1

Introduction

Scimitar syndrome is a rare type of partial pulmonary venous return in which all right pulmonary veins connect to the inferior vena cava [ ]. Many infants with scimitar syndrome do not have pulmonary hypertension. However, some associated with severe pulmonary hypertension have poor prognoses, with a mortality rate of up to 45 % [ , ]. The association between these genetic abnormalities, phenotypes, and prognoses remains unclear. In addition, scimitar syndrome, characterized by multiple malformations, is not well recognized. Herein, we report a new case of fatal infantile scimitar syndrome with multiple complications, chromosomal 3p26.1–26.3 microdeletion, and 12q23.2–24.3 microduplication diagnosed using chromosomal microarray analysis (CMA).

2

Case description

A 34-year-old pregnant woman underwent a thorough fetal examination. Fetal echocardiography revealed a male fetus with scimitar syndrome, with an abnormal return of all of the right pulmonary veins to the inferior vena cava, left fetal pleural effusion, and the presence of a single umbilical artery. The patient had no family history of congenital heart disease or other malformations. The infant was born at 37 weeks of gestation, with a weight of 2639 g (50th percentile), length of 45.0 cm (15th percentile), head circumference of 32.0 cm (33rd percentile), and Apgar scores of 6 at minute 1, and 8 at minute 5. After birth, the infant was diagnosed with scimitar syndrome along with multiple other congenital heart anomalies (atrial septal defect (ASD) and multiple minor muscular ventricular septal defects (VSDs)). Physical examination revealed low-set and crumpled ears, hypertelorism, ptosis, a depressed and wide nasal bridge, a short neck, downturned mouth corners, micrognathia, anteverted nares, and a funnel chest. Magnetic resonance imaging revealed hypoplasia of the corpus callosum. The infant also presented with dyspnea due to left pleural effusion and chylothorax, requiring thoracic drainage until the 8th day of life. Hypertrophic pyloric stenosis was diagnosed, and Ramstedt surgery was performed on the 28th day of life. Due to feeding difficulties, the patient required enteral tube nutrition. Persistent pulmonary arterial hypertension developed on the 2nd day of life, prompting the administration of nitric oxide inhalation for 4 days. Severe pulmonary hypertension, characterized by comparable pressures in the left and right ventricles, persisted without improvement. Thoracoabdominal contrast-enhanced computed tomography also revealed cardiovascular malformations associated with the scimitar vein, with no signs of lung hypoplasia or aortopulmonary collaterals ( Fig. 1 A ). Additionally, no signs of pulmonary vein stenosis, pulmonary congestion, or lung abnormalities were observed. At one month of age, paroxysmal cyanosis and frequent desaturation occurred after a urinary tract infection. Echocardiography revealed a flattened ventricular septum with right-to-left shunting through multiple VSDs and no evidence of left ventricular dysfunction, indicating worsening pulmonary arterial hypertension ( Fig. 1 B). Despite the administration of oxygen therapy, nitric oxide, sildenafil citrate, and bosentan hydrate, prolonged hypoxia exacerbated pulmonary hypertension and led to the progression of respiratory acidosis. Owing to frequent pulmonary arterial hypertensive crises, the patient required ventilatory management and received intravenous epoprostenol sodium and selexipag in the intensive care unit at the age of two months. Despite receiving multidisciplinary treatment, the patient died 44 days after admission to the intensive care unit due to the progression of pulmonary arterial hypertension. Postnatal G-banding chromosomal testing revealed a 46, XY karyotype, add (3) (p26) ( Fig. 2 A ). CMA was performed to examine chromosome 3 of unknown origin. The analysis revealed a copy number loss of 3p.26.1–26.3 (minimum chr3: 62,199–6,517,900; maximum chr3: 62,199–6,541,934) (6.5 Mb), a copy number gain of 12q23.2–24.3 (minimum chr12: 102,896,121–133,743,506; maximum chr12: 102,869,918–133,747,247) (30.8 Mb), and a karyotype of 46,XY,der(3)t(3;12)(p26.1;q23.2) arr[GRCh 37] 3p26.1p26.3(62,199_6,541,934)x1,12q23.2q24.3(102,869,918_133,747,247)x3 ( Fig. 2 B). The cause of this unbalanced translocation remains unclear as the parents declined chromosomal testing.

Thoraco-abdominal contrast-enhanced computed tomography showed Scimitar syndrome, with abnormal drainage of the entire right pulmonary vein into the inferior vena cava (white arrow) (A); echocardiography showed a flattened ventricular septum with right-to-left shunting via multiple small muscular ventricular septal defects, thus indicating severe pulmonary hypertension (B).

