Expanding the clinical and molecular spectrum of FOXG1- and ZBTB18-associated neurodevelopmental disorders.

Introduction The zinc finger BTB domain-containing protein ZBTB18 binds to FOXG1 to form a transcriptional repressive complex involved in neuronal differentiation. Disruption of the components of this complex results in chromosome 1q43-q44 deletion syndrome/intellectual developmental disorder 22 or in FOXG1 syndrome. Case presentation This study reports on five patients with cognitive and behavioral impairment, seizures, microcephaly, and/or congenital brain abnormalities. Whole exome sequencing identified deleterious ZBTB18 variants in three patients and deleterious FOXG1 variants in the remaining patients. We have detected a missense variant within the BTB domain of ZBTB18 in two affected monozygotic twins. In addition, we observed agenesis of the septum pellucidum in a missense FOXG1 carrier with a severe FOXG1 syndrome. Conclusion Although the ZBTB18 zinc finger domains harbor the majority of known deleterious variants, we report a novel de novo rare missense variant within the BTB domain. The agenesis of the septum pellucidum observed in a missense FOXG1 carrier could be considered as a novel clinical feature associated with FOXG1 syndrome. The severe FOXG1 syndrome in this patient contrasts with the milder phenotype expected for a missense. Genetic or environmental factors may explain this phenotypic variability in FOXG1 syndrome.

Hormonal contraception and blood lead levels in inner-city adolescent girls.

STUDY OBJECTIVE: Physiological states of estrogen deficiency can lead to bone demineralization. Lead is stored in bone and may be released into blood during demineralization. The contraceptive injection depomedroxyprogesterone acetate (DMPA) is associated with estrogen deficiency and bone demineralization and, we hypothesized, may be associated with toxic blood lead levels in adolescents at high risk for lead exposure. We sought to compare blood lead levels in inner-city adolescent girls using DMPA with levels in those using oral contraceptive pills (OCP) and those taking no hormones and to examine the influence of lead exposure and reproductive history on blood lead levels in the total sample. DESIGN: Cross-sectional survey of a clinical convenience sample. SETTING: Inner-city adolescent clinic in an academic medical center. PARTICIPANTS: 174 females aged 13-21 years; 86% minority ethnicity. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Measurement of blood lead levels and an 82-item questionnaire examining lead exposure and reproductive history. RESULTS: 28 subjects were using DMPA, 25 used OCPs, and 121 used no hormones. Mean blood lead level in the total sample of 174 was 1.6 mug/dL, SD = 1.1. Many subjects had environmental risk factors for lead exposure and 15% reported one or more past pregnancies. Mean blood lead levels for subjects with the various environmental and reproductive risk factors ranged from 1.2 microg/dL to 2.0 microg/dL and were not different from levels for subjects without such risk factors. Mean blood lead levels for subjects in the 3 hormonal groups were significantly different (2.1 vs. 1.2 vs.1.5 microg/dL in DMPA, OCP, and no hormone groups respectively, P = 0.007). We dichotomized the blood lead levels into "High" > or =4 microg/dL, or "Low" <4 microg/dL. We found that a significantly higher proportion of girls using DMPA (4/28) than those not using any hormone (2/121) had "High" levels (P = 0.012). CONCLUSIONS: Despite reported high-risk exposure to lead and the possibility of long-term accumulation of lead in bone, we did not find elevated blood levels in our sample. However, DMPA-treated girls were significantly more likely to have higher mean blood lead levels than OCP users and non-hormone users. In addition, DMPA users were more likely to have blood lead levels more than two standard deviations above the mean for the sample as a whole than untreated girls. Further studies are needed to examine low-level lead poisoning in adolescents and the consequences of contraceptive choices on bone health.

Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial.

Osteopenia is a serious medical complication of anorexia nervosa, with no known effective treatment. We conducted a double-blinded, randomized trial comparing alendronate (10 mg daily) with placebo in 32 adolescents with anorexia nervosa (mean age, 16.9 +/- 1.9 yr). All subjects received 1200 mg elemental calcium and 400 IU vitamin D daily and received the same multidisciplinary treatment for their eating disorder. Bone mineral densities (BMDs) of the lumbar spine and femoral neck were measured by dual energy x-ray absorptiometry at baseline and after 1 yr of treatment. Twenty-nine subjects completed the study. Femoral neck and lumbar spine BMDs increased 4.4 +/- 6.4% and 3.5 +/- 4.6% in the alendronate group compared with increases of 2.3 +/- 6.9% and 2.2 + 6.1% in the control group (P = 0.41, femoral neck; P = 0.53, lumbar spine). From baseline to follow-up, BMD increased significantly at the femoral neck (P = 0.02) and lumbar spine (P = 0.02) in those receiving alendronate, but did not increase in those assigned placebo (P = 0.22, femoral neck; P = 0.18, lumbar spine). At follow-up, body weight was the most important determinant of BMD. BMD was significantly higher in subjects who were weight-restored compared with those who remained at low weight (P = 0.002, femoral neck; P = 0.04, lumbar spine). After controlling for body weight, treatment group assignment still had an independent effect at the femoral neck. We conclude that in adolescents with anorexia nervosa, weight restoration is the most important determinant of BMD, but treatment with alendronate did increase the BMD of the lumbar spine and femoral neck within the group receiving alendronate, but not compared with placebo in the primary analysis. Until additional studies have demonstrated efficacy and long-term safety, the use of alendronate in this population should be confined to controlled clinical trials.

The female athlete triad.

The female athlete triad is a syndrome consisting of disordered eating, amenorrhea, and osteoporosis. The syndrome is increasing in prevalence as more women are participating in sports at a competitive level. Behaviors such as intense exercise or disordered eating patterns can lead to dysregulation of the hypothalamic-pituitarian-ovarian (HPO) axis, resulting in amenorrhea. Hypothalamic amenorrhea can lead to osteoporosis and increased fracture risk. Adolescents may particularly be at risk because it is during this crucial time that females attain their peak bone mass. Prevention of the female athlete triad through education and identification of athletes at risk may decrease the incidence of long-term deleterious consequences. Treatment of the female athlete triad is initially aimed at increasing caloric intake and decreasing physical activity until there is resumption of normal menses. Treatment of decreased bone mineral density and osteoporosis in the adolescent population, however, is controversial, with new treatment modalities currently being investigated in order to aid in the management of this disorder.