Alternative titles; symbols
ORPHA: 217563; DO: 12120;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p11.2 | Surfactant metabolism dysfunction, pulmonary, 1 | 265120 | Autosomal recessive | 3 | SFTPB | 178640 |
A number sign (#) is used with this entry because of evidence that pulmonary surfactant metabolism dysfunction-1 (SMDP1) is caused by homozygous or compound heterozygous mutation in the gene encoding surfactant protein B (SFTPB; 178640) on chromosome 2p11.
Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (Clark and Clark, 2005).
A clinically similar disorder characterized by respiratory distress (267450) can affect preterm infants, who show developmental deficiency of surfactant.
Acquired PAP (610910) is an autoimmune disorder characterized by the presence of autoantibodies to CSF2 (138960).
Genetic Heterogeneity of Pulmonary Surfactant Metabolism Dysfunction
See also SMDP2 (610913), caused by mutation in the SPTPC gene (178620) on 8p21; SMDP3 (610921), caused by mutation in the ABCA3 gene (601615) on 16p13; SMDP4 (300770), caused by mutation in the CSF2RA gene (306250) on Xp22; and SMDP5 (614370), caused by mutation in the CSF2RB gene (138981) on 22q12.
Moulton et al. (1992) reported 2 pairs of sibs from 2 unrelated families with neonatal respiratory distress associated with pulmonary alveolar proteinosis beginning within hours of birth. All were full-term infants and 3 had mature lung profiles. Radiographic studies showed an early granular pattern followed by lung opacification. All died within 16 to 190 days. Moulton et al. (1992) postulated an inborn error in surfactant processing.
Nogee et al. (1993) reported a full-term male infant with surfactant metabolism dysfunction and neonatal respiratory failure who died at 5 months despite intensive supportive treatment with mechanical ventilation and corticosteroids. Open-lung biopsy at age 3 months showed pulmonary alveolar proteinosis with alveoli filled with eosinophilic, granular, PAS-positive material. There were also foamy alveolar macrophages, desquamated alveolar epithelial cells, and extensive interstitial fibrosis with hyperplasia of type II alveolar epithelial cells. Nineteen years earlier, a sister born at term died of respiratory failure at age 1 month. Autopsy revealed alveolar proteinosis and changes consistent with bronchopulmonary dysplasia. Immunoblotting showed absence of the surfactant B protein and mRNA in the proband's lungs and increased amounts of surfactant proteins C and A in alveolar epithelial cells. In an addendum, Nogee et al. (1993) noted that a third affected sib had been born into the family. There was no detectable protein B in the amniotic and lung-lavage fluid, but markedly increased amounts of surfactant protein C were present. The parents were unrelated.
Wallot et al. (1999) reported 5 full-term infants, born of a consanguineous kindred of Kurdish descent, who had fatal neonatal respiratory failure shortly after birth. All had pulmonary hypertension and all died despite intensive care. Lung tissue biopsy of 2 infants showed pulmonary alveolar proteinosis. Alveolar walls were thickened with interstitial fibrosis and inflammatory cells and the alveolar spaces were filled with foamy or granular protein-rich exudate and many desquamated cells. Immunostaining of lung tissue demonstrated significantly decreased surfactant SPB and increased SPA (178630) and SPC. One infant also had misalignment of lung vessels, which may have caused pulmonary hypertension. Wallot et al. (1999) noted that the concurrence of misalignment of lung vessels and congenital alveolar proteinosis due to SPB deficiency had not been described before.
Tredano et al. (1999) reported a full-term female infant with severe respiratory failure developing hours after birth. She had deep cyanosis, progressive tachydyspnea, hypoxemia, and diffuse, symmetric lung opacifications on chest x-ray. She was managed by mechanical ventilation, but died at age 27 days. Bronchoalveolar lavage fluid showed complete absence of SPB. However, unlike other patients, pro-SPC was processed to the active peptide.
Yusen et al. (1999) found that heterozygous relatives of surfactant protein B-deficient infants did not have clinically apparent lung disease.
Chetcuti and Ball (1995) reviewed surfactant protein B deficiency.
