The acronym VACTERL association refers to a rare class of congenital abnormalities that may manifest concurrently. The elements (V) vertebral anomalies, (A) anal atresia, (C) cardiac defects, (TE) tracheoesophageal fistula, (R) renal anomalies, and (L) limb defects are associated with this association [¹]. According to estimates, the incidence is between one in 10,000 and one in 40,000 live births [²].

It is thought to be an uncommon finding that VACTERL is linked to urinary tract malformation and pulmonary hypoplasia [³,⁴], as demonstrated by a study where all five neonates with pulmonary agenesis and VACTERL association died during the neonatal period. The morbidity is increased by pulmonary hypoplasia [⁴]. Despite the lack of a complete understanding of the etiological factors, familial clustering suggests the presence of inherited factors [⁵]. The presence of the congenital malformations mentioned above is used to make the clinical diagnosis of VACTERL association in addition to imaging, such as MRI for vertebral abnormalities, echocardiography for cardiac defects, and radiological studies for tracheoesophageal and renal anomalies. Prenatal imaging techniques can detect some anomalies; however, technical and resource limitations may hinder early diagnosis in low-resource settings. Surgery remains the primary treatment method [⁶]. In contrast to numerous other disorders whose hereditary origins have been identified in recent years, the causes of the VACTERL association are still mostly unknown. This can be attributed to various factors, such as the disease’s typical sporadic nature, overlapping conditions, and likely clinical and causal heterogeneity. This study aims to present the first documented case of VACTERL association in Syria, which is of particular significance due to the co-occurrence of pulmonary hypoplasia and genitourinary anomalies, features rarely reported in the literature, in addition to highlighting the challenges of managing complex congenital anomalies in resource-limited settings.

We discussed the case of a 20-month-old infant boy who was hospitalized due to frequent coughing, lethargy, and nursing difficulties, as reported by his mother when he was 1 month old. Upon clinical examination, the infant showed urethral epispadias, a delay in psychomotor development, and failure to thrive. His surgical history pointed to five surgical interventions: repair of the bladder inversion at one day of life, repair of the tracheal esophageal fistula (TE) at four months of life, repair of the inguinal hernia at nine months of life, repair of the anal atresia in the first few days of life, and repair of the diaphragmatic hernia at fourteen months of life. The mother, who was 23 years old, had a history of one miscarriage and was consanguineous with her husband in the second degree. Still, other than that, her family history was uneventful. A blood test performed upon admission revealed elevations in leukocytes (WBC \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$32.8 \times 10^9 \,\uparrow$\end{document}32.8×109↑), CRP (43 mg/dl), and iron-deficiency anemia (Fe: 15 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\mu$\end{document}μg/dl \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\downarrow$\end{document}↓; TIBC: 345 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\mu$\end{document}μg/dl \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\uparrow$\end{document}↑). Further testing revealed the presence of yeast-like fungi and pyuria, respectively, in the stool culture and urine analysis. After a diagnostic ultrasound of both kidneys, the right kidney’s second-degree hydronephrosis was discovered, as seen in and . Using Tc-99m DTPA (diethylene triamine pentaacetate), a dynamic renal scintigraphy was performed to evaluate kidney function. After 15 minutes, the right kidney’s cavities and ureter showed signs of severe ascites, which were treated with a Lasix injection. Additionally, there was a protracted and postponed spontaneous emptying time. The kidney responded to the diuretic injection satisfactorily; however, at the end of the imaging, emptying was incomplete, suggesting the presence of vesicoureteral reflux. The glomerular filtration rate was 45 ml/min, and the relative function of the right kidney was 44%. Yet, radiography revealed dysplasia of the acetabular cavity in both legs, as illustrated in . Additionally, an anteroposterior chest radiograph was taken, which suggested pneumothorax because it showed a reduction in the capacity of the left lung. As seen in , the right lung also had larger dendritic fissures or inflammatory infiltrates. Following the injection of 4 mCi of Tc-99m macroaggregated albumin (MAA), lung scintigraphy was performed. The scintigraphy findings were a weakly vascularized left lung (fixation rate of 3%), together with the collapse of the lower segment of the upper lobe of the right lung (fixation rate of 97%). The results indicate that the left lung is hypoplastic. While an echocardiography showed no abnormalities, an upper gastroscopy revealed symptoms of esophagitis and an esophageal stricture in the upper and middle third of the esophagus.

Surgical corrections for congenital anomalies (anal atresia, TEF, bladder inversion, inguinal hernia, diaphragmatic hernia) were performed, and the patient was then treated medically for the sequelae. The management of this complex case addresses both the congenital anomalies and the acute medical issues. Given the patient’s history of multiple surgical interventions for congenital malformations (bladder inversion, tracheoesophageal fistula, inguinal hernia, anal atresia, diaphragmatic hernia), surgical and post-surgical care is ongoing and critical. The presence of VACTERL association in conjunction with left lung hypoplasia, bladder inversion, epispadias, and right kidney hydronephrosis requires a multidisciplinary setup involving pediatric surgeons, urologists, nephrologists, pulmonologists, and developmental pediatricians. Unfortunately, the treatment was not completely documented, and the patient was not carefully followed up following the surgery due to financial considerations.

