Tangier disease with heterozygous mutations in the ABCA1 gene: A case report

Abstract

BACKGROUND

The unusual and extensive endoscopic changes in the gastrointestinal mucosa drew our clinical attention, ultimately leading to the diagnosis of a rare case of Tangier disease with a heterozygous mutation in the ABCA1 gene. Tangier disease is an extremely rare autosomal recessive disorder caused by mutations in the ABCA1 gene, and is classified as a genetic metabolic disease. To date, more than 100 cases of Tangier disease have been reported worldwide, and there is currently no unified diagnostic standard, with clinical manifestations serving as an important basis for diagnosis.

CASE SUMMARY

A 34-year-old male patient underwent gastrointestinal endoscopy during a routine health check-up at our outpatient clinic, which revealed abnormal changes in the intestinal mucosa. Pathology indicated foam cell aggregation. Further auxiliary tests showed an abnormal lipid profile, extremely low serum levels of high-density lipoprotein cholesterol and apolipoprotein A-I, accompanied by massive splenomegaly. Genetic testing subsequently confirmed the rare diagnosis of Tangier disease.

CONCLUSION

The unusual and extensive gastrointestinal mucosal abnormalities detected under endoscopy reflect the core pathophysiological changes of Tangier disease, massive deposition of cholesteryl esters in the mononuclear phagocyte system-rich gastrointestinal mucosa, leading to foam cell infiltration. This indicates that the identification of gastrointestinal mucosal abnormalities have diagnostic and therapeutic guidance value. Early recognition of Tangier disease is essential for appropriate management, including monitoring for potential cardiovascular and neurological complications. Genetic testing is crucial for confirming the diagnosis, especially in cases with a suggested family history.

Key Words: Tangier disease; ABCA1 gene; Gastrointestinal mucosal abnormalities; Splenomegaly; High-density lipoprotein cholesterol; Case report

Core Tip: We report a rare case of Tangier disease. The final diagnosis was established based on abnormal gastrointestinal mucosal changes found on endoscopy, the patient’s medical history and family history, and gene tests. Tangier disease is a rare inherited metabolic disorder characterized by familial high-density lipoprotein deficiency. The main features of this disease include extremely low plasma high-density lipoprotein levels and cholesterol accumulation in tissue macrophages, which can involve multiple organ systems. Therefore, early recognition and diagnosis are crucial for guiding clinical management.

INTRODUCTION

This case is presented as a rare disease ultimately diagnosed due to clinical attention owing to abnormal changes in the gastrointestinal mucosa. Tangier disease was first described by Fredrickson and colleagues in 1961, and it was subsequently noted that these patients not only had severe high-density lipoprotein cholesterol (HDL-C) deficiency, but moderate hypertriglyceridemia and decreased levels of low-density lipoprotein-cholesterol (LDL-C)[1]. This rare disease is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and in 109 cases outside Japan[2]. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level can be less than 25 mg/dL with 20 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL[2]. The hallmark of Tangier disease is cholesterol ester deposition in macrophages throughout the body; not only in the tonsils, resulting in orange tonsils, but also in Schwann cells, resulting in neuropathy, and in lymph nodes, liver, spleen, and intestinal mucosa. Cholesterol ester deposition in macrophages within the intestinal mucosa results in a yellowish appearance. Endoscopically observed “numerous yellowish-brown spotted lesions” and “yellowish-white mucosal changes” are the macroscopic manifestations of cholesteryl ester deposition. These changes, which lack inflammatory infiltration or ulceration, differ from infectious or ischemic bowel disease and represent one of the specific markers of gastrointestinal involvement in Tangier disease[3-5]. Although patients tend to have decreased LDL-C levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available; therefore, early identification and prevention of atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking.

CASE PRESENTATION

Chief complaints

A 34-year-old male patient underwent gastrointestinal endoscopy during a routine health check-up at our outpatient clinic, which revealed unusual and extensive gastrointestinal mucosal abnormalities in the duodenal bulb, terminal ileum, and colorectum.

History of present illness

The patient had no significant abdominal pain, diarrhea, or other related symptoms.

