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Pediatric Department, Centre Intercommunal de Créteil, Créteil, FranceInserm, Unité 955, Equipe 5, Créteil, FranceDHU Ageing Thorax Vessel Blood, Créteil, France
Sixteen subjects diagnosed with ILD associated with NKX2-1 mutations were reviewed.
•
Four new variants were identified in 13 children and 3 adults.
•
Lung phenotype due to NKX2-1 mutations is heterogeneous.
•
Lung symptoms may be associated with neurological or hypothyroidism or isolated.
•
Most of the patients progressively evolve to interstitial lung fibrosis.
Abstract
We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease.
Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5–95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5–29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24–71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation.
In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.
Inherited surfactant metabolism diseases represent 10–15% of the cause of neonatal respiratory distress syndrome (RDS) in full term newborns and of infiltrative lung disease (ILD) in older children [
]. Pulmonary surfactant is a multi-molecular complex that is secreted into the alveolar airspace to form a thin layer at the air-liquid interface, preventing alveolar atelectasis. It is composed of phospholipids (80–90%) and proteins (10–15%), among which 2–3% are specific proteins called surfactant protein A, B, C and D (SP-A, SP-B, SP-C and SP-D, respectively) [
]. SP-B and SP-C are two hydrophobic proteins, synthesized by alveolar type II cells as pro-peptides (pro-SP-B and pro-SP-C). Their intracellular trafficking includes processing through lamellar bodies where surfactant proteins and lipids are assembled into bilayer membranes by ABCA-3 (adenosine triphosphate-binding cassette transporter A3) [
], a member of the NKX2 transcription factor family. NKX2-1 was initially identified as a nuclear protein binding the promoter of the thyroglobulin gene. However, various studies have later shown that NKX2-1 is also expressed in the brain and the lungs [
PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations.
]. Homozygous mice lacking NKX2-1 expression die shortly after birth, lack lung parenchyma and thyroid gland, and exhibit defects in the ventral region of the forebrain, including the absence of pituitary gland [
The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.
]. In humans, autosomal dominant NKX2-1 mutations are associated with brain-lung-thyroid syndrome, combining varying degrees of congenital hypothyroidism, neurological features (neonatal or early childhood hypotonia evolving to benign hereditary chorea) and pulmonary symptoms [
]. While both neurological and pulmonary features are responsible for the disease morbidity, lung disease is mainly responsible for the mortality. Various pulmonary phenotypes have been described, including RDS in term infants, ILD in children, and more recently in adults [
]. Management of the diseases associated with NKX2-1 mutations is still a matter of debate, one of the principal issues being the lack of large randomized clinical trials, and treatment is usually based on the severity of the disease and the expertise in each centre [
]. The aim of this study was to describe the pulmonary phenotypes in patients with NKX2-1 mutations, including the clinical and radiological features, course of treatment and outcome.
2. Materials and methods
2.1 Study population
We retrospectively identified through the French Rare Lung Disease Network (RespiRare®) 16 subjects with NKX2-1 mutation and associated pulmonary phenotype, who were followed in 8 hospitals throughout France (Centre Intercommunal de Creteil, Creteil; Centre Hospitalier Regional Universitaire, Lille; Hôpital Armand Trousseau, Paris; Hôpital Robert Debré, Paris,; Hôpital Bichat, Paris; Hôpital la Timone, Marseille; Centre Hospitalier Regional Universitaire, Tours, France), and 1 in Argentina (Hospital de Niños Ricardo Gutierrez, Buenos Aires).
Pulmonary phenotypes associated with NKX2-1 mutations were defined as RDS in newborns at > 37-week gestation with severe hypoxemic respiratory failure and diffuse lung disease on chest radiography, or as ILD in older children or adults with a diagnosis based on clinical features and high-resolution CT (HRCT) scanning. Patients with asthma or recurrent lung infections and carrying a NKX2-1 mutation were excluded from the study. Four patients including 2 members of a same family, have been reported previously [
Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
J. Neurol. Neurosurg. Psychiatry.2012; 83: 956-962
Table 1Clinical description of the 16 patients with NKX2-1 mutation and a respiratory phenotype.
