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Background: The diagnosis of depression or anxiety treated by SSRIs has become relatively common in women of childbearing age. However, the impact of gestational SSRI treatment on newborn thyroid function is lacking. We explored the impact of gestational SSRI treatment on newborn thyroid function as measured by the National Newborn Screening (NBS) Program and identified contributory factors., Methods: An observational large-scale study of mother-infant dyads of liveborn infants delivered between 2011 and 2022. The Israeli NBS Program thyroid dataset [total thyroxine (TT4) obtained between 36-72 h after delivery] was linked with the electronic medical records of mothers and their infants born at Lis Maternity and Women's Hospital, to generate a unified database. The MDClone big data platform was utilized to extract maternal, perinatal, and neonatal characteristics from the medical records of mother-infant dyads. Only term liveborn infants born to mothers without documented thyroid disease and/or chronic medication administration, except for SSRIs, were included in order to minimize potential confounding effects on the infant's thyroid function. Group stratification relied on the documentation of gestational SSRIs treatment. The variables of interest were maternal, pregnancy, delivery, and perinatal characteristics of the mother-infant dyads. Multivariable forward linear regression model was applied to evaluate explanatory variables for newborn total thyroxine (TT4) levels., Results: Out of 105,928 infant-mother dyads, 2321(2.2%) mothers had been treated with SSRIs during pregnancy. The SSRI-treated mothers were older (34.8 ± 4.7 vs 32.6 ± 4.8 years, p < 0.001) and had a higher pre-pregnancy body mass index (23.4 ± 4.5 vs 22.7 ± 4.1, p < 0.001), but similar mean weight gain (13 kg) during pregnancy. Cesarean delivery was more common among SSRI-treated mothers than in the general population (p < 0.001). Infants of SSRI-treated mothers had lower WHO-classified birthweight z-scores (-0.25 ± 0.93 vs -0.04 ± 0.92, p < 0.001) and a higher rate of small-for-gestational-age infants (13.4% vs 8.2%, p < 0.001). A multivariable forward linear regression model revealed that SSRI treatment during pregnancy was not a significant contributor to TT4 levels (p = 0.497)., Conclusions: SSRI treatment during pregnancy had no direct effect upon the newborn's adaptation of the hypothalamic-pituitary-thyroidal axis, but several other maternal and delivery characteristics were revealed to possibly impact newborn thyroid function., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Institutional Review Board (IRB) of the the Tel Aviv Medical Center (IRB No. 0030–22-TLV) according to the Declaration of Helsinki. Informed consent by the participants was waived since the data were retrieved from the subjects’ medical records and all personal identification was anonymized. The data were handled in accordance with the principles of Good Clinical Practice and in compliance with ethical standards. This study was also performed in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C>T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G>A; p. Ala163Thr and c.985A>G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 >5 μM and C5/C2>0.2 and C5/C3>4 flagging only those likely to have the classic symptomatic phenotype., (© 2024 SSIEM.)

Objectives: The incidence of congenital hypothyroidism (CH) has increased worldwide over the last decades, mainly due to the lowering of screening thresholds, resulting in the increased identification of newborns with transient CH. Several studies have reported the prevalence and the predictive parameters of transient CH, but reports on the long-term outcome are rare. This study aimed to assess the long-term course of neonates with transient CH., Design: Neonates diagnosed with transient and permanent CH between the years 1998 and 2018 at the Pediatric Endocrine Institute of Ha'Emek Medical Center were enrolled in the study. Data were retrieved retrospectively from medical files., Results: A total of 76 newborns (45M, 59%) with transient CH and 53 (25M, 47%) with permanent CH were included in the study. The major causes of transient CH were prematurity (29%) and subclinical hypothyroidism (30%). During retrospective follow-ups of up to 23 years, reinitiation of levothyroxine therapy was not required, apart from four patients with underlying syndromic etiologies. Neurodevelopmental impairment occurred in 16% of children with transient CH compared with 29.4% in the permanent CH group., Conclusions: Transient CH is frequent among preterm infants but is generally limited to infancy. Subclinical hypothyroidism frequently presents as overt hypothyroidism at birth, but in most cases, the requirement for levothyroxine supplemental therapy is limited to the first years of life, suggesting that long-term follow-up of thyroid function tests may be unnecessary for non-syndromic children. The high rate of neurodevelopmental impairment in newborns with transient CH emphasizes the need for neurodevelopmental monitoring in these patients., Significance Statement: A high rate of transient CH has been identified over the past decades following the lowering of TSH screening thresholds. The long-term outcome of transient CH has been evaluated in a few studies with inconclusive results. In the current study, we assessed the long-term outcomes of transient CH for up to 23 years. We found that 29% of cases were attributed to prematurity and 30% to subclinical hypothyroidism. No morphological anomalies were identified. Only syndromic patients (three with Down syndrome and one with Coffin-Lowry syndrome) required levothyroxine supplemental therapy at the time of the study, indicating that long-term thyroid function monitoring may be unnecessary. The high prevalence of neurodevelopmental impairment suggests the need for close neurodevelopmental monitoring in this population.

Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Context: Central congenital hypothyroidism (CCH) is a thyroid hormone deficiency at birth caused by inadequate pituitary stimulation of the thyroid gland. Although primary CH has been studied extensively, studies on CCH are sparse., Objectives: To assess the prevalence of CCH in Israel and describe its clinical features, neonatal screening results, and outcomes., Design: Multicenter cross-sectional retrospective chart review., Setting: Nine pediatric endocrine units throughout Israel., Patients: Patients diagnosed with CCH in 1987-2021 were categorized into early (within 14 days of life) and late (after 14 days) diagnosis groups. Newborn screening (NBS) results were retrospectively retrieved from the national NBS program dataset., Results: CCH prevalence in Israel was about 1:42,800 live births. Subjects were 94 patients (54 males), of these, 84% had multiple pituitary hormone deficiencies and 16% had isolated CCH. The median age at diagnosis was 50 days (range, 1-8760), with 66% having moderate to severe hypothyroidism. NBS detected only three infants. Early diagnosis occurred in 34% due to hypopituitarism, while 66% were diagnosed later due to growth and developmental delays. Neurodevelopmental sequelae included mental retardation (12%), learning difficulties (18%), delayed speech (27%), and motor clumsiness (19%), with no significant differences in outcomes between early and late diagnosis., Conclusions: Despite high rates of neurodevelopmental sequelae, no differences were found between early and late diagnosis groups. Further research is needed to assess the impact of delayed diagnosis on neurological outcomes in newborns with CCH. Improved strategies for detecting CHH in newborns are also necessary., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy. Unawareness of this rare disease leads to delays in diagnosis., Objective: The aims of this study were to describe the clinical and molecular characteristics of patients with genetically confirmed GNAS mutations and to evaluate their long-term outcomes., Methods: A retrospective search for all patients diagnosed with PHPIA in 2 referral centers in Israel was conducted., Results: Nine children (8 females) belonging to 6 families were included in the study. Five patients had GNAS missense mutations, 2 had deletions, and 2 had frameshift mutations. Four mutations were novel. Patients were referred at a mean age of 2.4 years due to congenital hypothyroidism (5 patients), short stature (2 patients), or obesity (2 patients), with a follow-up duration of up to 20 years. Early obesity was observed in the majority of patients. Elevated parathyroid hormone was documented at a mean age of 3 years; however, hypocalcemia became evident at a mean age of 5.9 years, about 3 years later. All subjects were diagnosed with mild to moderate mental retardation. Female adult height was very short (mean -2.5 SD) and 5 females had primary or secondary amenorrhea., Conclusion: Long-term follow-up of newborns with a combination of congenital hypothyroidism, early-onset obesity, and minor dysmorphic features associated with PHPIA is warranted and molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Graves' disease has been associated with adverse pregnancy, labor and delivery, and neonatal outcomes. Thyroid function levels, assessed during newborn screening (NBS), can serve as indicators of the adaptation in the hypothalamic-pituitary-thyroid axis. We utilized data from the national thyroid NBS program to investigate the characteristics of the mother-infant dyad of term infants born to mothers with past or active Graves' disease. Methods: The dataset of the Israeli NBS for thyroid function was linked with the electronic records of a tertiary medical center to generate a unified database of mothers and their term infants born between 2011 and 2021. The MDClone big data platform extracted maternal, pregnancy, disease course, labor and delivery, and neonatal characteristics of the mother-infant dyads. Results: Out of 103,899 registered mother-infant dyads, 292 (0.3%) mothers had past or active Graves' disease. A forward multivariate linear regression demonstrated that Graves' disease did not significantly affect NBS total thyroxine (tT4) levels ( p  = 0.252). NBS tT4 levels in infants born to mothers with active Graves' disease were higher than those observed in the general Israeli population ( p  < 0.001). Mothers with Graves' disease more frequently used assisted reproductive technology (12.7% vs. 9.0%, respectively, p  = 0.012; odds ratio [OR] = 1.46 [CI 1.03-2.07], p  = 0.031), and had more gestational hypertension (3.9% vs. 1.1%, p  < 0.001; OR = 3.53 [CI 1.92-6.47], p  < 0.001), proteinuria (2.5% vs. 0.9%, p  < 0.001; OR = 3.03 [CI 1.43-6.45], p  = 0.004), cesarean sections (26.4% vs. 19.7%, p  = 0.029; OR = 1.46 [CI 1.13-1.90], p  = 0.004), prelabor rupture of membranes (15.4% vs. 4.1%, p  < 0.001; OR = 4.3 [CI 3.13-5.91], p  < 0.001), and placental abnormalities (5.1% vs. 2.0%, p  < 0.001; OR = 2.64 [CI 1.57-4.44]; p  < 0.001). Their infants had lower adjusted birthweight z -scores (-0.18 ± 0.94 vs. -0.03 ± 0.90, p  = 0.007) and were more likely to be small for gestational age (12.0% vs. 8.1%, p  = 0.005; OR = 1.54 [CI 1.08-2.19], p  = 0.018). Conclusions: Neonatal thyroid function levels were affected by maternal Graves' disease only when the disease was active during gestation. Moreover, maternal Graves' disease was also associated with an increased risk of adverse outcomes for the mother-infant dyad.

Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by variants in PCCA or PCCB, both sub-units of the propionyl-CoA carboxylase (PCC) enzyme. PCC is required for the catabolism of certain amino acids and odd-chain fatty acids. In its absence, the accumulated toxic metabolites cause metabolic acidosis, neurologic symptoms, multi-organ dysfunction and possible death. The clinical presentation of PA is highly variable, with typical onset in the neonatal or early infantile period. We encountered two families, whose children were diagnosed with PA. Exome sequencing (ES) failed to identify a pathogenic variant, and we proceeded with genome sequencing (GS), demonstrating homozygosity to a deep intronic PCCB variant. RNA analysis established that this variant creates a pseudoexon with a premature stop codon. The parents are variant carriers, though three of them display pseudo-homozygosity due to a common large benign intronic deletion on the second allele. The parental presumed homozygosity merits special attention, as it masked the causative variant at first, which was resolved only by RNA studies. Arriving at a rapid diagnosis, whether biochemical or genetic, can be crucial in directing lifesaving care, concluding the diagnostic odyssey, and allowing the family prenatal testing in subsequent pregnancies. This study demonstrates the power of integrative genetic studies in reaching a diagnosis, utilizing GS and RNA analysis to overcome ES limitations and define pathogenicity. Importantly, it highlights that intronic deletions should be taken into consideration when analyzing genomic data, so that pseudo-homozygosity would not be misinterpreted as true homozygosity, and pathogenic variants will not be mislabeled as benign., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest related to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may develop refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. Newborn screening has the potential to identify and enable treatment of affected individuals before they become significantly ill. Methods: Measuring orotic acid as part of expanded newborn screening using flow injection analysis tandem mass spectrometry. Results: Since the addition of orotic acid measurement to the Israeli routine newborn screening program, 1,492,439 neonates have been screened. The screen has identified ten Muslim Arab newborns that remain asymptomatic so far, with DBS orotic acid elevated up to 10 times the upper reference limit. Urine organic acid testing confirmed the presence of orotic aciduria along with homozygous variations in the UMPS gene. Conclusion: Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotic aciduria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Staretz-Chacham, Damseh, Daas, Abu Salah, Anikster, Barel, Dumin, Fattal-Valevski, Falik-Zaccai, Hershkovitz, Josefsberg, Landau, Lerman-Sagie, Mandel, Rock, Rostami, Saraf-Levy, Shaul Lotan, Spiegel, Tal, Ulanovsky, Wilnai, Korman and Almashanu.)

Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives., (© 2022 SSIEM.)

Severe iodine deficiency during pregnancy has substantial hormonal consequences, such as fetal brain damage. Data on the potential effects of mild-to-moderate iodine deficiency on the thyroid function of pregnant women and their newborns are scarce and divergent. We investigated the association between iodine intake in pregnancy and maternal and neonatal thyroid function in a region with mild-to-moderate iodine deficiency. Pregnant women’s iodine status was evaluated using an iodine food frequency questionnaire, serum thyroglobulin (Tg), and urinary iodine concentration (UIC). Neonatal thyrotropin (nTSH) values were measured after birth. Obstetrics and anthropometric data were also collected. Among the 178 women (median age 31 years) included in the study, median (interquartile range) estimated dietary iodine intake, Tg and UIC were 179 (94−268) μg/day, 18 (11−33) μg/L, and 60 (41−95) μg/L, respectively. There was a significant inverse association of iodine intake with Tg values among the study population (β = −0.2, F = 7.5, p < 0.01). Women with high free triiodothyronine (FT3) values were more likely to exhibit an estimated iodine intake below the estimated average requirement (160 μg/day, odds ratio [OR] = 2.6; 95% confidence interval [CI], 1.1−6.4; p = 0.04) and less likely to consume iodine-containing supplements (OR = 0.3, 95% CI, 0.1−0.8; p = 0.01). It is possible that thyroid function may be affected by iodine insufficiency during pregnancy in regions with mild-to-moderate iodine deficiency. The relatively small sample size of the studied population warrants further investigation.

Background: Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance., Objective: We report a 5-year summary of the NBS program for SCID in Israel., Methods: Immunologic and genetic assessments, clinical analyses, and outcome data from all infants who screened positive were evaluated and summarized., Results: A total of 937,953 Guthrie cards were screened for SCID. A second Guthrie card was requested on 1,169 occasions (0.12%), which resulted in 142 referrals (0.015%) for further validation tests. Flow cytometry immune-phenotyping, T cell receptor excision circle measurement in peripheral blood, and expression of TCRVβ repertoire for the validation of positive cases revealed a specificity and sensitivity of 93.7% and 75.9%, respectively, in detecting true cases of SCID. Altogether, 32 SCID and 110 non-SCID newborns were diagnosed, making the incidence of SCID in Israel as high as 1:29,000 births. The most common genetic defects in this group were associated with mutations in DNA cross-link repair protein 1C and IL-7 receptor α (IL-7Rα) genes. No infant with SCID was missed during the study time. Twenty-two SCID patients underwent hematopoietic stem cell transplantation, which resulted in a 91% survival rate., Conclusions: Newborn screening for SCID should ultimately be applied globally, specifically to areas with high rates of consanguineous marriages. Accumulating data from follow-up studies on NBS for SCID will improve diagnosis and treatment and enrich our understanding of immune development in health and disease., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study is to evaluate the effect of the coronavirus disease 2019 (COVID-19) pandemic national lockdown period on the rate of singleton preterm births in Israel., Study Design: This is a population-based cohort study of 3,41,291 singleton infants born in the months of January to July 2017 to 2020. Multivariable logistic regression analyses were used to estimate the influence of period and year on the rates of preterm births during the lockdown period (11 th March - 5 th May 2020) compared with rates before (January 1 st 2020 - March 10 th 2020), and after the lockdown (May 6 th 2020-June 30 th 2020) and to the corresponding periods in 2017to 2019., Results: During the lockdown period the preterm birth rate (primary outcome) decreased by 9.7% from 5.05 to 4.56% in the pre-lockdown period ( p  = 0.006), an adjusted decrease of -0.52% (95% confidence interval -0.89%; -0.15%), odds ratio 0.898 (95% confidence interval 0.832; 0.970)., Conclusion: The rate of singleton preterm births declined by 9.7% during the COVID-19 pandemic national lockdown period in Israel., Key Points: · A 10% decline in all preterm deliveries was observed during the COVID-19 pandemic national lock-down period.. · The lock-down might influence environmental changes which contribute to the decrease in preterm deliveries.. · Changes in lifestyle, and societal behavior might contribute to the decrease in preterm deliveries.., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Maternal thyroid disease is considered as a risk factor for abnormal thyroid function at birth, as well as for long-term morbidity in offspring. The potential harmful effects on the neonate had led to the clinical practice of thyroid function assessment in infants born to mothers with thyroid disease during pregnancy. In this study, we evaluated the usefulness of routine thyroid function tests for every newborn of a mother with thyroid dysfunction., Methods: Data were collected retrospectively from the medical files of mothers diagnosed with thyroid disease and their infants (496 mother-neonate pairs). All mothers with diagnosed thyroid disease who gave birth in the years 2016-2019 at our medical center were included., Results: Hypothyroidism was the most common maternal diagnosis (91.4%), among which 48.7% had Hashimoto's thyroiditis. Hyperthyroidism was diagnosed in 8.6% of the cohort - 71.6% of them with Graves' disease. None of the newborns was diagnosed with congenital hypothyroidism in the screening program. Thyroid-stimulating hormone was >10 mIU/L in 14.6% and >20 mUI/L in 2.2%; all had free thyroxine within normal range. Serum thyroid function test identified four infants with thyroid disease; two had congenital hypothyroidism not related to maternal thyroid disease, one had transient familial congenital hypothyroidism and one had neonatal Graves' disease., Conclusions: Thyroid function testing for all newborns of mothers with thyroid dysfunction seems redundant. However, in cases of congenital hypothyroidism in siblings, thyroid function test, in addition to newborn thyroid screening, is recommended, and more careful follow-up is indicated. In maternal Graves' disease, thyroid function test on days 2-3 of life is recommended.

