Title: Living with Alveolar capillary dysplasia with misalignment of the
pulmonary veins – case report
Authors
Renata Wrobel Folescu Cohen
Instituto Fernandes Figueira IFF/FIOCRUZ Rio de Janeiro, RJ, Brazil
Universidade do Estado do Rio de Janeiro (UERJ) Rio de Janeiro, RJ,
Brazil
Universidade Federal do Rio de Janeiro (UFRJ) Rio de Janeiro, RJ,
Brazil
Universidade do Estado do Rio de Janeiro (UERJ) Rio de Janeiro, RJ,
Brazil
Evanice Lima de Marca
Hospital Pediátrico Jutta Batista, Rede Dor Rio de Janeiro, RJ, Brazil
Universidade do Estado de São Paulo, São Paulo, SP, Brazil
Dafne Dain Gandelman Horovitz
Instituto Fernandes Figueira IFF/FIOCRUZ, Rio de Janeiro, RJ, Brazil
Hospital Pediátrico Jutta Batista, Rede Dor, Rio de Janeiro, RJ,
Brazil
Henrique de Campos Reis Galvão
Diagnósticos da América S.A., DASA, São Paulo, SP, Brazil.
Diagnósticos da América S.A., DASA, São Paulo, SP, Brazil.
Diana Carolina Salazar Bermeo
Diagnósticos da América S.A., DASA, São Paulo, SP, Brazil.
Instituto Fernandes Figueira IFF/FIOCRUZ, Rio de Janeiro, RJ, Brazil
To the editor,
Alveolar capillary dysplasia with misalignment of the pulmonary veins
(ACD/MPV) is a rare and lethal disorder mainly involving the vascular
development of the lungs. The clinical presentation is characterized by
respiratory distress and cyanosis caused by severe pulmonary
hypertension (PH) and insufficient oxygen uptake. 95% of ACD/MPV
patients are born at full term with normal Apgar scores and develop
symptoms within the first 24 hrs of life. In up to 80% of the cases,
associated malformations are found, for which surgery is occasionally
needed1. These malformations predominantly affect the
gastrointestinal tract, but also may affect the cardiovascular and
urogenital systems. The mortality of ACD/MPV is almost
100%1. Atypical, milder cases of ACD/MPV patients
that present after 24 hrs of life or survive beyond the neonatal period
have occasionally been described2. The current gold
standard to unambiguously diagnose ACD/MPV is histological examination
of the lungs. In most studies, cases were diagnosed postmortem by
autopsy3.
It is postulated that the milder phenotype of atypical ACD/MPV patients,
including late presenters and long-term survivors, is correlated with
the extent of affected lung tissue. A recent study showed a
heterogeneous non-uniform distribution of histological findings in all
atypical ACD/MPV patients4.
Recently, Sen et al5 have reported genomic deletions
and point mutations in the FOXF1 gene (OMIM 601089) in chromosome
16q24.1 in unrelated patients with histopathological verified ACD/MPV.
So far, 42 FOXF1 variants and 24 genomic and genic deletions identified
in the 16q24.1 region have been reported. All patients have died in the
first 4 months of life.
This case report describes a patient as a late presenter and long-term
survivor of ACD/MPV with a non previously described de novo variant in
FOXF1. Informed consent statement was obtained from parents. Written
informed consent to participate in this study was provided by the
participant legal guardian. This study was approved by the Instituto
Fernandes Figueira Ethical Committee, under the ethical approval number
59963822.0.2001.5269 (chILD - RJ).
CASE REPORT:
Full-term female born to non-consanguineous parents. GII/PII mother was
38yo and pregnancy was uneventful; Apgar scores 9/10, phototherapy
needed for 4 days due to jaundice. There was no respiratory distress,
nor congenital abnormalities were detected. Pulse oximetry was 98%
(upper end lower limbs), transfontanelle and doppler ultrasound were
normal. Family history negative for congenital cardiac or lung disease.
At nine months she presented cough and wheezing and received salbutamol
and prednisolone at home. At 14mo, there was a new respiratory distress,
with no response to Salbutamol, Prednisolone and antibiotics, requiring
her first ICU admission: Her weight was 8.4kg; pulse oximetry:96% with
oxygen therapy support. She presented increased AP diameter, intercostal
retraction, reduced air flow with crackling sounds in both lungs and
hepatosplenomegaly.
On admission, laboratorial exams revealed: Hb:10.6g/dL; Hto:34%;
RDW:18,4%; platelets:196000/mm3;
WBC:2100/mm3; Reticulocytes:13,4%; Serum
iron:17mcg/dL; Ferritin:24ng/ml; Transferrin:267mg/dL; HIV and
mycoplasma serology were negative. Nasopharyngeal material was negative
for SARASCOV2, RSV, Influenza A and B. Immunoglobulin and lymphocytes
were normal for age.
