Opening pandora’s box: incidental findings among infants referred from neonatal screening for metabolic disorders.

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Bahar Kulu, Pelin Teke Kısa, Sevil Yıldız, Özge Kamer Karalar Pekuz, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6277306/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Newborn screening refers to series of tests conducted within the first hours or days of a newborn's life to prevent severe health complications, including death. The study aims to investigate and document other findings and diseases that are incidentally detected through physical examination or laboratory results in infants referred due to elevated phenylalanine levels or biotinidase deficiency as a result of newborn screening. Methods: 792 newborns were referred and evaluated due to their dried blood phenylalanine levels above 120 μmol/L or biotinidase enzyme activity below 65 U. A total of 737 patients were included in the study. The demographic characteristics, reasons for referral, plasma phenylalanine and blood biotinidase levels as well as incidental pathological examination and laboratory findings at the time of referral were recorded for these patients. Results : A total of 25 (3.4%) patients were diagnosed with incidental conditions during screening, 16 of them (66.6%) were initially referred for biotinidase deficiency. Four patients were diagnosed with classical galactosemia, one per with lipoprotein lipase (LPL) deficiency, cystinuria, CPT II deficiency, Duchenne muscular dystrophy. Four patients had congenital heart disease, two were diagnosed with Down Syndrome, two had surgical problems as Hirschsprung's disease and diaphragmatic hernia. Four others had infectious and respiratory diseases, and other four patients had hyperbilirubinemia, feeding problems, extensive hemangioma and microcephaly. Conclusion : A systematic evaluation should be conducted carefully to identify incidental diseases especially for early recognition of conditions detected through newborn screening programs. Newborn screening phenylketonuria biotinidase deficiency incidental findings What is Known The goal of newborn screening is early detection and treatment of all newborns with treatable conditions that otherwise cause both mortality and morbidity, in early presymptomatic period. What is New: Newborn screening programs are highly effective in preventing inborn errors of metabolism and offer additional benefits by facilitating detection of incidental conditions. Introduction Newborn screening programs (NSP) are intended for diseases with high prevalence, severe health impacts and known treatments where early diagnosis can prevent morbidity and mortality. These programs vary significantly across countries due to differences in population size, per capita income, healthcare systems, insurance coverage and implementation [ 1 ]. NSP plays a crucial role in public health initiatives worldwide, serving as an indicator of a nation’s healthcare development [ 2 ]. In Turkey, screening for two hereditary metabolic disorders – phenylketonuria (PKU) and biotinidase deficiency (BD) has been part of the national program since 2007. NSP now covers nearly all newborns across the country [ 3 ]. Screening results showing blood phenylalanine (Phe) levels below 120 µmol/L are considered normal whereas above 240 µmol/L are urgently referred to pediatric metabolic disease clinics. If Phe levels are between 120–240 µmol/L, reanalysis is performed with a new blood sample, if it is still high infant is referred to these clinics. For BD, enzyme activity levels above 65 U are considered normal, when it’s reduced, a repeat blood sample is collected. If activity remains low, patient’s immediately referred to pediatric metabolism clinics. Incidental findings refer to unexpected results that are not part of the primary objectives of NSP but are detected during the diagnostic evaluation process. A notable example is elevated phenylalanine (Phe) since phenylalanine catabolism occurs in the liver, it can rise in any condition that impairs liver functions, as well as in situations where systemic hemodynamics are disturbed, such as heart failure [ 4 , 5 ]. Studies have reported that patients referred for phenylketonuria screening were also diagnosed with other liver-affecting diseases, as well as metabolic disorders such as classic galactosemia and citrin deficiency [ 6 ]. In addition, some underlying diseases can also be diagnosed through examinations and additional tests. The aim of this study is to investigate and document incidental findings and other diseases observed through physical examination or laboratory results in infants referred to pediatric metabolic disorders units, due to elevated Phe or BD in NSP. Methods This is a descriptive and retrospective study from three different metabolic disorders clinics of tertiary care hospitals, between 2021 and 2024. The Ethics Committee approved (No: 2024/12 − 05) study and protocol was designed in compliance with the Declaration of Helsinki, 1964. Of the 792 infants referred, 737 were included in the study. Fifty-five infants were excluded due to missing data. Demographic characteristics, reasons for referral, plasma phenylalanine and blood biotinidase levels, incidental pathological findings from physical examinations and laboratory tests were recorded. Due to absence of expanded NSP in Turkey, additional metabolic evaluations are routinely conducted for all referred newborns, including blood glucose, alanine aminotransferase (ALT) levels, galactose-1-phosphate uridyltransferase (GALT) activity, tandem mass spectrometry (MS/MS), analysis of carnitine and acylcarnitine profiles from dried blood spots and urinary organic acid analysis. All infants were asymptomatic for BD and PKU on admission. Partial BD was defined as blood biotinidase activity between 10–30% while complete deficiency was classified as activity below 10% [ 7 ]. Those diagnosed with BD received oral biotin treatment 5–20 mg/day [ 8 ]. Hyperphenylalaninemia was defined as a plasma phenylalanine level exceeding 120 µmol/L [ 9 ]. Statistical analysis was performed using the IBM SPSS Statistics for Windows, version 28.0 (IBM Corp., Armonk, NY, USA). Normality of distribution of numerical variables was evaluated using the Kolmogorov-Smirnov test. Numerical variables were expressed as mean ± standard deviation while categorical variables were presented as number and percentage (%). Results Total of 737 patients were included in the study. Of these, 480 (65.1%) were referred for biotinidase enzyme activity below 65 U, and 257 (34.9%) referred for phenylalanine levels exceeding 120 µmol/L, 410 (53%) were male, with a mean gestational age of 38.0 ± 1.3 weeks (range: 35–40 weeks). Eight infants were born before 38 weeks. Of these, two were 36 weeks, and one was 35 weeks old with phenylalanine level of 840 µmol/L and total bilirubin level 21 mg/dL (239.4 µM) (Pt 24). Phenylalanine-restricted diet and phototherapy implemented. Two infants which were born at 36 weeks had heart murmur and echocardiographic evaluation revealed atrial septal defect (Pt 11) and pulmonary stenosis (Pt 13), respectively. A total of 25 (3.4%) patients were diagnosed with incidental conditions during screening, with 16 (66.6%) initially referred for suspected biotinidase deficiency. A history of consanguinity was present in 14 (56%) of these cases. Among 25 patients, 14 (56%) were symptomatic with cardiac murmur, hypotonia, lipemic serum, signs of infection, dehydration, abdominal distention which were not associated with the screened disorders. Table 1 presents the demographic characteristics, additional diagnoses, and treatment processes for these 25 patients. The clinical features and disease categories of these patients are further detailed below. Table 1 Demographic characteristics, additional diagnoses, and treatment processes for 25 patients. Patient (Pt) Ageday Gender Co. NS a Phe b Biotinidase activity c Genotype, phenotypic classification, type of BD* Clinical symptoms, labarotory findings Incidental diagnosis Genotype Treatment Pt 1 12 M - PKU 144/39 8.1 PAH gene normal GALT activity 6) Galactose-free diet Pt 2 23 F + PKU 318/240 7.5 HPA Hyperbilirubinemia, hypertransaminasemia Classical galactosemia GALT : c.855G > T (p.K285N) Galactose-free diet Pt 3 20 M + PKU 228/420 6.4 HPA Vomitting, hyperbilirubinemia, hypertransaminasemia Escherichia coli induced sepsis, classical galactosemia GALT : c.563A > G (p.Q188R) Galactose-free diet, antibiotic therapy Pt 4 4 M + BD 102 3.5 c.1270G > C (p.D424H) Hz BD Hyperbilirubinemia, hypertransaminasemia, thrombocytopenia Classical galactosemia GALT : pGLN188Arg (c.563A > 6) Galactose-free diet, antibiotic therapy Pt 5 20 F + BD 40.2 3.33 ** c.1270G > C (p.D424H) Hom. Partial BD Milky (lipemic) appearance of serum, triglyceride level 2500 mg/dL Lipoprotein lipase (LPL) deficiency LPL : NA Biotin 5 mg/day, MCT oil, restriction of dietary fat Pt 6 11 F - BD 57 2.75 ** c.235C > T (p.Arg79Cys) Partial BD Urinary cystine level: 3350 ug/dL Cystinuria SLC7A9 : c.313G > A Biotin 5 mg/day High fuid intake, alkalinization Pt 7 17 M - BD 48 4.1 c.1330G > C (p. Asp444His) Hz BD Acylcarnitine abnormality (Carnitine, C0 ↓, C16↑, C18:1 ↑) Fatty acid oxidation disorder (CPT II deficiency) CPTII : c.338C > T L-carnitine: 20 mg/kg Pt 8 6 M + PKU 228/187 3.02 ** PAH : Hz c.506G > A and Hz IVS10-11G > A HPA Biotinidase activity 30.1% HPA and Hz BD together BTD : c.1330G > C (p.Asp444His) Biotin 5 mg/day Pt 9 20 M + PKU 192/246 5.8 HPA Clinical features of DS, heart murmur DS, ASD 47, XY + 21 Symptomatic therapy Pt 10 11 F - BD 66 4.27 BTD : c.410G > A Hz BD Clinical features of DS, microcephaly DS 47, XX + 21 Symptomatic therapy Pt 11 10 M - BD 81 3.9 BTD : N Heart murmur ASD - Follow-up by ped. cardiology Pt 12 20 F - BD 45 2.8 BTD : c.410G > A Hom. Partial BD Heart murmur VSD - Biotin 5 mg/day Follow-up by ped. cardiology Pt 13 23 F - PKU 126 5.7 HPA Heart murmur Pulmonary valvular stenosis - Follow-up by ped. cardiology Pt 14 18 F + BD 66 2.68 BTD : c.1324delG, c.1330G > C Hom Partial BD Hemangioma on the right side of face Infantile hemangioma - Biotin 5 mg/day Treated with oral propranolol therapy Pt 15 12 M + BD 90 3.56 *** BTD : c.1336G > C (p. Asp446His) Hom Partial BD Hypotonia, weakness, serum creatine kinase: 12000 U/L Duchenne muscular dystrophy - Biotin 5 mg/day Followed up by ped. neurology Pt 16 10 M - BD 96 3.7 BTD : c.1595C > T c.1330G > C Partial BD Tachypnea Pneumoniae - Antibiotic therapy Pt 17 20 F + BD 45 2.7 BTD : N Bullous dermatosis Staphylococcus epidermidis infection - Antibiotic therapy Pt 18 10 M - PKU 168 6.2 HPA Poor sucking, vomiting, hypotonia Neonatal infection - Antibiotic therapy Pt 19 11 F + BD 72 2.8 *** BTD : NA Stridor, tachypnea Transient tachypnea of the newborn - Biotin 5 mg/day Intensive care monitoring Pt 20 17 F + BD 78 3.8 BTD : c.1330G > C (p.D444H) Hz BD Abdominal distantion Hirshprung's disease - Operated Pt 21 35 M + PKU 138 8.2 HPA Respiratory distress Diaphragmatic hernia - Operated Pt 22 13 F + BD 54 1 BTD : c.98_104delGCGGCTG insTCC c.470G > A Profound BD Hypotonia, seizures, Vitamin B12 level 98 pg/mL Epileptic seizures, vitamin B12 deficiency - Levatiracetam, biotin 40 mg/day, vitamin B12 therapy Pt 23 22 F - BD 48 4.2 BTD : c.1330G > C (p. Asp444His) Hz BD Dehydration, poor weight gain Malnutrition - Breastfeeding, supported with formula Pt 24 10 F + PKU 840 4.8 PKU PAH : Compound heterozygous c.165del c.898G > T Indirect hyperbilirubinemia (21 mg/dL) Indirect hyperbilirubinemia - Phenylalanine-restricted diet, phototheraphy Pt 25 9 M - BD 72 3.6 BTD : N Nonpalpabl testis Nonpalpabl undescended testis - Pediatric clinical care follow up Abbreviations : ASD: Atrial septal defect, BD: Biotinidase deficiency, Co.: Consanguinity, CPT II: Carnitine palmitoyltransferase II, DS: Down syndrome, GALT: Galactose-1-phosphate uridyltransferase, HPA: Hyperphenylalaninemia, Hom: Homozygous, Hz: Heterozygous, N: Normal, NA: Not available, NS: Neonatal screening, Phe: Phenylalanine, PKU: Phenylketonuria, PAH: Phenylalanine hydroxylase, VSD: Ventricular septal defect. a Newborn screening test that the patient was referred. b Normal value for Phe: <120µmol/L. c Quantitative testing in plasma performed for biotinidase activity, the measurement unit is nmol/min/mL and the reference range is: 4.4–12.0 nmol/min/mL, more than one measurement was available, the highest level was used for classification. *Phenotypic classification: profound BD; activity below 10%, partial BD; activity between 10–30%, Hz BD; activity between 30.1–66.5%, HPA: blood phenylalanine levels < 120 µmol/L without any treatment. ** Considering the importance of early treatment and the potential for irreversible complications of BD, patients were treated with a dose of 5mg/day biotin. *** Partial BD and symptomatic patients who received biotin an initial dose of 10mg/daily and gradually reduced to 5mg. Four patients were diagnosed with classical galactosemia. One patient (Pt 1) was initially referred on the 12th day of life due to elevated phenylalanine, but repeated tests showed normal phenylalanine levels ( 3.00) and free galactose was 69.1 mg/dL (< 5 mg/dL). Breastfeeding was discontinued, and a galactose-free diet was initiated. Two other patients with galactosemia (Pts 2 and 3) were presented with hyperphenylalaninemia, elevated direct bilirubin, and increased liver enzymes (AST: 678 U/L, ALT: 543 U/L). One of these infants also developed E. coli sepsis. Both were admitted to the neonatal intensive care unit for 22 and 26 days, respectively. During their hospital stay, plasma phenylalanine levels fluctuated between 120 and 360 µmol/L. The fourth patient (Pt 4) diagnosed with galactosemia, who had biotinidase deficiency with 38% enzyme activity was hospitalized due to thrombocytopenia (platelet count: 92.000/mm³), coagulation disorders, elevated liver enzymes, and sepsis, requiring treatment with ampicillin, amikacin, and vancomycin. GALT activity in this patient was 1.00 U/g, with total and free galactose levels measuring 97.6 mg/dL and 84.1 mg/dL, respectively. Genetic testing confirmed classical galactosemia in all four patients. The identified GALT gene variants were c.563A > G (p.Q188R), c.855G > T (p.K285N), and c.563A > 6 (p.Gln188Arg), with all patients carrying these mutations in homozygous form. All were started on a galactose-free formula and closely monitored. A 20-day-old female (Pt 5), with parental consanguinity, was initially referred for BD. Due to lipemic appearance of her serum, triglyceride levels found as 2500 mg/dL (N < 150 mg/dL). She was pre-diagnosed with lipoprotein lipase (LPL) deficiency. After three months of treatment, her triglyceride levels decreased to 750 mg/dL, and biotinidase activity at that time was 3.64 nmol/min/mL. Genetic testing revealed a homozygous pathogenic variant in BTD . Pt 6, referred for BD, revealed cystine excretion levels in urine amino acid analysis above 3350 µmol/g creatinine (N: 0-200 µmol/g). Repeated urine tests confirmed elevated excretions of cystine (3291 µmol/g), arginine (465 µmol/g; N: 0-110), and lysine (7196 µmol/g; N: 0-180), consistent with cystinuria. Molecular analysis identified a heterozygous pathogenic variant, c.313G > A, in the SLC7A9 gene. Pt 7, referred for BD had creatine kinase (CK) level of 209 U/L and free carnitine level of 6 µmol/L(N:>20µmol/L) by MS/MS, echocardiogram revealed hypertrophic cardiomyopathy and molecular testing identified heterozygous pathogenic c.338C > T missense variant in CPT2 gene. Patient was diagnosed with carnitine palmitoyl transferase II (CPT II) deficiency. During family screening, an asymptomatic 4-year-old sibling showed elevated CK (353 U/L; N: 0-171). Molecular analysis confirmed same CPT2 variant, resulting CPT II deficiency. A 6-day-old infant (Pt 8), with elevated phenylalanine levels (230 µmol/L) and partial BD at the same time with hyperphenylalaninemia. Another common group of diseases identified among infants referred through NSP was congenital heart diseases. Physical examinations revealed ASD in two patients (Pts 9 and 11), VSD in one (Pt 12) and pulmonary stenosis in another (Pt 13). One patient with ASD was also diagnosed with Down syndrome. In total, two patients (Pts 9,10) exhibited with Down syndrome. Genetic testing confirmed trisomy 21 in both. Pt 14 which was referred due to BD, had huge hemangioma and propranolol treatment was initiated by pediatric hematology. Pt 15, referred for BD was hypotonic and serum CK was 12.000 U/L (N: 26–192 U/L). Testing for alpha-1,4-glucosidase enzyme activity and GAA genetic analysis ruled out infantile Pompe disease. However, pathogenic variant in the DMD gene was identified during neuromuscular disease screening, leading to a diagnosis of Duchenne Muscular Dystrophy. Pts 16,17 and 18, exhibited severe infection symptoms such as pneumonia, bullous skin lesions, sepsis, and needed antibiotic treatment. Additionally, Pt 19 was admitted to neonatal intensive care unit because of transient tachypnea of newborn. Following initiation of biotin supplementation, patient benefited from treatment and was discharged. Two patients required surgical intervention due to comorbid conditions. Pt 20, referred for BE, had difficulties with defecation, abdominal distension was observed, and she was diagnosed with Hirschsprung's disease and finally underwent surgery. Pt 21, a 35-day-old infant referred due to elevated phenylalanine levels, exhibited respiratory distress and was subsequently diagnosed with diaphragmatic hernia. Pt 10, referred for BD had stigmatas complied with Down syndrome and head circumference measured − 2.5 SDS. Chromosomal analysis confirmed trisomy 21 (47, XX + 21). Pt 22, 13 days old infant with hypotonia diagnosed with complete BD. Her vitamin B12 level was critically low at 98 pg/mL, though other metabolic screening results were normal she experienced seizure at three months old. Biotin dose increased up to 40 mg/day, no further seizures occurred. Whole exome sequencing revealed two pathogenic variants: c.98_104delGCGGCTG insTCC and c.470G > A in BTD gene. Pt 23 referred for BD, presented with dehydration and 15% weight loss, attributed to inadequate breast milk intake with no diarrhea, vomiting, or infection. After nutritional support she gained weight and was discharged. Pt 24 was presented with indirect hyperbilirubinemia and successfully treated with phototherapy and Pt 25 was diagnosed with undescended testis. Discussion Significant progress has been made