Patient
Family
Gender
Mutation
Pulmonary phenotype
Neurologic phenotype
Thyroid phenotype
1
1
Ma
c.714G>A
RDS with IV
Hypotonia, chorea
Hypothyroidism
2
1
Ma
c.714G>A
RDS with IV
Hypotonia, psychomotor delay
Hypothyroidism, thyroid defect
3
Ma
c.344dup
RDS with NIV
Hypotonia, psychomotor delay, chorea
Hypothyroidism, thyroid ectopy
4
Fe
c.583C>T
RDS with IV
Hypotonia
Hypothyroidism
5
Fe
c.876_877del
RDS with IV
Hypotonia, psychomotor delay, chorea
Hypothyroidism, thyroid defect
6
3
Ma
c.463+2T>C
RDS with NIV
Hypotonia, psychomotor delay, chorea
Hypothyroidism, thyroid agenesis
7
Fe
c.344dup
RDS with IV
Hypotonia, psychomotor delay, chorea
None
8
2
Fe
c.175_176del
ILD at 7M
None
None
9
Fe
c.572G>T
ILD at 4M
None
None
10
Fe
c.267dupG
ILD with fibrosis at 40Y
Chorea
Hypothyroidism during pregnancy
11
3
Fe
c.463+2T>C
ILD with respiratory insufficiency at 25Y
Chorea
hypothyroidism
12
2
Ma
c.175_176del
ILD at 30Y
None
None
13
Ma
c.728G>A
RDS with IV
None
None
14
Ma
Del14q13q13
RDS with IV
Hypotonia, psychomotor delay, chorea
Hypothyroidism, normal segmentation
15
Fe
Del14q13.3q21.1
ILD at 7Y
Psychomotor delay
None
16
Fe
Del14q12q21
RDS
Psychomotor delay, ataxia
None
Ma: male. Fe: female. RDS: respiratory distress syndrome. IV: invasive ventilation. NIV: non invasive ventilation. ILD: infiltative lung disease. Y: years; M: months; Patients 4, 5, 6 and 11 were published as letter, case report or series
Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
J. Neurol. Neurosurg. Psychiatry.2012; 83: 956-962
NKX2-1 encodes 2 NKX2-1 protein isoforms: a 371 amino acid peptide (NM_003317.3, 2 exons) and a 401 amino acid peptide (NM_001079668.2, 3 exons). Although the shorter transcript sequence is the most commonly expressed isoform, we choose to use HGVS nomenclature applied to the longer transcript to prevent confusion. NKX2-1 sequencing was performed by the Genetic Department at each centre. Briefly, EDTA blood samples were collected after obtaining informed consent from the patients or their parents (patients <18 years old), and used to extract leukocyte genomic DNA. Specific primers were used to amplify the coding regions and the intron-exon boundaries of the NKX2-1 gene (primers sequence available on request) using polymerase chain reaction (PCR). The PCR products were subjected to direct Sanger sequencing. Pathogenicity of novel variants was evaluated depending on the affected domain, the type of mutation (frameshift or deletions vs non-sense), absence in the databases, and in silico analysis by the Alamut software (Interactive Biosoftwares). For each mutation, the de novo or inherited status was reported if the parents' DNA was available. The 3 patients harboring a deletion of the whole gene were identified by FISH using a locus-specific BAC mapping to NKX2-1 at 14q13.3 (RP11-1083E2).
2.3 Design
The following data were retrieved from the patients' medical records and from the RespiRare® database:
•
Family history, clinical presentation, association with neurological and/or thyroid symptoms;
•
Chest radiography or HRCT reports, lung function tests, bronchoscopy and bronchoalveolar lavage fluid (BALF) reports, lung biopsy report;
Data were expressed as mean ± interquartile (IQ). The study was granted a limited waiver of Authorization requirement, and was approved by our institutional review board.