History of past illness

The patient had a long history of thrombocytopenia and splenomegaly. According to the patient’s recollection, thrombocytopenia had been present since childhood. At that time, bone marrow aspiration and biopsy were performed at a hospital in Shanghai, which ruled out acute hematologic diseases. However, the patient did not pursue follow-up visits or reexaminations, and specific medical records are unavailable. Additionally, the patient underwent tonsillectomy 27 years ago, but no relevant surgical records could be retrieved.

Personal and family history

Both of the patient’s parents have long-standing thrombocytopenia and splenomegaly, as well as mild dyslipidemia. They denied consanguineous marriage. Gastrointestinal endoscopy did not reveal similar mucosal changes as seen in the patient.

Physical examination

On physical examination, splenomegaly was noted, with the spleen palpable below the umbilicus.

Laboratory examinations

Initial results of laboratory tests were as follows: Platelets 62 × 10⁹/L (normal range: 125-350 × 10⁹/L), total cholesterol 0.75 mmol/L (normal range: 3.29-4.99 mmol/L), triglycerides 0.74 mmol/L (normal range: 0.11-2.03 mmol/L), HDL-C 0.08 mmol/L (normal range: 0.91-1.71 mmol/L), LDL-C 0.18 mmol/L (normal range: 2.07-3.1 mmol/L), apoA-I 0.05 g/L (normal 1.00-1.6 g/L), and apolipoprotein B 0.20 g/L (normal range: 0.6-1.10 g/L). Preoperative testing, including the T-SPOT.TB test for tuberculosis infection, tumor markers, antinuclear antibodies, antineutrophil cytoplasmic antibodies, erythrocyte sedimentation rate, and routine stool examination, were all negative.

Imaging examinations

In 2022 and 2026, gastroscopy revealed diffuse yellowish-white granular protrusions in the duodenal bulb, resembling a tofu-like appearance. In 2022, 2024, and 2026, colonoscopy demonstrated extensive yellowish-white proliferative and elevated lesions in the mucosa of the terminal ileum, with variable lesion sizes and focal confluent patches. In 2022, 2024, and 2026, the mucosa of the entire colon appeared pale, with numerous yellowish-brown spotted lesions. The rectal mucosa appeared yellowish-white with numerous yellowish-brown spotted lesions. In 2022, capsule endoscopy revealed yellowish-white, dense, granular proliferative changes in portions of the jejunum and ileum, similar to the mucosal changes seen in the duodenal bulb (Figure 1). Pathological biopsy revealed chronic inflammation of the mucosa with lymphoid follicle infiltration in the lamina propria and submucosa, along with aggregation of foamy cells. Immunohistochemical staining revealed CD68 positivity, confirming a macrophage origin (Figure 2).

Figure 1 Endoscopic findings from 2022, 2024, and 2026 showing the duodenal bulb, terminal ileum, colon, jejunum and ileum. A and B: Gastroscopy revealed diffuse yellowish-white granular protrusions in the duodenal bulb, resembling a tofu-like appearance in 2022 and 2026; C-E: Colonoscopy demonstrated extensive yellowish-white proliferative and elevated lesions in the mucosa of the terminal ileum, with variable lesion sizes and focal confluent patches in 2022, 2024, and 2026; F-H: The mucosa of the entire colon appeared pale, with numerous yellowish-brown spotted lesions observed in 2022, 2024, 2026; I-K: The mucosa of the rectum appeared yellowish-white with numerous yellowish-brown spotted lesions in 2022, 2024, and 2026; L and M: Capsule endoscopy revealed yellowish-white, dense, granular proliferative changes in portions of the jejunum and ileum, similar to the mucosal changes seen in the duodenal bulb in 2022.

Figure 2 Pathology images. A-C: Biopsy revealed chronic inflammation of the mucosa with lymphoid follicle infiltration in the lamina propria and submucosa, along with aggregation of foamy cells; D-F: Immunohistochemical staining revealed CD68 positivity, confirming a macrophage origin (× 200).

