Hava Peretz

A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families

We have screened for CDKN2A germline mutations in 49 Jewish families with two or more cases of melanoma. The Val59Gly mutation, one of the three different alterations identified among these families, was also detected independently in two kindreds from France and one from Spain. The impact of the Val59Gly substitution on the function of the cyclin-dependent kinase inhibitor p16INK4a, a product of the CDKN2A gene, was assessed by protein–protein interaction and cell proliferation assays and related to potential structural alterations predicted by molecular modeling. Seven microsatellite markers in the vicinity of the CDKN2A gene were used to determine whether the mutation in these families is identical by descent, or represents a mutational hotspot in the CDKN2A gene. Our results show that the Val59Gly substitution impairs p16INK4a function, and this dysfunction is consistent with structural predictions. All melanoma-affected individuals tested in the families under study harbor this mutation. Interestingly, the Israeli pedigree includes an affected individual who is homozygous for the Val59Gly mutation. A common haplotype of microsatellite markers has been demonstrated for mutation carriers in all four pedigrees. The Israeli pedigree and one of the French melanoma families are of Moroccan and Tunisian Jewish descent, respectively, and the other families originate from regions of France and Spain close to the Pyrenees. We conclude that the Val59Gly mutation is a major contributor to melanoma risk in the families under study and that it may derive from a single ancestral founder of Mediterranean (possibly Jewish) origin.

Highly elevated lactate dehydrogenase level in a healthy individual: A case of macro‐LDH

Macroenzymes are complexes of serum enzymes with a plasmatic protein. They have a higher molecular weight and a more prolonged serum half‐life than those of unbound enzymes. Although macroenzymes may be found in the serum of post‐myocardial infarction patients, they are not usually associated with any specific disease. Their presence, however, can use an elevation in the serum levels of an enzyme, possibly leading to errors in diagnosis. We report a patient with extremely elevated serum levels of lactate dehydrogenase (LDH) due to the formation of complexes with immunoglobulin G. She had undergone a myriad of clinical examinations until the macroenzyme responsible for this finding was detected. We also review the literature on the clinical significance of macro‐LDH. We propose that awareness of this rare and probably benign phenomenon can spare the patient from the distress of exhaustive investigations. Am. J. Hematol. 55:39‐40, 1997.

Glycohaemoglobin as a determinant of increased fibrinogen concentrations and low‐grade inflammation in apparently healthy nondiabetic individuals

Objective  To determine the potential role of glycohaemoglobin as a possible determinant of increased fibrinogen concentrations and low‐grade inflammation in a group of apparently healthy, nondiabetic individuals not expressing clinically overt atherothrombosis.

Apolipoprotein-e genotype and the risk of developing cholelithiasis following bariatric surgery: a clue to prevention of routine prophylactic cholecystectomy

Background: Obesity and especially rapid weight loss following bariatric surgery are known risk factors for cholelithiasis. Since the risk may be high, prophylactic cholecystectomy has been advocated. Apolipoprotein (Apo) E, an important carrier protein in cholesterol metabolism and trafficking, is believed to play a role in gallstone pathogenesis. In particular, the Apo E4 allele has been suggested to be associated with cholesterol cholelithiasis. The aim of this study was to assess the incidence of postoperative cholelithiasis in our patient population and to determine a possible correlation with the Apo-E genotype. Methods: 134 morbidly obese patients undergoing gastric restrictive surgery [laparoscopic assisted gastric banding (LAGB) or silastic ring vertical gastroplasty (SRVG)] had abdominal ultrasound before and 6 to 12 months after operation, to determine the presence of gallstones. None of the patients enrolled in the study had gallstones before surgery.They did not have a prophylactic cholecystectomy or receive bile salt treatment. Apo-E genotypes were determined by Polymerase Chain Reaction restriction enzyme analysis. Results: 10 patients (7.5%) developed postoperative cholelithiasis. The incidence of cholelithiasis in each ApoE genotype was: E2/E3 - 1/20 (5%), E3/E3 - 3/91 (3%), E3/E4 - 6/21 (29%), and E4/E4 - 0/2. ApoE allele frequencies in the study population were identical to those of a healthy control population. The mean BMI dropped from 43.6 to 29.4 kg/m2. Conclusions: The occurrence of postoperative gallstones was low in our population. However, in subjects with the Apo-E3/E4 genotype, the incidence is of practical significance. These data suggest that Apo-E genotyping may be useful in selecting patients for gallstone prevention (surgical or medical) when undergoing bariatric surgery.Further testing in larger patient populations may be able to give more definite guidelines in the future.

Pheochromocytoma due to unilateral adrenal medullary hyperplasia

We describe two male patients, aged 17 and 47 years, with clinical and biochemical features of pheochromocytoma. Both patients had normal‐sized adrenal glands on abdominal CT scan and abnormal unilateral uptake of I‐123 metaiodobenzylguanidine (MIBG) on scintigraphy. The surgical adrenalectomy revealed normal macroscopic glands in both patients. Histological examination showed adrenal medullary hyperplasia with adrenal cortico‐medullary ratios of 2 : 1 and 4 : 1. Unilateral adrenalectomy resulted in amelioration of symptoms and normalization of catecholamines excretion. DNA examination for RET proto‐oncogene revealed no mutations in exons 10, 11, 13, 14 and 16. Our results suggest that diffuse adrenal medullary hyperplasia may be the initial pathological change in the adrenal gland leading, subsequently, to the development of nodular hyperplasia and adrenal medullary tumor. These results indicate that the syndrome of pheochromocytoma may occur as an unilateral adrenal medullary hyperplasia in patients without evidence for multiple endocrine neoplasia.