Congenital hypothyroidism is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated. Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis is familial, and congenital hypothyroidism caused by organification defects is often recessively inherited. The candidate genes associated with this genetically heterogeneous disorder form two main groups: those causing thyroid gland dysgenesis and those causing dyshormonogenesis. Genes associated with thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital hypothyroidism, and Gsα and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8), associated with different complex syndromes that include congenital hypothyroidism. Among those causing dyshormonogenesis, the thyroid peroxidase and thyroglobulin genes were initially described, and more recently PDS (Pendred syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene defects. There is also early evidence for a third group of congenital hypothyroid conditions associated with iodothyronine transporter defects associated with severe neurological sequelae. This review focuses on the genetic aspects of primary congenital hypothyroidism.

https://jmg.bmj.com/content/jmedgenet/42/5/379.full.pdf

Genetics of congenital hypothyroidism

Background: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults.Methods: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient’s or family’s quality of life, and death.Results: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be e...

/pdf/an-official-american-thoracic-society-clinical-practice-2ujvvcpf03.pdf

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity in one case. Additionally, our review shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.

Five new TTF1/NKX2.1 mutations in brain–lung–thyroid syndrome: rescue by PAX8 synergism in one case

This study represents the first national epidemiological survey of primary immunodeficiency diseases in Norway. Uniform questionnaires were sent out in April 1998 to all hospital departments considered relevant. As of February 1999, a total of 372 patients have been registered, of whom 69 patients are deceased. With a population of 4.45 million people, the total prevalence of primary immunodeficiency diseases in Norway February 1, 1999 is 6.82 per 100.000 inhabitants. Distribution between the main immunodeficiency diagnoses is (a) antibody deficiencies 50.8%, (b) combined deficiencies included other immunodeficiency syndromes 12.4%, (c) complement deficiencies 21.0%, (d) phagocytic disorders 6.7%, (e) and immunodeficiency associated with other congenital diseases 9.1%. Compared to previous reports from other European countries, there is a smaller proportion of antibody deficiencies due to few IgA deficiencies registered and a large proportion of complement deficiencies due to many patients with hereditary angioedema.

/pdf/primary-immunodeficiency-diseases-in-norway-4bgwujm4gz.pdf

Primary immunodeficiency diseases in Norway.

Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy.

/pdf/interstitial-lung-diseases-in-children-5cmt19bpt5.pdf

Interstitial Lung Diseases in Children

Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1.


 
 
 Type of funding sources: None.
 
 
 
 Left ventricular hypertrophy (LVH) and microvascular dysfunction are hallmarks of hypertrophic cardiomyopathy (HCM). We hypothesized that microvascular dysfunction contributes to LV myocardial deformation impairment.
 
 
 
 Prospective evaluation of adult patients with HCM (patients with "end-stage" HCM, prior septal reduction therapy or epicardial coronary artery disease were excluded). All underwent a cardiac magnetic resonance (CMR) protocol (1.5-T), from which the following parameters were analysed: maximal LV wall thickness (MLVWT), T1 and T2 mapping, extracellular volume, late gadolinium enhancement (LGE) and stress perfusion. Three-dimensional strain analysis was obtained by using feature-tracking from cine images. Results were stratified according to the 16 American Heart Association segments. Multivariate regression analyses for longitudinal, circumferential and radial strain were performed.
 
 
 
 A total of 1200 myocardial segments were analysed (Table 1) (75 patients, 63% male, age 54.6 ± 14.7 years) including 61% with asymmetric septal LVH, 29% with apical LVH, 8% with concentric LVH, 28% exhibiting LV outflow tract obstruction. The mean MLVWT was 20 ± 4.5mm.
 Higher values of longitudinal strain (lower deformation) were found in segments with MLVWT ≥15mm (β-estimate: 2.31, 95% CI 0.91-3.70, p < 0.001) and in patients with obstructive HCM (β-estimate: 2.44, 95% CI 1.15-3.72, p < 0.001]) (Table 2). No association was found between perfusion defects, LGE and longitudinal strain.
 Higher values of circumferential strain (lower deformation) were found in segments with MLVWT 12-14mm (β-estimate: 2.31, 95% CI 1.36-3.25, p < 0.001), MLVWT ≥15mm (β-estimate: 5.29, 95% CI 4.47-6.12, p < 0.001), with perfusion defects (β-estimate: 2.75, 95% CI 2.0-3.5, p < 0.001), with LGE (β-estimate: 2.49, 95% CI 1.77-3.22, p < 0.001) and in patients with obstructive HCM (β-estimate: 1.25, 95% CI 0.44-2.06, p = 0.003).
 Lower radial strain values were found in segments with MLVWT 12-14mm (β-estimate: -10.64, 95% CI -13.95 to -7.33, p < 0.001), with MLVWT ≥15mm (β-estimate: -20.67, 95% CI -23.36 to -17.97, p < 0.001), with perfusion defects (β-estimate: -10.60, 95% CI -13.08 to -8.13, p < 0.001), and with LGE (β-estimate: -10.49, 95% CI  -12.86 to -8.11) (table 2).
 Diabetes, hypertension and BMI > 25 kg/m2 were also associated with impaired myocardial deformation. Male gender correlated with worse radial and circumferential strain values.
 No association was found between parametric mapping values and LV myocardial deformation.
 