Objectives: Childhood obesity and iodine deficiency are global public health concerns. Whether maternal iodine status mediates overweight in infancy has yet to be explored. We aimed to assess the relationship between maternal iodine status and infant birth weight, including small and large for gestational age (SGA and LGA, respectively)., Methods: A prospective study was carried out among 134 mother-infant pairs from Israel. Maternal iodine intake and status were estimated via questionnaire and serum thyroglobulin (Tg), respectively. Estimated iodine intake below the Recommended Daily Allowance for iodine sufficiency in pregnancy (220 μg/d) considered Inadequate. Maternal and neonatal thyroid function and anthropometric measurements, as well as maternal thyroid antibodies were also tested., Results: After screening, 118 participants met the inclusion criteria (distributed trimesters I, II and III: n = 3, n = 21, and n = 94, respectively). There was a negative association of iodine intake with Tg values among the study population. Maternal median Tg value was higher than the sufficiency cutoff (16.5 vs 13 µg/L), indicating insufficient iodine status. No SGA cases were found. Inadequate iodine intake was associated with maternal isolated hypothyroxinemia (OR = 3.4; 95% CI 1.2, 9.9) and higher birthweight (including macrosomia and LGA) rates. A suggestive association of elevated Tg with a greater risk of LGA was observed. Offsprings' birth weight percentiles were associated with Tg values in pregnant women with suggestive sufficient iodine status (n = 62, R 2  = 0.11, p < 0.05)., Conclusions: Iodine status during pregnancy can be associated with newborn anthropometric index. Maternal inadequate iodine intake may alter fetal growth and might increase the risk of LGA among newborns. These initial findings support the need to further study the impact of iodine deficiency on newborns overweight in Israel and elsewhere., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pregnancy and parturition reflect the complex interaction between physiological conditions of the mother and her offspring, and fetal health characteristics may affect maternal health throughout pregnancy and delivery. We aimed to investigate the characteristics of the mother-infant dyad of term infants detected as having congenital hypothyroidism (CH). Methods: A retrospective cohort study of 108,717 term infants delivered liveborn at Lis Maternity and Women's Hospital between 2010 and 2017. Infants were detected by the National Newborn Screening Program as having CH (131, 0.12%). Three years of surveillance in the Pediatric Endocrine Clinic revealed that 65 infants had transient CH and 66 had permanent CH. Data on maternal, pregnancy, delivery, and perinatal characteristics of the mother-infant dyads were retrieved from the hospital's electronic database. Results: Mode of delivery differed: a higher proportion of deliveries of CH infants required vacuum assistance, and more infants with CH were born through a cesarean section compared with the general population ( p  < 0.001). Medication during labor also differed, with higher rates of oxytocin ( p  < 0.001) and antibiotics ( p  = 0.008) administered to mothers of CH infants. A multivariate logistic regression model revealed an increased demand for oxytocin administration during the labor of a CH infant in a hypothyroidism severity-dependent manner, expressed as a threefold risk associated with permanent but not transient CH. Conclusions: Our findings of increased utilization of medical interventions during the labor and delivery of CH infants suggest that the prenatal fetal thyroid function may affect the development and progress of labor and delivery, in response to oxytocin.