VACTERL association (VA) is an acronym for a group of non-random co-occurrence congenital malformations defined as three or more of the following defections: vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula/esophageal atresia (TEF/EA), renal anomalies (R), limb abnormalities (L) [¹]. Prior studies had shown that only < 1% of patients had all 6 anomalies together [⁸]. There is a slight male predominance, where Fifty-eight percent of cases were males [¹]. Vertebral abnormalities are present in 60-80% of cases, atresia in 90%, heart defects in 40-80%, tracheoesophageal fistula in 50 to 80%, and limb abnormalities in half of the cases [⁹]. Although the exact cause of VACTERL is unknown, a mix of genetic, environmental, or multifactorial abnormalities is considered the cause. The cause of these defects remains idiopathic, but it has been hypothesized that a mesodermal differentiation problem may be involved in the early stages of the first trimester [⁸]. Some studies have shown some correlation with consanguinity, where these features were found significantly more commonly in first-degree relatives than in the general population [¹⁰]. However, no single gene or mutation has been definitively linked to the syndrome, and research continues to explore potential genetic and epigenetic causes. Furthermore, environmental factors, such as maternal diabetes, certain medications, or prenatal infections, have been implicated in increasing the risk of VACTERL [¹¹].

Although VACTERL consists of six malformations, where three must be present for diagnosis, these malformations can co-occur with other pulmonary and genitourinary anomalies [⁶]. In a study conducted by Knowles et al., all five babies with pulmonary agenesis as a part of the VACTERL association were either stillborn or died in the neonatal period [¹²]. On the other hand, physicians should be highly suspicious of GU anomalies, even in patients with a VACTERL association who do not have anorectal or renal anomalies. Research on 100 patients with VACTERL association found that GU problems affect 21 percent of the population and are distributed as follows: in males, 20% had hypospadias, 20% had GU fistulae, and 10% of each had ambiguous genitalia (with hypospadias); hypospadias plus more severe defects (not specified); cryptorchidism only; cryptorchidism and a GU fistula; hypospadias and a GU fistula; and hypospadias and hydrocele and of the females, 56% had cloacal anomalies, 33% had GU fistulae, and 11% had a didelphys uterus [⁶].

In his case report, Yang et al. 2019 reported an unusual VACTERL case compounded by several unusual airway problems, such as the bridging bronchus, airway malacia, and complete tracheal rings [¹³]. In a 2023 publication, Alwan et al. describe a case of pulmonary agenesis identified in conjunction with several other anomalies. While Alwan’s case is not directly related to VACTERL, the authors point out that pulmonary agenesis is known to present together with anomalies of multiple other organ systems, including the cardiovascular, skeletal, gastrointestinal, and genitourinary systems [¹⁴]. In 2020, Lookzadeh et al. reported a case of VACTERL association in a newborn with all six VACTERL criteria; notably, the limb and kidney defects were asymmetrical on either side of the body [¹⁵].

In the described case, three of the six distinctive findings of the VACTERL association—anal atresia, hydronephrosis of the right kidney, and tracheoesophageal fistula (TE) were present. In addition, co-occurrences of pulmonary malformations and hypoplasia of the left lung were present. Moreover, this case shows a unique presentation of genitourinary anomalies, where epispadias instead of hypospadias and bladder inversion were presented.

The diagnosis of VACTERL is primarily based on clinical examination, which may occur after birth, with three malformations sufficient to make the diagnosis [¹⁶]. However, diagnostic imaging techniques can be used to detect fetal pathology [⁷]. Technical and financial constraints prevented us from performing an MRI to assess the vertebral column or a VCU to confirm vesicoureteral reflux. The management of patients with VACTERL/VATER association typically focuses on surgical correction of specific congenital anomalies, such as anal atresia, certain types of cardiac malformations, and/or tracheoesophageal fistula in the immediate postnatal period, followed by long-term medical management of the congenital malformations’ sequelae [¹⁶], which is exactly what our patient received. Research on the long-term outcomes of patients with VACTERL association is limited, but some studies provide insight into the prognosis and follow-up care for affected individuals. In general, the prognosis depends on the severity of the anomalies present and the success of surgical interventions [¹⁰].

Given that this is the first case reported in Syria, it is critical to emphasize the importance of conducting thorough examinations and investigations for all VACTERL-related elements when a child exhibits these characteristics. Furthermore, because VACTERL is an association of multiple malformations, healthcare providers must be vigilant for malformations that do not necessarily fit into the typical VACTERL elements. After all, early detection and management are critical for providing appropriate care to patients and avoiding future complications. While the findings provide valuable insights, they are preliminary and based on a single case. Further studies are needed to validate these observations. The literature supports the multifactorial etiology of VACTERL and highlights environmental and genetic factors such as consanguinity, which were also observed in this case. However, more studies will be essential to better understand the interplay of these factors and improve diagnostic and therapeutic approaches.