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We describe a 3-generation family with lacrimo-auriculo-dento-digital syndrome (LADD). In addition to the well described abnormalities of ears, teeth, lacrimal apparatus and digits, the patients exhibit several previously undescribed anomalies, including minor facial anomalies (broad forehead, telecanthus, bulbous nasal tip, full jaw, ptosis and flared nostrils), involvement of the first and second toes, and congenital renal disease causing death in the neonatal period in 2 cases.
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PMID:Lacrimo-auriculo-dento-digital syndrome: evidence for lower limb involvement and severe congenital renal anomalies. 141 42

Leber's congenital amaurosis is a hereditary clinical disorder that may be associated with several different diseases. This study consists of a retrospective review of 43 cases. Twenty of our patients had fundus appearances that resembled retinitis pigmentosa. Five had normal-appearing fundi. The remainder had other, previously reported fundus abnormalities, with the exception of two patients who demonstrated a new fundus finding, a nummular pigmentary pattern. Other associated eye anomalies included cataracts, keratoconus, ptosis, and strabismus. The most frequent systemic associations were mental retardation, cystic renal disease, skeletal disorders, and hydrocephalus.
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PMID:Leber's congenital amaurosis. Retrospective review of 43 cases and a new fundus finding in two cases. 382 12

Coumarin is the basic structure of numerous naturally occurring compounds with important and diverse physiological activities. More than a thousand coumarin derivatives have been described, varying from simple coumarins containing alkyl and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl, or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were nominated by the Food and Drug Administration and the National Cancer Institute for study because of the widespread use of coumarin in perfumes, cosmetics, and other products as a fragrance, continued interest in coumarin compounds as flavor-enhancing agents for foods, and the interest in structure-activity relationships of this important group of compounds. Coumarin is believed to be metabolized to a 3,4-epoxide intermediate, which may be responsible for its toxic effects, while 3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received coumarin in corn oil by gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All female rats and four male rats receiving 400 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female rats were similar to those of the controls. There were no clinical signs of organ-specific toxicity, and there was no evidence of impaired blood coagulation from measurements of capillary clotting time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN MICE: Groups of five male and five female mice received coumarin in corn oil by gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg, two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female mice were similar to those of the controls. Clinical findings of inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia were observed in some mice from the 300 and 600 mg/kg groups within the first several hours after dosing. Capillary clotting time and platelet counts of dosed mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38, 75,150, or 300 mg per kg body weight. Three male and three female rats receiving 300 mg/kg died. The mean body weight gains and final mean body weights of male rats that received 150 and 300 mg/kg were significantly lower than those of the controls. There were no clinical signs related to specific organ toxicity. Male and female rats receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and/or sorbitol dehydrogenase in males and females receiving 300 mg/kg were higher than those of controls. The absolute and relative liver weights of male and female rats that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose selected for the 2-year study was 100 mg/kg, which was just below the level at which mortality, lower final mean body weiody weights, and treatment-related liver lesions were observed in the 13-week study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received coumarin in corn oil by gavage at doses of 0, 19, 38, 75, 150, or 300 mg per kg body weight. Two male mice receiving 300 mg/kg died. The mean body weight gain and final mean body weight of surviving male mice that received 300 mg/kg were significantly lower than those of the controls. No clinical signs of toxicity were observed. Male and female mice receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin. The absolute and relative liver weights of males and females that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular hypertrophy was observed in male and female mice receiving 300 mg/kg. The high dose selected for the 2-year study was 200 mg/kg, which was just below the level at which mortality and liver lesions were observed in the 13-week study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered coumarin in corn oil by gavage at doses of 0, 25, 50, or 100 mg per kg body weight. After 15 months, 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: None of the male rats receiving 100 mg/kg and only two males receiving 50 mg/kg survived until the end of the study (vehicle control, 28/50; 25 mg/kg, 9/50; 50 mg/kg, 2/51; 100 mg/kg, 0/50). Survival of dosed female rats was similar to that of the controls (29/50, 38/50, 36/50, 30/50). The reduced survival in dosed male rats was primarily attributed to chemical-related exacerbation of spontaneously occurring renal disease. Final mean body weights of female rats that received 100 mg/kg and all dosed groups of male rats were lower than those of the controls. There were no clinical signs of toxicity in rats, other than nonspecific signs relating to debilitation as a result of renal or other spontaneous disease. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the values for one or more hematologic parameters including mean erythrocyte volume, mean erythrocyte hemoglobin in 50 and 100 mg/kg rats, and hematocrit or hemoglobin in 100 mg/kg rats were significantly lower than those of controls. Activated partial thromboplastin times were also significantly lower in 50 and 100 mg/kg males, while platelet counts were significantly higher. Activities of alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in 50 and 100 mg/kg male and 100 mg/kg female rats were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: The principal lesions associated with the administration of coumarin to rats for up to 2 years occurred in the liver, kidney, and forestomach. While the hepatic lesions were seen in all groups of males, they occurred only in the 50 and 100 mg/kg females. The lesions consisted of a spectrum of changes including hepatocellular necrosis, fibrosis, cytologic alteration, and increased severity of bile duct hyperplasia. The incidences of hepatocellular neoplasms were not increased in dosed rats. There was a chemical-related increase in the average severity of nephropathy in all groups of dosed male and female rats. There were corresponding increased incidences of parathyroid gland hyperplasia in all groups of dosed males, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, a low incidence of renal adenomas was seen in all groups of males and in 100 mg/kg females (males: vehicle control, 1/49; 25 mg/kg, 2/50; 50 mg/kg, 2/51; 100 mg/kg, 1/50; females: 0/49, 0/50, 0/50, 2/49). An evaluation of step sections identified additional individuals with renal tubule focal hyperplasia (males: 2/49, 12/50, 10/51, 6/50; females: 1/49, 0/50, 4/50, 2/49) and adenoma (males: 0/49, 4/50, 5/51, 4/50; females: 0/49, 0/50, 1/50,1/49) in the dosed groups. The incidences of forestomach ulcers in all groups of dosed male rats and in 100 mg/kg female rats were significantly greater than those of the controls (males: 7/48, 24/50, 35/51, 34/50; females: 1/48, 1/49, 6/50, 9/48). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 100 mg/kg coumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle during the 15-month recovery period. Similarly, a group of 30 male rats received 100 mg/kg coumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil during the 9-month recovery period. A group of 20 vehicle control male rats were necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. While chemical-related hepatic lesions were seen at both the 9- and 15-month interim evaluations, the incidences and severities of these lesions following the recovery period were generally similar to controls. Thus, the hepatic lesions produced by 9 or 15 months of exposure were reversible. In contrast to the liver lesions, the severity of nephropathy in male rats following the recovery period was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This is not unexpected, since nephropathy is a progressive degenerative disease that naturally increases in severity with age. The incidence of renal tubule hyperplasia in the 15-month stop-exposure group (dosed for 15 months followed by the recovery period) and the incidence of renal tubule adenoma in the 9-month stop-exposure group were significantly greater than those of the control group. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered coumarin in corn oil by gavage at doses of 0, 50, 100, or 200 mg per kg body weight for up to 2 years. After 15 months, 19 or 20 mice from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female mice was similar to that of the controls (males: vehicle control, 43/50; 50 mg/kg, 47/50; 100 mg/kg, 42/50; 200 mg/kg, 37/51; females: 33/50, 40/50, 42/51, 28/51). The mean body weights of 200 mg/kg male and female mice were lower than those of controls throughout much of the study. There were no clinical findings related to chemical administration. Hematology and Clinical Chemistry: Mean erythrocyte volume, mean erythrocyte hemoglobin, and hematocrit of 200 mg/kg males and mean erythrocyte volume of 200 mg/kg females were significantly lower than those of the controls. Blood platelet counts of 200 mg/kg males and females were significantly higher than those of controls. There were no biologically significant differences in enzyme activities between dosed and control mice. Pathology Findings: The principal toxic lesions associated with the administration of coumarin to mice occurred in the liver. The incidences of centrilobular hypertrophy in 100 and 200 mg/kg males and 200 mg/kg females were significantly greater than those of controls. The incidences of syncytial alteration in all male dose groups and in 200 mg/kg females were also significantly greater than controls. The incidences of eosinophilic foci, a putative preneoplastic lesion, and of hepatocellular adenoma were significantly greater in the 50 and 100 mg/kg females. Hepatocellular carcinomas occurred with low incidences in the dosed females, but none occurred in the controls. The overall incidence of hepatocellular neoplasms (benign and malignant combined) in the 50 and 100 mg/kg females (control, 8/50; 50 mg/kg, 27/49; 100 mg/kg, 31/51; 200 mg/kg, 13/50) exceeds the range in historical controls (range 2%-34%; 129/898, 14.4%) from recent NTP studies. The reason for a lack of liver response in 200 mg/kg female mice is not known, but may be due in part to the decrease in body weight. While the incidences of eosinophilic foci were marginally greater in dosed male mice, the incidences of hepatocellular neoplasms were similar among the dosed and control groups. The incidences of alveolar/bronchiolar adenomas were significantly greater in 200 mg/kg male and female mice than in the controls. Further, the incidence of alveolar/bronchiolar carcinoma in 200 mg/kg females was also significantly greater than in controls. The overall incidence of pulmonary neoplasms (benign and malignant combined) in the 200 mg/kg groups (males: 14/50, 9/50,15/50, 25/51; females: 2/51, 5/49, 7/49, 27/51) exceeds the range in historical controls (males: range 6%-28%; 166/900, 18.4%; females: range 0%-14%; 58/899, 6.5%) from recent NTP studies. The incidence of squamous cell papilloma of the forestomach in 50 mg/kg males was greater than that of the controls (2/50, 8/50, 2/50, 0/51) and also exceeds the range of this neoplasm in control male mice from recent NTP studies (range 0%-14%; 27/902, 3.0%). The incidence of squamous cell papilloma of the forestomach in 50 mg/kg female mice was also slightly increased (1/52, 5/50, 2/51, 2/51); however, the incidence did not exceed the NTP historical range (27/901, 3%; range, 0%-10%). GENETIC TOXICOLOGY: Coumarin induced gene mutations in Salmonella typhimurium strain TA100 in the presence, but not in the absence, of exogenous metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or TA1537, with or without S9. In Chinese hamster ovary cells, coumarin induced sister chromatid exchanges in the absence of S9, and chromosomal aberrations in the presence of S9. Coumarin did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated either as adults by feeding or injection, or as larvae by feeding. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male and female B6C3F1 mice administered coumarin by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. The administration of coumarin to rats was also associated with an increased severity of nephropathy in the kidney and of bile duct hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice was also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver. Synonyms: 5,6-benzo-alpha-pyrone, 2H-1-benzopyran-2-one, 2H-benzolblpyran-2-one, 1,2-oxo-1,2-benzopyran, 1,2-benzopyrone, cis-o-coumarinic acid lactone, coumarinic anhydride, cumarin, o-hydroxycinnamic acid lactone, kumarin, [2-propenoic acid, 3-(-2-hydroxyphenyl)-delta-lactone], Rattex, tonka bean camphor
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PMID:NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 89