Contrast-enhanced abdominal computed tomography (CT) showed marked splenomegaly, abdominal CT demonstrated a splenic longitudinal diameter of approximately 18.1 cm on a specific imaging plane (Figure 3A). The longest diameter of the spleen was 17.55 cm on small bowel magnetic resonance imaging (Figure 3B). Carotid Doppler, echocardiography and chest CT showed no significant abnormalities.

Figure 3 Abdominal computed tomography and small bowel magnetic resonance images. A: Abdominal computed tomography demonstrated a splenic longitudinal diameter of approximately 18.1 cm on a specific imaging plane; B: The longest diameter of the spleen was 17.55 cm.

Genome sequencing

Given the comprehensive clinical data, the involvement of multiple systems, and the presence of a family history, we considered the possibility of a genetic disorder. Genetic testing ultimately revealed a compound heterozygous mutation in the ABCA1 gene, with the two mutation sites inherited from the parents, confirming the diagnosis of Tangier disease. Whole exome sequencing of the patient revealed two heterozygous mutations in the ABCA1 gene: c.4060C>A:P.Pro1354Thr and c.1312-10G>A. The patient’s mother carries the c.4060C>A:P.Pro1354Thr mutation, while the father carries the c.1312-10G>A mutation. The variant ABCA1:c.4060C>A (p.Pro1354Thr), exon 29 (29/50), according to the American College of Medical Genetics and Genomics (ACMG) guidelines, is comprehensively classified as a variant of uncertain significance (VUS) based on PM2_P + PP3. For PM2_P, the frequency of this variant has not been reported in the general East Asian population. For PP3, multiple statistical methods predict that this variant has a deleterious effect on the gene or gene product, including predictions of conservation, evolution, and splicing impact. Sorting intolerant from tolerant predicts this variant to be deleterious; PolyPhen-2 predicts it to be probably damaging; the REVEL score was 0.927 (> 0.75 indicates damaging); the ClinPred score was 0.9984 (> 0.6 indicates damaging). This variant has not yet been archived in the ClinVar database. The variant ABCA1:c.1312-10G>A, intron 11 (11/49), according to the ACMG guidelines, is comprehensively classified as a VUS based on PM2_P + PP3. SpliceAI predicts that this variant affects splicing, and dbscSNV also predicts an impact on splicing. This variant has not yet been archived in the ClinVar database. The patient carries two different ABCA1 variants inherited from each parent, which is consistent with an autosomal recessive inheritance pattern. Although each variant is individually classified as a VUS, when a patient carries two rare, predicted deleterious variants and the clinical phenotype is highly consistent with Tangier disease, the combined effect of these two VUSs is highly likely to be pathogenic. Further validation of the ABCA1 gene locus in the patient’s daughter was conducted via Sanger sequencing, which confirmed the heterozygous variant ABCA1 (NM_005502.4):c.1312-10G>A (Figure 4; Table 1).

Figure 4 Genetic test results. A and B: Sanger sequencing chromatogram, the patient’s mother carries the c.4060C>A:P.Pro1354Thr mutation, the patient’s father carries the c.1312-10G>A mutation, and the patient’s daughter also carries the ABCA1 (NM_005502.4):c.1312-10G>A; C: Pedigrees.

Table 1 Two mutation sites in the patient’s ABCA1 gene.

Variant site	Nucleotide change	Amino acid change	Zygosity
Site 1 (exon 29)	c.4060C>A	p.Pro1354Thr	Heterozygous
Site 2 (intron 11)	c.1312-10G>A	– (splice region)	Heterozygous

FINAL DIAGNOSIS

Genetic testing confirmed the rare diagnosis of Tangier disease.

TREATMENT

Currently, there is no specific treatment for Tangier disease. Loss-of-function mutations in the ABCA1 gene are closely associated with reduced HDL levels. ABCA1 has long been considered a potential therapeutic target for the prevention and treatment of atherosclerotic cardiovascular disease. However, large-scale clinical trials of drugs targeting ABCA1 have failed to improve clinical outcomes. Future efforts are needed to identify novel treatment targets within the ABCA1 pathway[6].