about newborn screening program in Turkey since its inception in 1986. While screening rate for newborn infants was 4.7% in 1987, it increased to 97% by 2020 [ 10 ]. According to latest data, the number of newborns in 2023 was 934.000 (Turkish Statistical Institute). Of these newborns, 98% were screened and 2.237 infants with PKU, 3.143 with BD were detected. Among the referred newborns, 795 (35%) were diagnosed with PKU or hyperphenylalaninemia based on clinical and genetic evaluations, while 1.237 (39.5%) were definitely diagnosed with BD (Ministry of Health Screening Data, 2023). All newborns with positive screening results have been referred to pediatric metabolism clinics [ 11 ]. In these centers, biotinidase enzyme analysis (with colorimetric method) and plasma phenylalanine levels (with HPLC) are reanalyzed, additionally baseline metabolic disease screenings are conducted. In addition to screening metabolic diseases, a comprehensive evaluation from a general pediatrics perspective will help to ensure that incidental diseases are not overlooked. Analyzing incidental findings in these infants can reveal various conditions beyond primary diagnoses. This study documented various incidental diseases, including congenital anomalies, infectious diseases, genetic disorders, alongside different causes of secondary phenylalanine elevation. The high prevalence of consanguineous marriages in Turkey (20–25%) contributes to a greater incidence of hereditary metabolic diseases compared to other countries [ 12 ]. In our study, the rate of additional diseases in infants referred for hereditary metabolic diseases such as PKU and BD was found to be 3.4%, and the rate of consanguineous marriage among these infants' parents was 56%. Although the rate of incidental disease detection is not very high in the study, the prevalence of consanguineous marriages among detected cases is twice the national average. This also indicates that the prevalence of metabolic and incidental diseases is higher in consanguineous marriages. In a study from Spain since 1969, newborn screening programs demonstrated that frequency of incidental disease diagnoses is 1 in 1.140, excluding 24 diseases routinely screened [ 13 ]. However, in our country, only two metabolic diseases are screened, some hereditary metabolic diseases that are common in population, such as galactosemia, are not included in newborn screening program. Therefore, a higher rate may have been detected in our study. Also, diseases such as citrin deficiency, galactosemia, and type 1 tyrosinemia, which can lead to secondary phenylalanine elevation, particularly due to their association with liver disease, are included in newborn screening programs of many other countries but are not screened in Turkey [ 14 , 15 ]. In our study, four infants (4 out of 737, or 0.54%) were diagnosed with classical galactosemia. Cantley et al. researched infants with elevated phenylalanine levels from newborn screening and found that 117 out of more than 6 million babies were diagnosed with high phenylalanine, including 45 cases of galactosemia, 4 cases of citrin deficiency, and 1 case of methylmalonic acidemia; notably, 35% of infants could not be given a specific diagnosis [ 6 ]. Among our patients’ high occurrence of galactosemia, particularly in infants with elevated phenylalanine, aligns with existing literature [ 16 ]. The introduction of tandem mass spectrometry (MS/MS) technology into neonatal screening programs (NSP) marks a significant advancement, enabling the detection of over 40 metabolic disorders from dried blood samples [ 17 , 18 ]. This technology greatly enhances the early diagnosis and treatment of affected newborns. Unfortunately, expanded newborn screening is not conducted in every country. In this study, an asymptomatic infant referred due to BD had elevated creatine kinase levels and low free carnitine levels on MS/MS. Molecular analysis confirmed carnitine palmitoyltransferase II (CPT II) deficiency. Family screening revealed the same diagnosis in infant’s asymptomatic sibling also. Tandem MS in newborn screening enables early detection of fatty acid oxidation disorders. Cystinuria was incidentally identified in another infant of BD. It’s an inherited metabolic disorder resulting from transport defects of cystine and basic amino acids, such as ornithine, lysine, and arginine from renal proximal tubules and gastrointestinal tract. Its prevalence is approximately 1 in 7.000 which manifests with formation of urinary stones. A study conducted in Spain found that 10.5% of cystinuria cases identified through newborn screening developed kidney stones, typically around the age of seven [ 19 ]. Screening for cystinuria in newborns is important to take measures for kidney stone formation and management of any stone development. In this study, a serum sample of an infant (BD) was lipemic, leading to a diagnosis of lipoprotein lipase (LPL) deficiency upon further examination. LPL deficiency is an inherited disorder of lipoprotein metabolism that can result in hypertriglyceridemia and potentially life-threatening pancreatitis [ 20 ]. Santer et al. identified LPL deficiency in two Turkish patients with BD during newborn screening and reported that their biotinidase activities returned to normal after serum triglyceride levels decreased due to dietary management [ 21 ]. Elevated triglyceride levels in blood can lead to falsely low biotinidase levels measured by both fluorimetric and colorimetric methods, resulting in false-positive newborn screening outcomes. In our patient, although triglyceride level decreased to 750 mg/dL after dietary adjustments by third month, measured biotinidase activity remained at 3.64 nmol/min/mL. Additionally, pathogenic variants were found in both LPL and BTD genes. Beyond hereditary metabolic diseases, newborn screening can also detect other disease categories, some of which can be treated, while others can have complications that may be prevented or managed. In our study, patients presented with a diverse range of conditions, including structural cardiovascular defects, Down syndrome, Duchenne muscular dystrophy, pneumonia, staphylococcal skin infections and sepsis, transient tachypnea, seizures and epilepsy, feeding problems, dehydration, extensive hemangiomas, microcephaly, diaphragmatic hernias, undescended testis and Hirschsprung's disease. All infants diagnosed with hereditary metabolic diseases or other conditions were referred to the appropriate clinics for medical or surgical treatment based on their specific diagnoses, as well as for ongoing follow-up. These findings underscore the importance of a holistic approach in the evaluation of infants referred through newborn screening, combining a thorough history, physical examination, and additional laboratory testing as needed to facilitate early diagnosis and treatment. The primary limitation of our study was small patient sample size. Future studies involving larger cohort will yield more comprehensive insights into this topic. In countries where consanguineous marriages are common and birth rates are high, it is crucial to conduct systematic evaluations of infants referred from newborn screening programs to identify additional hereditary or acquired diseases. Abbreviations NSP Newborn screening programs PKU Phenylketonuria BD Biotinidase deficiency Phe Phenylalanine HPA Hyperphenylalaninemia Pt Patient Declarations Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Dokuz Eylül University (approval number: 2024/12 − 05). Informed consent Informed consent was obtained from the parents in this study. Competing interests The authors declare no competing interests Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contribution Authors’ contributions:B.K and P.T.K designed the study; B.K.,P.T.K.,S.Y.,E.E.,Ö.K.K.P,M.B. collected data; B.K.,P.T.K.,N.A . analysed the data,B.K.wrote the frst draft of the manuscript; P.T.K. and N.A. commented on previous versions of the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Acknowledgement - References Fabie NAV, Pappas KB, Feldman GL. The Current State of Newborn Screening in the United States. Pediatr Clin North Am. 2019 Apr;66(2):369-386. El-Hattab AW, Almannai M, Sutton VR. Newborn screening: History, current status, and future directions. Pediatr Clin North Am. 2018 Apr;65(2):389-405. Aktuğlu Zeybek AÇ. Newborn screening: From the past to the future. Turk Arch Pediatr. 2022 Sep;57(5):473-475. Waters PJ, Khashu M, Lillquist Y, et al. Neonatal hyperphenylalaninemia, perinatal hemochromatosis, and renal tubulopathy: a unique patient or a novel metabolic disorder? 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Pediatr Nephrol. 2023 May;38(5):1513-1521. Neelamekam S, Kwok S, Malone R, Wierzbicki AS, Soran H. The impact of lipoprotein lipase deficiency on health-related quality of life: a detailed, structured, qualitative study. Orphanet J Rare Dis. 2017 Sep 19;12(1):156. Santer R, Gokçay G, Demirkol M, Gal A, Lukacs Z. Hyperchylomicronaemia due to lipoprotein lipase deficiency as a cause of false-positive newborn screening for biotinidase deficiency. J Inherit Metab Dis. 2005;28(2):137-40. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6277306","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436922438,"identity":"bb700b6e-e6c9-487c-92d1-c42ba9774b28","order_by":0,"name":"Bahar Kulu","email":"","orcid":"","institution":"University of Health Sciences, Tepecik Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bahar","middleName":"","lastName":"Kulu","suffix":""},{"id":436922439,"identity":"866f7672-e446-4318-848b-4b7ff7264f7d","order_by":1,"name":"Pelin Teke Kısa","email":"","orcid":"","institution":"Dokuz Eylul University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Pelin","middleName":"Teke","lastName":"Kısa","suffix":""},{"id":436922442,"identity":"a4abb4a1-68e8-483b-a77b-d370bc20d552","order_by":2,"name":"Sevil Yıldız","email":"","orcid":"","institution":"University of Health Sciences, Bursa Yüksek İhtisas Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sevil","middleName":"","lastName":"Yıldız","suffix":""},{"id":436922446,"identity":"389cc17f-610b-40e0-974d-56f2cf274af5","order_by":3,"name":"Özge Kamer Karalar Pekuz","email":"","orcid":"","institution":"Dokuz Eylul University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Özge","middleName":"Kamer Karalar","lastName":"Pekuz","suffix":""},{"id":436922449,"identity":"da09088f-b683-476e-b8bd-9bc5bd2ed02d","order_by":4,"name":"Merve Bilen","email":"","orcid":"","institution":"Dokuz Eylul University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Merve","middleName":"","lastName":"Bilen","suffix":""},{"id":436922450,"identity":"2dbcc98f-9b66-4164-bed9-61c62580a3f7","order_by":5,"name":"Esra Er","email":"","orcid":"","institution":"University of Health Sciences Dr. Behçet Uz Child Disease and Pediatric Surgery Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Esra","middleName":"","lastName":"Er","suffix":""},{"id":436922451,"identity":"fa0cd2b2-8b8c-42fe-9179-dedb4d69444d","order_by":6,"name":"Nur Arslan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBADGQYG5gMSYOYBIrXwMDCwJcC0MDYQqYXHgDgt5hK5Dxh+7qnj4Z/d8/HGxzYGOb4bCeyPK/BosZyRbsDY8+wwj8Sds5stZ7YxGEveSGBsPINHi8GNNKCTDhzgYbiRu02at40hcQNICz6XgbQw/jlQxyN/I+eZ9N82hnqitDDzHGDmMbiRwybN2MaQYEBQy5lnDIdlDhzmMbyRZmzZc07CcOaZh40z8Wo5nsb48M2BOjm5G8kPb/wos5HnO5584CM+LSBwAIkNihriYnIUjIJRMApGAR4AAK6nT4aH13VIAAAAAElFTkSuQmCC","orcid":"","institution":"Dokuz Eylul University Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Nur","middleName":"","lastName":"Arslan","suffix":""}],"badges":[],"createdAt":"2025-03-21 11:53:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6277306/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6277306/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81443616,"identity":"3acf292a-29d8-48ed-aa27-48c8accd0ac2","added_by":"auto","created_at":"2025-04-26 15:31:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":809433,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6277306/v1/f9fd8d2b-4cc2-41e1-976e-f1d743806bb7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Opening pandora’s box: incidental findings among infants referred from neonatal screening for metabolic disorders.","fulltext":[{"header":"What is Known","content":"\u003cp\u003eThe goal of newborn screening is early detection and treatment of all newborns with treatable conditions that otherwise cause both mortality and morbidity, in \u0026nbsp;early presymptomatic period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is New:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNewborn screening programs are highly effective in preventing inborn errors of metabolism and offer additional benefits by facilitating detection of incidental conditions.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eNewborn screening programs (NSP) are intended for diseases with high prevalence, severe health impacts and known treatments where early diagnosis can prevent morbidity and mortality. These programs vary significantly across countries due to differences in population size, per capita income, healthcare systems, insurance coverage and implementation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. NSP plays a crucial role in public health initiatives worldwide, serving as an indicator of a nation\u0026rsquo;s healthcare development [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In Turkey, screening for two hereditary metabolic disorders \u0026ndash; phenylketonuria (PKU) and biotinidase deficiency (BD) has been part of the national program since 2007. NSP now covers nearly all newborns across the country [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Screening results showing blood phenylalanine (Phe) levels below 120 \u0026micro;mol/L are considered normal whereas above 240 \u0026micro;mol/L are urgently referred to pediatric metabolic disease clinics. If Phe levels are between 120\u0026ndash;240 \u0026micro;mol/L, reanalysis is performed with a new blood sample, if it is still high infant is referred to these clinics. For BD, enzyme activity levels above 65 U are considered normal, when it\u0026rsquo;s reduced, a repeat blood sample is collected. If activity remains low, patient\u0026rsquo;s immediately referred to pediatric metabolism clinics.\u003c/p\u003e \u003cp\u003eIncidental findings refer to unexpected results that are not part of the primary objectives of NSP but are detected during the diagnostic evaluation process. A notable example is elevated phenylalanine (Phe) since phenylalanine catabolism occurs in the liver, it can rise in any condition that impairs liver functions, as well as in situations where systemic hemodynamics are disturbed, such as heart failure [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Studies have reported that patients referred for phenylketonuria screening were also diagnosed with other liver-affecting diseases, as well as metabolic disorders such as classic galactosemia and citrin deficiency [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, some underlying diseases can also be diagnosed through examinations and additional tests.\u003c/p\u003e \u003cp\u003eThe aim of this study is to investigate and document incidental findings and other diseases observed through physical examination or laboratory results in infants referred to pediatric metabolic disorders units, due to elevated Phe or BD in NSP.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis is a descriptive and retrospective study from three different metabolic disorders clinics of tertiary care hospitals, between 2021 and 2024. The Ethics Committee approved (No: 2024/12\u0026thinsp;\u0026minus;\u0026thinsp;05) study and protocol was designed in compliance with the Declaration of Helsinki, 1964. Of the 792 infants referred, 737 were included in the study. Fifty-five infants were excluded due to missing data. Demographic characteristics, reasons for referral, plasma phenylalanine and blood biotinidase levels, incidental pathological findings from physical examinations and laboratory tests were recorded. Due to absence of expanded NSP in Turkey, additional metabolic evaluations are routinely conducted for all referred newborns, including blood glucose, alanine aminotransferase (ALT) levels, galactose-1-phosphate uridyltransferase (GALT) activity, tandem mass spectrometry (MS/MS), analysis of carnitine and acylcarnitine profiles from dried blood spots and urinary organic acid analysis.\u003c/p\u003e \u003cp\u003eAll infants were asymptomatic for BD and PKU on admission. Partial BD was defined as blood biotinidase activity between 10\u0026ndash;30% while complete deficiency was classified as activity below 10% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Those diagnosed with BD received oral biotin treatment 5\u0026ndash;20 mg/day [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Hyperphenylalaninemia was defined as a plasma phenylalanine level exceeding 120 \u0026micro;mol/L [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using the IBM SPSS Statistics for Windows, version 28.0 (IBM Corp., Armonk, NY, USA). Normality of distribution of numerical variables was evaluated using the Kolmogorov-Smirnov test. Numerical variables were expressed as mean \u0026plusmn; standard deviation while categorical variables were presented as number and percentage (%).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTotal of 737 patients were included in the study. Of these, 480 (65.1%) were referred for biotinidase enzyme activity below 65 U, and 257 (34.9%) referred for phenylalanine levels exceeding 120 \u0026micro;mol/L, 410 (53%) were male, with a mean gestational age of 38.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 weeks (range: 35\u0026ndash;40 weeks). Eight infants were born before 38 weeks. Of these, two were 36 weeks, and one was 35 weeks old with phenylalanine level of 840 \u0026micro;mol/L and total bilirubin level 21 mg/dL (239.4 \u0026micro;M) (Pt 24). Phenylalanine-restricted diet and phototherapy implemented. Two infants which were born at 36 weeks had heart murmur and echocardiographic evaluation revealed atrial septal defect (Pt 11) and pulmonary stenosis (Pt 13), respectively.\u003c/p\u003e \u003cp\u003eA total of 25 (3.4%) patients were diagnosed with incidental conditions during screening, with 16 (66.6%) initially referred for suspected biotinidase deficiency. A history of consanguinity was present in 14 (56%) of these cases. Among 25 patients, 14 (56%) were symptomatic with cardiac murmur, hypotonia, lipemic serum, signs of infection, dehydration, abdominal distention which were not associated with the screened disorders. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the demographic characteristics, additional diagnoses, and treatment processes for these 25 patients. The clinical features and disease categories of these patients are further detailed below.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics, additional diagnoses, and treatment processes for 25 patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003cp\u003e(Pt)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgeday\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhe\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBiotinidase activity\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGenotype,\u003c/p\u003e \u003cp\u003ephenotypic classification,\u003c/p\u003e \u003cp\u003etype of BD*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eClinical symptoms,\u003c/p\u003e \u003cp\u003elabarotory findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eIncidental diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e144/39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ePAH\u003c/em\u003e gene normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGALT activity \u0026lt;%1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClassical galactosemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eGALT\u003c/em\u003e: pGLN188Arg\u003c/p\u003e \u003cp\u003e(c.563A\u0026thinsp;\u0026gt;\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eGalactose-free diet\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e318/240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHyperbilirubinemia, hypertransaminasemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClassical galactosemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eGALT\u003c/em\u003e:\u003c/p\u003e \u003cp\u003ec.855G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.K285N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eGalactose-free diet\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e228/420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eVomitting,\u003c/p\u003e \u003cp\u003ehyperbilirubinemia, hypertransaminasemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eEscherichia\u0026nbsp;coli\u003c/em\u003e\u003c/p\u003e \u003cp\u003einduced sepsis,\u003c/p\u003e \u003cp\u003eclassical galactosemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eGALT\u003c/em\u003e: c.563A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Q188R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eGalactose-free diet, antibiotic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ec.1270G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003e(p.D424H)\u003c/p\u003e \u003cp\u003eHz BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHyperbilirubinemia, hypertransaminasemia, thrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eClassical galactosemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eGALT\u003c/em\u003e: pGLN188Arg\u003c/p\u003e \u003cp\u003e(c.563A\u0026thinsp;\u0026gt;\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eGalactose-free diet, antibiotic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.33\u003cb\u003e**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ec.1270G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003e(p.D424H)\u003c/p\u003e \u003cp\u003eHom. Partial BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMilky (lipemic) appearance of serum, triglyceride level 2500 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eLipoprotein\u0026nbsp;lipase\u003c/p\u003e \u003cp\u003e(LPL)\u0026nbsp;deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eLPL\u003c/em\u003e: NA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day,\u003c/p\u003e \u003cp\u003eMCT oil, restriction of dietary fat\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.75\u003cb\u003e**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ec.235C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003cp\u003e(p.Arg79Cys)\u003c/p\u003e \u003cp\u003ePartial BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eUrinary cystine level: 3350 ug/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCystinuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eSLC7A9\u003c/em\u003e: c.313G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day\u003c/p\u003e \u003cp\u003eHigh fuid intake,\u003c/p\u003e \u003cp\u003ealkalinization\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ec.1330G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003e(p. Asp444His)\u003c/p\u003e \u003cp\u003eHz BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAcylcarnitine abnormality (Carnitine, C0 \u0026darr;, C16\u0026uarr;, C18:1 \u0026uarr;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eFatty acid oxidation disorder (CPT II deficiency)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eCPTII\u003c/em\u003e: c.338C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eL-carnitine: 20 mg/kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e228/187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.02\u003cb\u003e**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ePAH\u003c/em\u003e: Hz\u003c/p\u003e \u003cp\u003ec.506G\u0026thinsp;\u0026gt;\u0026thinsp;A and Hz IVS10-11G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBiotinidase activity 30.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHPA and Hz BD together\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.1330G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003e(p.Asp444His)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e192/246\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eClinical features of DS, heart murmur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDS, ASD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e47, XY\u0026thinsp;+\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSymptomatic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.410G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003cp\u003eHz BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eClinical features of DS, microcephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e47, XX\u0026thinsp;+\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSymptomatic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHeart murmur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eASD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eFollow-up by ped. cardiology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.410G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003cp\u003eHom. Partial BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHeart murmur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eVSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day Follow-up by ped. cardiology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHeart murmur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePulmonary valvular\u0026nbsp;stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eFollow-up by ped. cardiology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.1324delG, c.1330G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003eHom Partial BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHemangioma on the right side of face\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eInfantile hemangioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day\u003c/p\u003e \u003cp\u003eTreated with oral propranolol therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.56\u003cb\u003e***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.1336G\u0026thinsp;\u0026gt;\u0026thinsp;C (p. Asp446His)\u003c/p\u003e \u003cp\u003eHom Partial BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHypotonia,\u003c/p\u003e \u003cp\u003eweakness, serum creatine\u0026nbsp;kinase: 12000 U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDuchenne muscular dystrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day\u003c/p\u003e \u003cp\u003eFollowed up by ped. neurology\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.1595C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003cp\u003ec.1330G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003ePartial BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTachypnea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePneumoniae\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAntibiotic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBullous dermatosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAntibiotic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePoor sucking, vomiting, hypotonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNeonatal infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAntibiotic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.8\u003cb\u003e***\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: NA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eStridor,\u003c/p\u003e \u003cp\u003etachypnea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTransient tachypnea of the newborn\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBiotin 5 mg/day\u003c/p\u003e \u003cp\u003eIntensive care monitoring\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.1330G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003e(p.D444H)\u003c/p\u003e \u003cp\u003eHz BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAbdominal distantion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHirshprung's\u003c/p\u003e \u003cp\u003edisease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eOperated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eRespiratory distress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDiaphragmatic hernia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eOperated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e:\u003c/p\u003e \u003cp\u003ec.98_104delGCGGCTG insTCC c.470G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003cp\u003eProfound BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHypotonia,\u003c/p\u003e \u003cp\u003eseizures,\u003c/p\u003e \u003cp\u003eVitamin B12 level 98 pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eEpileptic seizures, vitamin B12 deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLevatiracetam, biotin 40 mg/day, vitamin B12 therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: c.1330G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003cp\u003e(p. Asp444His)\u003c/p\u003e \u003cp\u003eHz BD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDehydration,\u003c/p\u003e \u003cp\u003epoor weight gain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMalnutrition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBreastfeeding, supported with formula\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e840\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003cp\u003e\u003cem\u003ePAH\u003c/em\u003e: Compound heterozygous\u003c/p\u003e \u003cp\u003ec.165del c.898G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIndirect hyperbilirubinemia\u003c/p\u003e \u003cp\u003e(21 mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eIndirect hyperbilirubinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ePhenylalanine-restricted diet,\u003c/p\u003e \u003cp\u003ephototheraphy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt 25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eBTD\u003c/em\u003e: N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNonpalpabl\u003c/p\u003e \u003cp\u003etestis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNonpalpabl undescended testis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ePediatric clinical care follow up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003cem\u003eAbbreviations\u003c/em\u003e: ASD: Atrial septal defect, BD: Biotinidase deficiency, Co.: Consanguinity, CPT II: Carnitine palmitoyltransferase II,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eDS: Down syndrome, GALT: Galactose-1-phosphate uridyltransferase, HPA: Hyperphenylalaninemia, Hom: Homozygous,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eHz: Heterozygous, N: Normal, NA: Not available, NS: Neonatal screening, Phe: Phenylalanine, PKU: Phenylketonuria, PAH: Phenylalanine hydroxylase, VSD: Ventricular septal defect.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003ea\u003c/sup\u003eNewborn screening test that the patient was referred.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003eb\u003c/sup\u003eNormal value for Phe: \u0026lt;120\u0026micro;mol/L.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003ec\u003c/sup\u003eQuantitative testing in plasma performed for biotinidase activity, the measurement unit is nmol/min/mL and the reference range is: 4.4\u0026ndash;12.0 nmol/min/mL, more than one measurement was available, the highest level was used for classification.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e*Phenotypic classification: profound BD; activity below 10%, partial BD; activity between 10\u0026ndash;30%, Hz BD; activity between 30.1\u0026ndash;66.5%, HPA: blood phenylalanine levels\u0026thinsp;\u0026lt;\u0026thinsp;120 \u0026micro;mol/L without any treatment.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003cb\u003e**\u003c/b\u003eConsidering the importance of early treatment and the potential for irreversible complications of BD, patients were treated with a dose of 5mg/day biotin.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003cb\u003e***\u003c/b\u003ePartial BD and symptomatic patients who received biotin an initial dose of 10mg/daily and gradually reduced to 5mg.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFour patients were diagnosed with classical galactosemia. One patient (Pt 1) was initially referred on the 12th day of life due to elevated phenylalanine, but repeated tests showed normal phenylalanine levels (\u0026lt;\u0026thinsp;120 \u0026micro;mol/L). However, patient's galactose-1-phosphate uridyltransferase (GALT) enzyme activity was 0.67 U/g (reference\u0026thinsp;\u0026gt;\u0026thinsp;3.00) and free galactose was 69.1 mg/dL (\u0026lt;\u0026thinsp;5 mg/dL). Breastfeeding was discontinued, and a galactose-free diet was initiated. Two other patients with galactosemia (Pts 2 and 3) were presented with hyperphenylalaninemia, elevated direct bilirubin, and increased liver enzymes (AST: 678 U/L, ALT: 543 U/L). One of these infants also developed \u003cem\u003eE. coli\u003c/em\u003e sepsis. Both were admitted to the neonatal intensive care unit for 22 and 26 days, respectively. During their hospital stay, plasma phenylalanine levels fluctuated between 120 and 360 \u0026micro;mol/L. The fourth patient (Pt 4) diagnosed with galactosemia, who had biotinidase deficiency with 38% enzyme activity was hospitalized due to thrombocytopenia (platelet count: 92.000/mm\u0026sup3;), coagulation disorders, elevated liver enzymes, and sepsis, requiring treatment with ampicillin, amikacin, and vancomycin. GALT activity in this patient was 1.00 U/g, with total and free galactose levels measuring 97.6 mg/dL and 84.1 mg/dL, respectively. Genetic testing confirmed classical galactosemia in all four patients. The identified \u003cem\u003eGALT\u003c/em\u003e gene variants were c.563A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Q188R), c.855G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.K285N), and c.563A\u0026thinsp;\u0026gt;\u0026thinsp;6 (p.Gln188Arg), with all patients carrying these mutations in homozygous form. All were started on a galactose-free formula and closely monitored.\u003c/p\u003e \u003cp\u003eA 20-day-old female (Pt 5), with parental consanguinity, was initially referred for BD. Due to lipemic appearance of her serum, triglyceride levels found as 2500 mg/dL (N\u0026thinsp;\u0026lt;\u0026thinsp;150 mg/dL). She was pre-diagnosed with lipoprotein lipase (LPL) deficiency. After three months of treatment, her triglyceride levels decreased to 750 mg/dL, and biotinidase activity at that time was 3.64 nmol/min/mL. Genetic testing revealed a homozygous pathogenic variant in \u003cem\u003eBTD\u003c/em\u003e. Pt 6, referred for BD, revealed cystine excretion levels in urine amino acid analysis above 3350 \u0026micro;mol/g creatinine (N: 0-200 \u0026micro;mol/g). Repeated urine tests confirmed elevated excretions of cystine (3291 \u0026micro;mol/g), arginine (465 \u0026micro;mol/g; N: 0-110), and lysine (7196 \u0026micro;mol/g; N: 0-180), consistent with cystinuria. Molecular analysis identified a heterozygous pathogenic variant, c.313G\u0026thinsp;\u0026gt;\u0026thinsp;A, in the \u003cem\u003eSLC7A9\u003c/em\u003e gene. Pt 7, referred for BD had creatine kinase (CK) level of 209 U/L and free carnitine level of 6 \u0026micro;mol/L(N:\u0026gt;20\u0026micro;mol/L) by MS/MS, echocardiogram revealed hypertrophic cardiomyopathy and molecular testing identified heterozygous pathogenic c.338C\u0026thinsp;\u0026gt;\u0026thinsp;T missense variant in \u003cem\u003eCPT2\u003c/em\u003e gene. Patient was diagnosed with carnitine palmitoyl transferase II (CPT II) deficiency. During family screening, an asymptomatic 4-year-old sibling showed elevated CK (353 U/L; N: 0-171). Molecular analysis confirmed same \u003cem\u003eCPT2\u003c/em\u003e variant, resulting CPT II deficiency. A 6-day-old infant (Pt 8), with elevated phenylalanine levels (230 \u0026micro;mol/L) and partial BD at the same time with hyperphenylalaninemia. Another common group of diseases identified among infants referred through NSP was congenital heart diseases. Physical examinations revealed ASD in two patients (Pts 9 and 11), VSD in one (Pt 12) and pulmonary stenosis in another (Pt 13). One patient with ASD was also diagnosed with Down syndrome. In total, two patients (Pts 9,10) exhibited with Down syndrome. Genetic testing confirmed trisomy 21 in both. Pt 14 which was referred due to BD, had huge hemangioma and propranolol treatment was initiated by pediatric hematology. Pt 15, referred for BD was hypotonic and serum CK was 12.000 U/L (N: 26\u0026ndash;192 U/L). Testing for alpha-1,4-glucosidase enzyme activity and \u003cem\u003eGAA\u003c/em\u003e genetic analysis ruled out infantile Pompe disease. However, pathogenic variant in the \u003cem\u003eDMD\u003c/em\u003e gene was identified during neuromuscular disease screening, leading to a diagnosis of Duchenne Muscular Dystrophy. Pts 16,17 and 18, exhibited severe infection symptoms such as pneumonia, bullous skin lesions, sepsis, and needed antibiotic treatment. Additionally, Pt 19 was admitted to neonatal intensive care unit because of transient tachypnea of newborn. Following initiation of biotin supplementation, patient benefited from treatment and was discharged. Two patients required surgical intervention due to comorbid conditions. Pt 20, referred for BE, had difficulties with defecation, abdominal distension was observed, and she was diagnosed with Hirschsprung's disease and finally underwent surgery. Pt 21, a 35-day-old infant referred due to elevated phenylalanine levels, exhibited respiratory distress and was subsequently diagnosed with diaphragmatic hernia. Pt 10, referred for BD had stigmatas complied with Down syndrome and head circumference measured \u0026minus;\u0026thinsp;2.5 SDS. Chromosomal analysis confirmed trisomy 21 (47, XX\u0026thinsp;+\u0026thinsp;21).