We report a case of a 13 year old boy with non-familial, multiple blue rubber bleb nevi (BRBN). He also had additional dysmorphic anomalies including a low hairline, low set ears, narrow nares, ptosis, hypotelorism, a high arched palate and downward slanting of the outer canthi. Skeletal deformities included a short, slightly webbed neck, kyphosis, cubitus valgus, non-traumatic luxation of the head of the right radius and a short left little and index fingers. He had no evidence of gastrointestinal lesions or bleeding, congenital heart or renal disease or enchondromata. The boy was mentally slow compared to his peers. He had normal chromosomes. The absence of gastrointestinal bleeding or iron deficiency anaemia is inconsistent with Bean's syndrome and the lack of enchondromata in this patient militates against the diagnosis of classical Maffucci syndrome. Some of his physical features are obviously similar to those observed in a Noonan's syndrome yet the presence of extensive BRBN would be an extremely unusual finding. Since the overall picture does not fit into any of the classical categories mentioned above, the constellation of his features has yet to find a specific syndrome. It may, however, represent an overlap between them or, possibly, a new syndrome.
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PMID:A patient with extensive blue rubber bleb nevi associated with multiple congenital anomalies: an overlap or a new syndrome? 1456 63

Meckel syndrome (MKS) is a rare lethal autosomal recessive disorder characterized by the presence of occipital encephalocele, cystic kidneys, fibrotic changes of the liver and polydactyly. Joubert syndrome (JS)-related disorders (JSRDs) or cerebello-oculo-renal syndromes (CORS) are a group of recessively inherited conditions characterized by a molar tooth sign (MTS) on cranial MRI, a set of core clinical features (developmental delay/mental retardation, hypotonia, ataxia, episodic breathing abnormalities, abnormal eye movements) and variable involvement of other systems including renal, ocular, central nervous system, craniofacial, hepatic, and skeletal. A significant clinical overlap between MKS and JSRD/CORS has been recognized in the literature. We describe a group of 10 Hutterite patients, of which 7 had been previously diagnosed with MKS, with a JSRD. Clinical features include variable early mortality, cognitive handicap, a characteristic dysmorphic facial appearance, hypotonia, ataxia, abnormal breathing pattern, nystagmus, and MTS on MRI. Additional features include occipital encephalocele, posterior fossa fluid collections resembling Dandy-Walker malformation, hydrocephalus, coloboma, and renal disease. This JSRD is a recognizable dysmorphic syndrome characterized by hypertelorism, deep-set eyes, down-slanting palpebral fissures, ptosis, arched eyebrows with medial sparseness, square nasal tip, short philtrum with tented upper lip, open mouth with down-turned corners, and posteriorly rotated low-set ears. Renal disease is present in 70% of patients and is characterized by cystic kidneys, abnormalities in renal function and hypertension. Homozygous deletions of NPHP1 and the known loci for JS/JSRD and MKS were excluded by identity-by-descent mapping studies suggesting that this condition in the Hutterites represents yet another locus for a JSRD.
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PMID:Meckel syndrome in the Hutterite population is actually a Joubert-related cerebello-oculo-renal syndrome. 1760 1

We report a 40-year old woman with bilateral partial ptosis, complete external ophthalmoplegia, and weakness and fatiguability of upper limbs. She was on treatment for hypertension for 5 months at the time of admission. She was found to have generalised myasthenia gravis and membranous nephropathy with end-stage renal disease. Her symptoms and signs improved within 2 months on treatment with neostigmine and prednisolone. It is postulated that either thymic hyperplasia or the subclinical stage of a thymoma may be the underlying aetiological factor in this patient.
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PMID:Case of generalised myasthenia gravis with membranous nephropathy. 1859 Feb 68