Echocardiogram presented situs solicitus; levocardia; concordant
atrioventricular and arterial ventricle connections; intact interatrial
and interventricular septa; pulmonary trunks and branches were confluent
and without obstruction; pulmonary venous drainage to the right atrium;
dilation of the right cavities; significant right ventricular (RV)
systolic overload; mild RV systolic dysfunction, normal left ventricular
function. Systolic pressure in the pulmonary artery (SPPA) was 70mmHg.
Inferior vena cava with normal caliber.
Thorax high resolution computed tomography (HRCT) showed extensive
diffuse ground-glass opacity in both lungs (FIG1-A,B). Bronchoscopy
revealed: hyperemia and moderate mucosal edema with thick and yellowish
secretion in the main bronchi. The secretion collected from bronchial
lavage was negative for pyogenic germs, fungi, mycobacteria, andPneumocystis jirovecci. She was discharged home using sildenafil,
captopril, furosemide + hydrochlorothiazide, spironolactone and
carvedilol.
She progressed with worsening respiratory pattern and hypoxemia, being
readmitted at 16mo. New exams showed negative viral and SARSCOV-2 panel;
negative blood cultures; echocardiogram: SPPA 88-100mmHg. Salbutamol,
fluticasone, sildenafil, Captopril furosemide, hydrochlorothiazide,
spironolactone and carvedilol were maintained. A new HRCT scan detected
ground-glass opacities affecting both lungs (FIG1-C,D), with the
appearance of septal thickening and diffuse thickening of the bronchial
walls.
After this, she underwent a lung biopsy and the histopathological report
(FIG2) showed muscular hypertrophy of the middle layer of medium and
small pulmonary arteries; reduction of capillary loops in the
microcirculation along the alveolar septa; ectasia and tortuosity of
pulmonary veins and lymphatics; misalignment of pulmonary veins adjacent
to the terminal bronchiole; discrete inflammatory infiltrate represented
mainly by small lymphocytes; there were no signs of malignancy. Perls
staining was positive for macrophages with hemosiderin. Electron
microscopy showed abnormal lamellar bodies of varying shapes and sizes
with dense inclusions inside. Heteromorphic mitochondria with cristae
fusion. There was no evidence of glycogenosis or storage diseases. No
ciliary abnormalities were detected.
She was discharged with regular monitoring by a pediatric cardiologist
and pulmonologist, and receiving sildenafil, captopril and furosemide,
spironolactone, carvedilol, hydrochlorothiazide, salbutamol and
fluticasone.
In parallel, exome analysis was carried out. A heterozygous variant in
the FOXF1 gene was identified (NM_001451.3: c.359A>T;
p.(His120Leu)), classified as probably pathogenic, considering that the
variant is absent on populational databases, in silico algorithms
predict damaging impact of the variant on protein function, parental
testing for the variant was negative and this indivudual phenotype is
highly specific for the disease.
Thus, the diagnosis of alveolar-capillary dysplasia with misalignment of
pulmonary vessels was confirmed.
During the last two years, she has been receiving the same medication,
and was admitted in hospital por 3 times due to respiratory exacerbation
following viral infection. She needed during admission period, oxygen
supplementation, non invasive ventilation, antibiotics and systemic
corticosteroids. Cardiac catheterization at 3yo showed a high pulmonary
artery pressure (100mmHg) and Bosentana was started after this exam.
CONCLUSION
Infants affected with ACD/MPV usually develop respiratory distress and
severe pulmonary hypertension, have no sustained response to supportive
treatments, and die early in life. Few patients with ACD/MPV have been
reported beyond the neonatal period. One report describing two siblings
shows that a patient with less severe symptoms has a patchy pattern of
capillary deficiency and abnormal distal air space, which may be
correlated with the late onset. All infants with pathogenic/probably
pathogenic variants in the FOXF1 gene, responsible for ACD/MPV, have
died in the first 4 months of life. Our case, however, shows a 3yo girl
with ACD/MPV carrying a de novo variant in FOXF1, which
configurates quite a long survival with ACD/MPV. This is a missense
mutation, absent in population databases with predicted in silico impact
in the protein function. Based in normal parental investigation and
compatible pathologic study, we considered it as phenotype-causing.
Further studies will be needed to clarify the phenotypic difference
between the above patient and the previously reported cases. Although
phenotypical differences are present, genetic testing could contribute
to earlier detection and allows adequate consultation about the
prognosis and the process of decision-making.