G-banding revealed an additional chromosome of unknown origin (A); CMA revealed a copy number loss of 3p.26.1–26.3 (min chr3: 62,199–6,517,900, max chr3:62,199–6,541,934) and gain of 12q23.2–24.3 (min chr12: 102,896,121–133,743,506, max chr12:102,869,918–133,747,247) (B). RV, Right Ventricular; LV, Left Ventricular.

3

Discussion

Scimitar syndrome is commonly associated with hypoplasia of the right pulmonary artery and lungs. It is complicated by cardiac diseases, such as ASD, VSD, tetralogy of Fallot, aortic coarctation, pulmonary artery hypoplasia, airway lesions, and aortopulmonary collaterals [ ]. The cardiovascular phenotype varies, and the infantile type, complicated with both congenital heart disease and pulmonary hypertension, have a poor prognosis [ ]. Recent CMA and whole-genome sequencing studies have revealed that the phenotype of scimitar syndrome, along with many other cardiac diseases and severe pulmonary hypertension, may be derived from various genes. Additionally, the prognosis may be influenced by the presence of coexisting genetic abnormalities [ ]. These 10 patients with chromosomal abnormalities or gene mutations experienced complications, including gastrointestinal, musculoskeletal, and neurological disorders, such as poor feeding, pyloric stenosis, scoliosis, vertebral anomalies, and developmental delay, alongside cardiopulmonary disease. Scimitar syndrome and its associated multiple malformations are heterogeneous, with variations in genotypes. We confirmed a new case of scimitar syndrome complicated by physical anomalies, with a loss of 3p.26.1–26.3 and a gain of 12q23.2–24.3.

3p deletion syndrome is a rare genomic disorder characterized by growth retardation, intellectual disability, hypotonia, and altered facial features involving the eyes, ears, and nose. Notably, 43 % of affected individuals also develop congenital heart disease [ ]. Previous studies have documented patients with 3p25, 3p25–26, and 3p26 deletions and altered features, as observed in our patient ( Table 1 ) [ ]. Data from the DECIPHER database indicated that the following features are commonly observed in those with a copy number loss in chr3:62,199–6,517,900 regions (106 patients) and consistent with those in our patient: low-set ears (25/106), hypertelorism (20/106), ptosis (22/106), short stature (39/106), small for gestational age (22/106), high palate (22/106), hypotonia (30/106), microcephaly (38/106), micrognathia (28/106), and intellectual disability (52/106). Among the patients with a copy number loss in this region, some developed cardiovascular disorders, such as ASD (9/106), VSD (7/106), tetralogy of Fallot (2/106), and mitral regurgitation (2/106). Notably, only one patient presented with pulmonary hypertension complicated by ASD.

Table 1

Literature reviews of patients with pure 3p26 deletion.

Patient (year)	Our patient	Cargile et al. [ ] −2002	Gunnarsson et al. [ ] −2010	Cuoco, et al. [ ] −2011	Riess et al. [ ] −2012	Tassano et al. [ ] −2014	Juan-Perez et al. [ ] −2018	Tsuboyama et al. [ ] −2019	Fu et al. [ ] −2021
Region of deletion	3p26.1–26.3	3p25.3–26.2	3p25.3–26.3	3p26.3	3p25.3–26.1	3p26	3p26	3p26	3p25.3–26.3
Deletion Size (Mb)	6.5	4.5	1.6	1.5	1.2	0.9	0.2	0.6	10.1
Cardiovascular anomaly	Scimitar syndrome		ASD						VSD
	PH		VSD
	ASD		Cor triatrium
	Multiple VSDs		Anomaly of vein
Digestive/genitourinary disorder	Pyloric stenosis	Gastroesophageal reflux							Gastro-esophageal reflux
	Sacral dimple	Sacral dimple
Neurological or growth features
Developmental delay		+	+	+	+	+	+		+
Growth retardation	+	+
Brain malformation	+			+
Hypotonia	+	+	+		+			+	+
Seizure/abnormal EEG			+	+			+	+	+
Craniofacial features
Ptosis	+	+	+						+
Strabismus					+	+
Low-set and/or malformed ears	+	+	+
Hypertelorism	+	+	+						+
Depressed nasal bridge	+	+	+		+				+
Short neck	+
Microcephaly			+		+	+		+
Micrognathia	+	+						+
Extremity features	+	+	+	+		+	+

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