A 3.5-year-old girl freshly diagnosed with CCHS was transferred to our hospital for further evaluation. The girl was born at term by cesarean section from healthy non-consanguineous parents. She developed respiratory insufficiency during the first hours of life requiring constant lung ventilation. Extubation attempts were unsuccessful due to bradypnea (10–15 breaths per minute), desaturations (SpO2 up to 60%–75%), and hypercapnia (values are not available) during sleep. After one of the extubations, lung bleeding occurred, and arteriovenous malformation S4 of the left lung was diagnosed on a CT scan. The girl developed clonic seizures at the age of 3 months, which resolved after phenobarbital administration. She required prolonged ventilation, extubation attempts were still unsuccessful, with an episode of cardiorespiratory arrest, and was tracheostomized at the age of 4 months. Subsequently, being undiagnosed, the girl was not ventilated appropriately with long periods of self-breathing during sleep, which resulted in desaturations. Decannulation to mask ventilation at 36 months failed due to intolerance, followed by re-tracheostomy. The spontaneous breathing during sleep was insufficient; however, ventilation was still sporadic. The girl suffered frequent pneumonias and tracheitis with purulent bloody sputum. On echocardiography, ventricular septal defect, 4 mm atrial septal defects, and coronary right ventricular fistula (CAF) were diagnosed, and considered hemodynamically nonsignificant. However, chronic heart failure developed: dilation of the right chambers of the heart, right ventricle hypertrophy, pulmonary hypertension (calculated systolic pressure in the right ventriculum 70 mmHg), hepatomegaly developed by the age of 18 months, and ejection fraction was 64%–72% by Teichholz. By the age of 42 months, ejection fraction decreased to 49% and ascites developed. Episodes of sick sinus and atrioventricular dissociation with bradycardia (37–51 beats per minute, pauses up to 2,255 ms) were first diagnosed at the age of 19 months. At further evaluations, heart rhythm improved; however, episodes of bradycardia during daytime persisted. The girl suffered constipation since birth and megacolon or dolichosigma was suspected due to ultrasound and irrigography findings. Apart from that, thrombocytopenia persisted (80–124 × 10 × 9/L at 12–36 months). At the age of 42 months, first episode of hypoglycemic seizures took place (blood glucose level 1.38 mmol/L, sodium 120 mmol/L, and chloride 77 mmol/L). Genetic test was done only at the age of 3.5 years. Initially, a blood sample of the patient was sent to a commercial genetic testing laboratory for whole-exome sequencing (WES) analysis. WES was carried out using SureSelect All Exon V7 target enrichment kit (Agilent Technologies, CA, United States) and Illumina NovaSeq 6000 instrument with average target region coverage of ∼170× (98.8% of targeted nucleotides with coverage >10×). The laboratory provided us with a report with WES results including genetic variants possibly related with the clinical phenotype and secondary incidental findings in genes recommended by the ACMG (). Based on WES data, the girl has a missense variant of uncertain significance—chr19:g.38993563 G>C, NM_000540.3:c.7879G>C (p.Val2627Leu) (rs914804033)—in RYR1 gene, in which pathogenic variants are known to be associated with malignant hyperthermia susceptibility (OMIM # 145600) but seemingly not with a CCHS condition. Moreover, WES allowed us to reveal a rare genetic variant in cardiac homeobox gene NKX2-5: chr5:g.172661909 C>G, NM_004387.4: c.178G>C, (p.Glu60Gln), (rs766199339). Notably, no PHOX2B variations were mentioned in the report. Then, PHOX2B sequencing was performed in the Research Centre for Medical Genetics, Moscow; afterward, results were validated in our institution by bidirectional Sanger sequencing. The sequencing procedure was carried out using the BigDye Terminator Sequencing Kit (Applied Biosystems) and Genetic Analyzer