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Neonatal screening and a new cause of congenital central hypothyroidism.

ABSTRACT: Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.

SUBMITTER: Tajima T

PROVIDER: S-EPMC4208260 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Neonatal screening and a new cause of congenital central hypothyroidism.

Tajima Toshihiro T Nakamura Akie A Morikawa Shuntaro S Ishizu Katsura K

Annals of pediatric endocrinology & metabolism 20140930 3

Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the abs ...[more]

PMID: 25346914

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Project description:BackgroundMaternal hypothyroidism has been reported to have concerns over neonatal outcomes, not only in the context of neurocognitive development but also in the short term as birth weight and neonatal jaundice.Patients and methodsWe conducted a cross-sectional retrospective study on 638 cases who delivered live births in the Aga Khan University Hospital after ethical approval. Data were collected on hypothyroid pregnant females who were diagnosed before conception or during their antenatal visits during the year 2008-2016. Neonatal outcomes were noted for birth weight, maturity, and neonatal jaundice, neonatal hypothyroidism, neonatal respiratory distress syndrome, sepsis, hypocalcaemia, congenital anomalies, need for intensive care admission, and neonatal death. Subgroup analysis was performed on the timing of diagnosis of maternal hypothyroidism. Data analysis was performed on Statistical Package for the Social Sciences version 20.0.ResultsNeonatal jaundice was the most common neonatal outcome (37.6%) in our cohort of 662 live births. Nearly 15% required intensive care unit admission, however, neonatal death was very rare. The most common clinically significant congenital anomalies were cardiovascular defects, whereas Mongolian spots were the commonest congenital condition to report. There is a statistically significant association between low birth weight (OR 1.86, 95% CI 1.0-3.2, p ≤ 0.05) and congenital anomalies (OR 2.39, 95% CI 1.4-4.0, p ≤ 0.05) with women diagnosed with hypothyroidism before pregnancy.ConclusionWe report the neonatal outcomes and spectrum of congenital anomalies of hypothyroid pregnancies diagnosed before and during conception for the first time from the region of Pakistan.KEY MESSAGEOverall, none of the neonates of hypothyroid pregnancies developed congenital hypothyroidism.Cardiovascular defects in these neonates imply extensive screening and monitoring during pregnancy.Low birth weight and congenital anomalies are associated with the timings of diagnosis of hypothyroidism in pregnancy.

Project description:Background: Neonatal thyrotropin (TSH) on dried blood spot (DBS), the most common screening strategy for primary congenital hypothyroidism (CH), is influenced by numerous factors that may hinder a true CH diagnosis. A second test can thus be performed to clarify the initial findings, although its application varies among screening programs. Objectives: The aim of this study was to evaluate the effect of maternal and neonatal factors on neonatal TSH levels and offer practical screening recommendations. Methods: We retrospectively analyzed screening data of 62,132 neonates born in Abruzzo, an Italian region considered mildly iodine deficient, between 2011 and 2016. We then performed a multiple linear regression to model the relationship between TSH (the dependent variable) and 13 independent variables extracted from blood collection cards. Results: Most neonates (53,551 of 62,132, 86%) had normal TSH and no clinical indications for a second screening. A minority (1,423, 2.3%) had elevated TSH in the initial DBS, which was confirmed in 97 cases (7%) on a second screen. The remaining neonates (6,594, 10.6%) had a normal initial TSH but underwent a second test in accordance with screening protocols, and were found to have delayed TSH elevation in 23 cases (0.4%). Those 120 newborns (97 + 23), considered highly suspicious for primary CH, were referred to a pediatrician for confirmatory testing and excluded from subsequent analysis of factors influencing TSH levels. Sex (? regression coefficient, ? = 1.11 female to male, 95% CI 1.09, 1.12) and age at collection (? = 0.78 day 5 to days 2-3, 95% CI 0.74, 0.83) affected neonatal TSH, suggesting the utility of specific nomograms. In addition, prematurity (? = 0.85 term to preterm, 95% CI 0.80, 0.91), dopamine use (? = 0.71, 95% CI 0.62, 0.81), and birth weight (? = 1.40 normal vs. very low, 95% CI 1.05, 1.89) strongly influenced neonatal TSH. Conclusions: Neonatal TSH is influenced by several factors supporting the delineation of local sex- and age-adjusted TSH cutoffs, and the universal adoption of a second TSH test in neonates at risk of missed primary CH diagnosis.