3. Results
3.1 Genetic features
Twelve different NKX2-1 mutations were identified in the 16 included patients (Fig. 1). All subjects were heterozygous for their mutation. The 12 mutations comprised 3 deletions of the whole gene and 9 point mutations, including 4 novel mutations (c.175_176del, c.267dup, c.714G>A, c.728G>A) (Fig. 1). Three point mutations (c.583C>T, c.714G>A, c.728G>A) resulted in an amino-acid substitution in the homeodomain (functional domain of NKX2-1 that allows DNA binding), and one (c.572G>T) was located just before the homeodomain. Four mutations induced a frameshift (c.175_176del, c.344dup, c.267dup, c.876_877del), 3 of which being located before the homeodomain. One mutation was an intronic nucleotide substitution (c.463+2T>C), which altered the splice donor site of intron 2, and thus was predicted to cause abnormal splicing. Six mutations were de novo (c.344dup, c.267dup, c.876_877del, c.583C>T, c.572G>T, c.728G>A), whereas 3 were inherited (c.175_176del, c.463+2T>C, c.714G>A). The c.344dup was found in two unrelated patients. For the 3 patients with deletion of the whole gene, the inherited status remained unknown because the parents' DNA was unavailable.
Fig. 1Diagram of the NKX2-1 gene (NM_001079668.2) showing the localization of the mutations identified in our patient cohort. The shaded box represents the homeodomain in exon 3. Grey boxes indicate the patients with only a respiratory phenotype. The family cases are in the same box. New mutations are in bold.
No correlation was found between the type or site of the mutation, the severity of lung disease, or the association with neurological or thyroid abnormalities.
3.2 Clinical characteristics
Clinical characteristics are summarized in Table 1. Among the 16 patients, 9 (56%) presented with brain-lung-thyroid syndrome, 3 (19%) had neurological and lung symptoms and 4 (25%) had only pulmonary symptoms. Thyroid symptoms were found in 9 patients (56.3%), including congenital hypothyroidism in 6 and late-onset hypothyroidism in 3. Neurological symptoms were identified in 10 patients (62.5%) and comprised neonatal hypotonia with psychomotor delay in 10, and chorea during childhood in 3. Two patients from the 3 with whole gene deletion also displayed an excessive vasovagal response and a facial dysmorphology associated with cholesteatoma. The median age at diagnosis was 36 months (IQ 3.5–95). Ten children (62.5%) presented as neonatal RDS, and had neonatal signs of breathing difficulties (tachypnea, chest wall in drawing, cyanosis, nasal flaring, grunting, apnea and/or dyspnea). Six of them (60%) developed ILD later in life. Six other patients had ILD, including 2 who were diagnosed in the first year of life with an association of failure to thrive and tachypnea or cough, one diagnosed at seven years old and 3 who were diagnosed in adulthood, one of them having lung fibrosis at diagnosis. Thus, a total of 12 patients (75%) were diagnosed with ILD. Abnormal physical exam, defined as the presence of crackles or wheezing, was found in 10 of the 16 patients (62.5%).
3.3 Paraclinical findings
HRCT was performed in 13 patients, resulting in ILD diagnosis in 11 (84.6%) with findings ranging from mild to diffuse ground glass opacities (n = 5), cysts (n = 1), infiltrates (n = 7), atelectasis (n = 2) and fibrosis (n = 2) (Fig. 2). In children, HRCT showed a significant improvement over time in all the patients still alive with a decrease of ground-glass opacities (Fig. 3). BALF analysis was performed in 6 patients, showing normal total cell counts in all patients, but for some, an increase percentage of neutrophils (n = 3) or lymphocytes (n = 1). Lung biopsies were performed in 3 patients (patient 4, 9 and 15) and were abnormal in 2 (patient 4 and 15), showing septal thickening, intra-alveolar macrophage accumulation, hyperplasia of alveolar type II cells, and presence of amorphous material stained with periodic acid-Schiff. Blood-gas analysis was performed in 7 patients (patient 5, 6, 9–12, and 15), showing hypoxemia (PaO2 ≤ -2SD) in 6 (86%) (patient 5, 6, 9, 11 and 15). Lung function tests were performed in 5 patients (patient 9–12 and 14), and 2 of them exhibited restrictive syndrome (patient 10 and 11) as indicated by a total lung capacity (TLC) < 80% of predicted value or a reduction of forced expiratory volume in 1 s (FEV-1) and forced vital capacity (FVC) with a FEV-1/FVC ratio > 0.7 (Table 2). Six patients, 3 children and 3 adults, underwent a 6-min walk test (patient 8, 10, 11, 12, 14 and 15). Two of the 3 children showed desaturation (defined as a fall in oxygen saturation to 92% or less during the 6-min walk test), whereas 2 of the 3 adults showed desaturation (defined as a fall in oxygen saturation to 89% or less during the 6-min walk test).
