Edwin W. Naylor

Gardner's syndrome. Recent developments in research and management.

In recent years, a number of comprehensive reviews have been written on inherited intestinal polyposis syndromes (1–7), but none has dealt specifically with Gardners syndrome and none has focused on basic research being carried out in an attempt to under-stand this syndrome and to improve the medical management of affected patients. A better understanding of this rare genetic disorder is essential for surgeons, gastroenterologists, cancer researchers, and geneticists alike. To the clinician, it poses difficult challenges in management; to the cancer researcher, it presents a rare opportunity to study very early premalignant transformations; and to the geneticist, it poses exciting questions at the cellular, chromosomal, and molecular levels.

Adrenal adenomas in a patient with Gardner's syndrome

Gardners syndrome is an autosomal dominant condition characterized by multiple colorectal polyposis, associated with various soft‐ and hard‐tissue tumors. The occurrence of adrenal adenomas in patients with the syndrome has not been fully appreciated. The following is a report of a member of the original Utah kindred #109, first described in the early 1950s, who was found at autopsy to have bilateral adrenal adenomas. A review of the literature resulted in the identification of six cases with adrenal adenomas and one with a primary adrenal carcinoma. The association with the syndrome of these adrenal tumors, as well as other endocrine tumors, especially thyroid tumors, is discussed.

Intermittent non-ketotic dicarboxylic aciduria in two siblings with hypoglycaemia: An apparent defect in β-oxidation of fatty acids

Two siblings with intermittent hypoglycaemia, lethargy and coma associated with fatty infiltration of the liver are reported. Urine contained C6 to C14-dicarboxylic acids.

Penetrance and expressivity of the gene responsible for the Gardner syndrome

The Gardner syndrome is an autosomal dominant condition characterized by multiple polyposis of the colon, associated with various soft‐ and hard‐tissue tumors. Our original kindred, first reported in the early 1950s has been updated and serves as the basis for a discussion of the penetrance and expressivity of the gene responsible for the syndrome. The family consists of 188 members spread over six generations, with 28 individuals clearly documented as having the syndrome. Using two different methods of calculating penetrance, the responsible gene was found to be fully penetrant. This observation was confirmed by an analysis of 160 additional sibships from the literature. This estimation of penetrance is considerably higher than has been previously reported. The expressivity of the gene, however, is quite variable, and this is illustrated using examples from both our kindred and the literature.

Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet.

A brother and sister aged 11 and 17 years have been reported previously to have hyperargininaemia and arginase deficiency: they were treated with a semi-synthetic diet consisting of fat, carbohydrate, minerals, vitamins and essential amino acids in amounts equivalent to 0.55–0.65 g protein kg−1 day−1 for 2 years. Plasma arginine levels fell from 0.50–0.90 µmol/l to 0.13–0.30 µmol/l (normal range 0.02–0.15). Increased concentrations of arginine in the cerebrospinal fluid (CSF) fell from 0.069–0.098 µmol/l to 0.040–0.056 µmol/l (normal mean ± SD=0.020±0.006). Dibasic aminoaciduria returned to normal within 1 week. Substitution of the keto-acid analogues of five essential amino acids in the formula lowered arginine concentrations further, but proved to be unpalatable. Urinary concentrations of orotic acid, uridine and uracil fell toward normal but remained increased, even when the plasma ammonia concentration was measured as normal. Both patients showed a stable clinical improvement.

A rapid screening test for Duchenne muscular dystrophy using dried blood specimens

A very simple fluorescent spot screening test for the detection of elevated creatine kinase activity in dried blood specimens is described. The assay uses reagents commercially available in kit form and modifies the procedure for use with whole blood spotted on filter paper. Additional amounts of diadenosine pentaphosphate had to be added to the reaction mixture to inhibit the excess adenylate kinase present in erythrocytes. The sensitivity and reliability of the test is demonstrated. This qualitative assay has the potential for use as a mass neonatal screening test for Duchenne muscular dystrophy.

