Congenital Heart Defects and Skeletal Malformations Syndrome (CHDSKM) Associated with the ABL1 Gene in a Peruvian patient: Case Report

Abstract

We present the clinical case of a 20-year-old male patient who presented recurrent pneumothorax on 5 occasions; in addition, he revealed a history of skeletal malformations in the hands and joint hypermobility. A genetic panel for connective tissue disorders was performed, in which a heterozygous variant in the gene was detected ABL1: (NM_007313.2): c.199T>C (p.Trp67Arg), which was classified as probably pathogenic, which is why the diagnosis of Heart Defects and Skeletal Malformations Syndrome was confirmed (CHDSKM).

Introduction

Congenital Heart Defects and Skeletal Malformations Syndrome (CHDSKM; MIM:617602) is a rare syndrome for which fewer than 30 confirmed cases have been described; caused by germline pathogenic variants in the ABL1 gene. The clinical manifestations and symptoms are varied, including cardiac malformations (ventricular septal defects, atrial septal defects, and aortic root dilation), in addition to varied connective tissue manifestations. Likewise, some patients show a developmental delay during childhood, recurrent pneumothorax, diaphragmatic hernias, and gastrointestinal, genitourinary, neurological, and dermatological conditions, among others.^{1 -5}

We present the case of a Peruvian patient with CHDSKM associated with a probable pathogenic variant in the gene ABL1.

Case Report

A 20-year-old male patient was admitted to the emergency room with sudden pleuritic pain, NYHA class IV dyspnea, tachycardia, and an evident decrease in thoracic amplexation (Table 1). A chest X-ray was taken, and a pneumothorax on the left side was found to be under tension (Figure 1), then pleural drainage was placed by emergency thoracostomy.

Table 1.

Summary Chart of General Features of the Patient.

Age/sex	Thorax	Renal	Endocrine	Urological	Musculoskeletal	Gastrointestinal	Genetic	Cardiac
24/M	- Recurrent pneumothorax; first episode at age 20, last at age 21. - Bilateral apical subpleural bullae - Mild pectus excavatum	- Left renal agenesis - Moderate to severe right hydronephrosis	Hypothyroidism since age 14	- Cryptorchidism - History of hypospadias	- Pain in interphalangeal, temporomandibular, and cervical regions since age 13, refractory to conventional therapy - Mandibular hypoplasia - Joint hypermobility - Clinodactyly - Camptodactyly	- History of umbilical and epigastric hernia - Chronic gastritis with refractory GERD - Severe esophageal dysmotility	Heterozygous variant in ABL1 (NM_007313.2): c.199T>C (p.Trp67Arg), classified as Likely Pathogenic	No abnormalities on TTE or ECG

Figure 1.

Left-sided tension pneumothorax (red arrow). Absence of vascular markings in the left hemithorax with increased radiolucency, and mediastinal and cardiac shift to the right.

As an important antecedent, the patient is the product of a second pregnancy of consanguineous parents (first cousins). At birth he presented right renal agenesis, unilateral cryptorchidism, hypospadias, umbilical and epigastric hernia, and at the age of 14 he was diagnosed with hypothyroidism. From the age of 13, he presented persistent pain in the interphalangeal joints, in the temporomandibular region, and the cervical area, the latter improved with muscle de-escalation and infiltration with lidocaine. In addition, he presented partial and momentary relief when using electrotherapy with the Transcutaneous Electrical Nerve Stimulation (TENS) method and the ineffectiveness of the use of conventional therapy with daily exercises, hot compresses, and infrared radiation.

Likewise, from the age of 14 years, he presented chronic gastritis with persistent gastroesophageal reflux, and constant esophageal dysmotility using an esophagogram with barium contrast and manometry with impedancemetry, concluding: (1) UEG type I: hypotensive lower esophageal sphincter, (2) Severe ineffective esophageal motility without peristaltic reserve, (3) Normal pharyngoesophageal coordination, (4) Incomplete transit of the esophageal bolus.

At that same age, the patient presented to the cardiology service for a follow-up evaluation after an isolated syncopal episode, likely related to a stressful situation. A Doppler echocardiogram was performed, which showed normal systolic and diastolic function of both the left and right ventricles, normal wall thickness, normal chamber sizes, and normal valves and pericardium. A Holter monitor was also placed, which showed no arrhythmias or ST-segment deviations.

Physical examination revealed mandibular hypoplasia, minimal pectus excavatum, joint hypermobility, clinodactyly, and camptodactyly in the fourth and fifth fingers of both hands (Figure 2), a thin, thin skin that allowed the venous network to be transparent. Likewise, the patient does not have an intellectual disability or a history of neurodevelopmental disorders. Based on the clinical picture, the possibility of a connective tissue disorder was initially raised, considering the possibility of Ehler-Danlos syndrome. A cardiological evaluation was performed, including transthoracic echocardiography and electrocardiography, which revealed no abnormalities.

Figure 2.

Bilateral clinodactyly and camptodactyly of the fourth and fifth fingers (red arrow). Mild curvature of the second and third fingers bilaterally (yellow arrow). The patient also had a long-standing history of pain in the interphalangeal joints.

After 2 weeks of admission, the patient developed recurrent pneumothorax; The study with a computed thoracic tomography, found subpleural apical bullae in both lungs; therefore, a thoracoscopic bullectomy was scheduled electively, only on the affected side. He was discharged in good general condition, with indications for care and control by an outpatient clinic.

