Non-Invasive Diagnosis of Alveolar Capillary Dysplasia on ECMO utilizing Whole Exome Sequencing: A Case Report

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ESPR474
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History

Male infant delivered via cesarean section at 36+1 weeks to a 27-year-old G2P1 mother with a history of cholestasis and polyhydramnios due to non-reassuring fetal heart tracings. APGARS 6 and 8 at 1 and 5 minutes respectively with infant requiring positive pressure ventilation for decreased tone and poor respiratory effort. He required intubation and quickly escalated to high frequency oscillatory ventilation due to hypoxic respiratory failure and persistent pulmonary hypertension of the newborn (PPHN). Bilious replogle output was also noted. He was transferred to our tertiary institution for management of hypoxic respiratory failure and possible gastric outlet obstruction.

In spite of maximum medical therapy, infant's clinical status deteriorated with oxygenation index >30 on inhaled nitric oxide and multiple inotropes, leading to veno-venous ECMO (VV-ECMO) cannulation. Infant continued with supra-systemic right ventricular (RV) pressures on VV-ECMO and evolving RV dysfunction requiring sildenafil, aprostadil to offload the RV and trepostinil as adjunct therapies. 

There was no pertinent family history.


Admission Physical Examination

Vital Signs: Temp (C): 37.9     HR: 190  RR: 51. BP: 92/34.    SpO2: 88% on FiO2 100%

Weight: 2616g (25-50%)                  

Length: 47cm (25-50%)      

Head Circumference: 34cm (50-75%)

Physical examination revealed a pale, intubated and sedated infant with slightly low set ears and widely spaced nipples. Breath sounds were clear and equal bilaterally.  Heart sounds were normal with no murmurs. Replogle in-situ draining bilious output, nontender, and non-distended abdomen with hypoactive bowel sounds and umbilical lines in place. Hypotonic with mild sandal gap deformity of toes.


Investigations

Complete blood count:

WBC 16.6 x10-3 cells/mcL (6-18)

Hb 12.1 g/dL (10.6-16.4)

Hct 35.9% (32-50)

Platelets 167 x 10-3 cells/mcL (150-450)


Basic metabolic profile

Na 140 mmol/L (134-142)

K 3.3 mmol/L (3.5-5.6)

Cl 113 mmol/L (96-110)

CO2 15 mmol/L (20-28)

BUN 11 mg/dL (4-14)

Creatinine 0.91 mg/dL (0.2-0.4)

Glucose 133 mg/dL (70-105)

Calcium 7.6 mg/dL (8.9-10.5)

Ionized calcium 1.10 mmol/L (0.95-1.5)


On admission:

Arterial Blood gas: pH: 7.37 pCO2: 27 pO2: 44 Bicarbonate 16 Base deficit -8 Lactate: 4.0 mmol/L

Oxygenation Index: 31.8   

A-a gradient: 665.6


Prior to ECMO:

Arterial Blood gas (on HFOV and iNO 20ppm): pH: 7.17 pCO2: 44 pO2: 30 Bicarbonate 16 Base deficit -12 Lactate: 2.9 mmol/L

Oxygenation Index: 53.3

A-a gradient: 677.5


Chest and abdomen radiograph: Pneumomediastinum with bilateral haziness of both lung fields and a large gastric bubble with no distal air (Figure 1).


Echocardiogram DOL1 (pre-ECMO cannulation):Large primum atrial septal defect. Small, inlet ventricular septal defect. Moderate patent ductus arteriosus with unrestrictive, bidirectional shunt.The right ventricular systolic pressure (RVSP) estimate is 85 mmHg + the right atrial pressure. (BP=75/53). Mildly dilated main pulmonary artery.The branch pulmonary arteries measure small for patient's body surface area.Moderately dilated and mildly hypertrophied right ventricle with mildly decreased systolic function.Preserved left ventricular systolic function with abnormal interventricular septal motion.