Project description:Congenital Hypothyroidism occurs in 1:3500 live births and is therefore the most common congenital endocrine disorder. A spectrum of defective thyroid morphology, termed thyroid dysgenesis, represents 80% of permanent CH cases. Although several candidate genes have been implicated in thyroid development, comprehensive screens failed to detect mutation carriers in a significant number of patients with non-syndromic TD. Due to the sporadic occurrence of TD, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its aetiology. Recently, the use of array CGH technique has provided the ability to map these variations genomewide with high resolution. We performed an array CGH screen of 74 TD patients to determine the role of copy number variants (CNV) in the aetiology of the disease. We identified novel CNVs in 8.75% of all patients that have not been described as frequent variations in the healthy population. Affected patients presented with athyreosis or thyroid hypoplasia and in one case with associated heart malformation. We selected 74 patients with thyroid dysgenesis for array CGH analysis. All individuals were detected in neonatal screening programs and abnormal thyroid gland morphology was subsequently confirmed by ultrasound examination. Intragenic mutations in NKX2-1, FOXE1 and NKX2.5 had been previously excluded in phenotype characteristic individuals. PAX8 mutations were excluded in all patients with hypoplastic thyroids by direct sequencing of the coding exons 1-11. The study was approved by the local ethics committee. Genomic DNA of all subjects as well as of healthy controls was isolated from peripheral blood leucocytes using the Qiagen DNA blood mini kit (Qiagen, Hilden, Germany). Array-comparative genomic hybridization was carried as described previously {Erdogan, 2006 #142; Pinkel, 1998 #151}. In brief, sonicated patient- and control DNA was labeled by random priming with Cy3-dUTP and Cy5-dUTP (Bioprime Array CGH, Invitrogen, Carlsbad, CA), respectively, and hybridized onto a submegabase resolution tiling path BAC array, consisting of ~ 36 000 BAC clones obtained from several sources as described elsewhere {Fiegler, 2003 #198; Ishkanian, 2004 #196; Krzywinski, 2004 #197} . Step-by-step protocols are also provided at http://www.molgen.mpg.de/~abt_rop/molecular_cytogenetics/. Arrays were scanned with the G2565BA Agilent Microarray Scanner System (resolution 10 µm; PMT 100 % for Cy3/Cy5, respectively) (Agilent Inc. Santa Clara, CA) and analyzed using GENEPIX Pro 5.0 Software. Analysis and visualization of array CGH data were performed with our software package CGHPRO {Chen, 2005 #143}. For the assessment of copy number gains and losses, we used conservative log2 ratio thresholds of 0.3 and -0.3, respectively. Deviant signal intensity ratios involving three or more consecutive BAC clones were considered to be potentially pathogenic, unless they were covered by more than one known DNA copy number variant, as listed in the Database of Genomic Variants (http://projects.tcag.ca/variation/) or covered by > 50% of their length at least once in our reference set of 600 samples. Potentially pathogenic CNVs were verified by array CGH on a 244k oligonucleotide array from Agilent following the manufacturer’s instructions (Protocol-No. G4410-90010). Confirmed CNVs were tested for inheritance by co-hybridization of parental DNA on BAC arrays as described above. All chromosome coordinates are referring to the UCSC Genome Browser Assembly May 2004 (hg17/ NCBI Build 35; available at: http://genome.ucsc.edu/cgi-bin/hgGateway?hgsid=99195739&clade=vertebrate&org=Human&db=hg17). Cytoscape {Shannon, 2003 #201} was used for the elucidation of potential interactions between genes within the intervals of interest.

Dataset Information

Neonatal screening and a new cause of congenital central hypothyroidism.

Publications

Neonatal screening and a new cause of congenital central hypothyroidism.

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