Inherited disorders of pulmonary surfactant metabolism due to recessive loss-of-function mutations in the genes encoding surfactant protein-B (SP-B, MIM #178640) and the ATP binding cassette family member A3 (ABCA3, MIM #601615) present as lethal surfactant deficiency in the newborn period (1
). Approximately 35 loss of function mutations have been identified in the SP-B gene (SFTPB
, NCBI gene ID: 6439) which is localized to chromosome 2p12-11.2, and over 150 loss of function mutations have been identified in the ABCA3
, (NCBI gene ID: 21), which is localized to chromosome 16p13.3 [(3
) and unpublished data]. All previously reported cases have resulted from homozygous or compound heterozygous expression of the mutated alleles, and either confirmed or assumed to be inherited from each parent, in which case a 25% risk of recurrence would be predicted. Alternative mechanisms of inheritance have not been previously reported.
Uniparental disomy (UPD) occurs when a chromosome pair is inherited from only one parent. It is termed isodisomy when a single parental chromosome is duplicated and is termed heterodisomy when both copies of a single chromosome pair are present. Segmental uniparental iso- or hetero- disomy results from crossing over between a single chromosome pair. The frequency with which UPD occurs is probably rare, and any estimates are likely to be biased by ascertainment (7
). Cases of maternally derived UPD most commonly involve chromosomes 7, 14, 15, and 16 and are identified more frequently than cases of paternally derived UPD, which most often involve chromosomes 6 and 15 (extensive reviews of UPD can be found in References 7
). No specific phenotype has been directly attributed to uniparental disomy for chromosomes 2 or 16, however, single gene defects that become manifest through reduction of a recessive allele to homozygosity have been reported (9
). In this report, we describe the first cases of inherited surfactant deficiency resulting from uniparental disomy.
Patient with SP-B deficiency
This 3.0 kg term male infant was the first child of non-consanguineous parents born via Cesarean for fetal distress after an uneventful pregnancy. Apgar scores were 6 and 9 at 1 and 5 minutes, respectively. The child developed respiratory distress with diffuse haziness on chest radiograph. He required intubation within 24 hours of age and received surfactant with a transient improvement in oxygenation. He received additional surfactant at 5 and 6 days with limited response, and thus proceeded to lung biopsy at 8 days of age. A persistent pneumothorax following the biopsy prompted three attempts at pleurodesis with tetracycline. Due to progressive respiratory dysfunction, he subsequently required high frequency ventilation and neuromuscular blockade. There was no response to administration of granulocyte-macrophage colony stimulating factor or hydroxychloroquine. Immunohistochemical analysis of the lung biopsy revealed absence of SP-B and intra-alveolar accumulation of pro surfactant protein-C (SP-C), and genetic analysis revealed that he was homozygous for the g.1549C>GAA (121ins2) mutation in SFTPB
). The infant progressively deteriorated and expired at 30 days of age. The parents are of Western European descent and the family history is negative for respiratory disease.
Patient 1 with ABCA3 deficiency
This 3.7 kg term male infant was born to a 27 year old Gravida 3 with an uneventful pregnancy and delivery. Apgar scores were 8 and 8 at 1 and 5 minutes, respectively. The child developed respiratory distress with diffuse haziness on chest radiograph and required intubation at approximately 36 hours of age, coincident with development of a pneumothorax requiring thoracostomy tube placement. Due to progressive respiratory dysfunction, he subsequently was managed with inhaled nitric oxide and high frequency ventilation. Open lung biopsy performed at 13 days of age revealed pneumocyte hyperplasia and finely granular intra-alveolar eosinophilic material, consistent with a disorder of surfactant metabolism. With electron microscopy, dense inclusions within the lamellar bodies were identified, as reported previously with ABCA3 deficiency (4
). Sequence analysis of ABCA3
revealed a novel homozygous A>G transition in the second nucleotide of codon 914 (c.2741A>G) that changes lysine to arginine (p.K914R) and is predicted to be “not tolerated” by SIFT (http://blocks.fhcrc.org/sift/SIFT.html
) and “potentially damaging” by Polyphen (http://genetics.bwh.harvard.edu/pph/
). This variant has not been identified in over 600 non-ethnically matched chromosomes that have been evaluated through ongoing analyses in our laboratories. Continuing deterioration and the likelihood that the respiratory process was irreversible prompted listing for lung transplantation at 3 months of age; lung transplantation was performed at 5 months of age.
Two older siblings from a previous marriage are healthy. There was no history of consanguinity: the mother is of Mexican ancestry, the father is of Mexican and Irish ancestry. The family history is negative for respiratory disease.
Patient 2 with ABCA3 deficiency
This 3.3 kg term female infant was born to a 29 year old prima gravida via elective Cesarean. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively and she was discharged after an uneventful hospital course. Over the first 2 weeks, she exhibited poor weight gain and developed pallor and hypoxemia, which prompted hospitalization. Chest radiography and computed tomography demonstrated interstitial infiltrates; the hypoxemia improved with nasal cannula oxygen. Lipid laden macrophages in bronchoalveolar lavage fluid prompted evaluation for aspiration as well as disorders of surfactant metabolism. Deteriorating gas exchange and increasing infiltrates on chest imaging prompted fundoplication and gastrostomy tube placement at 5 weeks of age, following which she was unable to be extubated. Progressive respiratory dysfunction necessitated high frequency ventilation; corticosteroids and hydroxychloroquine failed to provide any improvement in gas exchange. Sequence analysis of ABCA3
revealed a homozygous C>T transition in codon 147 that changes a proline to leucine (c.440C>T; p.P147L) and is predicted to be deleterious by SIFT and Polyphen. This variant was previously identified in two unrelated subjects with respiratory dysfunction and another deleterious mutation in ABCA3
) and unpublished data]. Continuing deterioration and the likelihood that the respiratory process was irreversible prompted listing for lung transplantation at 2 months of age; lung transplantation was performed at 3 months of age.
There is no history of consanguinity: the mother is of German descent and the father is of German and Native American descent. The family history is negative for respiratory disease.
Patient 3 with ABCA3 deficiency
This 3.8 kg term male infant was born to a 25 year old Gravida 2 via elective Cesarean for pregnancy-induced hypertension and footling breech. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. He rapidly developed respiratory failure and required intubation and surfactant administration. Chest radiograph demonstrated bilateral streaky infiltrates. He was briefly extubated at 24 hours of life, but developed a pneumothorax that required thoracostomy tube placement, re-intubation, and high frequency ventilation. He had transient responses to repeated surfactant and corticosteroid administration, but each subsequent course was less effective. Sequence analysis of ABCA3 revealed a homozygous 3 nucleotide insertion in exon 8 (c.806_807insGCT). This finding prompted discussions regarding lung transplantation, which ultimately the parents declined and the infant expired at 6 weeks of age.
An older sibling is healthy. There is no history of consanguinity: the parents are of Western European descent. The family history is negative for respiratory disease.