AB3100 (Applied Biosystems/Hitachi, Japan). The primers were designed using the NCBI Primer Blast tool (Gene ID: 8929, NG_008243.1; exon 1: F 5′-AATTTTGTTGGCGGTTCGGG-3′, R 5′-TAGGCTCTGCTGGTAGTAAGGA-3′; exon 2: F 5′-AATCCAGTATTTCTGATCGGCCA-3′, F 5′-TGAAAGCACTATCTCAAGTCCGT-3′; exon 3a F 5′-CATACTGCTCTTCACTAAGGCG-3′, R 5′-GAGGGTGTTAAAACAAGCCGA-3′; exon 3b F 5′-GGCCCTCAATGAAAAAGCCA-3′, R 5′-TCCTCGGGCAAAAAGTCTGA-3′). Target sequencing of PHOX2B protein-coding regions allowed us to identify a novel heterozygous genetic variant in the exon 3: NM_003924.4: c.735_791dup, (p.Ala248_Ala266dup) (). The 57-bp duplication corresponds to 13 GCN (alanine) repeats plus 6 adjacent amino acids (Gly-Gly-Leu-Ala-Ala-Ala). It represents a non-frameshift duplication leading to the protein elongation (+19 amino acids). Both clinically healthy parents demonstrated a normal PHOX2B sequence. After the diagnosis had been made at the age of 44 months, the girl was transported to our hospital. By admission, she was ventilated through a tracheostomy tube 3–5 h per night followed by awakening and subsequent unsuccessful attempts to resume ventilation caused by overventilation in REM sleep. The girl's height was 87 cm (−3.14 SD), weight was 11 kg (−2.55 SD), and weight-to-height ratio was −0.89 SD. Respiratory support was adjusted under tcCO2 monitoring: ST rate 25/min, Pi 15 cm Н2О, Pimax 21, EPAP 5 сm Н2О, FiO2-21%, Tin-0,7 s. The vital need for mechanical ventilation during sleep was explained to the parents. Echocardiography showed muscular ventricular septal defect (2 mm), atrial septal defect (2–3 mm), ejection fraction of 62.5% (by Teichholz), and systolic pulmonary artery pressure of 36 mmHg. On 48-h Holter ECG, heart rate appeared normal, but there was sinus arrhythmia with pauses up to 1,248 ms, QTc prolongation up to 511 ms, and a decrease in heart rate variability with no nighttime increase in the high-frequency component of variability. Ophthalmologic examination discovered divergent alternating strabismus OU and retinal angiopathy OU. Neurologic status was as follows. The girl maintained head upright all the time, sat and stood without support, walked independently well, kicked a ball forward, and threw a ball over hand. The girl could not run, jump, and walk upstairs. Her understanding of the addressed speech was full. She used pincer grasp, held the pen, but could not copy shapes (circle, square, etc.) or imitate vertical line. Denver Developmental Screening test at age of 4 years showed MQ = 0.62 (N ≥ 0.75) and DQ = 0.57 (N ≥ 0.7). Her cranial innervation was intact. She had muscle hypotonia, with muscle strength of 5 points in limbs according to the MRС scale (Medical Research Council scale for power of muscle), valgus flat foot. Tendon reflexes were normal. There were no meningeal and cerebral symptoms. Hirschsprung's disease was suspected due to chronic constipation, an increase in the volume of the abdomen (). Irrigography showed narrowing of the rectum and sigmoid colon with pronounced suprastenotic expansion (). A laparoscopy with a biopsy of the colon was performed, histology showed aganglionosis, which indicates Hirschsprung’s type I disease. A colostomy was done on the descending colon. After the surgery, bloating decreased, and ventilation improved. Five months later, the girl was readmitted. Her height was 89 cm (−3.21 SD), weight was 14.25 kg (−0.9 SD), and weight-to-height ratio was +1.67 SD. LS Swenson pull-through was performed. After surgery, the ventilation settings were adjusted with the lower settings needed during REM sleep. Heart rate normalized with maximum QTc of 470 ms. Echocardiography data slightly improved: ejection fraction: 64.6% (by Teichholz) and systolic pulmonary artery pressure: 25 mmHg. Another hypoglycemic episode took place at 48 months of age (glucose 2.1–2.35 mmol/L without electrolyte disorders). Afterward, glucose levels were kept under dynamic control; no more hypoglycemic episodes were registered. The disease course is showed in.