Dunbar et al. (2000) reported 2 unrelated patients of French Canadian descent with a milder form of pulmonary surfactant metabolism dysfunction. The phenotype of both patients was less severe than that reported in other patients with SPB deficiency. The first child underwent bilateral lung transplant at age 4 months and the second child survived to age 6 years with persistent oxygen requirement. The older child developed pulmonary hypertension and right ventricular hypertrophy. Lung tissue biopsy of both patients showed variable alveolar septal widening with increased cellularity and type II pneumocyte hyperplasia. Alveolar spaces were filled with granular eosinophilic material admixed with foamy macrophages and desquamated pneumocytes. Type II pneumocytes contained numerous abnormal lamellar bodies. Advanced staining techniques identified residual SPB in tissue from both patients, although higher levels were observed for the older patient. Both patients had a homozygous mutation in the SFTPB gene (178640.0005) that resulted in a splice site mutation and residual protein activity. The findings indicated that there may be variability in phenotypic expression of surfactant B deficiency and that those with some residual protein activity may survive past the first months of life.
The transmission pattern of SMDP1 in the families reported by Nogee et al. (1994) was consistent with autosomal recessive inheritance.
In 3 affected sibs with fatal neonatal respiratory failure and surfactant protein B deficiency, Nogee et al. (1994) identified a homozygous mutation in the SFTPB gene (121ins2; 178640.0001). Both unaffected parents and 2 of 3 healthy sibs were heterozygous for the mutation. The same mutation was found in 2 unrelated infants who died from alveolar proteinosis; 1 of these patients was reported by Moulton et al. (1992).
DeMello et al. (1994) identified the 121ins2 mutation in 4 of 7 infants from 6 families with congenital surfactant B deficiency associated with pulmonary alveolar proteinosis.
In an infant with fatal neonatal respiratory distress and pulmonary alveolar proteinosis due to surfactant B deficiency, Wallot et al. (1999) identified a homozygous mutations in the SFTPB gene (178640.0002). The patient was born to consanguineous Kurdish parents and had 4 similarly affected relatives.
In a full-term infant with severe neonatal respiratory distress, Tredano et al. (1999) identified compound heterozygosity for 2 mutations in the SFTPB gene (178640.0001; 178640.0003).
Associations Pending Confirmation
For discussion of a possible association between pulmonary surfactant metabolism dysfunction and variation in the RAB5B gene, see 179514.0001.
Prenatal Diagnosis
Stuhrmann et al. (1998) performed prenatal diagnosis in a family in which congenital pulmonary alveolar proteinosis due to the common 121ins2 mutation in the SFTPB gene had caused the death of an 8-week-old child. Chorionic villus sampling was performed in 2 subsequent pregnancies. DNA analysis revealed homozygosity for the codon 121 mutation in the first fetus, and the pregnancy was terminated. Homozygosity for the parental wildtype alleles was detected in the following prenatal diagnosis, and a healthy child was born.
Surfactant B deficiency is generally not responsive to surfactant therapy, although some patients may show some initial response. Hamvas et al. (1997) reported successful treatment of surfactant B deficiency with lung transplantation in 2 affected infants.
In a review of the disorder, Whitsett and Weaver (2002) stated that approximately 10% of full-term infants who presented with unexplained respiratory failure had mutations in the SFTPB gene.
The incidence of surfactant B deficiency has been estimated at 1 in 1.5 million births (Clark and Clark, 2005).
Teja et al. (1981) reported 4 sibs, including 2 males, with infantile onset of respiratory insufficiency. The parents were second cousins, indicating autosomal recessive inheritance. The 2 girls and 1 of the boys had onset of respiratory insufficiency at the age of 4 to 7 months with death 1 to 3 months thereafter. One of the boys was admitted to hospital at the age of 16 months because of failure to thrive. He was cachectic with clubbing of the fingers. Chest radiographs showed bilateral pulmonary infiltrates with hilar prominence. Remarkably, he survived for the next 17 years with progression of the disorder and fibrosis and honeycombing apparent on radiographic studies, but died at age 19. Open lung biopsies and/or autopsy demonstrated pulmonary alveolar proteinosis in all cases. Although surfactant studies were not reported, the clinical phenotype and mode of inheritance are suggestive of SFTPB deficiency.
Yei et al. (1994) demonstrated transfection of the human SPB gene into rabbit lung endothelium using an adenovirus vector.