\u003c/p\u003e \u003cp\u003ePt 22, 13 days old infant with hypotonia diagnosed with complete BD. Her vitamin B12 level was critically low at 98 pg/mL, though other metabolic screening results were normal she experienced seizure at three months old. Biotin dose increased up to 40 mg/day, no further seizures occurred. Whole exome sequencing revealed two pathogenic variants: c.98_104delGCGGCTG insTCC and c.470G\u0026thinsp;\u0026gt;\u0026thinsp;A in \u003cem\u003eBTD\u003c/em\u003e gene. Pt 23 referred for BD, presented with dehydration and 15% weight loss, attributed to inadequate breast milk intake with no diarrhea, vomiting, or infection. After nutritional support she gained weight and was discharged. Pt 24 was presented with indirect hyperbilirubinemia and successfully treated with phototherapy and Pt 25 was diagnosed with undescended testis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSignificant progress has been made about newborn screening program in Turkey since its inception in 1986. While screening rate for newborn infants was 4.7% in 1987, it increased to 97% by 2020 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. According to latest data, the number of newborns in 2023 was 934.000 (Turkish Statistical Institute). Of these newborns, 98% were screened and 2.237 infants with PKU, 3.143 with BD were detected. Among the referred newborns, 795 (35%) were diagnosed with PKU or hyperphenylalaninemia based on clinical and genetic evaluations, while 1.237 (39.5%) were definitely diagnosed with BD (Ministry of Health Screening Data, 2023). All newborns with positive screening results have been referred to pediatric metabolism clinics [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In these centers, biotinidase enzyme analysis (with colorimetric method) and plasma phenylalanine levels (with HPLC) are reanalyzed, additionally baseline metabolic disease screenings are conducted. In addition to screening metabolic diseases, a comprehensive evaluation from a general pediatrics perspective will help to ensure that incidental diseases are not overlooked. Analyzing incidental findings in these infants can reveal various conditions beyond primary diagnoses. This study documented various incidental diseases, including congenital anomalies, infectious diseases, genetic disorders, alongside different causes of secondary phenylalanine elevation.\u003c/p\u003e \u003cp\u003eThe high prevalence of consanguineous marriages in Turkey (20\u0026ndash;25%) contributes to a greater incidence of hereditary metabolic diseases compared to other countries [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In our study, the rate of additional diseases in infants referred for hereditary metabolic diseases such as PKU and BD was found to be 3.4%, and the rate of consanguineous marriage among these infants' parents was 56%. Although the rate of incidental disease detection is not very high in the study, the prevalence of consanguineous marriages among detected cases is twice the national average. This also indicates that the prevalence of metabolic and incidental diseases is higher in consanguineous marriages.\u003c/p\u003e \u003cp\u003eIn a study from Spain since 1969, newborn screening programs demonstrated that frequency of incidental disease diagnoses is 1 in 1.140, excluding 24 diseases routinely screened [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, in our country, only two metabolic diseases are screened, some hereditary metabolic diseases that are common in population, such as galactosemia, are not included in newborn screening program. Therefore, a higher rate may have been detected in our study. Also, diseases such as citrin deficiency, galactosemia, and type 1 tyrosinemia, which can lead to secondary phenylalanine elevation, particularly due to their association with liver disease, are included in newborn screening programs of many other countries but are not screened in Turkey [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, four infants (4 out of 737, or 0.54%) were diagnosed with classical galactosemia. Cantley et al. researched infants with elevated phenylalanine levels from newborn screening and found that 117 out of more than 6\u0026nbsp;million babies were diagnosed with high phenylalanine, including 45 cases of galactosemia, 4 cases of citrin deficiency, and 1 case of methylmalonic acidemia; notably, 35% of infants could not be given a specific diagnosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among our patients\u0026rsquo; high occurrence of galactosemia, particularly in infants with elevated phenylalanine, aligns with existing literature [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe introduction of tandem mass spectrometry (MS/MS) technology into neonatal screening programs (NSP) marks a significant advancement, enabling the detection of over 40 metabolic disorders from dried blood samples [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This technology greatly enhances the early diagnosis and treatment of affected newborns. Unfortunately, expanded newborn screening is not conducted in every country. In this study, an asymptomatic infant referred due to BD had elevated creatine kinase levels and low free carnitine levels on MS/MS. Molecular analysis confirmed carnitine palmitoyltransferase II (CPT II) deficiency. Family screening revealed the same diagnosis in infant\u0026rsquo;s asymptomatic sibling also. Tandem MS in newborn screening enables early detection of fatty acid oxidation disorders.\u003c/p\u003e \u003cp\u003eCystinuria was incidentally identified in another infant of BD. It\u0026rsquo;s an inherited metabolic disorder resulting from transport defects of cystine and basic amino acids, such as ornithine, lysine, and arginine from renal proximal tubules and gastrointestinal tract. Its prevalence is approximately 1 in 7.000 which manifests with formation of urinary stones. A study conducted in Spain found that 10.5% of cystinuria cases identified through newborn screening developed kidney stones, typically around the age of seven [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Screening for cystinuria in newborns is important to take measures for kidney stone formation and management of any stone development.\u003c/p\u003e \u003cp\u003eIn this study, a serum sample of an infant (BD) was lipemic, leading to a diagnosis of lipoprotein lipase (LPL) deficiency upon further examination. LPL deficiency is an inherited disorder of lipoprotein metabolism that can result in hypertriglyceridemia and potentially life-threatening pancreatitis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Santer et al. identified LPL deficiency in two Turkish patients with BD during newborn screening and reported that their biotinidase activities returned to normal after serum triglyceride levels decreased due to dietary management [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Elevated triglyceride levels in blood can lead to falsely low biotinidase levels measured by both fluorimetric and colorimetric methods, resulting in false-positive newborn screening outcomes. In our patient, although triglyceride level decreased to 750 mg/dL after dietary adjustments by third month, measured biotinidase activity remained at 3.64 nmol/min/mL. Additionally, pathogenic variants were found in both \u003cem\u003eLPL\u003c/em\u003e and \u003cem\u003eBTD\u003c/em\u003e genes.\u003c/p\u003e \u003cp\u003eBeyond hereditary metabolic diseases, newborn screening can also detect other disease categories, some of which can be treated, while others can have complications that may be prevented or managed. In our study, patients presented with a diverse range of conditions, including structural cardiovascular defects, Down syndrome, Duchenne muscular dystrophy, pneumonia, staphylococcal skin infections and sepsis, transient tachypnea, seizures and epilepsy, feeding problems, dehydration, extensive hemangiomas, microcephaly, diaphragmatic hernias, undescended testis and Hirschsprung's disease. All infants diagnosed with hereditary metabolic diseases or other conditions were referred to the appropriate clinics for medical or surgical treatment based on their specific diagnoses, as well as for ongoing follow-up. These findings underscore the importance of a holistic approach in the evaluation of infants referred through newborn screening, combining a thorough history, physical examination, and additional laboratory testing as needed to facilitate early diagnosis and treatment.