Fig. 2(A) HRCT from a three-month-old girl (Patient 8) showing heterogeneous ground-glass opacities. (B) HRCT from a three-year-old girl (Patient 9) displaying paraseptal emphysema associated with widespread cystic airspaces and diffuse ground-glass opacities (black arrows). (C) Initial HRCT in a forty-five-year-old female (Patient 10) showing association of paraseptal emphysema, septal thickening and fibrosis.
Fig. 3Changes in HRCT findings in Patient 5. (A) At 8 months, initial HRCT findings consisted of bilateral alveolar consolidations and ground-glass opacities. The HRCT scan at 3 years (B) and 9 years (C) after treatment with a combination of methylprednisolone pulse (3 years), azithromycin (1.5 years) and Hydroxychloroquine (1 year) showed progressive improvement with a decrease in the ground-glass opacities pattern.
The data are expressed in percentage of predicted values. FEV-1: forced expiratory volume in 1 s; FVC: Forced vital capacity; TLC: Total lung capacities; DLCO: diffusing capacity factor of the lung for carbon monoxide.
Treatments and outcomes are summarized in Table 3. The median follow-up was 36 months (IQ 24–71.5). During the neonatal period, the patients who required invasive ventilation (70%) received 1 or 2 doses of exogenous surfactant (Curosurf®). Two patients benefited from non-invasive ventilation (20%). Eight patients (50%) received supplemental oxygen support with a median duration of 18 months (IQ 2.5–29). Due to a failure to thrive, 4 patients (25%) had enteral feeding through a gastrostomy tube. With the exception of 4 patients who presented with an isolated RDS in the first month of life and two patients who were less symptomatic (no complain, but abnormal HRCT), the others (n = 10, 62.5%) benefited from long-term treatment with oral or pulse steroids. Among those, 8/16 (50%) also received azithromycin, and 4/16 (25%) hydroxychloroquine. Steroid treatment was stopped in 3 patients following respiratory improvement, but they were still dyspneic and required long-term oxygen therapy. Patient 16 received only azithromycin treatment, which improved her condition. Patient 14 was treated with oral steroids for exacerbations during childhood, resulting in adrenal insufficiency and osteoporosis with multiple bones fractures. Most adult patients who were treated with oral steroids exhibited steroid side effects: Patient 11 experienced bulimia, insomnia and Cushing's syndrome and patient 5 developed hypokalemia and reduction of bone density. Patient 6 developed neutropenia after the introduction of hydroxychloroquine, and the treatment was interrupted. At the end of the follow-up, among the 11 children who received oxygen supplementation, 1 deceased of respiratory failure at 18 months of age, 2 were on continuous oxygen supplementation, 3 had nocturnal oxygen supplementation and 5 were weaned off oxygen. One children underwent a lung lobectomy for a focal chronic lung infection (patient 15). Among the adults (n = 3), none of them received for oxygen supplementation, one patient was at end-stage respiratory failure at the time of data collection, and was waiting for lung transplantation.
Table 3Respiratory status and treatment at the end of the follow-up.