Interval Echocardiograms: DOL 3- RVSP estimate is 63 mmHg + the right atrial pressure, qualitatively decreased right ventricular systolic function with normal left ventricular systolic function

DOL 8- RVSP estimate is 117 mmHg + the right atrial pressure

DOL 11- RVSP estimate is 70 mmHg + the right atrial pressure

DOL 12- RVSP estimate is 111 mmHg + the right atrial pressure


Chest Computed Tomography Angiography: Asymmetric enlargement of the main pulmonary artery, withrelatively smaller caliber of the right and left pulmonary arterial branches (left smaller than right). Left sided and tortuous origin of the right pulmonary artery. Diffuse lung haziness, related to residual pulmonary edema with dependent atelectasis.


Renal ultrasound: Bilateral pelvocaliectasis and ureterectasis with a suggestion of thickening of the bladder wall.


Whole Exome Sequence: Denovo Heterogenous FOXF1 deletion.


Final Diagnosis

Alveolar Capillary Dysplasia 


Discussion

Alveolar Capillary Dysplasia (ACD) is a rare, lethal, neonatal developmental lung disorder which typically presents in the first 48 hours of life with severe hypoxemia and refractory persistent pulmonary hypertension. The true incidence of ACD is unknown with a slight male predominance (60%) in reported cases. 

Pathogenesis is not fully understood, though postulated theories include; failure of fetal lung vascularization in response to an unknown teratogen, early prenatal insult leading to deficient pulmonary capillary bed and a possible genetic mechanism. 

There are no known prenatal risk factors and neonates often present with PPHN, cyanosis and respiratory insufficiency which quickly progresses to fulminant respiratory failure. Distinguishing ACD from other causes of PPHN is extremely difficult in the initial period. Evaluation for ACD is essential for all infants with unfavorable responses to mainstay therapies for PPHN, especially those whose symptoms recur following successful weaning from ECMO, as seen in our patient.

ACD is associated with extrapulmonary findings which are present in 50-80% of cases. Most commonly implicated are the gastrointestinal, genitourinary and cardiac systems. Gastrointestinal manifestations include atresias, intestinal malrotation, omphalocele and annular pancreas. Urogenital anomalies include bilateral ureteropelvic junction obstruction with hydronephrosis, posterior urethral valves, bladder hypertrophy, bicornuate uterus and cryptorchidism. Cardiovascular anomalies include hypoplastic left heart syndrome, patent ductus arteriosus, atrial septal defect, bicuspid aortic valve and absent right umbilical artery.  Our patient exhibited a number of extrapulmonary manifestations, such as bilateral hydronephrosis, atrial septal defect, patent ductus arteriosus and concern for duodenal atresia.

The gold standard for diagnosis is the histologic examination of lung tissue, with approximately 90% of diagnoses made on autopsy. Early diagnosis is vital in these cases to avoid prolonged invasive, futile and costly interventions unlikely to alter the prognosis or clinical course of disease. Surgical biopsy can yield a diagnosis; however, it is often risky especially while on ECMO and usually deferred in critically ill neonates like our patient. Early suspicion with timely genetic testing, as in our case, can play a pivotal role in the management of affected infants without the added risks imposed by transportation and/or surgery while on ECMO. The FOXF1, FOXC2 and FOXL1 genes on chromosome 16q24.1-q24.2 have been implicated in the pathogenesis of ACD. In this case, with the multiple extrapulmonary manifestations, unremitting PPHN, exclusion of other differentials and a high index of suspicion for ACD, expedited whole exome sequence with targeted gene testing was sent early in the ECMO course and diagnosis was confirmed without open lung biopsy. The patient was successfully decannulated after 10 days on ECMO, however, died at 41 days of life despite continued medical management with pulmonary vasodilators given fatal condition. 





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St Christopher's Hospital for Children
St Christopher's Hospital for Children
Drexel University College of Medicine/St Christopher's Hospital for Children
Drexel University College of Medicine/St Christopher's Hospital for Children

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