Thrombospondin domain1-related congenital chylothorax in an infant with maple syrup urine disease: a challenging case

Case presentation

A male infant was born, at 34 6/7 weeks of gestation to a consanguineous couple. The mother was gravida 8, para 3 and abortion 4. Two older siblings have MSUD and one has genetically proven brittle cornea syndrome with high myopic astigmatism.

The prenatal scan at 33+6 gestation showed moderate to severe bilateral pleural effusion more on the right side, a rim of abdominal ascites, skin edema of <2 cm, slightly dilated third ventricle, echogenic bowel and an amniotic fluid Index of 19 cm.

He was delivered via a spontaneous vaginal delivery weighing 2.77 kg (>50th centile), and APGAR scores of 8 and 9 at 1 and 5 min respectively. He had weak cry but soon developed severe respiratory distress. He required intubation after which he was shifted to the Neonatal Intensive Care Unit (NICU). Physical examination at birth revealed a newborn appropriate for gestational age, head circumference: 33 cm (50th centile), length 49 cm (above the 50th centile). There were no obvious dysmorphic features, normal anterior fontanel, mild skin edema, no murmurs, and decreased air entry bilaterally. He had no organomegaly, and normal male genitals.

Chest X-ray showed bilateral pleural effusions, more prominent on the right side (Figure 1). Bilateral Chest tubes were inserted. Initial pleural fluid analysis showed a picture suggestive of chyle with 100% lymphocytosis, no growth or microorganisms seen, and triglycerides level 0.3 mmol/L.

Figure 1:

Chest X-rays.

(A) Chest X-ray on day one of life showing bilateral pleural effusion. (B) Chest X-ray after bilateral chest tubes insertion.

At 12 h of life, he developed hypotension and desaturation with significant pre- and post-ductal difference in SpO₂, needing 100% O₂. He received a dose of surfactant. Echocardiogram revealed severe pulmonary hypertension, large patent ductus arteriosus (PDA) 4 mm, and aneurysmal atrial septal defect (ASD), both of which with right to left shunt. He received fluid boluses and started on inhaled nitric oxide (iNO) and sildenafil for severe pulmonary hypertension. He received two inotropes for hemodynamic instability. Chest tubes continued to drain significant amount of chyle, which contributed to coagulation derangement and gastric bleeding, which were treated with vitamin K and multiple transfusions of fresh frozen plasma (FFP). Coagulopathy is postulated to be due to loss of coagulation factors in chyle [9].

Due to family history of MSUD, plasma amino acids profile was sent. On the second day of life, leucine was 228 μmol/L (reference range, 45–160), and alloisoleucine was 11 μmol/L (normally <5), confirming a diagnosis of MSUD. Repeat plasma amino acids profile on the fifth day of life revealed leucine of nearly 900 μmol/L with alloisoleucine of 50 μmol/L. Total parental nutrition (TPN) could not be started due to unavailability of BCAAs-free TPN. During this period, he received intravenous dextrose to maintain glucose infusion rate (GIR) of 10 mg/kg/h. Once the hemodynamic instability improved, MSUD Anamix infant formula (leucine, isoleucine and valine free formula) was commenced and gradually the volume was built up as per tolerance. Pleural fluid changed to milky color after starting enteral feeds and triglycerides levels in pleural fluid subsequently increased to 1.5 mmol/L. The nutritional management of MSUD contributed to significant challenge in the management of congenital chylothorax in the infant due to significant high content of long-chain triglycerides in MSUD Anamix infant formula which contributed to continued large volumes of chyle drainage. Octreotide infusion was started at a dose of 1 μg/kg/h, and gradually increased up to 3 μg/kg/h, which resulted in significant gradual improvement in volumes of chyle drainage. Low fat normal infant formula, rich in medium chain triglycerides (MCT) could not be used initially owing to the content of leucine in natural protein sources. However, once leucine was within therapeutic targets, natural protein source to provide daily requirements of BCAAs was added to MSUD Anamix using Monogen formula (low fat, MCT-rich infant formula).