Fig. 4 summarizes the data from the 3 families with inherited NKX2-1 mutations. In the first family, the 2 sons (patient 1 and 2) suffered from brain-lung-thyroid syndrome and had a similar respiratory phenotype (RDS). The c.714G>A mutation was inherited from their mother who presented only with late-onset hypothyroidism. In the second family, the daughter (patient 8) suffered from severe RDS needing long-term supplemental oxygen support, and carried the same c.175_176del mutation as her father (patient 12) who was diagnosed with ILD later in life during an ICU hospitalization for severe viral respiratory infection. In the third family with a c.463+2T>C mutation, the son (patient 6) was diagnosed when 2 months old after severe respiratory symptoms, while his mother (patient 11) was diagnosed with a mild pulmonary phenotype when she was 26 years old. The 2 patients with full gene deletion had a suggestive family history, but genetic analysis could not be performed. The father of patient 14 presented with hypothyroidism, chorea and ILD, and died at 50 years old due to end-stage chronic lung insufficiency. Mother of patient 15, reported to have cognitive impairment and chronic respiratory symptoms, died at 35 years old due to pulmonary adenocarcinoma.
Fig. 4Clinical characteristics of patients with NKX2-1 familial mutations.
We report here the clinical presentation, treatment modalities and outcome in 16 patients with a respiratory disease due to a NKX2-1 mutation. This study involved multiple centers because of the rarity of these mutations. The clinical presentation was heterogeneous ranging from brain-lung-thyroid syndrome (56%) to isolated respiratory phenotype (25%) and neurological symptoms associated with respiratory phenotype (19%). The Supplemental Table 1 summarized the clinical presentations of the 104 published cases of patients with NKX2-1 mutation [
Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis.
]. The respiratory phenotype was found in 53 patients, but was very heterogeneous, including neonatal RDS, recurrent pneumoniae, asthma, recurrent pneumothorax, supplemental oxygen support, hypoxemia, ILD, lung fibrosis, or respiratory insufficiency. Because it is difficult to directly link the presence of NKX2-1 mutation with relatively common respiratory disease in childhood such as asthma, or recurrent respiratory tract infections, we have intentionally decided to exclude such patients in this series. Among these patients (Fig. 5), 44 presented with brain-lung-thyroid syndrome, 4 with thyroid dysgenesis, 3 suffered from neurological symptoms, and 2 had isolated pulmonary symptoms. The very low number of isolated pulmonary phenotypes reported in the literature may be due to a recruitment bias, as NKX2-1 was originally described as a thyroid transcription factor, and only a few functional studies have described pulmonary phenotypes due to NKX2-1 mutation. RDS in full-term newborns was the first identified clinical presentation [
]. Hamvas et al. reported 21 patients with respiratory disease due to NKX2-1 mutation. Among them, 17 (80%) presented with a neonatal RDS that evolved into ILD for 1 patient, 3 (14%) presented with isolated ILD (diagnosis between 4 months and 7 years old), and one patient suffered from pulmonary fibrosis at 26 years old [
]. We showed similar results in our cohort with 10 (62.5%) neonatal RDS, including 6 evolving into ILD, 3 ILD diagnosed during childhood and 3 ILD diagnosed during adulthood.
Fig. 5“Distribution of symptoms in the 105 published cases (in italic) and in our 16 patients (in bold)” and not 15 patients.
]. Two of them were frameshift mutations, predicted to cause non-functional or absent NKX2.1 protein, and thus haploinsufficiency. We noticed intra-familial clinical variability in the 3 families of our cohort where members had the same NKX2-1 mutation. Patients presented with different phenotypes with a respiratory disease occurring at birth or diagnosed only in adulthood. The phenotype may be extremely severe as shown by Hamvas et al. (7 deaths; 4 patients transplanted) and in the present study (one death and one patient waiting for lung transplant). In our study, children seemed to be more severely affected than their carrier parents, who, in most of the cases, did not experience significant symptoms and were diagnosed after molecular analysis. This could be due to possible mosaicism in the parents, which was not detectable with leukocyte DNA, or to phenotypic heterogeneity as has been already shown in genetic disorders of pulmonary surfactant, particularly in those associated with SFTPC mutations [
]. Two of the 3 patients with whole gene deletion exhibited symptoms that are usually not observed in the brain-lung-thyroid triad syndrome. Other patients with large chromosomal deletion of chromosome 14 encompassing the NKX2-1 gene and several others have been previously reported to have dysfunction of the thyroid, lung, and central nervous system [
]. Haplo-insufficiency for other genes within the deleted region may have contributed to the phenotypic variability, as shown in previous reports on individuals with oligodontia harboring chromosomal deletions encompassing NKX2-1 and PAX9 [
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.