Background: Small for gestational age (SGA) and large for gestational age (LGA) newborns are at increased risk for developmental, metabolic and cardiovascular morbidities., Aims: To compare the metabolic biomarkers of SGA and LGA infants with those of appropriate for gestational age (AGA) newborns in order to shed more light on a possible pathogenesis of those morbidities., Study Design: An observational retrospective study., Subjects: 70,809 term newborns divided into AGA, SGA, LGA, and severe subcategories (<3rd percentile or ≥97th percentile)., Outcome Measures: 18 metabolites were measured by dried blood tandem mass spectrometry and compared in between groups in univariate and multivariate logistic regression., Results: SGA newborns had a significant likelihood for elevated methionine, proline, free carnitine, and reduced valine levels compared to AGA newborns (P < .0001). Severe SGA showed more apparent trends including elevated leucine. LGA newborns had a significant likelihood for low citrulline, glutamine, proline, tyrosine, and elevated leucine levels (P ≤ .0033). Severe LGA newborns showed the same trends, with the exception of citrulline and glutamine., Conclusions: SGA and LGA newborns demonstrate distinct metabolic biomarkers in newborn screening. Most of the altered metabolites in the SGA group were elevated while those in the LGA group were decreased in comparison to AGA newborns. These trends were more apparent in the severe SGA subgroup while they mostly remained the same in the severe LGA subgroup. Whether these metabolic changes are involved with or can predict long-term outcome awaits further trials., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Thyroid peroxidase (TPO) deficiency is the most common enzymatic defect causing congenital hypothyroidism (CH). We aimed to characterize the long-term outcome of patients with TPO deficiency., Methods: Clinical and genetic data were collected retrospectively., Results: Thirty-three patients with primary CH caused by TPO deficiency were enrolled. The follow-up period was up to 43 years. Over time, 20 patients (61%) developed MNG. Eight patients (24%) underwent thyroidectomy: one of them had minimal invasive follicular thyroid carcinoma. No association was found between elevated lifetime TSH levels and the development of goiter over the years., Conclusions: This cohort represents the largest long-term follow up of patients with TPO deficiency. Our results indicate that elevated TSH alone cannot explain the high rate of goiter occurrence in patients with TPO deficiency, suggesting additional factors in goiter development. The high rate of MNG development and the risk for thyroid carcinoma indicate a need for long-term follow up with annual ultrasound scans.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect caused by a deficiency of the electron-transfer flavoprotein (ETF) or the electron-transfer flavoprotein dehydrogenase (ETFDH). There are three phenotypes of the disease, two neonatal forms and one late-onset. Previous studies have suggested that there is a phenotype-genotype correlation. We report on six patients from a single Bedouin tribe, five of whom were sequenced and found to be homozygous to the same variant in the ETFDH gene, with variable severity and age of presentation. The variant, NM&#95;004453.3 ( ETFDH ): c.524G>A, p.(R175H), was previously recognized as pathogenic, although it has not been reported in the literature in a homozygous state before. R175H is located near the FAD binding site, likely affecting the affinity of FAD for EFT:QO. The single homozygous ETFDH pathogenic variant was found to be causing MADD in this cohort with an unexpectedly variable severity of presentation. The difference in severity could partly be explained by early diagnosis via newborn screening and early treatment with the FAD precursor riboflavin, highlighting the importance of early detection by newborn screening.

Background: An association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation., Methods: Audiometry was undertaken prospectively in 66 patients aged 3-21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies., Results: HI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT 4 ) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT 4 levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 μg/dL, p = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies., Conclusions: Our findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT 4 therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness., Competing Interests: All authors have nothing to disclose., (Copyright © 2020 by S. Karger AG, Basel.)

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS., (© 2020 SSIEM.)

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.

Performing thyroid function tests (TFT) at 2 weeks of age in neonates of mothers with hypothyroidism, despite having a newborn screening program, is a debated approach. We examined whether there is an additional clinical benefit in TFT at 2 weeks of age in neonates born to mothers with hypothyroidism, in addition to the neonatal screening program. We performed a retrospective study which included all newborns of mothers with a diagnosis of hypothyroidism and gave birth in a single regional hospital between the years 2010 and 2016. Data were collected from a computerized medical record system of the hospital and the community clinics, and from Israel's national newborn screening program. Main outcome measure was results of serum TFT in comparison to the results of the neonatal screening test. There were 1392 newborns eligible according to the study criteria. Of these, 1033 underwent a newborn screening test, and serum TFT at least 2 weeks after birth. Eight babies with congenital hypothyroidism were detected independently by both the newborn screening program and at the TFT performed at 2 weeks of age.Conclusions: No added clinical benefit was found in retesting newborns of hypothyroid mothers for thyroid function in addition to the newborn screening program. What is Known • Performing thyroid function test 2 weeks after birth is a common practice in newborn to a mother with hypothyroidism. • Neonatal screening program for thyroid function is also done in these newborns. What is New • No newborn was found to have a normal newborn screening test but abnormal serum thyroid function test. • No added clinical benefit was found in retesting newborns of hypothyroid mothers for thyroid function in addition to the newborn screening program.

Background: Maple syrup urine disease is a rare autosomal-recessive aminoacidopathy, caused by deficient branched-chain 2-keto acid dehydrogenase (BCKD), with subsequent accumulation of branched-chain amino acids (BCAAs): leucine, isoleucine and valine. While most cases of MSUD are classic, some 20% of cases are non-classic variants, designated as intermediate- or intermittent-types. Patients with the latter form usually develop normally and are cognitively intact, with normal BCAA levels when asymptomatic. However, intercurrent febrile illness and catabolism may cause metabolic derailment with life-threatening neurological sequelae. Thus, early detection and dietary intervention are warranted in intermittent MSUD., Patients and Methods: We describe eight patients from four unrelated families, diagnosed with intermittent MSUD. Their presenting symptoms during metabolic crises varied from confusion and decreased consciousness, to ataxia, and acute psychosis. Molecular confirmation of MSUD was pursued via sequencing of the BCKDHA, BCKDHB and DBT genes., Results: All affected individuals were found to harbor bi-allelic pathogenic variants in either BCKDHB or DBT. Of the seven variants, four variants in BCKDHB (p.G101D, p. V103A, p. A221D, p. Y195C) and one variant in DBT (p.K427E) were not previously described., Conclusions: While newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis., Competing Interests: Declaration of competing interest All authors state that they have no competing interests to declare., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: To assess the clinical and neurological outcomes in newborns with primary congenital hypothyroidism presented with delayed TSH elevation (dTSH), and to define parameters that may predict the evolution of transient vs. permanent hypothyroidism in these newborns., Design and Patients: An observational study was performed of a cohort of 113 children with a history of dTSH., Measurements: Birth parameters, thyroid screening results, thyroid gland imaging, levothyroxine dose and neurological outcome were compared between newborns with spontaneous recovery and children with a final diagnosis of either transient or permanent hypothyroidism., Results: Of the children with a history of dTSH, 93% demonstrated recovery, either spontaneously or following levothyroxine treatment (transient hypothyroidism). Newborns with spontaneous recovery demonstrated milder thyroid dysfunction at the newborn screening compared to those who started levothyroxine treatment. Levothyroxine dose was lower in children with transient vs. permanent hypothyroidism only during the first 6 months of life; otherwise, these groups were similar in birth parameters, thyroid screening results and gland images. Seventeen out of 61 children (28%) that underwent neurological assessment demonstrated a developmental delay. Duration of treatment was highly variable in children with transient hypothyroidism., Conclusions: Thyroid dysfunction is transient in most cases of dTSH. No reliable parameters can predict a priori transient vs. permanent hypothyroidism., (© 2020 John Wiley & Sons Ltd.)

