Chest
Volume 144, Issue 4, October 2013, Pages 1199-1206
Journal home page for Chest

Original Research
Genetic and Developmental Disorders
A Mutation in TTF1/NKX2.1 Is Associated With Familial Neuroendocrine Cell Hyperplasia of Infancy

https://doi.org/10.1378/chest.13-0811Get rights and content

Background

Neuroendocrine cell hyperplasia of infancy (NEHI) is a childhood diffuse lung disease of unknown etiology. We investigated the mechanism for lung disease in a subject whose clinical, imaging, and lung biopsy specimen findings were consistent with NEHI; the subject's extended family and eight other unrelated patients with NEHI were also investigated.

Methods

The proband's lung biopsy specimen (at age 7 months) and serial CT scans were diagnostic of NEHI. Her mother, an aunt, an uncle, and two first cousins had failure to thrive in infancy and chronic respiratory symptoms that improved with age. Genes associated with autosomal-dominant forms of childhood interstitial lung disease were sequenced.

Results

A heterozygous NKX2.1 mutation was identified in the proband and the four other adult family members with histories of childhood lung disease. The mutation results in a nonconservative amino acid substitution in the homeodomain in a codon extensively conserved through evolution. None of these individuals have thyroid disease or movement disorders. NKX2.1 mutations were not identified by sequence analysis in eight other unrelated subjects with NEHI.

Conclusions

The nature of the mutation and its segregation with disease support that it is disease-causing. Previously reported NKX2.1 mutations have been associated with “brain-thyroid-lung” syndrome and a spectrum of more severe pulmonary phenotypes. We conclude that genetic mechanisms may cause NEHI and that NKX2.1 mutations may result in, but are not the predominant cause of, this phenotype. We speculate that altered expression of NKX2.1 target genes other than those in the surfactant system may be responsible for the pulmonary pathophysiology of NEHI.

Section snippets

Case History

The proband was born at 39 weeks' gestation with birth weight 3,120 g. There were no neonatal respiratory or other health concerns. Family members noted that she had rapid breathing in the first weeks of life, and she had trouble breastfeeding. Medical evaluations were prompted at 4 months of age due to failure to thrive. At that time, tachypnea and hypoxemia were prominent, and supplemental oxygen was initiated. There were no symptoms of cough, fever, wheezing, or acute infection. Results of

Genetic Investigations

Based on the apparent autosomal-dominant pattern of disease in this family and the known variability of the lung disease associated with SFTPC mutations, this gene was first sequenced in the proband and her mother, with no mutations identified. With the recent recognition of the potential role of NKX2.1 mutations in causing diffuse lung disease in children, we subsequently sequenced NKX2.1 in the proband and found that she is heterozygous for a G to T transversion in codon 191 of NKX2.1 that is

Discussion

NEHI is a distinct entity with well-described clinical, physiologic, radiographic, and histologic features. The incidence and prevalence of NEHI are unknown, although the disorder is felt to be rare. Although mortality due to NEHI has not been reported, it results in significant morbidity in young children.2, 3, 6 Most children require supplemental oxygen for years, and many need additional nutritional support, including via gastrostomy tube in some cases. Hospitalization and overall

Acknowledgments

Author contributions: Dr Nogee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Young: contributed to study inception and data acquisition and analysis; drafted the manuscript; provided critical input and helped revise the final version of the manuscript; and approved the final version of the manuscript.

Dr Deutsch: contributed to data acquisition and analysis; provided critical input and helped revise

References (48)

  • DE Johnson et al.

    Pulmonary neuroendocrine cells in pediatric lung disease: alterations in airway structure in infants with bronchopulmonary dysplasia

    Anat Rec

    (1993)
  • DE Johnson et al.

    Pulmonary neuroendocrine cells in hyaline membrane disease and bronchopulmonary dysplasia

    Pediatr Res

    (1982)
  • DE Johnson et al.

    Changes in bombesin, calcitonin, and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and after prolonged mechanical ventilation

    Am Rev Respir Dis

    (1988)
  • E Cutz et al.

    Pulmonary neuroendocrine cells and neuroepithelial bodies in sudden infant death syndrome: potential markers of airway chemoreceptor dysfunction

    Pediatr Dev Pathol

    (2007)
  • DG Perrin et al.

    Hyperplasia of bombesin-immunoreactive pulmonary neuroendocrine cells and neuroepithelial bodies in sudden infant death syndrome

    Pediatr Pathol

    (1991)
  • MB Schindler et al.

    Increased respiratory system resistance and bronchial smooth muscle hypertrophy in children with acute postoperative pulmonary hypertension

    Am J Respir Crit Care Med

    (1995)
  • ME Sunday et al.

    Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease

    Lab Invest

    (1988)
  • J Popler et al.

    Familial neuroendocrine cell hyperplasia of infancy

    Pediatr Pulmonol

    (2010)
  • V Kolla et al.

    Thyroid transcription factor in differentiating type II cells: regulation, isoforms, and target genes

    Am J Respir Cell Mol Biol

    (2007)
  • SE Wert et al.

    Genetic disorders of surfactant dysfunction

    Pediatr Dev Pathol

    (2009)
  • JE Bullard et al.

    ABCA3 mutations associated with pediatric interstitial lung disease

    Am J Respir Crit Care Med

    (2005)
  • JE Bullard et al.

    Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation

    Pediatr Res

    (2007)
  • JA Wambach et al.

    Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome

    Pediatrics

    (2012)
  • ED Austin et al.

    Genetics of pulmonary arterial hypertension

    Semin Respir Crit Care Med

    (2009)
  • Cited by (0)

    Funding/Support: This work was supported by grants through the National Institutes of Health [HL54703, Dr Nogee]; American Thoracic Society/chILD Foundation/chILD (Lung) Foundation-UK (Dr Young); and the Eudowood Foundation (Dr Nogee).

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    View full text