Given the rarity and complexity of the chylothorax encountered, Whole Exome Sequencing (WES) was outsourced to Medical Neurogenetics. MSUD was attributed to homozygous c.663_670del (p.Lys222asnfs*56) in DBT. Interestingly, he was also found to have a homozygous likely pathogenic c.1322_1329del (p.Arg441Glnfs*66), identified in THSD1 gene. This variant is the deletion of eight base pairs starting at nucleotide position 1322, which is predicted to result in a change of the amino acid at position 441 from an arginine to a glutamine and a shift in the reading frame thereafter. A termination or STOP codon is predicted 65 amino acids beyond this change. The available data justify the classification as likely pathogenic.

The infant continued to have a stormy and prolonged course in the NICU, systematically summarized as follows (Figure 2):

Figure 2:

Timeline of major events in patient’s progress during NICU stay.

Persistent pulmonary hypertension (PPHN) clinically improved on sildenafil and inhaled nitric oxide (iNO), which was weaned off after 3 days with maximized medical and supportive care for chylothorax (chest tube drainage, octreotide, sildenafil, adding low fat formula to MSUD Anamix), chylothorax eventually improved. However, three attempts to wean off octreotide resulted in recurrence and recollection of pleural fluids needing chest tube draining; hence octreotide was continued subcutaneously at dose of 10 μg/kg/dose Q8hr along with enteral sildenafil.

His course was complicated with multiple episodes lung collapses and air leaks (Figure 3), and chronic lung disease (Figure 4). Two attempts of extubation failed due to severe respiratory distress, respiratory failure and chest X-ray showing lung collapses despite maximum non-invasive positive pressure ventilation and pre-extubation course of dexamethasone and diuretics. As a result of continued dependence on positive pressure ventilation, decision was made to resort to tracheostomy to continue ventilatory support. After tracheostomy, he was gradually transitioned to pressure support ventilation and subsequently, he was gradually transitioned to home respiratory support via tracheostomy. After transition to home ventilation, initially he required high ventilatory parameters which were gradually weaned to lower settings.

Figure 3:

Chest X-rays (CXR) at different stages of infant’s course.

(A) CXR at day 7 of life showing right-sided pneumothorax despite off chest tube in situ. (B) and (C) CXRs at day of life 9 and 10, respectively, showing right upper lobe collapse and pneumothorax. (D) CXR at 5 months of age showing tracheostomy in situ, small right upper lobe atelectasis and right lower lobe cystic changes of chronic lung disease.

Figure 4:

Computed tomogram scan of chest at about 3 months of age showing evidence of chronic lung disease changes.

(A) Coronal view. (B) Axial view.

Brain ultrasound on day of life two was normal. MRI brain at 3 weeks of age showed mild symmetric prominence of lateral ventricles and signal changes in keeping with MSUD. Of note, at about 5 month of age the patient was noted to have a well-defined 3 × 4 cm flat erythematous, blanchable patch on the lumbar region, suspicious of nevus/capillary malformation. MRI of spine showed sacral spina bifida occulta with incomplete closure of the osseous tissue posterior laminae at S3-S5.

He was eventually discharged from the hospital at 5 month of age on home BiPAP ventilation via tracheostomy: inspiratory positive airway pressure (IPAP) 12 cmH₂O, expiratory positive airway pressure (EPAP) 6 cmH₂O with rate of 25/min, off oxygen (which he tolerated very well), sildenafil, subcutaneous octreotide Q8hly, and full enteral feeds of MSUD Anamix mixed with Monogen, with BCAAs within therapeutic range. With optimal management of bronchospasm with inhaled corticosteroids; budesonide and leukotriene receptor antagonist; montelukast, prevention of aspiration with NGT feeding for swallowing incoordination and anti-reflux medication, good tracheostomy care and chest physiotherapy, there is significant decline in exacerbation and hospitalization secondary to respiratory illness. Currently, he is able to be off respiratory support for total of 3 h duration while awake. Up until the ag e of 19 months, he had no acute metabolic decompensations requiring hospital admission. His leucine level in plasma ranged between 2 μmol/L to 1,029 μmol/L over the past 18 months, with a median of 92 μmol/L. Screening developmental assessment at the age of 19 months revealed developmental age of 12–14 months. At the age of 19 months, he was proportionately thriving, with weight of 10.5 kg (28th centile), length of 82 cm (29th centile), and head circumference of 47 cm (33rd centile).