Esophageal Stricture and Dermal Pathology Related to Compound Heterozygous Mutations in the TNXB Gene

Abstract

The Ehlers–Danlos' syndrome (EDS) constitutes a group of connective tissue disorders that are clinically and genetically heterogeneous. Mutations in the TNXB gene have been recognized as pathogenic causing classical-like EDS due to tenascin-X deficiency. Here, we have reported a unique case of compound heterozygous mutation in TNXB gene leading to esophageal stricture and scarred skin in a 7-year-old boy who presented to us with impacted foreign body in esophagus. The child was also having tendency to atrophic skin scarring secondary to trivial trauma.

Introduction

The Ehlers–Danlos' syndrome (EDS) constitutes a group of connective tissue disorders that are clinically and genetically heterogeneous. Generally, patients present with musculoskeletal and cutaneous manifestations including joint hypermobility, skin hyperextensibility and tissue fragility, easy bruising, and atrophic scarring in the classical form of EDS (cEDS).

Background

Mutations in the TNXB gene have been recognized as pathogenic causing classical-like EDS due to tenascin-X deficiency. Tenascin-X deficiency or classical-like form of EDS (clEDS) resembles phenotypically the cEDS, with hyperextensible skin, generalized joint hypermobility, and a variable tissue fragility as the main clinical features. ¹ However, unlike classical EDS, atrophic scarring is absent in patients with clEDS. Gastrointestinal (GI) complications have been rarely reported with this type of EDS. EDS is a heterogeneous connective tissue disorder. The original Villefranche classification scheme of 1998 for EDS has now been replaced by the 2017 modified EDS classification scheme. The common types include the classical, the hypermobile, the vascular, and some very rare miscellaneous forms. This list includes forms that were not described in the earlier Villefranche scheme including the clEDS which is due to deficiency of the tenascin XB protein. Here, we have reported a case of compound heterozygous mutation in TNXB gene leading to esophageal stricture and scarred skin. Mutations in TNXB gene have been recognized as pathogenic causing clEDS due to tenascin-X deficiency. TNXB gene encodes tenascin XB, a glycoprotein of the extracellular matrix (ECM) predominantly located in the outer reticular lamina of the basement membrane which modulates the adhesion of cells to their ECM. ²

Clinical Features

The clinical relevance of TNX deficiency was first proposed in 1997 by the identification of a patient presenting both congenital adrenal hyperplasia and an EDS-like phenotype. In 2001, it was first demonstrated that isolated TNX deficiency resulted in an autosomal recessive form of EDS, resembling the classical type, however lacking atrophic scarring. ³ A study done in TNXB deficient mice showed progressive skin hyperextensibility, similar to that of individuals with EDS. ⁴ Later, TNX deficiency was officially classified as clEDS, with generalized joint hypermobility, hyperextensibility, easy bruisability, soft and/or velvety skin without atrophic scarring as typical clinical symptoms. Another unique feature was the stricture formation in the esophagus due to impaction of food. Extra-articular symptoms in clEDS mainly in GI and cardiovascular complications were not found to be associated with certain mutations, which been reported after the third to fourth decade. ^{5 6 7 8} Although rare, GI manifestations can lead to life-threatening conditions. Spontaneous perforation of hollow organs is a complication mainly seen in patients with vascular EDS (vEDS) due to mutations in COLLIII and has been very rarely reported in other EDS subtypes. ⁹ A higher prevalence of GI condition seems to exist in clEDS, compared with other non-vEDS, ranging from tracheal or esophageal rupture to spontaneous perforation of colon, diverticula, or small intestine. The reported GI complications in patients with clEDS are rectal prolapse, sinus piriformis perforation by a transesophageal ultrasound probe in a 57-year-old patient, gastric ulcer in a 16-year-old patient, and bowel perforation due to diverticulitis in a 48-year-old patient. ^{5 6 7 8 9 10}

Diagnosis

The diagnosis of the EDS is made clinically on the basis of specific signs and symptoms in patient, some of which are joint hypermobility, atrophic skin scarring, velvety skin, and easy bruisability. These are genetic disorders, and several different genes have been found to be mutated in different subtypes including COL5A1 , COL5A2 , COL1A1 , COL3A1 , TNXB , PLOD1 , COL1A2 , FKBP14 , and ADAMTS2 . Genetic tests can confirm the diagnosis and subtype of EDS.

Treatment

There is no specific treatment for EDS currently available to the patient community. The symptoms of EDS subtypes vary, so the treatment also. The main aspects of management include cardiac function, physical therapy, pain management and prevention of complications, and psychological follow-up as needed. Complications such as wound healing problems, excessive bleeding, aortic dissection, hernia, rectal prolapse, and hollow organ perforation may need surgical intervention.

