This infant with cerebral dysgenesis, thyroid hemiagenesis, euthyroid sick syndrome, respiratory insufficiency, and a haploid interstitial deletion of 14q12–21.3 encompassing the TTF-1 gene locus is presumed to have had TTF-1 deficiency syndrome. More than half of the 46 patients reported with this syndrome had pulmonary disease, most often manifesting in the neonatal period as respiratory distress syndrome requiring mechanical ventilatory support (9
). Recurrent pulmonary infection was another common manifestation, with some patients developing chronic interstitial lung disease (9
). Several died from respiratory failure at various ages and one young adult died with metastatic lung carcinoma (5
The pulmonary pathology in this syndrome has been illustrated in only one case report and briefly noted in another (10
). The first describes a term infant who developed acute respiratory failure and pulmonary hypertension at birth and died at 40 days. The lungs at autopsy showed impaired pulmonary branching with simplification of the architecture and a low alveolar count. Fibrous thickening of septa and alveoli filled with macrophages were interpreted as suggestive of surfactant insufficiency (11
). The second report describes a term infant who developed respiratory distress beginning in the second week of life (10
). At 11 months, a lung biopsy showed interstitial fibrosis, chronic inflammation, and alveoli filled with macrophages and PAS-positive material, and a diagnosis of alveolar proteinosis was rendered. This child developed restrictive chronic lung disease, had recurrent pulmonary infections, and died at the age of 23 years with metastatic pulmonary large cell carcinoma. The lungs at autopsy also had interstitial fibrosis and severe emphysema.
The pulmonary disease in the infant in our report is unusual in several aspects. First, being near-term, his risk of developing HMD was low and yet the initial pulmonary symptoms, chest radiograph, and improvement with surfactant administration were consistent with mild HMD. Second, although the subsequent clinical course bore some similarity to CLD/BPD, the level of ventilatory support he received does not usually result in CLD/BPD. Third, the CT scan in this infant was most notable for bilateral, discrete “cysts” predominantly posteriorly and symmetrically distributed, unlike the irregularly distributed emphysematous change without cysts in CLD/BPD. Last, the pathologic features were also unusual. Although enlarged alveoli were reminiscent of those seen in CLD/BPD, there was more variation in size and many were exceptionally large, round, and cyst-like. Simplified and enlarged alveoli as seen in this infant may also be observed in Wilson-Mikity syndrome (20
), Down syndrome (22
), primary pulmonary hypoplasia, and in association with other congenital abnormalities (23
). Wilson-Mikity syndrome was described in preterm infants before the use of mechanical ventilation. In this syndrome, symptoms began after the first week of life and progressed to maximum severity within 2 months, with the majority of infants improving slowly over the ensuing months, unlike the clinical course in this infant. Chest radiographs and pathology in Wilson-Mikity syndrome are believed to be within the spectrum of CLD/BPD (24
TTF-1 has been shown to play an important role in pulmonary branching morphogenesis and surfactant homeostasis. TTF-1 knockout mice have a rudimentary bronchial tree but do not develop lungs (25
). Heterozygous mice appear either unaffected (25
) or have a predominantly neurologic phenotype (6
). However, mice bearing a homozygous mutant allele of TTF-1, in which seven serine phosphorylation sites were mutated, exhibited hypoplastic lungs with dilated or cystic peripheral structures, reduced terminal alveolar saccules, and diminished vasculogenesis, as well as abnormalities in surfactant protein and CCSP expression (26
). TTF-1 is also important for type II pneumocyte differentiation, because it is a major activator of functional lung-specific genes and plays a role in the synthesis and regulation of the surfactant-associated proteins A, B, and C, as well as the phospholipid transporter, ABCA3 (27
), and CCSP (25
The pulmonary morphology in this infant included extensive emphysematous change and cyst-like airspaces, similar to findings in mice bearing homozygous TTF-1 phosphorylation mutations (26
). In addition, the diminished number of airway generations in this infant indicates that branching morphogenesis of the bronchial tree was disrupted, a process that is normally complete by 16 weeks of gestation (17
). Diminished immunoreactivity for SP-A and ABCA3 in this infant's lung, as well as the irregular distribution pattern for SP-B and proSP-C expression, supports experimental observations regarding the role of TTF-1 in type II pneumocyte differentiation and surfactant protein synthesis and regulation (25
). The improvement of symptoms with surfactant administration in this infant and in another child with TTF-1 deficiency (7
) is clinical evidence supporting a surfactant abnormality component. In contrast to genetic disorders of surfactant function (i.e., SP-B and ABCA3 deficiencies), wherein lamellar bodies are reduced, absent, or abnormally formed (30
), or alveolar proteinosis, wherein there is accumulation of phospholipid membranes and abnormal tubular myelin (34
), the ultrastructure of the lamellar bodies in this infant appeared normal and were abundant in alveolar lumens. Tubular myelin was not seen, but is generally not observed in lung specimens routinely examined by electron microscopy (Reference [35
] and personal observations, A.R.P-A.). In this infant the pulmonary morphology and abnormal surfactant protein expression are consistent with TTF-1 deficiency syndrome.
The intensity of TTF-1 protein immunostaining in this infant's lung () was similar to an age-matched control except for the irregular distribution of type II pneumocytes. The detection of TTF-1 is not surprising because in haploinsufficiency, a single allele results in a functional, although reduced, amount of protein with the difference generally not detectable by immunohistochemistry. In humans, heterozygous loss of function of the TTF-1 gene occurs with missense mutations, nonsense mutations, and partial or complete deletions and is associated with varying phenotypes (5
). In some, neurological disease predominates, whereas in others, pulmonary disease is dominant (6
). The phenotypic pulmonary abnormalities resulting from TTF-1 haploinsufficiency appear to vary in severity from minimal to marked. Because TTF-1 regulates the expression of many downstream genes, interactions among these target genes may influence the severity of disease (36
It is not possible to exclude that genes other than TTF-1 encompassed by the chromosomal deletion in this infant might have also played a role in the pathogenesis of the pulmonary disease or other phenotypic abnormalities. For example, the PAX-9 gene, vicinal to TTF-1, which influences the morphogenesis of the vertebral column, limbs, and pharyngeal pouch derivatives (37
), might have played a role in the ear and limb asymmetry, dolichocephaly, abnormal ribs, and intrapericardial thymic tissue observed in this infant.
In conclusion, we describe the pulmonary pathology in an infant with TTF-1 deficiency syndrome. The abnormal pulmonary morphogenesis and altered expression of surfactant-associated proteins parallels that observed in experimental murine TTF-1 haploinsufficiency and may explain the respiratory difficulties in this syndrome.