Congenital short bowel syndrome (CSBS) is a rare congenital disorder that is clinically characterized by a reduction in the length of the small intestine at birth. Compared with length of the small intestine of normal full-term infants (190–280 cm) (1, 2), the mean length in patients with CSBS is about 50 cm (3). The incidence of CSBS is <1 in one million births (4). The symptoms of CSBS are bilious vomiting, growth retardation, diarrhea, or gastrointestinal obstruction, most of which are accompanied by intestinal malrotation (5). CSBS is associated with a high mortality rate (6), but does not affect mental development (3, 7).

CSBS was first reported by Hamilton in 1969 (8). The exact pathogenesis is still unclear. Related hypotheses include interruption or delay of small intestine elongation and rotation due to lack of space in the umbilical cord during fetal development (8), defects in neurointestinal development (9), or vascular obstruction or ischemic damage to the primitive midgut (5). In 2012, Van et al. (10) found that knock-down of the coxsackie and adenovirus receptor-like membrane protein (CLMP) homologous gene in zebrafish resulted in significant shortening of the intestine and lack of goblet cells in the midgut, suggesting that CLMP is necessary for normal small intestinal development. It was speculated that recessive mutation of CLMP gene could lead to CSBS in humans.Homozygous and compound heterozygous mutations of CLMP in CSBS patients suggest that the inheritance pattern of the disease is autosomal recessive.

The CLMP gene is located on chromosome 11 (11q24.1), which encodes a transmembrane protein and co-localizes with the tight junction-related protein zonula occludens-1 as an adhesion molecule. It is one of the tight junction components of the epithelium (11), which is expressed in different tissues during embryonic development including the intestine (12). Since tight junction markers such as ZO-1 and its related nucleic acid binding proteins play an important role in cell proliferation (13, 14), and CLMP is co-localized with tight junction proteins, it is speculated that the loss of function of CLMP may affect the proliferation of small intestinal cells, leading to shortening of the small intestine at birth. Wang et al. examined the biopsies of five CSBS children with CLMP mutation and found chromatin clumps and pyknosis in the intermuscular nuclei of these patients, suggesting that CLMP gene mutation may affect the development of intestinal nerve plexus (15).In addition, a mutation in the filamin A (FLNA) gene was found in male patients with CSBS, which is related to the X-linked inheritance pattern (16).

We report a Chinese family with CSBS and analyzed their clinical features, treatment, and prognosis. The new homozygous deletion mutation of CLMP gene exons 3–5 was identified as the cause of CSBS in this family by using whole exon sequencing (WES) and quantitative PCR (qPCR).

CSBS refers to congenital shortening in the length of small intestine. It is a rare clinical condition. Wilmore et al. (25) proposed that full-term infants with the small intestinal length <75 cm are likely to have symptoms and signs of SBS. Only 74 cases have been reported since the first description by Hamilton in 1969 (8). Among the 74 cases, The age of patients at the time of diagnosis vary between 33 weeks of gestational age and 15 years old. The male-to-female ratio is 1.55 (45 males, 29 females). The main clinical manifestations of CSBS include biliary vomiting, abdominal distension, chronic diarrhea. Intestinal malrotation was identified in 70 cases. Most patients with CSBS have other abnormalities such as intestinal adhesions, intestinal atresia, pyloric hypertrophy, persistent patent ductus arteriosus, central nervous system malformations, common dorsal mesentery, absence of the appendix, and colon involvement. The diagnosis of CSBS mostly depends on early intestinal obstruction symptoms, imaging examination and surgical exploration.

In this study, we reported that two siblings in a family developed intestinal obstruction after birth, mainly manifested as vomiting. UGI and laparotomy found that both patients had intestinal shortening accompanied by malrotation. After genetic examination, homozygous deletion of exons 3–5 of CLMP gene was found in both siblings. There were heterozygous mutations in both parents, but no associated phenotype, suggesting an autosomal recessive inheritance of the disease. CLMP exons 3–5 encode amino acids at positions 63 to 227, which are located in two key domains of the protein (Ig-like C2-type 1, Ig-like C2-type 2). Through biological analyses, we found that the deletion of these amino acids can lead to the loss of protein function, thus predicting the pathogenicity.

According to literature review, a total of 18 children with CSBS have been confirmed to have CLMP mutations by genetic tests so far (Table 1). All CLMP gene mutations reported in the literature can lead to the loss of protein function, and the clinical manifestations of the reported cases are limited to the intestines. Summarizing these cases, no specific mutation types were found to be associated with specific clinical phenotypes.

Langhorst et al. (26) studied CLMP-deficient mouse models and found that the mutant mice had malrotation of the intestine but no significant change in the length of the intestine compared to wild-type mice. The lack of CLMP gene can lead to a decrease in intestinal smooth muscle cells and ureteral junction protein 43, causing impaired intestinal, ureteral motor function, and functional obstruction. Thus, in addition to impaired intestinal motility, CLMP-deficient mice also have severe bilateral hydronephrosis. Alves et al. (21) described two patients with CLMP mutation [C.508C>T (Exon 4); P. (R170^*)] and found that besides reduced intestinal length, the patients also had an obstruction of the ureteropelvic junction, similar to the mouse model. However, the same changes were not seen in other cases. Therefore, how CLMP variant types are associated with clinical phenotypes still needs further study.

To date, there is no cure for CSBS. The management of CSBS includes the maintenance of growth and development, promotion of intestinal adaptation, and prevention of complications (27). In the early stage of intestinal adaptation (1–3 months), it is necessary to maintain fluid and acid-base balance (28). The use of parenteral nutrition (PN) is inevitable and indispensable, but the long-term use of PN is often accompanied by several complications such as liver failure and sepsis (29), which are the most common causes of death in these patients. Negri et al. (30) noted in their study that the mortality of CSBS was 60.6%, and the main cause of death was malnutrition and/or sepsis. The survival rate was 30.6% before 2008 and 80.4% after 2008. The survival rate of children with CSBS has improved due to better nutritional management practices. For children with CSBS, early EN is of great importance to promote intestinal adaptation. In the early stage, the selection of milk and feeding methods needs to be continuously improved according to the condition of child until the intestinal tolerance is established in order to improve the prognosis.

CSBS is one of the rare neonatal diseases. The loss of CLMP function is one of possible pathogenetic mechanisms for its development. CSBS is diagnosed by UGI, laparotomy, and genetic testing. These children require early EN with PN support to reduce complications and mortality. At present, the specific role of CLMP in the development of small intestine is still unclear, and further studies on the pathogenic mechanism of CLMP gene are needed. Parents of a child with CSBS with CLMP gene mutations can seek prenatal diagnosis for early detection and intervention in subsequent pregnancies.

The datasets for this article are not publicly available due to the Regulations of the People's Republic of China on the Administration of Human Genetic Resources in 2019. Requests to access the datasets should be directed to the corresponding authors (Xin-Zhu Lin, xinzhufj@163.com; Yan-an Wu, wyaslyy@126.com).

The studies involving human participants were reviewed and approved by Ethics Committee of Maternal and Child Health Hospital of Xiamen city. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

F-fO and M-jL: responsible for article writing and genetic testing. L-bM: help with text revision and genetic interpretation. X-ZL and Y-aW: provide writing ideas and guidance. All authors contributed to the article and approved the submitted version.

This work was supported by Young Investigator Research Program of Xiang'an Hospital of Xiamen University, China (No. PM202103050004).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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