OUTCOME AND FOLLOW-UP

In a recent follow-up endoscopy at our hospital in January 2026, new mucosal lesions were observed in the oropharynx and esophagus compared to previous examinations. Numerous round nodular elevated lesions with a yellowish surface were seen in the pharynx and tongue. Scattered granular hyperplasia with yellowish discoloration was noted in the lower esophagus. However, no abnormal changes were observed in the pharyngeal and esophageal mucosa in 2022 (Figure 5).

Figure 5 Comparison of local endoscopic findings between 2022 and 2026. A and B: No significant abnormalities were observed in the oropharyngeal mucosa in 2022; C and D: Numerous round nodular elevated lesions with a yellowish surface were seen in the pharynx and tongue in 2026; E: No significant abnormalities were observed in the esophageal mucosa in 2022; F and G: Scattered granular hyperplasia with yellowish discoloration was noted in the lower esophagus in 2026.

DISCUSSION

Tangier disease is a rare autosomal recessive metabolic disorder caused by mutations in the ABCA1 gene, typically presenting between the ages of 30 and 60 years[1,2]. This condition is caused by mutations in the ABCA1 gene located on chromosome 9q31[7]. Loss of ABCA1 function leads to impaired cellular cholesterol transport, disrupted maturation of nascent HDL-C, and rapid degradation of apoA-I, resulting in extremely low circulating levels of HDL-C and apoA-I[8]. This affects multiple organs and leads to a series of pathological changes. Cholesterol accumulates in various systems throughout the body, particularly in the reticuloendothelial system (mononuclear phagocyte system)[9]. Clinical features include hyperplastic yellow-orange tonsils and hepatosplenomegaly, with approximately half of patients developing peripheral neuropathy. Our patient had a history of childhood tonsillectomy for unknown reasons. As a result of his comprehensive medical history, this was considered to be related to Tangier disease. Relevant literature also indicates that most cases of Tangier disease are diagnosed based on tonsil enlargement[10], orange-yellow tonsils are the most characteristic clinical manifestation of Tangier disease in children and adolescents. In the present study, the patient presented with multisystem involvement and a positive family history, prompting genetic evaluation. Whole-exome sequencing identified compound heterozygous mutations in the ABCA1 gene: c.4060C>A (p.Pro1354Thr) and c.1312-10G>A, inherited from the mother and father, respectively, consistent with an autosomal recessive inheritance pattern. According to ACMG guidelines, each variant is individually classified as a VUS based on PM2_P and PP3 criteria. However, a VUS classification does not imply benignity. Given that the patient carries two rare, in silico-predicted deleterious variants in trans, and the clinical phenotype is highly consistent with Tangier disease, the combined effect of these two VUSs is highly likely to be pathogenic. The c.4060C>A variant is absent in East Asian populations, predicted to be deleterious by multiple algorithms (REVEL 0.927, ClinPred 0.9984), and alters a conserved residue. The c.1312-10G>A variant is predicted to disrupt splicing by SpliceAI and dbscSNV. Segregation analysis confirmed that the unaffected daughter carried only the paternal variant. Although functional studies are lacking, the genetic and clinical evidence strongly supports the diagnosis of Tangier disease. This case highlights that in the appropriate clinical context, compound heterozygous VUSs in ABCA1 can be reclassified as likely pathogenic. Clinical manifestations are an important diagnostic basis, and genetic testing for mutation analysis can confirm the diagnosis.

