Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency.

OBJECTIVE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. DESIGN: Clinical review of patients with nonsense MC2R mutations. PATIENTS: Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. RESULTS: Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. CONCLUSION: Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.

Dehydrated hereditary stomatocytosis is associated with neonatal hepatitis.

Dehydrated hereditary stomatocytosis (DHSt) is an inherited haemolytic anaemia associated with increased red cell membrane permeability to Na(+) and K(+). It is increasingly recognized that a syndrome of self-limiting perinatal ascites can accompany the haemolysis. The cause of the perinatal ascites is unknown, and it has been argued that this could be due to cardiovascular, hepatic or lymphatic problems. We describe the case of a 16-year-old girl who presented neonatally with abnormal liver function tests and ascites. She was extensively investigated at that time. A liver biopsy showed hepatitis and fatty changes. Her ascites resolved within 6 months. At the age of 15 years, she developed an episode of acute haemolysis and was re-investigated. A diagnosis of DHSt was made. Pseudohyperkalaemia, due to ex vivo loss of K(+) from red cells, was present. This study confirms the previously noted association of DHSt, pseudohyperkalaemia and perinatal ascites, and suggests that the latter is of predominantly hepatic origin.

Nevirapine use in HIV-1-infected children.

OBJECTIVES: To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART). METHODS: A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines. RESULTS: Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards. Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens-Johnson syndrome. CONCLUSION: Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.

Antiretroviral drug resistance among HIV-1 infected children failing treatment.

High levels of HIV-1 replication occur following perinatal infection and antiretroviral drugs may not fully suppress viral load during the early years of childhood. Adherence to treatment may also be difficult among children. These two factors will contribute to development of drug resistance but limited paediatric data are available. This study has, therefore, evaluated the prevalence of drug resistance among children and assessed the contribution of adherence to failing therapy. Samples from 26 children who had experienced virological failure to antiretroviral therapy were tested for drug resistance using the Visible Genetics TRUGENE trade mark HIV-1 genotyping assay. HIV-1 subtype was determined using a peptide-based EIA and drug adherence determined by physician assessment. Twenty-four children were black African, 23 of whom were infected with a non-B subtype. HIV RNA sequence data was obtained for 21 of the 26 children; at treatment failure resistance mutations were detected in the protease gene of 7 (33%) and the reverse transcriptase gene of 19 (90%). A lower proportion of children had evidence of drug resistance at nadir and no resistance mutations were detected prior to treatment. Genotypic resistance was common in those treated with lamivudine (10/11, 91%), nevirapine (6/8, 75%), and zidovudine (7/11, 64%). The prevalence of mutations was lower among those receiving other nucleoside reverse transcriptase inhibitors and protease inhibitors. In 50% of children, drug adherence was >90%. Antiretroviral drug resistance was common among this group of children failing therapy, the majority of whom were infected with non-B subtypes of HIV-1. As adherence to treatment was low in 50%, this was likely to be an important contributory factor.

Low complication rate associated with cesarean section under spinal anesthesia for HIV-1-infected women on antiretroviral therapy.

BACKGROUND: Elective cesarean section decreases the likelihood of vertical human immunodeficiency virus (HIV) transmission from mother to infant. This study aimed to determine whether cesarean section done with spinal anesthesia on HIV-1-infected pregnant women taking antiretroviral therapy is associated with intraoperative hemodynamic instability, postoperative complications, or changes in immune function or HIV-1 viral load. METHODS: A case-controlled study was conducted over a 3-year period in a London academic hospital. Forty-four women infected with HIV-1 and a control group of 45 HIV-negative women undergoing cesarean sections were included. The main outcome measures included intraoperative blood pressure, heart rate, blood loss, and ephedrine requirements, and postoperative infective complications, blood transfusion, changes in blood HIV-1 viral load and lymphocyte subsets, and time to hospital discharge. RESULTS: There were no differences in hemodynamic stability and postoperative complications between the HIV-infected group and the controls. There was an acute postoperative increase in the CD4T lymphocyte count (P = 0.01), but the CD4T:CD8T ratio and viral load did not change. CONCLUSIONS: Elective cesarean section under spinal anesthesia for women infected with HIV-1 taking antiretroviral therapy was not associated with intraoperative or postoperative complications.