Transplant results in adults with Fanconi anaemia

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76–87%), acute graft‐versus‐host disease (GvHD) grade II–IV in 22% (95% CI 16–28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20–33). Non‐relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow‐up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non‐sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.     

Phenotypes of adults with Fanconi anaemia

The long-term outcomes of adults with Fanconi anaemia (FA) have improved with advances in haematopoietic stem cell transplantation (HSCT) and more detailed follow-up and screening guidelines. The phenotype of those who survive to adulthood may differ from the typical presentation of FA. We collected retrospective clinical data on adults with FA who received their care at the Cincinnati Children's Hospital Medical Center. In our final cohort of 52 patients, there were 29 females and 23 males, with median (range) age of 21 (18–37) years. Overall, 42 patients (81%) were alive at last follow-up. In all, 36 adults (69%) had undergone HSCT, including eight who had developed myelodysplasia or acute myeloid leukaemia. Eight (15%) developed squamous cell carcinoma. Endocrine complications were common, including hypothyroidism (42%), diabetes (10%), low body mass index (31%) and low bone mineral density (51%). The majority of adults with FA were employed (52%) or full-time students (13%). A significant subset of patients with FA are surviving into adulthood without requiring HSCT. Endocrine abnormalities and the development of solid tumours complicate adulthood. With improved survival outcomes following HSCT and more aggressive malignancy screening protocols, ongoing longitudinal analysis will be important to further characterise this cohort and the phenotype of untransplanted adults with FA.     

Spontaneous Fanconi syndrome in the dog

Three dogs with spontaneous renal tubular defects similar to idiopathic Fanconi syndrome are characterized. Renal clearance studies revealed a fractional reabsorption of glucose ranging from 31% to 82%. Abnormal glucose thulium values were present in all dogs. A generalized aminoaciduria occurred in two dogs while one had aminoaciduria characteristic of canine cystinuria. Fractional reabsorption of phosphate ranged from 47% to 79%. In vitro uptake of alpha-methyl-D-glucoside was significantly depressed (p less than 0.001). In vitro uptake of amino isobutyric acid was similar to controls. Renal biopsy revealed nonspecific interstitial change in two dogs and normal histology in the other. These animals represent a useful new model for the study of renal tubular transport defects.     

Melatonin attenuates ifosfamide-induced Fanconi syndrome in rats

Regarding the mechanisms of ifosfamide (IFO)-induced nephrotoxicity and hemorrhagic cystitis, several hypotheses have been put forward, among which oxidative stress and depletion of glutathione (GSH) are suggested. This investigation elucidates the role of free radicals in IFO-induced toxicity and the protection by melatonin. Wistar albino rats were injected intraperitoneally with saline (0.9% NaCl; control-C group), melatonin (Mel group; 10 mg/kg daily for 5 days) or ifosfamide (50 mg/kg daily for 5 days; IFO group) or IFO + Mel. On the 5th day (120 hr) after the first IFO dose, animals were killed by decapitation and trunk blood was collected. Kidney and bladder tissues were obtained for biochemical and histological analysis. Urine was collected 24 hr before the rats were killed. The results demonstrated that IFO induced a Fanconi syndrome (FS) characterized by wasting of sodium, phosphate, and glucose, along with increased serum creatinine and urea. Melatonin markedly ameliorated the severity of renal dysfunction induced by IFO with a significant decrease in urinary sodium, phosphate, and glucose and increased creatinine excretion. Moreover, melatonin significantly improved the IFO-induced GSH depletion, malondialdehyde accumulation and neutrophil infiltration in both renal and bladder tissues. In the kidney, Na+,K+ -ATPase activity which was significantly reduced by IFO, was increased with melatonin treatment. Increased collagen contents of the kidney and bladder tissues by IFO treatment were reversed back to the control levels with melatonin. Our results suggest that IFO causes oxidative damage in renal and bladder tissues and melatonin, via its antioxidant effects, protects these tissues. These data suggest that melatonin may be of therapeutic use in preventing acquired FS due to IFO toxicity.     

Familial hyperinsulinism presenting in adults.

Two adult siblings presented with recurrent syncope due to severe hyperinsulinemic hypoglycemia. Exploratory laparotomy in the elder sibling showed a grossly normal pancreas, but histologic examination revealed islet cell hyperplasia. Neither sibling has any evidence of the multiple endocrine neoplasia type 1 syndrome, nor is there any other family history to suggest this diagnosis. To our knowledge, this is the first report of adult-onset familial hyperinsulinism without other manifestations of multiple endocrine neoplasia type 1 syndrome. A simple provocative test for hyperinsulinism was also suggested by these cases. Because the initial patient related his symptoms to exercise, we used treadmill exercise in both patients to diagnose hyperinsulinism and observe its response to therapy.     