Case

A 7-year-old boy presented to the casualty with a history of acute onset, recurrent, nonprojectile vomiting with drooling. Any attempt at oral intake was followed by an immediate regurgitation of undigested food and liquids. There were no visible symptoms of diarrhea, fever, abdominal pain, foreign body ingestion, or constipation and no history of similar episodes in the past was observed. Conservative management at the primary center at his home town—intravenous fluids antiemetics and antibiotics—did not help. At the time of evaluation at the casualty at our center, he had mild dehydration but normal vitals, temperature 98°F, pulse rate 110/minute, respiratory rate 16/minute, no pallor, no icterus, no lymphadenopathy, and no edema. His height was 127 cm (70th percentile) and weight was 24 kg (50th percentile), and there were no signs of overt malnutrition. The jugular venous pressure was visible just above the clavicle. There was no abdominal rigidity or guarding, no cardiac murmurs, no hepatosplenomegaly, and bowel sounds were auscultated. Other organ systems functions were unremarkable. The initial work-up including routine tests and chest X-ray and ultrasound of the abdomen was unremarkable, and in view of the poor response to conservative management, an upper GI endoscopy was undertaken that revealed an impacted almond in the lower esophagus and this was retrieved endoscopically ( Fig. 1 ). The upper GI endoscopy was otherwise unremarkable. An upper GI barium contrast revealed a short-segment stricture of the mid-esophagus, 3 cm in length ( Fig. 2 ), which was dilated on a subsequent therapeutic endoscopy. The trivial trauma related to an impacted almond leading to the likely formation of a mid-esophagus stricture prompted further questioning, and it turned out that the child was susceptible to poor healing following minor trauma and the healing process was slow with a tendency to both hypotrophic scars at places and keloid-like scarring at others. He first had a soft tissue infection around the lips and nose as an infant, and had developed subtle scarring around the philtrum of the nose, ala nasi, and the chin ( Fig. 3 ). Similar scarring due to a burn injury was seen on the chest wall and the child was susceptible to easy bruising. The ears had a deformed tragus and deformed ear lobules, related to previous soft tissue infection.

Fig. 1.

Almond in esophagus on endoscopy.

Fig. 2.

Upper gastrointestinal contrast study showing stricture.

Fig. 3.

Scarred skin lesions.

He however did not have joint dislocations and the family history did not reveal similarly afflicted parents, siblings, or cousins. A re-examination of the skin and the musculoskeletal system was undertaken and scars were seen around the nose, mouth, ears, and the chest wall. However, the skin was mildly hyperextensible and the joints did not reveal hypermobility. There was no blue discoloration of the sclera and hernias observed on abdominal examination. Both feet were normal. Clinical exome sequencing of the patient showed compound heterozygous variation in TNXB gene in which missense variant (c.9784C > T) in exon 29 that resulted in the amino acid substitution from arginine to cysteine, at codon 3262 (p.Arg3262Cys) and also, heterozygous missense variant (c.4820T > C) in exon 13 that resulted in the amino acid substitution from phenylalanine to serine, at codon 1607 (p.Phe1607Ser). In gene sequencing, mutations were annotated using published variants in the literature and diseases databases. Common variants were filtered based on allele frequency in 1000 Genome Phase 3, Exome Aggregation Consortium (v1.0), gnomAD (v2.1), Exome Variant Server, Single Nucleotide Polymorphism Database (v151), and internal population database. The TNXB gene variation was compatible with a diagnosis of clEDS in our patient. On follow-up to 6 months, the patient was asymptomatic, and our patient did not have generalized hypermobility of joints but had skin elasticity similar to that found in classical type EDS. Since he is only 7 years old, there is the likelihood of hypermobility of joints developing with age. Furthermore, our patient differed from the classical type in demonstrating hypertrophy of scars at some sites of injuries and burns while having atrophic scarring at the patellae (at variance with the expected clEDS). However, in this child, esophageal stricture was present which was not reported before. Although delayed wound healing with wound dehiscence upon suture removal and widened scars have been reported in ∼50% of TNX-deficient patients present, atrophic scarring is reported to be absent in patients with clEDS. ¹¹ In this peculiar case, scarred skin lesions at multiple sites were present. However, the child did not have many typical symptoms of EDS such joint hypermobility, joint subluxation, or any cardiac involvement. As many case reports showed appearance of symptom as age advances, the child may develop other symptoms in future. Also, newer phenotypic clinical findings are likely to be described in both the classical EDS and the clEDS by other investigators as more cases come to light, given the heterogeneity of molecular pathogenesis related to each genetic variant of EDS. Moreover, it is likely that some of these may have overlapping clinical features and defy phenotypic classifications. This case underscores the need for genetic testing in all EDS cases regardless of their phenotypic manifestations with a view to understanding the complex, interplay between genes and EDS phenotypes.