Eleven months after discharge, the patient presented a new episode of minimal spontaneous pneumothorax, and the decision was made to manage conservatively. A week later, the patient returned with dyspnea with small exertion and pleuritic pain of the same characteristics as the episode of a year ago. A thoracostomy was performed for placement of new drainage associated with the Heimlich valve system (Figure 3), for comfort and possible long-term outpatient management.

Figure 3.

Chest tube connected to a Heimlich valve system (red arrow), placed via thoracostomy, allowing for ambulatory management.

Within the Cardiovascular and Thoracic Surgery Service, a medical meeting was held, where the possibility of a left segmentectomy was defined, in the event of repeating the event once again. During his stay, the patient makes a favorable recovery but presents another episode of pneumothorax and is scheduled for surgery. A thoracotomy with excision of bullae assisted by video-thoracoscopy (Figure 4) was performed, which was effective and without repetition of another event to date.

Figure 4.

Thoracotomy with bulletomy assisted by video-assisted thoracoscopic surgery (VATS).

A genetic panel of 70 genes for connective tissue disorders (Igenomix, Spain) was performed, in which a heterozygous variant was found in the gene ABL1 (NM_007313.2): c.199T>C (p.Trp67Arg), which was initially classified as a variant of uncertain meaning. Subsequently, a search for the genetic variant was carried out in both parents, with negative results, which concluded that it is a de novo variant. The variant was reanalyzed according to the recommendations established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), where this variant is absent in population cohorts as gnomAD (PM2); moreover, since there is a previously reported pathogenic variant, which affects the same amino acid (Clinvar ID: 1699204) (PM5). On the other hand, it is a de novo variant (PM6). Based on the criteria, the variant was reclassified as probably pathogenic, thus having a diagnosis of Congenital Heart Defects and Skeletal Malformations Syndrome associated with ABL1.

The patient, now 24 years old, has remained free of pneumothorax recurrences for 3 years. However, surveillance with non-contrast chest computed tomography (CT) continues to demonstrate persistent bilateral apical bullae. He remains under follow-up for persistent symptoms of chronic gastritis and gastroesophageal reflux disease (GERD), which have shown only a partial response to pharmacotherapy. Regarding his musculoskeletal status, he continues to experience chronic arthralgia, which is managed with needling therapy administered bimonthly. From a cardiovascular standpoint, the patient remains asymptomatic. Recent evaluations, including a stress test, transthoracic echocardiogram, and electrocardiogram (EKG), were within normal limits.

Discussion

Congenital heart defects and musculoskeletal malformation syndrome is an autosomal dominant pathology associated with variants in the ABL1 gene, of which there is no prevalence; the clinical manifestations are quite varied among the reported patients, and variants in the ABL1 gene are scarce.^{1 -5}

Wang et al (2017) described individuals with this diagnosis from 4 unrelated families. Some of them had dysmorphic facial features, congenital heart defects, skeletal abnormalities, gastrointestinal conditions, and genital abnormalities in male patients. Three patients showed joint hypermobility. How to mention this syndrome usually presents atrial defects ventricular septum, and aortic root dilation, but the patient in the present study does not currently have it. CHDSKM, in most cases, exhibits cardiac involvement from birth or in the first few years of life.

Chen et al, reported 2 patients with CHDSKM (a 30-year-old male and a 20-year-old female), who had spontaneous pneumothorax, both 16 years of age. It is said that the male patient had 2 episodes, while the patient only had 1, resolving the condition through a bullectomy with talc. The patient described in this case report presented 5 episodes of spontaneous pneumothorax and the episodes were resolved with VATS.

In addition, the patient was known in the gastroenterology service for chronic gastritis associated with GERD without improvement directly related to the hypotensive esophageal sphincter and the null contractibility of the muscle. Esophageal dysmotility in this patient is severe and 90% of swallows failed peristalsis and 10% had fragmented peristalsis; Esophageal bolus transit was incomplete in 100% of swallows. In other reports of this condition, “problems or abnormalities gastrointestinal” however, the findings are not usually specified.^{1 -3}

Spencer et al reported on a 15-year-old male patient with the presence of gastrointestinal reflux secondary to esophageal dysmotility with gastric stenosis that required several dilations. This picture is like the clinical condition of our patient; however, he did not undergo surgical procedures or procedures that involved dilating the stomach; but in the care of the Gastroenterology service, it was observed that the treatment over time was increasingly ineffective in alleviating the symptoms.

CHDSKM can be presented as a phenocopy of Van den Ende-Gupta syndrome (SVDEG) ⁴ and it is suggested that those individuals who show a combined clinical manifestation of arachnodactyly and blepharophobiasis should be subjected to echocardiography while awaiting molecular test results. In our patient, SVDEG was not considered due to the presence of recurrent pneumothorax, which is not characteristic of this syndrome. CHDSKM has several features that overlap with other connective tissue disorders, and Ehler-Danlos Syndrome was initially considered as a diagnostic possibility. However, the patient’s history of multi-system involvement necessitated molecular studies, which ultimately led to the definitive diagnosis.

In addition, a case has been described of a 30-year-old male clinically diagnosed with CHDSKM (without molecular confirmation) but also presented with congenital hemiplegia, which raises the possibility of an expanded phenotype or a different genetic syndrome. ⁵

Conclusion

This case report deals with a new germline variant of the ABL1 gene, associated with a rather rare and complex syndrome, such as CHDSKM. It is observed that the clinical manifestations in all cases are varied. In the patient described, the large number of episodes of spontaneous pneumothorax and severe esophageal dysmotility stand out, which contribute to the clinical enlargement described above.