Context: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants., Objective: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates., Design: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA., Participants: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program., Results: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%., Conclusions: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide., (Copyright © 2019 Endocrine Society.)

The alpha subunit of IL-7 receptor (IL7R7α) is critical for the differentiation of T cells, specifically for the development and maintenance of γδT cells. Mutations in IL7RA are associated with Severe Combined Immunodeficiency (SCID). Infants with IL7RA deficiency can be identified through newborn screening program. We aimed at defining the immunological and genetic parameters that are directly affected by the IL7RA mutation on the immune system of five unrelated patients which were identified by our newborn screening program for SCID. The patients were found to have a novel identical homozygote mutation in IL7RA (n.c.120 C>G; p.F40L). Both surface expression of IL7Rα and functionality of IL-7 signaling were impaired in patients compared to controls. Structural modeling demonstrated instability of the protein structure due to the mutation. Lastly the TRG immune repertoire of the patients showed reduced diversity, increased clonality and differential CDR3 characteristics. Interestingly, the patients displayed significant different clinical outcome with two displaying severe clinical picture of immunodeficiency and three had spontaneous recovery. Our data supports that the presented IL7RA mutation affects the IL-7 signaling and shaping of the TRG repertoire, reinforcing the role of IL7RA in the immune system, while non-genetic factors may exist that attribute to the ultimate clinical presentation and disease progression.

Newborn screening (NBS) programs for severe combined immunodeficiency (SCID), using the TREC-based assay, have enabled early diagnosis, prompt treatment, and eventually changed the natural history of affected infants. Nevertheless, it was believed that some affected infants with residual T cell, such as patients with MHC II deficiency, will be misdiagnosed by this assay. A full immune workup and genetic analysis using direct Sanger sequencing and whole exome sequencing have been performed to a patient that was identified by the Israeli NBS program for SCID. The patient was found to have severe CD4 lymphopenia with an inverted CD4/CD8 ratio, low TREC levels in peripheral blood, abnormal response to mitogen stimulation, and a skewed T cell receptor repertoire. HLA-DR expression on peripheral blood lymphocytes was undetectable suggesting a diagnosis of MHC II deficiency. Direct sequencing of the RFX5 gene revealed a stop codon change (p. R239X, c. C715T), which could cause the patient's immune phenotype. His parents were found to be heterozygote carriers for the mutation. Whole exome sequencing could not identify other potential mutations to explain his immunodeficiency. The patient underwent successful conditioned hematopoietic stem cell transplantation from healthy matched unrelated donor and is currently well and alive with full chimerism. Infants with MHC class II deficiency can potentially be identified by the TREC-based assay NBS for SCID. Therefore, MHC II molecules (e.g., HLA-DR) measurement should be part of the confirmatory immune-phenotyping for patients with positive screening results. This will make the diagnosis of such patients straightforward.

Background: Some neonates develop idiopathic hyperbilirubinemia (INHB) requiring phototherapy, yet with no identifiable causes. We searched for an association between abnormal thyroid levels after birth and INHB., Methods: Of 5188 neonates, 1681 (32.4%) were excluded due to one or more risk factors for hyperbilirubinemia. Total thyroxine (TT4) and thyroid stimulating hormone values were sampled routinely at 40-48 hours of age and measured in the National Newborn Screening Program., Results: Of the 3507 neonates without known causes for hyperbilirubinemia, 61 (1.7%) developed INHB and received phototherapy. Univariate analyses found no significant association between mode of delivery and INHB (vacuum-delivered neonates were a priori excluded). Nonetheless, in cesarean-delivered (CD) neonates, two variables had significant association with INHB: TT4 ≥ 13 µg/dL and birth at 38-38.6 weeks. In vaginally delivered (VD) born neonates, INHB was associated with weight loss > 7.5% up to 48 hours of age. Multivariate logistic regression analysis showed a strong effect of mode of delivery on possible significant association with INHB. In CD neonates, such variables included: TT4 ≥ 13 µg/dL [P = 0.025, odds ratio (OR) 5.49, 95% confidence interval (CI) 1.23-24.4] and birth at 38-38.6 weeks (P = 0.023, OR 3.44, 95% CI 1.19-9.97). In VD neonates, weight loss > 7.5% (P = 0.019, OR 2.1, 95% CI 1.13-3.83) and 1-min Apgar score < 9 (P < 0.001, OR 3.8, 95% CI 1.83-7.9), but not TT4, showed such an association., Conclusions: INHB was significantly associated with birth on 38-38.6 week and TT4 (≥ 13 µg/dL) in CD neonates, and with a weight loss > 7.5% in VD neonates. We herein highlight some acknowledged risk factors for neonatal hyperbilirubinemia, and thus minimize the rate of INHB.