Our patient underwent gastroscopy, colonoscopy, and capsule endoscopy, and has been followed up for over four years. To date, no single case with complete endoscopic data has been reported in the national or international literature. In the reported cases, abnormalities were observed during either gastroscopy or colonoscopy alone. Notably, no significant gastric mucosal abnormalities were identified in our case during the four-year follow-up, even though it has been reported that the gastric mucosa is one of the most common sites where abnormalities are observed in Tangier disease[4,11]. During gastroscopy, numerous tiny yellowish-white changes can be seen in the gastric antral mucosa, and pathology showed a large number of foam cell aggregations in the lamina propria. The mucosal changes observed during colonoscopy in this case are similar to those mentioned in the literature[12], and the entire colon showed diffuse, continuous yellowish-white turbidity with scattered multiple, dense tiny brownish round spots. However, the literature scarcely mentions the endoscopic findings of the terminal ileum. In our patient, the terminal ileum showed extensive yellowish-white proliferative and elevated lesions in the mucosa, with variable lesion sizes and focal confluent patches. Endoscopic mucosal biopsy pathology revealed foam cell accumulation. When macrophages in the lamina propria of the gastrointestinal mucosa take up large amounts of modified lipoproteins, they are unable to effectively efflux cholesterol, leading to the accumulation of cholesteryl esters within lysosomes and the transformation of these cells into foam cells. The aggregation of numerous foam cells beneath the mucosa of the rectum, colon, and other parts of the gastrointestinal tract gives the mucosal surface a characteristic yellowish-white or yellowish-brown spotted or patchy appearance. These lipid deposits in the lamina propria can be observed by routine white-light endoscopy.

Currently, there is no specific treatment available for Tangier disease. For patients with complications such as atherosclerosis, coronary heart disease, or cerebral infarction, treatments such as anti-platelet aggregation and lipid control can be administered. In addition, patients should engage in physical exercise to correct unbalanced eating habits and control the intake of high-calorie, high-fat, and high-protein foods. Therefore, early diagnosis and close monitoring of complications are of great significance in the treatment of premature coronary heart disease, early-onset diabetes, and neurological disorders.

More than 100 cases of Tangier disease have been reported worldwide. The initial manifestations typically involve the cardiovascular and nervous systems[13,14]. Our patient currently has no significant clinical gastrointestinal or cardiovascular symptoms. However, after three endoscopic surveillance procedures over a period of four years, new gastrointestinal mucosal lesions were found compared to previous findings, and the endoscopic appearance suggests that the disease has progressed. In addition, the patient has not yet shown significant clinical manifestations, especially in terms of neurological and cardiovascular diseases. We speculate that this may be related to the locations of the two mutation sites and the compound heterozygous mutation (rather than a homozygous mutation). If possible, we will further verify the site mutations. This may also be related to the patient’s young age, as age increases, cardiovascular and cerebrovascular symptoms may become more apparent. Therefore, close long-term follow-up is essential.

The parents of our patient denied consanguineous marriage. They are carriers of different mutation sites of the ABCA1 gene (i.e., heterozygotes). With this carrier status, the individual carries only one mutant allele, and thus presents with distinctive but mild clinical and biochemical features. Both parents have a history of splenomegaly and thrombocytopenia, with mild dyslipidemia, and no mucosal changes were observed during gastrointestinal endoscopy. These findings also indicate that the residual activity of one functional ABCA1 allele is sufficient for cholesteryl ester clearance in tissues. The cholesteryl ester efflux function in heterozygous carriers is adequate to maintain lipid homeostasis in most tissues, with only a detectable biochemical abnormality in HDL levels. Our patient has a daughter who also underwent Sanger sequencing, which indicated that she also carries one mutant allele. For carrier families, genetic counseling is essential in order to promptly identify potentially affected offspring and to facilitate early monitoring and preventive measures.

CONCLUSION

This case underscores the importance of remaining vigilant when encountering atypical and unusual endoscopic mucosal abnormalities. A thorough review of the patient’s medical history and comprehensive systemic examinations are essential for a complete and accurate diagnosis. Furthermore, genetic testing is particularly critical for the early diagnosis of rare genetic disorders such as Tangier disease. Although early recognition is essential for monitoring and prognostication of individuals, there is no appropriate management available for Tangier disease. Further research into the full spectrum of clinical manifestations of Tangier disease will help improve early detection and intervention strategies.

ACKNOWLEDGEMENTS

The authors thank all colleagues in the Department of Gastroenterology, Shaoxing Shangyu People’s Hospital, and The First Affiliated Hospital of Zhejiang University School of Medicine, for providing case information.