IHOP. Birth injury

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Phenotype-Gene Relationships
Location Phenotype Phenotype
MIM number Phenotype
mapping key Gene/Locus Gene/Locus
MIM number
16p13.3 Surfactant metabolism dysfunction, pulmonary, 3 610921 3 ABCA3 601615

Clinical Synopsis Phenotypic Series

A number sign (#) is used with this entry because surfactant metabolism dysfunction-3 (SMDP3) is caused by homozygous or compound heterozygous mutation in the ABCA3 gene (601615) on chromosome 16p13.

For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120).

Clinical Features
Shulenin et al. (2004) evaluated a total of 337 full-term infants with severe neonatal respiratory distress. Most patients were found to have identifiable causes, including malformation, infection, SMDP1 (47 infants, 14%), or SMDP2 (610913) (6 infants). Of 16 patients found to have pathogenic mutations in the ABCA3 gene, 11 died within the neonatal period, 2 died within 3 months of age, 1 died after lung transplantation, and 1 was lost to follow-up. Several of the families were consanguineous and all except 2 patients had a family history of the disease. Histologic findings, when performed, included desquamative interstitial pneumonitis (see DIP; 263000) and pulmonary alveolar proteinosis. Only 1 child, aged 6 years, survived, and she had chronic lung disease; only a heterozygous ABCA3 mutation was identified in this patient.

Kunig et al. (2007) reported a male infant who developed respiratory distress immediately after birth, with severe hypoxemia requiring intubation and mechanical ventilation. Echocardiography revealed a structurally normal heart with bidirectional shunting at the ductus arteriosus and right-to-left shunting at the atrial level, consistent with systemic levels of pulmonary artery pressure. The pulmonary hypertension persisted despite inhaled nitric oxide and high-frequency oscillatory ventilation. Extracorporeal membrane oxygenation (ECMO) was instituted; however, due to continued unresponsiveness over a 10-day period, the therapy was ultimately withdrawn, and the infant died. Chest radiographs early in the patient’s course showed mild parenchymal lung disease inconsistent with the degree of hypoxemia; lung biopsy excluded alveolar capillary dysplasia (265380) but was suggestive of surfactant dysfunction. Electron microscopy of a postmortem lung specimen revealed absence of lamellar bodies, consistent with ABCA3 deficiency.

Molecular Genetics
In 16 racially and ethnically diverse infants with severe neonatal surfactant metabolism dysfunction, Shulenin et al. (2004) identified 12 different homozygous or compound heterozygous mutations in the ABCA3 gene (see e.g., 601615.0001-601615.0006).

In a male infant who died in the neonatal period from surfactant-related respiratory failure, Kunig et al. (2007) identified homozygosity for a missense mutation in the ABCA3 gene (601615.0007). The authors noted that this patient differed from previously reported patients in that he did not present with the typical clinical signs of respiratory distress syndrome; his initial presentation was severe pulmonary hypertension that appeared to be out of proportion to the degree of lung disease.

Kaltenborn et al. (2012) studied the effects of 2 clinically relevant ABCA3 mutations, E292V and Q215K, alone and in combination with respiratory syncytial virus (RSV) infection. The authors noted that E292V has a prevalence of 1:277 in the United States and thus is the most common ABCA3 mutation reported in children (Garmany et al., 2008); the Q215K mutation was reported in a neonate who died of respiratory distress (Brasch et al., 2006). After stable transfection of A549 lung epithelial cells, alveolar type II cells expressing the ABCA3 mutations lost their epithelial cell differentiation and acquired a mesenchymal phenotype, and those effects were potentiated by RSV infection. Kaltenborn et al. (2012) suggested that impairment of epithelial function might be a mechanism by which ABCA3 mutations cause interstitial lung disease.

1. Brasch, F., Schimanski, S., Muhlfeld, C., Barlage, S., Langmann, T., Aslanidis, C., Boettcher, A., Dada, A., Schroten, H., Mildenbreger, E., Prueter, E., Ballmann, M., Ochs, M., Johnen, G., Griese, M., Schmitz, G. Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. J. Resp. Crit. Care Med. 174: 571-580, 2006.

2. Garmany, T. H., Wambach, J. A., Heins, H. B., Watkins-Torry, J. M., Wegner, D. J., Bennet, K., An, P., Land, G., Saugstad, O. D., Henderson, H., Nogee, L. M., Cole, F. S., Hamvas, A. Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediat. Res. 63: 645-649, 2008. [PubMed: 18317237, related citations] [Full Text: Nature Publishing Group]

3. Kaltenborn, E., Kern, S., Frixel, S., Fragnet, L., Conzelmann, K.-K., Zarbock, R., Griese, M. Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation. Hum. Molec. Genet. 21: 2793-2806, 2012. [PubMed: 22434821, related citations] [Full Text: HighWire Press]

4. Kunig, A. M., Parker, T. A., Nogee, L. M., Abman, S. H., Kinsella, J. P. ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn. J. Pediat. 151: 322-324, 2007. [PubMed: 17719949, related citations] [Full Text: Elsevier Science]

5. Shulenin, S., Nogee, L. M., Annilo, T., Wert, S. E., Whitsett, J. A., Dean, M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. New Eng. J. Med. 350: 1296-1303, 2004. [PubMed: 15044640, related citations] [Full Text: Atypon]

▸ Contributors: Marla J. F. O’Neill – updated : 10/2/2013
Creation Date: Cassandra L. Kniffin : 4/10/2007
▸ Edit History: carol : 10/02/2013

▾ Table of Contents for #610921
Phenotype-Gene Relationships
Clinical Features
Molecular Genetics
Phenotypic Series
Clinical Synopsis
Creation Date
Edit History
External Links for Entry:
▸ Protein
▸ Clinical Resources
▸ Animal Models

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About garyskeete

ASHWORTH MEDICINE-Professional Medical Assisting, Doctor of Science,Legal Assistant Diploma BSc Criminal Justice PhD Computational Neuroscience MD DSC Epigenetics
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