Severe combined immunodeficiency (SCID), the most severe form of T cell immunodeficiency, is detectable through quantification of T cell receptor excision circles (TRECs) in dried blood spots obtained at birth. Herein, we describe the results of the first year of the Israeli SCID newborn screening (NBS) program. This important, life-saving screening test is available at no cost for every newborn in Israel. Eight SCID patients were diagnosed through the NBS program in its first year, revealing an incidence of 1:22,500 births in the Israeli population. Consanguine marriages and Muslim ethnic origin were found to be a risk factor in affected newborns, and a founder effect was detected for both IL7Rα and DCLRE1C deficiency SCID. Lymphocyte subset analysis and TREC quantification in the peripheral blood appear to be sufficient for confirmation of typical and leaky SCID and ruling out false positive (FP) results. Detection of secondary targets (infants with non-SCID lymphopenia) did not significantly affect the management or outcomes of these infants in our cohort. In the general, non-immunodeficient population, TREC rises along with gestational age and birth weight, and is significantly higher in females and the firstborn of twin pairs. Low TREC correlates with both gestational age and birth weight in extremely premature newborns. Additionally, the rate of TREC increase per week consistently accelerates with gestational age. Together, these findings mandate a lower cutoff or a more lenient screening algorithm for extremely premature infants, in order to reduce the high rate of FPs within this group. A significant surge in TREC values was observed between 28 and 30 weeks of gestation, where median TREC copy numbers rise by 50% over 2 weeks. These findings suggest a maturational step in T cell development around week 29 gestation, and imply moderate to late preterms should be screened with the same cutoff as term infants. The SCID NBS program is still in its infancy, but is already bearing fruit in the early detection and improved outcomes of children with SCID in Israel and other countries.

Context: Delayed thyrotropin (TSH) elevation (dTSH) is defined as elevated TSH at the second neonatal screening (after normal TSH levels at the initial screening) in premature, low-birth-weight, and ill newborns, mostly in the neonatal intensive care unit (NICU) setting. The pathogenesis of dTSH is elusive., Objective: To identify the risk factors for dTSH development among newborns in the NICU., Design, Setting, and Patients: A retrospective medical record review of neonates with dTSH was conducted in eight university-affiliated NICUs. Two controls were selected for each patient, matched for sex and birth weight. The risk factors for dTSH were identified by univariate analysis, followed by multivariate analysis., Main Outcome Measures: Maternal variables, types of NICU treatments and procedures, syndromes, and various medical conditions were compared between dTSH patients and their matched controls., Results: We enrolled 100 dTSH patients and 200 matched controls and 46 variables were compared between the two groups. Twelve risk factors for dTSH were identified on univariate analysis: cesarean section, mechanical ventilation, patent ductus arteriosus (PDA), pneumothorax, and administration of cefotaxime, vancomycin, fluconazole, dopamine, ibuprofen, furosemide, insulin, and packed red blood cells. On multivariate analysis, four risk factors were identified: PDA and vancomycin, insulin, and furosemide administration. In 26 twin pairs, in which one twin had dTSH, all variables presented similarly in both twins., Conclusions: Although some variables had direct effects on pituitary-thyroid axis dysfunction, these variables, altogether, reflect the severity of the clinical conditions in the NICU, which is the common basis for dTSH., (Copyright © 2017 Endocrine Society)

Transient tachypnea of newborn is associated with hypothyroxinemia in animals via decreased stimulation of beta-adrenergic receptors and Na-K-ATPase activity. In 26 549 term neonates, serum total thyroxine <14 ug/dL, male sex, and elective cesarean delivery were significantly associated with greater risk for transient tachypnea of newborn., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To elucidate the incidence, clinical characteristics, and short-term outcome of delayed thyroid stimulating hormone (TSH) elevation (dTSH) in a large cohort of newborns admitted to the neonatal intensive care unit., Study Design: Data were gathered from a cohort of 13 201 newborns admitted to the neonatal intensive care unit born between January 1, 2008, and October 31, 2014, who underwent TSH measurements because of low T4 levels on the second screen. The data from the newborn screening program included gestational age, birth weight (BW), T4 levels, and short-term outcome., Results: Of 13 201 newborns, 333 (1:40) presented with dTSH (TSH >15 IU/L). dTSH had a peak proportion at gestational age of 37-39 weeks, and 66% of the patients had BW >1500 g. T4 levels in the 333 patients were negatively correlated with TSH levels (R = -0.505; P < .001), and significantly lower than levels in the other newborns: 5.9 ± 2.8 vs 7.6 ± 1.7 µg/dL; P < .001. TSH levels in dTSH newborns were already higher on the initial screen compared with the other newborns: 8.3 ± 5.2 vs 4.2 ± 3.7 IU/L; P < .001. Fifty-eight percent of 193 patients with dTSH were started on levothyroxine treatment., Conclusions: dTSH has a higher incidence than previously reported, especially among newborns with BW >1500 g. Relatively high TSH and low T4 levels on the initial and second screen respectively are predictors for dTSH. Levothyroxine treatment is required in most cases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: 3-Methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an inborn error of leucine catabolism. Tandem mass spectrometry newborn screening (NBS) programs worldwide confirmed 3MCCD to be the most common organic aciduria and a relatively benign disorder with favorable outcome. In addition, several asymptomatic 3MCCD mothers were initially identified following abnormal screening of their healthy babies and were appropriately termed maternal 3MCCD., Methods: This is a retrospective study that summarizes all the clinical, biochemical, and genetic data collected by questionnaires of all 3MCCD individuals that were identified by the extended Israeli NBS program since its introduction in 2009 including maternal 3MCCD cases., Results: A total of 36 3MCCD subjects were diagnosed within the 50-month study period; 16 were classified primary and 20 maternal cases. Four additional 3MCCD individuals were identified following sibling screening. All maternal 3MCCD cases were asymptomatic except for one mother who manifested childhood hypotonia. Most of the primary 3MCCD individuals were asymptomatic except for two whose condition was also complicated by severe prematurity. Initial dried blood spot (DBS) free carnitine was significantly lower in neonates born to 3MCCD mothers compared with newborns with primary 3MCCD (p = 0.0009). Most of the mutations identified in the MCCC1 and MCCC2 genes were missense, five of them were novel., Conclusions: Maternal 3MCCD is more common than previously thought and its presence may be initially indicated by low DBS free carnitine levels. Our findings provide additional confirmation of the benign nature of 3MCCD and we suggest to exclude this disorder from NBS programs.

