A case report of serpentine-like syndrome and review of literature

Serpentine-like syndrome (SLS) is a rare abnormality characterized by brachioesophagus, secondary intrathoracic stomach and vertebral anomalies, which are similar to the anatomical structures of snakes. To date, there are only nine reported cases of SLS, and most patients had a poor prognosis. Michael S. Katz et al. first discussed SLS in 2008 [1]. Obstetricians and neonatal paediatricians do not have sufficient knowledge about its characteristics. Hence, the actual number of SLS cases may be higher than that reported. In 2008, another case of SLS was described, and it was characterized by a congenital intrathoracic stomach, short oesophagus, hemivertebrae at the T5 level and complete gastric outlet obstruction [2].

Multiorgan abnormalities can be diagnosed prenatally via ultrasonography (US) and magnetic resonance imaging (MRI). US is advantageous as it is radiation-free and less time-consuming. Thus, it is considered an optimal examination method. However, due to the low spatial resolution of two-dimensional (2D) US, the whole lesion cannot be completely visualized. In addition, in SLS, some abnormalities cannot be directly diagnosed on 2D-US [3]. Advancements in three-dimensional (3D) US can provide opportunities for detecting multiorgan malformations. Hence, an accurate diagnosis, which is essential for adequate counselling and pregnancy management, can be obtained. Crystal Vue (Samsung Medison Co., Ltd., Seoul, South Korea) can improve the spatial resolution of ultrasonic images and can identify the important details of diseases. Hence, it can have a better diagnostic value in detecting multiple organ malformations [4].

Herein, we present a 34-year-old pregnant woman. The patient initially conceived via artificial insemination. However, her pregnancy was subsequently terminated. Next, she had her second artificial insemination and eventually got pregnant. During the first trimester of pregnancy, a nuchal translucency (NT) measuring 1.8 mm was detected. Moreover, the ductus venous was absent, and a cystic mass was detected in the thoracic cavity. The pregnant woman decided to continue with the pregnancy. Routine foetal ultrasonography and re-examination were performed at 16 and 17 weeks of gestation in another hospital, and the diagnoses differed ((the cystic structure in thoracic cavity VS congenital diaphragmatic hernia (CDH)). At 19 week gestation, 2D-US was conducted at our centre, and the following results were obtained (Fig. 1):

MRI was performed at 21-week gestation, and the following results were obtained (Fig. 1):

Three-dimensional US images were obtained at 23-week gestation and were post-processed with Crystal Vue. The following results were obtained:

The patient terminated the pregnancy, and an autopsy was then performed with the patient’s consent. The autopsy results were as follows:

The foetus was diagnosed with SLS due to the coexistence of brachioesophagus, secondary intrathoracic stomach and vertebral anomalies. Chorionic villus samples were obtained at 13 weeks of gestation. G-banded karyotype analysis was performed, and results did not reveal chromosomal abnormalities. Simultaneously, array comparative genomic hybridization and polymerase chain reaction Gene Scan did not show gene copy number variations. The whole genome sequence of humans was provided using the high-throughput sequencing technology. No pathogenic variants were identified. The likely pathogenic variants were found in MKS transition zone complex subunit 1 (MKS1, chr17:56284466, NM_017777.3: C.1387C > T) and docking protein 7 (DOK7, chr4:3494599, NM_173660.4: C.886C > T). Variants of uncertain significance were detected in microtubule actin crosslinking factor 1 (MACF1, chr1:39888093, NM_012090.4: c.9678G > C), beta 3-glucosyltransferase (B3GLCT, chr13:31789179, NM_194318.3: c.71-9 T > C) and RAB3 GTPase activating non-catalytic protein subunit 2 (RAB3GAP2, chr1:220325081, NM_012414.3: c.3893A > C). Two genetic specialists were consulted, and they confirmed that such variants were not associated with the clinical phenotype.

Snakes have an intrathoracic stomach and rachischisis-like spinal vertebrae. In 2008, Michael S. Katz et al. defined SLS as a condition characterized by foetal malformations such as short oesophagus, intrathoracic stomach and vertebral rachischisis. Moreover, in the same year, Alex W.K. Leung et al. reported a foetus presenting with the characteristics of SLS including thoracic hemivertebrae at the T5 level, short oesophagus and intrathoracic stomach. The current study assessed case reports about SLS in the English literature. In total, nine cases were included in our review, and the current case is the 10th.