 
 
 In patients with HCM, three-dimensional speckle tracking parameters for LV systolic function were particularly impaired in segments with LVH, microvascular dysfunction or fibrosis. LVH was associated with abnormal longitudinal, circumferential and radial strain while perfusion defects and LGE correlated with impaired circumferential strain and radial strain. Abstract Table 1: Characteristics of AHA segments  Abstract Table 2: Multivariate analysis


Microvascular dysfunction and myocardial fibrosis impact on left ventricular myocardial deformation in hypertrophic cardiomyopathy: per segment analysis by magnetic resonance imaging

Inflammation is known to be the root cause of the development of coronary artery disease (CAD). Subclinical inflammation is one of the key players in pathophysiology of CAD. An inflammatory response leads to the secretion of various adipokines and cytokines. There are various pro-inflammatory markers which could be used to determine the onset of disease, and one such marker is resistin adipokine. The present study evaluates and compares the circulatory concentration of resistin in CAD patients and controls for the determination of its association with CAD. In this study, 58 CAD patients were enrolled and were further subdivided into four groups as per the associated co-morbidities. Various anthropometric and biochemical parameters were assessed. The circulatory levels of resistin were found to be significantly elevated in CAD patients and their subgroups as compared to controls. We conclude that elevated resistin levels in CAD patients suggest a key role of resistin in the development of CAD. The present study also observed that co-morbidities like type 2 diabetes can act as one of the major factors for the elevated concentration of resistin in the circulation of CAD patients with diabetes.

pdf/evaluation-of-the-circulatory-levels-of-resistin-in-coronary-11u09pn6.pdf

Evaluation of the circulatory levels of resistin in coronary artery disease with associated co-morbidities


 
 
 Type of funding sources: None.
 
 
 
 While left ventricular hypertrophy (LVH) and myocardial fibrosis are frequently evaluated in hypertrophic cardiomyopathy (HCM), microvascular dysfunction is often overlooked. The aim of this study was to assess the association between wall thickness, microvascular dysfunction and tissue characteristics in HCM patients (P), comparing individual myocardial segments.
 
 
 
 Prospective evaluation of adult P with HCM (P with "end-stage" HCM, prior septal reduction therapy or epicardial coronary artery disease were excluded). All underwent a cardiac magnetic resonance (CMR) protocol (1.5-T), from which the following parameters were analysed: maximal LV wall thickness (MLVWT), T1 and T2 mapping, extracellular volume (ECV), late gadolinium enhancement (LGE) and stress perfusion. Results were stratified according to the 16 American Heart Association segments. Multivariate regression analyses for perfusion defects and tissue characteristics were performed.
 
 
 
 75 P (total of 1200 myocardial segments analysed), 63% male, mean age 55 ± 15 years, MLVWT of 20 ± 4.5mm (61% asymmetric septal LVH, 29% apical LVH and 8% concentric LVH). 28% presented LV outflow tract obstruction.
 MLVWT was greater in the basal and mid septum (table 1). Among the 424 segments (35.3%) with a perfusion defect, 286 (23.8%) had a defect only in the endocardial layer and 138 (11.5%) in both endocardial and epicardial layers with defects more often detected in hypertrophied segments. This association was verified in segments with MLVWT 12-14mm and MLVWT ≥15mm (OR 7.83, 95% CI 5.75-10.67, p < 0.001) (table 2). Among the 660 segments with normal MLVWT (≤11mm), 123 (19%) presented perfusion defects. A perfusion defect was more frequent in segments of obstructive HCM P (OR 1.48, 95% CI 1.13-1.92, p = 0.004).
 Microvascular dysfunction was associated with changes in tissue characteristics. For the same thickness, segments with perfusion defects had a higher T1 mapping (β-estimate 20.91, 95% CI 16.87-24.96, p < 0.001) and T2 mapping mean values than those without. Furthermore, regardless of MLVWT, segments with perfusion defects had LGE more often (OR 4.16, 95% CI 3.19-5.41, p < 0.001) and a higher ECV. On the other hand, among the 424 segments with a perfusion defect, 115 (27%) did not present LGE.
 MLVWT was associated with tissue characteristics. Comparing to non-hypertrophied segments, T1 mapping mean value was higher in segments with MLVWT 12-14mm and with ≥15mm (β-estimate 37.71, 95% CI 31.2-44.21, p < 0.001). Segments with MLVWT ≥15mm showed a significantly superior ECV mean value comparing to non-hypertrophied segments. LGE was more frequent in the more hypertrophied segments: MLVWT 12-14mm and ≥15mm (OR 9.02, 95% CI 6.42-12.67, p < 0.001) (Table 2).
 
 
 
 Microvascular dysfunction is more prevalent in obstructive HCM, particularly in the more hypertrophied segments. The presence of microvascular dysfunction is associated with diffuse tissue abnormalities and replacement fibrosis. Abstract Table 1: Characteristics of AHA segments  Abstract Table 2: Multivariable analyses


Segmental analysis of microvascular dysfunction and tissue characterization in hypertrophic cardiomyopathy by magnetic resonance imaging

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Papers

Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1.

Microvascular dysfunction and myocardial fibrosis impact on left ventricular myocardial deformation in hypertrophic cardiomyopathy: per segment analysis by magnetic resonance imaging

Evaluation of the circulatory levels of resistin in coronary artery disease with associated co-morbidities

Segmental analysis of microvascular dysfunction and tissue characterization in hypertrophic cardiomyopathy by magnetic resonance imaging