A 15-month-old boy was admitted to the Pediatric Oncology Unit in January 2020 for several episodes of brief respiratory arrest characterized by cyanosis, limb hypertonia, fixed gaze, altered level of responsiveness and resolution after strong stimulation manoeuvres. The symptoms were noticed by parents one month before the admission, more frequently during sleep. Parents referred also sporadic profuse sweating, and chronic constipation. When the patient was 3-month-old, he was diagnosed with cyanotic breath-holding spells. The mother told us that, after an uncomplicated pregnancy, a Caesarean section was performed due to obstetric problems. Birth weight was 2,750 g. The newborn physical examination revealed monolateral clubfoot, surgically treated in the early months of life.
Clinical Findings
Physical examination upon admission to our unit revealed mild hypotonia. Vital parameters monitoring (heart rate, respiratory rate, blood pressure and oxyhaemoglobin saturation [SO2]) showed apnoeas and desaturation episodes (from 1 to 10 episodes per day) more frequently during sleep (SO2 of 88–89% in ambient air), but also during wakefulness.
Timeline
December, 2019
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First episode of respiratory arrest
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January 3rd, 2020
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Hospitalization and diagnostic assessment
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February 27th, 2020
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Transfer to Bronchopneumology Unit
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Diagnostic assessment
During the respiratory arrests, arterial blood gas (ABG) showed hypoxia and hypercapnia. Blood exams including haematological, liver, pancreatic, thyroid, and renal functional index were unremarkable. Infectious disease tests were negative. Prolonged 8 hours electroencephalography during wakefulness and sleep revealed a diffuse slow pattern that might evoke a reflex anoxic epileptic pattern. Chest X-ray and cardiological evaluation, with electrocardiography, echocardiogram, and 24-hour Holter-ECG revealed no abnormal findings. Brain magnetic resonance imaging showed no abnormalities. Metabolic workup including plasma amino acids and urine organic acids were unremarkable. In order to exclude child abuse, a urine drug test was performed, with negative results. Otorhinolaryngologic evaluation revealed no abnormalities. A 24-hour pH multichannel intraluminal impedance testing showed gastro-esophageal reflux episodes that were not related to the desaturation episodes. Bronchoscopy was performed and revealed an extrinsic compression of the left posterolateral wall of trachea under cricoid narrowing. Chest/neck computed tomography angiography was performed, exhibiting a bovine aortic arch, described as an anatomic variant of human aortic branching without any pathological meaning. Polysomnography (PSG) was performed in order to establish the presence of hypoventilation and sleep-related breathing disorder. It showed rare obstructive apnoeas (obstructive apnoea index, 0.4) and central desaturating apnoeas/hypopneas in rapid eye movement (REM) sleep (central apnoea index 2.7). This evaluation excluded primary pulmonary, cardiac, neurological/oncological, gastroenterological, and metabolic causes of respiratory episodes. After genetic counseling, Chromosomal Microarray Analysis (CMA) and PHOX2B molecular analysis were requested. CMA was normal and PHOX2B analysis did not detect any pathogenic variant. Next Generation Sequencing performed in trio using the Twist Custom Panel (clinical exome – Twist Bioscience), revealed the de novo missense (NM_020630.4:c.2753T>C; NP_066124:p.Met918Thr; rs74799832) variant in the RET gene (Rearranged During Transfection Protooncogene, chr10:43,077,068-43,130,350; GRCh37/hg19, MIM *164761). Heterozygous RET pathogenic variants are associated to Central Hypoventilation Syndrome (MIM # 209880), Medullary thyroid carcinoma (MIM # 155240), multiple endocrine neoplasia IIA (MIM # 171400) and IIB (MIM # 162300) and pheochromocytoma (MIM # 171300). The p.Met918Thr variant can be classified as “Pathogenic” according to the ACMG guidelines assessed with Intervar and Varsome. Considering the correlations between RET mutations and neuroendocrine neoplasia, we performed abdominal ultrasound and neuroendocrine oncological markers resulting normal.
Therapeutic Intervention
The patient started proton pump inhibitor therapy (Lansoprazole 1 mg/kg/die) for one month without significant clinical improvement.
Follow-up and Outcomes
The child was moved to a specialised Bronchopneumology Unit in order to receive the best respiratory care.