Familial Turner syndrome

Seven women in three generations of a family have been affected by Turner syndrome. Turner phenotype in this family is the result of deletion of the entire short arm of one X chromosome. The short arm deletion is transmitted by carriers of a balanced X-1 translocation. Autoradiographic findings showed that the deleted X chromosome was late labeling in those persons with Turner syndrome, whereas the normal X chromosome was late replicating in carriers of the balanced translocation. The results of Xga typing of erythrocytes suggest that the Xg locus is on the short arm of the X chromosome. Because of the clinical implications, we believe that families of persons with structural chromosomal abnormalities should be studied to exclude familial transmission.     

Adult Fanconi syndrome and liver cirrhosis

A female presenting primary adult Fanconi syndrome and liver cirrhosis of obscure aetiology is described. The only other report of this association appeared over four decades ago and concerned a male patient who, however, was subsequently diagnosed as having Wilson's cirrhosis, a well-known cause of acquired Fanconi syndrome. Therefore, the present report is the first account of primary Fanconi syndrome with authentic cryptogenic liver cirrhosis. Since the chronic urinary amino acid leakage is not a pathogenetic mechanism of the cirrhotic process, we believe that this association in fortuitous.     

Familial pseudo-Wolff-Parkinson-White syndrome

INTRODUCTION: PRKAG2 plays a role in regulating metabolic pathways, and mutations in this gene are associated with familial ventricular preexcitation, hypertrophic cardiomyopathy, and atrioventricular conduction disturbances. Clinico-pathologic and experimental data suggest the hypothesis of a glycogen storage disease. OBJECTIVE: To report a unique pattern of clinical features observed in individuals with a mutant PRKAG2 from two unrelated families. METHODS AND RESULTS: We studied two large families and found a total of 20 affected individuals showing a combination of sinus bradycardia, short PR interval, RBBB, intra and infrahisian conduction disturbances often requiring a pacemaker, and atrial tachyarrhythmias. Three individuals died suddenly at a young age. No patient had the Wolff-Parkinson-White (WPW) syndrome, and only two patients (10%) had myocardial hypertrophy. We performed screening of the exons and exon-intron boundaries of PRKAG2. Genetic analysis revealed a missense mutation (Arg302Gln) in the affected individuals from both families. This mutation had been described before and has been associated with the familial form of the WPW syndrome and with a high prevalence of left ventricular hypertrophy. CONCLUSION: PRKAG2 mutations are responsible for a diverse phenotype and not only the familial form of the WPW syndrome. Familial occurrence of right bundle branch block, sinus bradycardia, and short PR interval should raise suspicion of a mutant PRKAG2 gene.     

Familial Cushing's syndrome

Cushing's syndrome has been demonstrated in four of seven siblings with clinical manifestations appearing around puberty in three of the four siblings. The only other associated findings in these cases were short stature and disturbed carbohydrate metabolism. Adenomatous hyperplasia of the adrenal glands was demonstrated in 3 of the patients, and a virilizing adrenal carcinoma in the fourth sibling. The pathogenesis of the adrenocortical disorders in these siblings is discussed.     

The adult presenting idiopathic Fanconi syndrome

The adult presenting Fanconi syndrome is a rare familial disorder. A 30-year follow-up of one of the original families in the literature is reported here. Two important points have emerged. Firstly, the inheritance in this family is dominant, not recessive as originally suggested, and there remains no good example in the literature of a recessive inheritance of this disorder. Second, in this family lactic aciduria and tubular proteinuria are probably the earliest manifestations of the disorder in childhood, with glycosuria and aminoaciduria developing in the second decade and osteomalacia from the start of the fourth decade. Glomerular function deteriorates slowly but is compatible with a normal lifespan.     

Familial nephrotic syndrome

Systematic pedigree information was obtained from 70 patients with idiopathic nephrotic syndrome; 16 patients were found to have familial nephrotic syndrome including 1 pair of affected monozygotic twins, 5 affected sibling pairs, 2 affected first cousins from a consanguineous family and 2 patients with sporadic cases from consanguineous families.Patients with familial and sporadic forms of the disease were compared by applying both clinical and histopathologic criteria. No significant differences were found between these groups, but both had a preponderance of males.In contrast to previous reports, the clinical course in the affected monozygotic twins was quite different, providing evidence for the importance of environmental influences on the course of this disease. Furthermore, in affected relatives neither the clinical course nor histopathologic classification was necessarily similar.The recurrence risk for siblings of patients with idiopathic nephrotic syndrome was 0.06. Several possible modes of inheritance were considered. Segregation analysis permitted the exclusion of simple recessive inheritance. The invariable concordance for the occurrence of nephrotic syndrome in both members of monozygotic twinships as well as the sex ratio renders a mixed model, with a small proportion of high risk recessive cases, equally unlikely. The available data are most consistent with a polygenic model which assumes a continuous distribution of disease liability with a discreet threshold effect.