Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort.

BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. METHODS: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. RESULTS: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (-1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. CONCLUSION: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.

Alteration in serum klotho levels in anorexia nervosa patients.

BACKGROUND & AIMS: Klotho is a trans-membrane protein which can be shed to act as a hormone; its blood levels may be regulated by the GH/IGF-1 axis. Klotho deficient mice exhibit short lifespan and characteristics of aging and malnutrition, including decreased fat and muscle mass, osteopenia, and impaired fertility. As anorexia nervosa (AN) is characterized by malnutrition and GH resistance, we hypothesized klotho levels would be altered in AN, and aimed to assess klotho levels in undernourished AN patients and changes in klotho following weight rehabilitation. PARTICIPANTS AND METHODS: 19 adolescent female AN inpatients (aged 16.1 ± 1.8 years) admitted to an inpatient service for eating disorders in a tertiary center were recruited. Blood samples were obtained on admission and after weight restoration (interval 4.0 ± 2.3 months) and analyzed for klotho, IGF-1, calcium, phosphorus, and alkaline phosphatase. RESULTS: Klotho levels on admission were lower than expected for age, and correlated with lumbar spine BMD Z-score (r = -0.81, p < 0.001) and alkaline phosphatase levels (r = 0.66, p = 0.003) but not with age, height-SDS, weight-SDS, BMI-SDS, or serum calcium, phosphorus and IGF-1 levels. Both IGF-1 and klotho levels increased significantly during hospitalization (IGF-1: 44 ± 17 nmol/l to 53 ± 11 nmol/l, p = 0.008; klotho: 1061 ± 421 pg/ml to 1519 ± 781 pg/ml, p = 0.008). CONCLUSIONS: Klotho levels are low in the acute stage of AN and increase with nutritional rehabilitation. Low klotho on admission may be secondary to low IGF-1 levels and may contribute to the clinical manifestations of AN. The role of klotho in the pathophysiology of AN and as a novel marker of disease severity should be further explored.

Sun Exposure and Protection Habits in Pediatric Patients with a History of Malignancy.

BACKGROUND: Survivors of childhood cancer are at high risk for developing non-melanoma skin cancer and therefore are firmly advised to avoid or minimize sun exposure and adopt skin protection measures. We aimed to compare sun exposure and protection habits in a cohort of pediatric patients with a history of malignancy to those of healthy controls. METHODS: Case-control study of 143 pediatric patients with a history of malignancy (aged 11.2±4.6 y, Male = 68, mean interval from diagnosis 4.4±3.8 y) and 150 healthy controls (aged 10.4±4.8 y, Male = 67). Sun exposure and protection habits were assessed using validated questionnaires. RESULTS: Patients and controls reported similar sun exposure time during weekdays (94±82 minutes/day vs. 81±65 minutes/day; p = 0.83), while during weekends patients spent significantly less time outside compared to controls (103±85 minutes/day vs. 124±87 minutes/day; p = 0.02). Time elapsed from diagnosis positively correlated with time spent outside both during weekdays (r = 0.194, p = 0.02) and weekends (r = 0.217, p = 0.01), and there was a step-up in sun exposure starting three years after diagnosis. There was no significant difference regarding composite sun protection score between patients and controls. Age was positively correlated with number of sunburns per year and sun exposure for the purpose of tanning, and was negatively correlated with the use of sun protection measures. CONCLUSIONS: Although childhood cancer survivors are firmly instructed to adopt sun protection habits, the adherence to these instructions is incomplete, and more attention should be paid to improve these habits throughout their lives. Since sunlight avoidance may results in vitamin D deficiency, dietary supplementation will likely be needed.

Maternal and infantile hypercalcemia caused by vitamin-D-hydroxylase mutations and vitamin D intake.