Table 1 shows the general information about pregnant women and their foetuses. There were two primiparas and five multiparas. Three articles did not include information about the history of pregnancy and childbirth. All multipara women (n = 5) had a history of adverse pregnancy. Of 10 foetuses, 5 were male and 5 female. Of five foetuses who underwent surgery, three (60%) died, and two (40%) survived with the help of assistive devices. Moreover, three foetuses died without surgery. In two cases, the pregnancy was terminated. Eight patients were misdiagnosed with CDH and one with pulmonary sequestration. Further, one patient was diagnosed with polyhydramnios and an absent gastric bubble.

Table 2 shows data about concomitant deformities. All patients presented with brachioesophagus, intrathoracic stomach and spinal deformity. Nine foetuses had normal karyotypes. However, the genetic results of one patient were unknown. Eight (80%) patients presented with deformities in the intestine, seven (70%) in the spleen, four (40%) in the lungs, four (40%) in the great vessel, three (30%) in the heart, three (30%) in the limbs, three (30%) in the liver, three (30%) in the gallbladder and cystic canal, two (20%) in the stomach outlet and two (20%) in the central nervous system.

The prognosis of SLS is poor, and the survival rate after surgery is 40%. The outcome of the surviving foetuses is poor. Fetoscopic endotracheal occlusion (FETO) can improve the survival rate of foetuses with CDH [10]. Left-sided diaphragmatic hernia is the most common type of CDH, and it may lead to intrathoracic stomach and pulmonary hypoplasia, which is similar to SLS. Intrathoracic stomach compression can impair the development of foetal lungs. FETO might improve the survival of foetuses with SLS. However, compared with CDH, FETO might be less beneficial in the foetus of our report. In CDH, the abdominal organs that herniated into the thoracic cavity are not fixed. Resistance from the hernia sac in CDH is lesser than that from the fixed intrathoracic stomach in our case. No genetic variant associated with the clinical phenotype was detected via G-banded karyotype analysis, array comparative genomic hybridization, polymerase chain reaction Gene Scan and the whole genome sequence of humans. The cause of SLS remains unclear. All multipara women (n = 5) had a history of adverse pregnancy. Hence, this factor can be correlated with SLS. In 8 of 10 cases, spinal deformities occurred in the cervicothoracic segment. This phenomenon might be attributed to unknown factors affecting the differentiation of the cervical vertebral body and oesophageal development. Hence, as there is no adhesion and fistula between the oesophagus and trachea, this condition may occur during the embryonic stage, which is after the foregut differentiates into the trachea and oesophagus and before the oesophageal lengthens. A short oesophagus may cause diaphragmatic dysplasia. In the embryonic stage, the dorsal mesentery of the oesophagus develops into the dorsal and median parts of the diaphragm [11]. Based on the current and previous reports, the oesophageal dorsal mesentery does not play a role in the development of diaphragmatic muscle in SLS, resulting in partial dysplasia in the dorsal and median parts of the diaphragm. In this case, the dorsal mesentery of the oesophagus might have fused with the adjacent visceral pleura. Our hypothesis could be validated by the autopsy results. That is, the serosa at the cardia was fixed in front of the C6 level, and the smooth muscle of the stomach was connected to the cartilage. The bilobar malformation of the right lung could possibly be caused by gastric compression in the chest or by failure in the division and development of the right lung bud during the different phases of lung development [12]. Spleen development starts in the 5th week of gestation, and its location changes with the stomach between the 6th and 7th weeks. Asplenia and polysplenia are rare congenital abnormalities of the spleen, 40–70% of them combined with other defects [13]. In our case, the foetal stomach and spleen developed in the thoracic cavity. In CDH, the position and morphology of the spleen and stomach were normal during the embryonic stage. Even if the spleen is in the hernia, it has a normal morphology, and its location is not fixed. In SLS, the spleen had an abnormal morphology, and its location is fixed.

Differential diagnosis

Differential diagnosis of other thoracic diseases

The length of the oesophagus, integrity of the diaphragm and location of the stomach are important for obtaining a differential diagnosis in SLS with CDH and other thoracic diseases. Since 2D-US remains the standard tool for morphology scan screening, foetal morphological features assessed via 2D-US should be further addressed in detail. Novel 3D-US rendering technique is effective for identifying the perception of depth while preserving context and surface information [17]. Moreover, it can detect the subtle structures of foetuses such as those of the oesophagus, diaphragm and stomach, and the relationships between different structures. Therefore, it has a greater diagnostic value for multiorgan malformations.