\u003c/p\u003e \u003cp\u003eThe primary limitation of our study was small patient sample size. Future studies involving larger cohort will yield more comprehensive insights into this topic. In countries where consanguineous marriages are common and birth rates are high, it is crucial to conduct systematic evaluations of infants referred from newborn screening programs to identify additional hereditary or acquired diseases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNSP Newborn screening programs\u003c/p\u003e\n\u003cp\u003ePKU Phenylketonuria \u003c/p\u003e\n\u003cp\u003eBD Biotinidase deficiency\u003c/p\u003e\n\u003cp\u003ePhe Phenylalanine\u003c/p\u003e\n\u003cp\u003eHPA Hyperphenylalaninemia\u003c/p\u003e\n\u003cp\u003ePt Patient\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval\u003c/h2\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Dokuz Eyl\u0026uuml;l University (approval number: 2024/12\u0026thinsp;\u0026minus;\u0026thinsp;05).\u003c/p\u003e\n\u003ch2\u003eInformed consent\u003c/h2\u003e\n\u003cp\u003eInformed consent was obtained from the parents in this study.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions:B.K and P.T.K designed the study; B.K.,P.T.K.,S.Y.,E.E.,\u0026Ouml;.K.K.P,M.B. collected data; B.K.,P.T.K.,N.A . analysed the data,B.K.wrote the frst draft of the manuscript; P.T.K. and N.A. commented on previous versions of the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003e-\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFabie NAV, Pappas KB, Feldman GL. The Current State of Newborn Screening in the United States. Pediatr Clin North Am. 2019 Apr;66(2):369-386.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eEl-Hattab AW, Almannai M, Sutton VR. Newborn screening: History, current status, and future directions. Pediatr Clin North Am. 2018 Apr;65(2):389-405.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAktuğlu Zeybek A\u0026Ccedil;. Newborn screening: From the past to the future. Turk Arch Pediatr. 2022 Sep;57(5):473-475.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWaters PJ, Khashu M, Lillquist Y, et al. Neonatal hyperphenylalaninemia, perinatal hemochromatosis, and renal tubulopathy: a unique patient or a novel metabolic disorder? Mol Genet Metab. 2005 Dec;86 Suppl 1: S148-52.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChen WS, Liu MH, Tsou YL, et al. Extensive dysregulation of phenylalanine metabolism is associated with stress hyperphenylalaninemia and 30-day death in critically ill patients with acute decompensated heart failure. J Am Heart Assoc. 2024;13(18):e035821.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCantley NWP, Barski R, Kemp H, et al. Incidental detection of classical galactosemia through newborn screening for phenylketonuria: A 10-year retrospective audit to determine the efficacy of this approach. Int J Neonatal Screen. 2023 Dec 22;10(1):2.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBorsatto T, Sperb-Ludwig F, Pinto LL, et al. Biotinidase deficiency: clinical and genetic studies of 38 Brazilian patients. BMC Med Genet. 2014 Sep 1; 15:96.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTankeu AT, Winckel GV, Elmers J, et al. Biotinidase deficiency: What have we learned in forty years? Mol Genet Metab. 2023;138(4):107560.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVan Wegberg A.M.J., MacDonald A, Ahring K, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017Oct 12;12(1):162.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSpenger et al. Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families.\u0026nbsp;Int. J. Neonatal Screen. 2021,\u0026nbsp;7, 32.\u003c/li\u003e\n \u003cli\u003eTezel B, Dilli D, Bolat H, et al. The development and organization of newborn screening programs in Turkey. J Clin Lab Anal. 2014;28(1):63-9\u003c/li\u003e\n \u003cli\u003e\u0026Ouml;zalp I, Coskun T, Tokol S, Demircin G, M\u0026ouml;nch E. Inherited metabolic disorders in Turkey. J Inherit Metab Dis. 1990;13(5):732-8.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSoria JLM, Galera RML, Ram\u0026iacute;rez AA, et al. \u0026nbsp;50 years of the neonatal screening program in Catalonia.\u0026nbsp;Rev Esp Salud P\u0026uacute;blica. 2020; 94: 16 de diciembre e202012177 (Spanish).\u003c/li\u003e\n \u003cli\u003eMart\u0026iacute;n-Rivada \u0026Aacute;,\u0026nbsp;Palomino P\u0026eacute;rez L, Ruiz-Sala P, et al. Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region. JIMD Rep. 2022 Jan 27;63(2):146-161.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCouce ML, B\u0026oacute;veda MD, Casti\u0026ntilde;eiras DE, et al. A newborn screening programme for inborn errors of metabolism in Galicia: 22 years of evaluation and follow-up. Orphanet J Rare Dis. 2024 May 17;19(1):202.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eShakespeare L, Downing M, Allen J, et al. Elevated phenylalanine on newborn screening: follow-up testing may reveal undiagnosed galactosaemia. Ann Clin Biochem. 2010 Nov;47(Pt 6):567-9.\u003c/li\u003e\n \u003cli\u003eWatson MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR, American College of Medical Genetics Newborn Screening Expert Group. Newborn screening: toward a uniform screening panel and system\u0026ndash;executive summary. Pediatrics. 2006;117(5 Pt 2): S296-307\u003c/li\u003e\n \u003cli\u003eWang D, Zhang J, Yang R, et al. Disease spectrum, prevalence, genetic characteristics of inborn errors of metabolism in 21,840 hospitalized infants in Chongqing, China, 2017-2022. Front Genet. 2024 May 28; 15:1395988. Erratum in: Front Genet. 2024 Jul 10; 15:1449534.\u003c/li\u003e\n \u003cli\u003ePi\u0026ntilde;ero-Fern\u0026aacute;ndez JA, Vicente-Calder\u0026oacute;n C, Lorente-S\u0026aacute;nchez MJ, Juan-Fita MJ, Egea-Mellado JM, Gonz\u0026aacute;lez-Gallego IC. Phenotypic characterization of a pediatric cohort with cystinuria and usefulness of newborn screening. Pediatr Nephrol. 2023 May;38(5):1513-1521.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNeelamekam S, Kwok S, Malone R, Wierzbicki AS, Soran H. The impact of lipoprotein lipase deficiency on health-related quality of life: a detailed, structured, qualitative study. Orphanet J Rare Dis. 2017 Sep 19;12(1):156.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSanter R, Gok\u0026ccedil;ay G, Demirkol M, Gal A, Lukacs Z. Hyperchylomicronaemia due to lipoprotein lipase deficiency as a cause of false-positive newborn screening for biotinidase deficiency. J Inherit Metab Dis. 2005;28(2):137-40.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Newborn screening, phenylketonuria, biotinidase deficiency, incidental findings","lastPublishedDoi":"10.21203/rs.3.rs-6277306/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6277306/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eNewborn screening refers to series of tests conducted within the first hours or days of a newborn's life to prevent severe health complications, including death. The study aims to investigate and document other findings and diseases that are incidentally detected through physical examination or laboratory results in infants referred due to elevated phenylalanine levels or biotinidase deficiency as a result of newborn screening.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e 792 newborns were referred and evaluated due to their dried blood phenylalanine levels above 120 μmol/L or biotinidase enzyme activity below 65 U. A total of 737 patients were included in the study. The demographic characteristics, reasons for referral, plasma phenylalanine and blood biotinidase levels as well as incidental pathological examination and laboratory findings at the time of referral were recorded for these patients.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e: \u003c/strong\u003eA total of 25 (3.4%) patients were diagnosed with incidental conditions during screening, 16 of them (66.6%) were initially referred for biotinidase deficiency. Four patients were diagnosed with classical galactosemia, one per with lipoprotein lipase (LPL) deficiency, cystinuria, CPT II deficiency, Duchenne muscular dystrophy. Four patients had congenital heart disease, two were diagnosed with Down Syndrome, two had surgical problems as Hirschsprung's disease and diaphragmatic hernia. Four others had infectious and respiratory diseases, and other four patients had hyperbilirubinemia, feeding problems, extensive hemangioma and microcephaly.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e: A systematic evaluation should be conducted carefully to identify incidental diseases especially for early recognition of conditions detected through newborn screening programs.\u003c/p\u003e","manuscriptTitle":"Opening pandora’s box: incidental findings among infants referred from neonatal screening for metabolic disorders.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-02 07:53:31","doi":"10.21203/rs.3.rs-6277306/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5de25957-cb4f-4b77-97cc-cc1a44ec02f5","owner":[],"postedDate":"April 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-26T15:23:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-02 07:53:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6277306","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6277306","identity":"rs-6277306","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}