Background: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations., Methods: The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH., Results: Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time., Conclusion: SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary-thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended.

Background: Enumeration of T cell receptor excision circles (TREC) was recently adopted as a neonatal screening assay for severe combined immunodeficiency (SCID). Enumeration of kappa-deleting recombination excision circle (KREC) copy numbers can be similarly used for early assessment of B cell lymphopenia., Objective: To assess the ability of TREC and KREC counts to identify patients with combined T and B cell immunodeficiency in a pilot study in Israel., Methods: We studied seven children born in Israel during the years 2010-2011 and later diagnosed with SCID, and an additional patient with pure B cell immunodeficiency. TREC and KREC in peripheral blood upon diagnosis and in their neonatal Guthrie cards were analyzed using real-time quantitative polymerase chain reaction, as were Guthrie cards with dried blood spots from healthy newborns and from normal and SCID-like controls., Results: The first features suggestive of SCID presented at age 3.1 +/- 2.4 months in all patients. Yet, the diagnosis was made 4.1 +/- 2.9 months later. Their TREC were undetectable or significantly low at their clinical diagnosis and in their originally stored Guthrie cards, irrespective of the amount of their circulating T cells. KREC were undetectable in six SCID patients who displayed B cell lymphopenia in addition to T cell lymphopenia. KREC were also undetectable in one patient with pure B cell immunodeficiency., Conclusions: TREC and KREC quantification are useful screening tests for severe T and B cell immunodeficiency. Implementation of these tests is highly important especially in countries such as Israel where a high frequency of consanguinity is known to exist.

Objective: Contradictory reports ascribe neonatal hyperthyrotropinemia (HT) to prematurity or small weight for gestational age. We aimed to evaluate the association between neonatal HT and birth weight (BW), recovery rate of the disorder, and possible association with perinatal stress., Design: Based on a neonatal screening database, a retrospective twin study was designed where within-pair differences in thyroid function were evaluated while controlling for differences in gestational age and thyroid-affecting environmental confounders., Methods: Two thousand five hundred and ninety-five twin pairs that were screened both for TSH and thyroxine (T(4)) over 3 years were included. TSH and T(4) levels were evaluated along with BW, birth order, gender, and 17-hydroxyprogesterone (17OHP) that was considered as a surrogate marker for stress., Results: Of all the twin pairs, 7.2% had neonatal HT. Among 156 pairs, HT was more prevalent in the smaller twins (64%; P<0.001), especially in the discordant pairs (76%; P=0.001). Seventy-five percent of the twins demonstrated a recovery within the first few weeks of life. 17OHP levels were similarly distributed between twins with and without HT. In a cohort of 1534 twin pairs with normal thyroid function, mean TSH levels were significantly higher in the smaller than in the larger twin in the whole group (4.1±3.2 vs 3.8±2.9 mIU/l; P<0.001) and especially among discordant twins (4.7±3.4 vs 3.8±3.0 mIU/l; P<0.001)., Conclusions: Elevated TSH levels are associated with low BW, both in infants with HT and in normal neonates. A rapid recovery rate is expected in most cases.

Background: Refeeding of elderly frail patients after food deprivation is commonly associated with a high mortality rate., Objective: To evaluate the effect of refeeding on metabolite fluctuation of blood carnitine fatty acids (15 compounds) and free amino acids (14 compounds)., Methods: Metabolite fluctuation was followed up in an exploratory, cohort, and noninterventional study in elderly and frail patients (84.5 ± 5 years) after a long period of food deprivation. Patients in the study group were refed by enteral nutrition (EN) and were followed up during 7 days for blood metabolites (n = 27). Patients in the control group (n = 26) had been fed by EN for more than 3 months. Refeeding was initiated with 10 kcal/kg/d and gradual increases of 200 kcal/d for 3 days afterwards. Blood metabolites were assayed in a sample of 25 µL., Results: On food deprivation, the concentrations of all even monocarboxylic carnitine fatty acids were much higher in the study group than in the EN control group (P < .01). Upon refeeding, a remarkable decrease in all carnitine fatty acids was observed. In addition, significant daily fluctuations were observed for most metabolites in the study group of the refed patients as compared with the EN control group (P < .01). The highest fluctuations were observed following refeeding in the 7 patients who later died., Conclusion: A significant metabolic instability is observed on refeeding even with a slow refeeding schedule of 10 kcal/kg/d. Measurement of metabolomics parameters may be used for the evaluation of malnutrition, refeeding status, and optimization of the enteral formula.