Pompe disease, Krabbe disease, and mucopolysaccharidosis type I were added to the newborn screen in Indiana in 2020. Clinical and laboratory teams collaborated to determine optimal strategies for first- and second-tier testing on newborn screen prior to referral to the metabolism clinic. Our metabolism clinic has worked with neurology, cardiology, and hematology/oncology departments to determine and execute best initial work-up, therapeutic, and ongoing surveillance approaches to manage patients diagnosed with one of these lysosomal disorders on newborn screen. In the first five years of this screening, 27 patients have been diagnosed with Pompe disease (three infantile-onset, 24 late-onset), 13 patients with Krabbe disease (one early infantile, 12 late-onset), and five patients with mucopolysaccharidosis type I (three severe phenotype, one with attenuated phenotype, one with possible attenuated disease). Our experience in caring for these individuals has helped to further refine second-tier testing and our clinical evaluation and management of these patients.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder most commonly caused by 21-hydroxylase deficiency and can lead to life-threatening adrenal crises in infancy if not detected early. In Pakistan, the true incidence of CAH remains unknown due to the absence of national newborn screening programs. This study evaluated the effectiveness of a CAH newborn screening program introduced in 2021 at tertiary and secondary care centers in Pakistan. A retrospective cohort analysis included newborns screened between January 2021 and August 2025 using dried blood spot (DBS) 17-hydroxyprogesterone (17-OHP) testing. During the study period, 39,729 live births occurred, of which 34,621 newborns (87.1%) underwent screening. A total of 189 infants (0.55%) screened positive. Five infants were confirmed to have salt-wasting CAH; three, identified through population-based screening alone, yielded an incidence of 7.6 per 100,000 live births. The positive predictive value was 2.65%, reflecting a high false-positive rate, particularly among premature infants, while no false-negative cases were identified during the available follow-up period. This study demonstrates the feasibility of CAH newborn screening in a resource-limited setting and provides the first incidence estimates from a Pakistani hospital cohort.
Haemoglobinopathies are an increasing health concern in Europe due to changing population demographics. In Italy, however, newborn screening (NBS) for haemoglobinopathies is not yet included in the national mandatory screening panel. The primary aim of this study was to estimate the prevalence of haemoglobinopathies in a population-based neonatal cohort from the Piedmont region; a secondary exploratory objective was to characterise neonatal HbA0 distribution and its association with molecular findings in selected samples. We conducted a retrospective, multicentre study of 2002 anonymised dried blood spot samples collected from term newborns 48–72 h after birth. Haemoglobin fractions were analysed by high-performance liquid chromatography (HPLC). HbA0 distribution was characterised in newborns without structural haemoglobin variants using descriptive statistics. Molecular analysis was performed in an intentionally selected subset of samples with HbA0 < 12%. HPLC identified 29 structural haemoglobin variants (22 HbS and 7 other variants), corresponding to a prevalence of 1.4%. After exclusion of these cases, HbA0 distribution was analysed in 1973 newborns. Mean HbA0 was 16.1% (SD 5.3), median HbA0 was 15.5% (Q1–Q3: 12.3–19.1), and the distribution showed moderate positive skewness. Overall, 448/1973 newborns (22.7%) had HbA0 < 12%. Among 12 selected newborns with HbA0 < 12% who underwent molecular testing, detectable β-globin gene mutations were identified in five. DNA extracted from stored dried blood spots was suitable for molecular analysis. Structural haemoglobin variants were identified in a non-negligible proportion of newborns in this Northern Italian cohort. HPLC provided effective first-line identification of the variants observed, whereas neonatal HbA0 showed substantial variability and an asymmetric distribution, supporting cautious interpretation of fixed absolute thresholds for suspected β-thalassaemia carrier status. Larger, systematically genotyped cohorts are required to assess the diagnostic performance of candidate HbA0 thresholds.
Expanded newborn screening (NBS) using tandem mass spectrometry (MS/MS) can identify multiple inborn errors of metabolism (IEMs), but regional disease and genetic spectra vary. We retrospectively analyzed 611,080 newborns screened at the Women and Children’s Hospital of Ningbo University from July 2014 to December 2024. Amino acids and acylcarnitines were measured by MS/MS, and 256 newborns with persistently abnormal profiles underwent molecular testing using a 94-gene IEM panel or whole-exome sequencing. The initial screen-positive rate was 1.51% (9204), with a 98.9% recall success rate and a repeat positive rate of 11.0% (1003/9106). Integrated diagnostic assessment identified 137 confirmed IEM cases, giving a screen-detected IEM rate of 1 in 4460. Confirmed cases comprised 44 amino acid, 47 organic acid, and 46 fatty acid oxidation disorders. The three most frequent disorders were phenylketonuria, 3-methylcrotonyl-CoA carboxylase deficiency, and primary carnitine deficiency, with the predominant variants being PAH c.728G>A, MCCC1 c.1679dup, and SLC22A5 c.1400C>G. Additionally, 90 newborns with abnormal results on repeat MS/MS testing had single heterozygous findings, complicating diagnostic interpretation. These data characterize the screen-detected IEM spectrum and recurrent genetic variants in Ningbo and highlight the importance of integrating biochemical and molecular findings for gene- and variant-specific diagnostic interpretation.
Newborn screening (NBS) is an effective public health intervention for the early detection of treatable congenital disorders, which may reduce the long-term healthcare burden and yield potential cost for families. Despite its proven benefits, NBS uptake remains limited in Pakistan, and little is known about the factors influencing parental acceptance in secondary care settings. This study aimed primarily to determine parental acceptance and refusal rates for newborn screening, and secondarily to explore parental perceptions, facilitators, and barriers to its uptake. A prospective cross-sectional observational study was conducted at the Aga Khan University Hospital secondary care facilities in Karachi, Pakistan. Data was collected using a structured, expert-reviewed, 5-point Likert response scale questionnaire. Descriptive statistics were used to summarize participant characteristics and responses. Of 179 enrolled parents, 147 (82.1%) accepted newborn screening, while 32 (17.9%) refused. Over a period of 6 months following pediatric counseling for all refusing parents, screening was successfully completed in 154 newborns (86.0%). Healthcare provider counseling, physician recommendation, and improved parental knowledge were the most commonly reported facilitators of acceptance, whereas cost, travel distance, waiting times, and concerns regarding screening outcomes were the most commonly reported barriers. Parental acceptance of newborn screening is influenced by awareness, education, and effective counseling. Strengthening parental education, improving communication by healthcare providers, and ensuring equitable access by addressing financial and policy barriers can support the expansion of sustainable national screening programs in low- and middle-income countries.