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deMello, D. E., Nogee, L. M., Heyman, S., Krous, H. F., Hussain, M., Merritt, T. A., Hsueh, W., Haas, J. E., Heidelberger, K., Schumacher, R., Colten, H. R. Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency. J. Pediat. 125: 43-50, 1994. [PubMed: 8021783] [Full Text: https://doi.org/10.1016/s0022-3476(94)70119-9]
Dunbar, A. E., III, Wert, S. E., Ikegami, M., Whitsett, J. A., Hamvas, A., White, F. V., Piedboeuf, B., Jobin, C., Guttentag, S., Nogee, L. M. Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation. Pediat. Res. 48: 275-282, 2000. [PubMed: 10960490] [Full Text: https://doi.org/10.1203/00006450-200009000-00003]
Hamvas, A., Nogee, L. M., deMello, D. E., Cole, F. S. Pathophysiology and treatment of surfactant protein-B deficiency. Biol. Neonate 67 (Suppl. 1): 18-31, 1995. [PubMed: 7647155] [Full Text: https://doi.org/10.1159/000244204]
Hamvas, A., Nogee, L. M., Mallory, G. B., Jr., Spray, T. L., Huddleston, C. B., August, A., Dehner, L. P., deMello, D. E., Moxley, M., Nelson, R., Cole, F. S., Colten, H. R. Lung transplantation for treatment of infants with surfactant protein B deficiency. J. Pediat. 130: 231-239, 1997. [PubMed: 9042125] [Full Text: https://doi.org/10.1016/s0022-3476(97)70348-2]
Moulton, S. L., Krous, H. F., Merritt, T. A., Odell, R. M., Gangitano, E., Cornish, J. D. Congenital pulmonary alveolar proteinosis: failure of treatment with extracorporeal life support. J. Pediat. 120: 297-302, 1992. [PubMed: 1341413] [Full Text: https://doi.org/10.1016/s0022-3476(05)80448-2]
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Nogee, L. M., Garnier, G., Dietz, H. C., Singer, L., Murphy, A. M., deMello, D. E., Colten, H. R. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J. Clin. Invest. 93: 1860-1863, 1994. [PubMed: 8163685] [Full Text: https://doi.org/10.1172/JCI117173]
Stuhrmann, M., Bohnhorst, B., Peters, U., Bohle, R. M., Poets, C. F., Schmidtke, J. Prenatal diagnosis of congenital alveolar proteinosis (surfactant protein B deficiency). Prenatal Diag. 18: 953-955, 1998. [PubMed: 9793979] [Full Text: https://doi.org/10.1002/(sici)1097-0223(199809)18:9<953::aid-pd364>3.0.co;2-j]
Teja, K., Cooper, P. H., Squires, J. E., Schnatterly, P. T. Pulmonary alveolar proteinosis in four siblings. New Eng. J. Med. 305: 1390-1392, 1981. [PubMed: 7300857] [Full Text: https://doi.org/10.1056/NEJM198112033052305]
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Tredano, M., van Elburg, R. M., Kaspers, A. G., Zimmermann, L. J., Houdayer, C., Aymard, P., Hull, W. M., Whitsett, J. A., Elion, J., Griese, M., Bahuau, M. Compound SFTPB 1549C-to-GAA (121ins2) and 457delC heterozygosity in severe congenital lung disease and surfactant protein B (SP-B) deficiency. Hum. Mutat. 14: 502-509, 1999. [PubMed: 10571948] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<502::AID-HUMU9>3.0.CO;2-C]
Tsubura, E., Kawase, I., Yamamura, Y. Hereditary metabolic diseases of the lung. Rec. Med. 26: 1727 only, 1974. Note: Cited by: Webster et al.: Am. J. Med. 69: 786-789, 1980.
Wallot, M., Wagenvoort, C., deMello, D., Muller, K.-M., Floros, J., Roll, C. Congenital alveolar proteinosis caused by a novel mutation of the surfactant protein B gene and misalignment of lung vessels in consanguineous kindred infants. Europ. J. Pediat. 158: 513-518, 1999. [PubMed: 10378403] [Full Text: https://doi.org/10.1007/s004310051132]
Whitsett, J. A., Weaver, T. E. Hydrophobic surfactant proteins in lung function and disease. New Eng. J. Med. 347: 2141-2148, 2002. [PubMed: 12501227] [Full Text: https://doi.org/10.1056/NEJMra022387]
Yei, S., Bachurski, C. J., Weaver, T. E., Wert, S. E., Trapnell, B. C., Whitsett, J. A. Adenoviral-mediated gene transfer of human surfactant protein B to respiratory epithelial cells. Am. J. Resp. Cell Molec. Biol. 11: 329-336, 1994. [PubMed: 8086169] [Full Text: https://doi.org/10.1165/ajrcmb.11.3.8086169]
Yusen, R. D., Cohen, A. H., Hamvas, A. Normal lung function in subjects heterozygous for surfactant protein-B deficiency. Am. J. Resp. Crit. Care Med. 159: 411-414, 1999. [PubMed: 9927351] [Full Text: https://doi.org/10.1164/ajrccm.159.2.9806033]