Newborn screening for adrenoleukodystrophy: International experiences and challenges.

X-linked adrenoleukodystrophy (XALD) is the most common leukodystrophy. It has an estimated incidence of around 1/17.000, and a variable phenotype. Following the passage of Aidens Law, New York became the first state to implement a newborn screening for XALD in 2013. Since then, 38 American states, Taiwan, and the Netherlands have included XALD in their NBS program, and Japan and Italy have ongoing pilot studies. Screening for XALD allows for early, potentially lifesaving treatment of adrenal insufficiency and cerebral demyelination but is also a complex subject, due to our limited understanding of the natural history and lack of prognostic biomarkers. Screening protocols and algorithms vary between countries and states, and results and experiences gained so far are important for the future implementation of XALD NBS in other countries. In this review, we have examined the algorithms, methodologies, and outcomes used, as well as how common challenges are addressed in countries/states that have experience using NBS for XALD. We identified 14 peer-reviewed reports on NBS for XALD. All studies presented methods for detecting XALD at birth by NBS using a combination of mass spectrometry and ABCD1 gene sequencing. This has allowed for early surveillance of presymptomatic XALD patients, and the possibility for early detection and timely treatment of XALD manifestations. Obstacles to NBS for XALD include how to deal with variants of unknown significance, whether to screen females, and the ethical concerns of an NBS for a disease where we have limited understanding of natural history and phenotype/genotype correlation.

Women With Turner Syndrome Are Both Estrogen and Androgen Deficient: The Impact of Hormone Replacement Therapy.

CONTEXT: Women with Turner syndrome (TS) suffer from hypergonadotropic hypogonadism, causing a deficit in gonadal hormone secretion. As a consequence, these women are treated with estrogen from the age of 12 years, and later in combination with progesterone. However, androgens have been given less attention. OBJECTIVE: To assess sex hormone levels in women with TS, both those treated and those nontreated with hormone replacement therapy (HRT), and investigate the impact of HRT on sex hormone levels. METHODS: At Aarhus University Hospital, 99 women with TS were followed 3 times from August 2003 to February 2010. Seventeen were lost during follow-up. Control group 1 consisted of 68 healthy age-matched control women seen once during this period. Control group 2 consisted of 28 young, eumenorrheic women sampled 9 times throughout the same menstrual cycle. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17ß-estradiol, estrone sulfate, DHEAS, testosterone, free androgen index, androstenedione, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were analyzed. RESULTS: All androgens, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were 30% to 50% lower in TS compared with controls (P < 0.01). FSH, LH, and estrone sulfate were more than doubled in women with TS compared with controls (P < 0.02). Using principal component analysis, we describe a positive correlation between women with TS receiving HRT, elevated levels of SHBG, and decreased levels of androgens. CONCLUSION: The sex hormone profile in TS reveals a picture of androgen deficiency, aggravated further by HRT. Conventional HRT does not normalize estradiol levels in TS.

Neonatal Screening for Congenital Adrenal Hyperplasia in Denmark: 10 Years of Experience.

INTRODUCTION: Early detection of salt-wasting congenital adrenal hyperplasia (SW-CAH) is important to reduce CAH-related morbidity. However, neonatal screening has shown to have a low positive predictive value (PPV), especially among preterm newborns. Here, the Danish CAH screening is evaluated by comparing incidence and morbidity of SW-CAH 10 years before and after introduction of screening. Furthermore, sensitivity, specificity, and PPV are determined. METHODS: All newborns in Denmark born during 1999-2018 and diagnosed with SW-CAH were identified in the Danish National Patient Registry and/or at the Department of Clinical Genetics, Rigshospitalet. Newborns with a positive neonatal CAH screening were identified at Statens Serum Institut. Correct diagnosis was evaluated by medical record review. RESULTS: A total of 65 newborns with SW-CAH were identified. The incidence of SW-CAH was 5:100,000 both before and after introduction of screening. Performance of sensitivity and specificity of the screening were 97% and 100%, respectively, and the PPV was 55% for the given period. Stratified according to gestational age, the PPV was 33% and 61% for pre -and fullterm newborns, respectively. Though not significant, the proportion of newborns presenting with SW-crisis decreased after introduction of screening from 29% versus 10% (p = 0.07). DISCUSSION AND CONCLUSION: Neonatal screening for SW-CAH has not led to an increase in the incidence of newborns diagnosed with SW-CAH. The screening algorithm has effectively identified newborns with SW-CAH. After 2009, there was a tendency toward a lower proportion of newborns with SW-crisis at diagnosis. Finally, the study emphasizes the benefits of using second-tier screening as well as repeated screening of premature newborns.

Sensitive and Robust LC-MS/MS Assay to Quantify 25-Hydroxyvitamin D in Leftover Protein Extract from Dried Blood Spots.

Neonatal dried blood spots (DBS) provide a remarkable resource for biobanks. These microsamples can provide information related to the genetic correlates of disease and can be used to quantify a range of analytes, such as proteins and small molecules. However, after routine neonatal screening, the amount of DBS sample available is limited. To optimize the use of these samples, there is a need for sensitive assays which are integrated across different analytic platforms. For example, after DNA extraction, protein extracts are available for additional analyses. We describe a sensitive and robust LC-MS/MS method for 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 optimized for leftover protein extracts from DBS, which has excellent recovery, precision, and accuracy.