Systolic anterior motion (SAM) of mitral valve is the prolapse of a mitral leaflet into the left ventricle outflow tract (LVOT) during systole, causing LVOT obstruction and mitral valve regurgitation. We report the case of a patient who developed SAM-induced hemodynamic instability during bleeding with a clinical picture resembling pulmonary edema. A 77-year-old woman was admitted to our emergency room for abdominal bleeding in polycystic renal disease. Upon arrival, she was normotensive, despite being anuric and acidotic. After infusion of fluids and packed red blood cells (total 3 680 mL in 6 hours) she developed atrial fibrillation and clinical and radiological signs of pulmonary edema. Sedation and non-invasive ventilation brought to immediate severe hypotension. A transesophageal echocardiogram showed an "empty" hypertrophic hypercontractile left ventricle, SAM with LVOT obstruction (intraventricular gradient 154 mmHg) and moderate-to-severe mitral regurgitation. With further fluid infusion hemodynamic stability and sinus rhythm were recovered. SAM, LVOT obstruction and mitral regurgitation disappeared. SAM is a rare but dangerous cause of hemodynamic instability. It has been described in patients with and without left ventricular hypertrophy, in presence of hypovolemia and sympathetic stimulation. In our case it presented with a misleading clinical picture of pulmonary edema simulating fluid overload in an actually hypovolemic patient. In fact, SAM-associated mitral regurgitation together with diastolic dysfunction and tachycardia induced a pulmonary edema whose treatment worsened hypovolemia and precipitated LVOT obstruction and hypotension. Further fluid infusion was resolutive. Echocardiography was fundamental for diagnosis and treatment.
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PMID:Systolic anterior motion causing hemodynamic instability and pulmonary edema during bleeding. 2066 Dec 9

A 66 year old woman with end-stage renal disease and liver cirrhosis due to chronic hepatitis C virus infection was introduced to hemodialysis therapy in 2003. In 2007, hepatocellular carcinoma was identified and the patient underwent radio frequency ablation (RFA) and ethanol injection therapy (EIT) under laparotomy. A large vaginal tumor was incidentally found at gynecological examination. Histological diagnosis was diffuse large B-cell lymphoma (Stage IE). During the first course of chemotherapy, the vaginal tumor began to prolapse from the vaginal wall due to an excellent response to the chemotherapy and finally was resected. The patient received another course of chemotherapy followed by radiotherapy. The vaginal tumor was undetectable in the follow-up imaging studies. Although patients with end-stage renal disease are at increased risk for several cancers, the occurrence of malignant lymphoma following hepatocellular carcinoma is rare. Furthermore, lymphomas arising from the female genital tract are very uncommon.
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PMID:Non-Hodgkin's lymphoma of the vaginal wall in a hemodialysis patient with hepatocellular carcinoma. 2169 6

A 74-year-old woman was admitted to our emergency room complaining of general weakness and anorexia that started 20 days earlier. She denied other underlying diseases that might have provoked chronic renal disease. Her serum creatinine was 12.35 mg/dL. A pelvic examination and computed tomography revealed severe bilateral hydroureteronephrosis with marked cortical thinning induced by total uterine prolapse. She was started on emergency hemodialysis due to her uremic symptoms and severe metabolic acidosis. Despite Foley catheter insertion and manual reduction of uterus for 1 month, renal function was not recovered. The department of gynecology was strongly opposed to performing a procedure to reverse the hydroureteronephrosis due to the irreversibility of her renal function. She is undergoing chronic maintenance hemodialysis. This is a case report of rare end-stage renal disease (ESRD) caused by obstructive uropathy due to pelvic organ prolapse (POP). We should consider POP as a cause of ESRD.
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PMID:Obstructive uropathy by total uterine prolapse leading to end-stage renal disease. 2255 23

Mitochondrial diseases are multisystem disorders: anemia, myopathy, lactic acidosis, CNS abnormality, endocrine abnormalities, renal disease, sensorineural deafness, and retinal involvement. The clinical abnormalities are heterogeneous, and they usually begin in childhood. Premature death occurs because of cardiac conduction defects. The onset is usually before 20 years of age. The fundus shows pigmentary retinopathy, with a salt-and-pepper appearance (Fig. 30.1), but vision remains good in most patients. Systemic involvement includes chronic progressive external ophthalmoplegia (CPEO), with ptosis being the most common complaint, and cardiomyopathy. Other variable features are short stature; cerebellar symptoms; weakness of muscles of the face, pharynx, trunk, or extremities; and progressive hearing loss. Full-field ERG does show evidence of generalized retinal dysfunction, involving both rods and cones. Skeletal muscle biopsy shows ragged red fibers and abnormal mitochondria.
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PMID:Mitochondrial Disorder: Kearns-Sayre Syndrome. 3057 3


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