、骨髓病理活检中检出组织胞浆菌,现予报道。     

Proboscis lateralis: a case report

A lateral proboscis usually occurs in the region of the inner canthus. We present a case of holoprosencephaly accompanied by an oblique facial cleft and an anterior encephalocele in which a proboscis lateralis occurred in a very lateral location.     

Acitretin embryopathy: a case report

BACKGROUND: Acitretin is an aromatic retinoid analog of vitamin A. Drugs of this group are well-known teratogenic agents. Nevertheless, acitretin embryopathy has been described only in fetuses. CASE: An infant was exposed to 10 mg/day of acitretin from the beginning of pregnancy until the 10th gestational week. At term, the newborn showed the following abnormalities: microcephaly, epicanthal folds, low nasal bridge, high palate, cup-shaped ears, anteverted nostrils, atrial septal defect, and bilateral sensorineural deafness. At 18 months of age, the patient showed microcephaly and neurodevelopmental delay. CONCLUSIONS: Our patient shows a pattern of anomalies resembling that observed in isotretinoin- and etretinate-exposed children. After ingestion, acitretin is partially converted into etretinate, and etretinate is partially metabolized into acitretin. A similar phenotype would therefore be expected after prenatal exposure to either drug. Moreover, in the present case, teratogenic effects were observed even though the dose was lower than in the previously reported acitretin embryopathy cases. Therefore, we propose that different retinoids, acitretin included, produce only one malformation pattern with variable phenotypic expression.     

Submandibular rhabdomyoma: a case report

BACKGROUND: The cytologic diagnosis of extracardiac rhabdomyoma is frequently hampered by its rarity and resemblance to various tumors. In this regard, the infrequent occurrence has hindered its prompt and early recognition. It is also confused with other tumors because of similarities in clinical and cytologic presentations. CASE: A submandibular rhabdomyoma occurred in an otherwise-healthy, 62-year-old man. The neoplasm was firstly diagnosed by fine needle aspiration cytology (FNAC. Complete local excision without radical surgery was performed. Histologic findings confirmed the cytologic diagnosis of adult rhabdomyoma. Treatment-related complications were minimal, and there was no evidence of recurrent disease 6 years later. CONCLUSION: Helpful FNAC features and immunocytochemical results permitted an early diagnosis and spared the patient unnecessary radical surgery.     

Pharyngeal actinomycosis: a case report

Actinomycetes are saprophytic bacteria of the oral cavity. They can produce a rare, chronic, and suppurative process that usually originates from the teeth and mandible and then involve the cervical region, especially in the sub-mandibular area. A case of actinomycosis occurring in the retropharyngeal space in a 74 year-old man is reported. It arose as a swelling behind the third lower left molar that had no lesion. The patient was treated successfully with antibiotic therapy. The clinical presentation and management of the case are discussed and the relevant literature is reviewed.     

Pseudodiastrophic dwarfism: a case report

On the occasion of one new possible observation of the pseudodiastrophic dworfism observed in a femal newborn, first child of young, non-consanguineous parents, authors discuss the differential diagnosis as well as the problem of genetic counselling in the present case since the child's father is a technician in radiology and exposed to X-rays during 7 years.     

Robinow Syndrome: a case report

We report a case with Robinow syndrome which has been rarely reported in the literature. A male newborn who had fetal face appearance (broad and prominent forehead, hypertelorism, small saddle nose, anteverted nostrils, glabellar nevus flammeus, malar hypoplasia, down-turned mouth and retrognathia), mesomelic limb shortening, hemivertebra and genital hypoplasia was diagnosed as Robinow syndrome. Elevated levels of both basal and stimulated testosterone and dihydrotestosterone were found along with normal baseline levels of gonadotropins. These endocrinologic studies were suggestive for an androgen insensitivity. Mental and motor development of the infant were normal at 3 and 6 months of age. Because of the high level of consanguineous marriages in Turkey, we may expect a higher incidence of the autosomal recessive form of the syndrome. This gives a high recurrence risk and makes prenatal diagnosis an important option for future pregnancies in the families.     

Multicystic nephroma: a case report

BACKGROUND: Cystic nephroma is an uncommon pediatric renal neoplasm. It needs to be differentiated from cystic partially differentiated nephroblastoma and from other renal neoplasms showing extensive cystic change. It is scantily reported in the cytology literature. CASE: A 7-month-old female with a left-sided abdominal lump was diagnosed as having cystic Wilms' tumor on computed tomography. Fine needle aspiration cytology showed cellular smears composed of monomorphic, round to oval cells, suggestive of a small round cell tumor, possibly rhabdomyosarcoma. However, histopathologic examination showed it to be a multicystic nephroma. On review of the cytologic smears, the blastemal component was absent. CONCLUSION: This case highlights 1 extreme and unexpected cytologic appearance of cystic nephroma; it may result in misdiagnosis.     

Fetus-in-fetu: report of a case

A 5 month-old female was brought to our clinic because of diarrhea and abdominal distension. A plain radiograph demonstrated a mass with a vertebral column in the right upper quadrant of the abdomen. At operation a mass was found to be retroperitoneal, well encapsulated, and connected to the abdominal aorta of the host by two small vessels; no other connections and adhesions were seen between the mass and the host. The ovaries, uterus, and other pelvic and abdominal viscera of the host were normal. The mass was diagnosed as a fetus-in-fetu. The fetus-in-fetu, encapsulated with an amniotic capsule, was covered with skin and had a top with long hair, two protuberances, an amniotic hernial sac, upper limbs with syndactylic fingers, a gluteal region, and lower limbs with polysyndactylic toes. A brain mass and a spinal cord were identified in the cranial cavity and the vertebral canal. Several spinal ganglia and a nerve plexus were found. A noselike structure, upper lip, maxillalike bone with teeth, tonguelike structure, intestines, ribs, bones of the extremities, and skeletal muscles were also identified. A cloacalike cyst was observed to have an opening in the external female genitalia. Microscopically, a small number of motor neurons were seen in the brain mass and the anterior horn of the spinal cord. In the spinal ganglia, ganglion cells were differentiated. The submucosal and myenteric plexuses were seen in the intestinal wall. Well-differentiated muscle fibers were often accompanied with myelinated nerve fibers. Hematopoiesis was observed in the cranial bone marrow. The presence of the sex chromatin was confirmed in the nuclei of motor neurons and polymorphonuclear leukocytes. Thus, the present fetus-in-fetu, which was connected to the abdominal aorta of the host by two vessels, was a monozygotic twin which developed within its own amniotic cavity.     

Multifocal fibromatosis: a case report

We present of rare case of multifocal fibromatosis in a 52 year-old women. In 1996, she was first evaluated for a tumour of the right breast and on the basis of the surgical specimen the extra-abdominal fibromatosis was diagnosed. Four years later, she was reevaluated for the tumor of the right lung, and then in 2001 for the lesion of the right parietal pleura. Microscopic examination of pulmonary and pleural lesions revealed histological pattern almost identical with the breast tumor. The recurrent lesions were located proximally to the primary one.