Surfactant protein C gene (SFTPC) mutation-associated lung disease: high-resolution computed tomography (HRCT) findings and its relation to histological analysis.
]. In the present cohort, HRCT scan confirmed lung involvement in patients with early or late respiratory symptoms, but also help to monitor the treatment response during the course of the disease. Analysis of BALF is also interesting as it allows to quantify lung inflammation but also to analyze the functional impact of NKX2-1 mutations on surfactant metabolism (Western-blot analysis), which may vary depending of the type of mutations [
]. Lung biopsy was rarely performed in the present study (3 patients), and showed a variable appearance from normal to fibrosis, with characteristics usually observed in surfactant disorders (macrophage accumulation, alveolar type II epithelial cells hyperplasia and accumulation of amorphous material colored with periodic acid –Schiff) [
]. With the exception of cutaneous pulse oximetry and blood gas analysis, functional studies are difficult to perform in these patients who have frequently neurological disorders. In our cohort, blood gas analysis was obtained in 7 patients, while 5 had lung volume measurement and 6 underwent the six-minute walk test. Consistent with previous studies showing late hypercapnia, we mainly observed hypoxemia in our patients [
]. Lung volumes may also be heightened by the neurological symptoms (hypotonia and chorea), and some patients improved after treatment with levodopa or tetrabenazine [
Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
J. Neurol. Neurosurg. Psychiatry.2012; 83: 956-962
]. However, due to the small number of patients and the absence of clinical trials, the choice of therapeutics remains highly dependent on the practice and experience of the different centers. According to the clinician consensus based on the Delphi method and the recent recommendations of European networks, it is now recognized that corticosteroids remain the mainstay for the management of ILD in children together with nutritional support, despite their known long-term toxicity [
An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.
]. Interestingly, in the present study, side effects were more often observed in adults treated with oral steroids than in children treated with intravenous steroids pulses. Although no study has assessed the efficacy and safety of macrolides in children with ILD, and azithromycin efficacy has only been reported in isolated cases of adult and pediatric ILD [
] in children with surfactant metabolism disorders. In the present study, nine patients were treated with azithromycin three times per week without significant side effects, but its efficacy remains unclear. Hydroxychloroquine has also been used and its efficacy has been reported in patients carrying SFTPC or ABCA3 mutations [
]. In our cohort, 4 patients received hydroxychloroquine with little evidence of its effectiveness. Although it could not be excluded that patients could have improved progressively in most of the cases, regardless of the molecule used, a combination therapy including methylprednisolone pulse, oral hydroxychloroquine and azithromycin may result in significant improvement.
In conclusion, we report a multicentric cohort of 16 patients with a NKX2-1 mutation and associated lung disease. In the light of the diverse phenotypes, we recommend to screen for NKX2-1 gene mutations in case of RDS in a full-term newborn or of ILD occurring later in childhood or adulthood, with or without thyroid and neurologic disorders. Furthermore, follow-up of patients carrying a NKX2-1 gene mutation with isolated thyroid and/or neurologic phenotypes should comprise, when possible, pulmonary exploration and imaging (taking into account the potential toxicity of repeat HRCT scans in children). Based on our current knowledge, symptomatic treatments must be initiated, and should include anti-inflammatory therapeutics. Given the low prevalence of the disease, international randomized control studies are needed to test newly developed treatment strategies. Experimental and functional studies are also needed to provide a better understanding of the heterogeneous phenotypes of lung disease associated with NKX2-1 mutations.
Conflict of interest statements
The authors have no competing interest and no conflicts of interest to disclose.
Acknowledgement
The authors wish to thank Dr. Martine Torres for her editorial assistance.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations.
The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.
Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene.
J. Neurol. Neurosurg. Psychiatry.2012; 83: 956-962
Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.
Surfactant protein C gene (SFTPC) mutation-associated lung disease: high-resolution computed tomography (HRCT) findings and its relation to histological analysis.
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