BACKGROUND: Hypercalcemia is caused by many different conditions and may lead to severe complications. Loss-of-function mutations of CYP24A1, encoding vitamin D-24-hydroxylase, have recently been identified in idiopathic infantile hypercalcemia and in adult kidney stone disease. The aim of this study was to investigate the genetics and clinical features of both infantile and maternal hypercalcemia. METHODS: We studied members of four unrelated Israeli families with hypercalcemia, namely, one woman during pregnancy and after delivery and three infants. Clinical and biochemical data were obtained from probands' medical charts. Genomic DNA was isolated from peripheral blood and CYP24A1 was sequenced. RESULTS: Typical symptoms of hypercalcemia associated with the intake of recommended doses of vitamin D developed in the infants and pregnant woman. Four different loss-of-function CYP24A1 mutations were identified, two of which are reported here for the first time (p.Trp134Gly and p.Glu315*). The infants from families 1 and 2, respectively, were found to be compound heterozygotes, and the infant from family 3 and the pregnant woman were found to be homozygous. CONCLUSIONS: This is the first report of maternal hypercalcemia caused by a CYP24A1 mutation, showing that not only infants are at risk for this complication. Our findings emphasize the importance of recognition, genetic diagnosis and proper treatment of this recently identified hypercalcemic disorder in this era of widespread vitamin D supplements.

High prevalence of vitamin D deficiency and insufficiency in adolescent inpatients diagnosed with eating disorders.

OBJECTIVE: Previous studies assessing vitamin D status in adolescents with eating disorders showed inconsistent results. The aim of the current study was to assess vitamin D status in a large cohort of adolescent inpatients with eating disorders and its relation to bone mineral density (BMD) and depression. METHOD: 25-Hydroxyvitamin D (25OHD), calcium, phosphorus, and alkaline phosphatase levels as well as BMD and depression were assessed on admission in 87 inpatients (aged 16 ± 2 years, females = 81) with eating disorders [anorexia nervosa (AN) = 64; bulimia nervosa (BN) = 5; eating disorders not otherwise specified-binge/purge type (EDNOS-B/P) = 18]. RESULTS: Mean 25OHD levels were 24.1 ± 7.5 ng/ml (25.0 ± 7.6, 25.4 ± 9.9, and 22.0 ± 9.9 ng/ml in patients with AB, BN, and EDNOS-B/P, respectively). Vitamin D deficiency (<15 ng/ml) was found in 7.8% of the patients, and insufficiency (15-20 ng/ml) in 22.2%. Only 16.7% had levels >32 ng/ml, considered optimal by some experts. No associations were found between 25OHD levels and BMD or comorbid depression. 25OHD levels during winter were significantly lower than summer levels (p < .001). Mean lumbar spine BMD z-score in patients with AN and EDNOS-B/P type was low (-1.5 ± 1.1) and correlated with body mass index standard deviation score (p = .03). DISCUSSION: Adolescents with eating disorders show a high prevalence of vitamin D deficiency and insufficiency. Given the risk of osteoporosis in this population, 25OHD levels found in this group may not offer optimal bone protection. Vitamin D levels should be routinely checked and supplementation should be administered as required.

Meconium ileus in patients with cystic fibrosis is not a risk factor for clinical deterioration and survival: the Israeli Multicenter Study.

OBJECTIVES: Patients with cystic fibrosis (CF) presenting with meconium ileus (MI) tend to have worse outcomes than those without MI. We evaluated the clinical characteristics and survival rates among Israeli patients with CF with and without MI after a prolonged follow-up (15-30 years). PATIENTS AND METHODS: A multicenter retrospective study. Forty-nine patients with CF, representing 13.8% of all patients with CF in Israel, presented with MI (current age 17.4 +/- 7.9 years) between 1975 and 2006. They were compared with 38 patients with CF (current age 19.3 +/- 6.5 years) without MI matched by sex and CF transmembrane conductance regulator mutation. RESULTS: A total of 66.2% of patients with MI and 73.6% without MI were followed for a prolonged period (24.9 +/- 2.7 years). Of the patients with MI, 31 were managed operatively, whereas 18 were treated successfully with gastrograffin enema, with similar clinical outcomes. Five patients in the MI group and 3 in the control group died during the study period. Bacterial colonization, z score of body mass index, and pulmonary function tests were similar in patients with and without MI in the long term. In younger patients, many clinical parameters were more prevalent in patients with MI (P = 0.004). However, these differences disappeared after the long-term follow-up (up to 31-years). CONCLUSIONS: Patients with CF presenting with MI had similar pulmonary function and nutritional status, as well as survival rates as did the control patients without MI. The distinct genetic mutation found in our population may explain in part the favorable results compared with other studies. In addition, it seems that early diagnosis and treatment of MI in patients with CF may be beneficial, subsequently lowering morbidity, and increasing survival.