DNA testing for fragile X syndrome in schools for learning difficulties

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

Growth, puberty and obesity after treatment for leukaemia

Final height, body proportions, pubertal growth and body mass index were studied retrospectively in 142 survivors of acute lymphoblastic leukaemia (ALL). Treatment consisted of combination chemotherapy and cranial irradiation (18 or 24 Gy). Significant standing height loss and disproportion, with a relatively short back, was seen in both radiation dose groups. Girls were more severely affected than boys. Pubertal growth was adversely affected, with a reduction in peak height velocity in both sexes. Puberty occurred early in girls but at the normal time in boys. Nearly half the group were obese at final height, with no significant difference in incidence between the sexes. The relative roles of cranial irradiation and chemotherapy in the disturbance of growth, puberty and body composition observed in survivors of childhood ALL remain unclear. The aetiology is almost certainly multifactorial, with radiation-induced growth hormone insufficiency, early puberty, steroids and chemotherapy all having a role.     

Renal transplantation and osteoporosis

A cross sectional study assessed the bone mineral density (BMD) of 20 young adult patients who received a renal transplantation in childhood. The BMD of the lumbar spine, mainly trabecular bone, and of the total body, mainly cortical bone, were measured and expressed as an SD score. Fourteen patients (70%) had a BMD SD score of the lumbar spine below -1, of whom six patients were below -2. Fifteen patients (75%) had a BMD SD score of the total body below -1, of whom seven patients were below -2, Both trabecular and cortical bone appeared to be involved in the osteopenic process. The cumulative dose of prednisone was inversely correlated to both lumbar spine and total body BMD SD score. In a multiple regression analysis the cumulative dose of prednisone appeared to be the only factor with a significant effect on BMD SD score. Most young adult patients who had received a renal transplantation in childhood had moderate to severe osteopenia. Corticosteroid treatment played a major part in the development of osteopenia in these patients.     

Ultrasound screening of families with abdominal aortic aneurysm

Recent observations suggest that first degree relatives of patients with an abdominal aortic aneurysm (AAA) are also at risk for the development of this disorder. The first degree relatives of 130 adults with known AAA were invited to attend for an ultrasound examination. Fifty-two eligible relatives (mean age 53 years, range 41–73) from 38 families underwent sonographic screening. Using standard ultrasound criteria no participants were identified with an asymptomatic AAA. Thus, ultrasound of families of patients with AAA has a low yield and may not be useful for screening purposes.     

Mitomycin-C induced hemolytic uremic syndrome: a case report and literature review

Hemolytic uremic syndrome spontaneously arises in a few patients with advanced cancer, but it is more commonly related to the use of certain chemotherapeutic agents. Mitomycin-C is, etiologically, the most common causative agent inducing hemolytic uremic syndrome, in a dose dependent manner. We report this syndrome, attributable to mitomycin-C at a cumulative dose of 40 mg/m2, in a gastric cancer patient. A 42-year-old female with stage III gastric cancer underwent radical gastrectomy and was given mitomycin-C at 10 mg/m2 intravenously every four weeks as adjuvant therapy. Hemolytic uremic syndrome was diagnosed three months after the last dose of mitomycin-C administration. The most prominent symptoms included pallor, hypertension and anasarca, with laboratory evidence of microangiopathic hemolytic anemia, azotemia and hyperkalemia. Her disease was progressive, but fortunately stabilized after staphylococcus column A dialysis. Her disease remained in remission for 24 months from the time of diagnosis, and then relapsed in the form of peritoneal carcinomatosis with partial intestinal obstruction.      

Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X

The benefits of achieving a long term event free survival of 60-70% by using increasingly intense treatment regimens must be weighed against the increased risk of treatment toxicity. From 1985 to 1990, 1612 children with childhood acute lymphoblastic leukaemia (ALL) in the UK were treated on MRC UKALL X with intensive induction therapy, central nervous system directed therapy (cranial irradiation and intrathecal methotrexate), and continuing treatment for two years. There was a randomisation to receive blocks of additional intensification treatment at five weeks, 20 weeks, not at all, or both. The five year disease free survival was 71% for children randomised to two blocks of intensification, a 14% improvement on children randomised to no intensification treatment. Treatment related mortality in this national multicentre study has been analysed for induction and first remission (including those after intensification treatment). There were 38 induction deaths, 2.3% and 53 deaths in first remission, 3.3% (including those from a second malignancy). Thirty one (84%) of the induction deaths followed an infection: bacterial in 22 and fungal in nine. Thirty seven infective remission deaths occurred: bacterial in 11, viral in 16, fungal in seven, and three caused by Pneumocystis carinii pneumonia. Ten of these deaths followed a block of intensification treatment. The majority of noninfective remission deaths followed the development of a second tumour. Risk analysis for an induction death showed girls and children with Down's syndrome to be at greater risk. For deaths in first remission analysis showed an increased risk for bone marrow transplant (BMT) patients and children with Down's syndrome. There was no effect of age and leucocyte count for either group. Most significantly when BMT patients were excluded from the analysis, intensification treatment did not increase the risk of remission death.