Enzymatic studies of urinary isomeric chondroitin sulfates from patients with mucopolysaccharidoses. The application of high performance liquid chromatography.

The high-performance liquid chromatographic (HPLC) method for the determination of unsaturated sulfated disaccharides is a comprehensive and reliable method which expedites ensymatic studies of isomeric chondroitin sulfates. Responses for these unsaturated disaccharides derived from urinary chondroitin sulfates were linear from 100 ng to 10 micrograms injected and good quantitation was obtained for 25 microliters or less of samples placed on the column. This method which is more sensitive and accurate than methods now being used has considerable potential for the chemical diagnosis of patients with mucopolysaccharidoses and for the clarification of glycosaminoglycan structure. The isomeric chondroitin sulfates in urines from patients with mucopolysaccharidoses were studied by enzyme digestion with chondroitinases followed by HPLC determination of the sulfated unsaturated disaccharides produced. Evaluation by HPLC of the unsaturated 4-sulfated disaccharide produced by digestion of the urinary GAG with chondroitinases ABC and AC revealed rapidly and quantitatively the large amounts of dermatan sulfate present in Hurler, Hunter, and Maroteaux-Lamy urines. Chondroitin 4-sulfate predominated in Sanfilippo urinary isomeric chondroitin sulfates whereas chondroitin 6-sulfate and chondroitin 4-sulfate were shown to be present in nearly equal amounts in Morquio urine. An oversulfated chondroitin sulfate was detected in small amounts in some of these urines. This was demonstrated by the detection of an unsaturated disulfated disaccharide after digestion with chondroitinase ABC but not with chondroitinase AC.

Urinary pyrimidine excretion in arginase deficiency

A high-performance liquid-chromatographic method was used to separate and identify uracil, uridine, pseudouridine and orotic acid after preliminary extraction in two patients (McKusick 20780). Urinary uracil excretion was 10–35 times normal in both patients with arginase deficiency. Uridine and orotic acid, not normally detected, were excreted in large amounts and were directly influenced by protein intake. Their excretions were correlated with urinary arginine excretion. Urinary uracil levels remained consistently high and showed minimal variations with increased protein intake or urinary arginine levels.The measurement of urinary pyrimidines appears to be useful for the detection, differential diagnosis and dietary monitoring of patients with urea cycle disorders. The data presented extends this observation to include patients with arginase deficiency.

Measurement of urinary pyrimidine bases and nucleosides by high-performance liquid chromatography.

A rapid procedure for the isolation, separation, identification and measurement of urinary pyrimidine bases and nucleosides by high-performance liquid chromatography (HPLC) is presented. The initial isolation of these compounds from urine was accomplished with small disposable ion-exchange columns. HPLC was performed on a silica gel column with a mobile phase composed of methylene chloride, methanol and 1 M aqueous ammonium formate buffer. Peaks were recorded at both 254 nm and 280 nm and the response ratio was used in combination with the elution volume for compound identification. The minimum detectable amount (signal-to-noise ratio = 2) ranged from 0.2 ng for uracil to 2.2 ng for cytidine. Linearity and recovery for thymine, uracil, uridine, pseudouridine, orotic acid and orotidine added to urine was demonstrated over almost a 10(3) concentration range. The potential application of this method for the study of inborn errors in the urea cycle is discussed.

Ultramicromethod for estimation of total glutathione in dried blood spots on filter paper.

Abstract An ultramicromethod for determination of total glutathione in dried blood specimens is described. Sample preparation involves elution of blood from a small disk of dried blood spotted on filter paper, without deproteinization. After enzymatic reduction of oxidized glutathione, total glutathione in the eluate is measured colorimetrically with 5,5′-dithiobis-(2-nitrobenzoic acid) reagent. The stability of the total oxidized glutathione in the dried blood spots is assessed. The method is checked by comparison with a spectrophotometric method that uses liquid blood specimens and the results are in good agreement. The method may be useful in early detection of 5-oxoprolinuria and some forms of nonspherocytic hemolytic anemia.