Overview

In 1960, Riley and colleagues first delineated a symptom complex in a series of patients from a single family, which they identified as an autosomal dominant trait [1]. The primary clinical manifestations included macrocephaly, pseudopapilledema, and multiple hemangiomata. Subsequently, in 1963, Lloyd and Dennis provided a more detailed account of what is now known as Cowden syndrome (CS) [2], named after the family in which the syndrome was initially identified. CS is primarily characterized by the presence of multiple hamartomas, an increased risk of developing thyroid or breast cancer, and its transmission through an autosomal dominant pattern. The genetic underpinning of CS is most commonly linked to a mutation in the PTEN gene, located on chromosome 10q23 [3]. This mutation is implicated in the majority of CS cases.

Case

A 58-year-old male patient was referred to our institute following the discovery of numerous gastric polyps at another hospital during an evaluation for dyspeptic symptoms. His medical history was notable for childhood seizures, for which he was receiving antiepileptic therapy. Additionally, he had been diagnosed with borderline autism by a psychiatrist. The patient reported a familial history of metastatic breast cancer in his paternal uncle, who also suffered from numerous intestinal polyps.

Upon detailed clinical examination, the patient exhibited coarsened facial features, macrocephaly, and distinct blackish pigmentation on his face (Fig. 1). Small papules were also observed on the dorsum of his hand (Fig. 2). Gastroduodenoscopy revealed several gastric and duodenal polyps, along with severe glycogenic acanthosis (Fig. 3) and multiple duodenal polyps (Fig. 4). Histopathological examination of the esophageal lesions identified a thick layer of clear cells laden with glycogen, notable papillomatosis, and acanthosis, with lamina propria papillae extending close to the surface (Fig. 5). Colonoscopy identified multiple hyperplastic polyps throughout the colon. An ultrasound of the neck revealed a multicystic goiter, with no signs suggestive of malignancy. Clinical examination of the breasts showed no abnormalities.

Fig. 1
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Facial characteristics include hyperpigmentation on the lips, many dark papules on the forehead, and macrocephaly with a large forehead

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Fig. 2
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A small papule on the middle finger

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Fig. 3
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One of the characteristics of CS, severe glycogenic acanthosis, on upper GI endoscopy

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Fig. 4
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There are several small polyps in the second part of the duodenum

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Fig. 5
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The esophageal lesion’s histopathology reveals acanthosis and papillomatosis, along with a thick layer of cells and clear cells packed with glycogen, as well as an expansion of the lamina propria next to the surface

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Given the high clinical suspicion of CS, we proceeded with PTEN gene mutation analysis. The analysis identified a heterozygous nonsense mutation in exon 5 of the PTEN gene (chr10:g.87933147C > T; depth 180 ×), leading to a premature protein truncation at codon 130 (p.Arg130Ter; ENST00000371953.8) and resulting in a stop codon. No other significant single-nucleotide variants (SNVs), insertions and deletions (INDELs), or copy number variants (CNVs) were detected in the assay. Owing to the absence of living first-degree relatives and the refusal of second-degree relatives to participate in genetic testing, further familial genetic investigation could not be conducted.

Discussion

Here, we report a case of a patient diagnosed with Cowden syndrome, with a heterozygous pathogenic variant in the PTEN gene. CS is an autosomal dominant disorder and is primarily attributed to mutations in the PTEN gene, a tumor suppressor gene, in approximately 80% of cases. PTEN, a dual-specificity phosphatase, functions both as a lipid and protein phosphatase, playing a critical role in cellular regulation. The lipid phosphatase activity is implicated in G1 cell cycle arrest and apoptosis through the PI3K/AKT pathway, while the protein phosphatase activity is involved in the mitogen-activated protein kinase (MAPK) pathway, which regulates cell survival. Consequently, PTEN is integral to cellular processes such as proliferation, migration, and apoptosis [4].

Apart from its phosphatase-dependent functions, PTEN also exhibits phosphatase-independent activities in both development and normal physiology, as well as in pathological states including diabetes and cancer. Other genes associated with CS include the succinate dehydrogenase B/D (SDHB/D) gene in about 10% of cases [5], KILLIN, phosphatidylinositol 4,5-bisphosphate-3 kinase catalytic subunit alpha (PIK3CA), and AKT1 genes.

Clinically, CS is often associated with macrocephaly, mucocutaneous lesions, benign and malignant thyroid lesions, gastrointestinal hamartomas, developmental delays, breast cancer, and benign breast disorders such as fibrocystic disease. Patients with CS are at an elevated risk for malignancies, particularly breast and thyroid cancers. Breast cancer is the most common malignancy associated with CS, occurring in 25 to 50% of cases. Non-medullary thyroid carcinoma accounts for 3 to 10% of cases [6], with other related cancers including colorectal, renal cell, cutaneous melanoma, and endometrial carcinomas (5 to 10%).

CS is also linked with multiple noncancerous lesions. These include benign hamartomatous overgrowth in various tissues, gastrointestinal polyps, diffuse glycogenic acanthosis, benign breast disease, and arteriovenous malformation with hemangioma (24–34%). Kay et al. suggest that colonic polyps and diffuse glycogenic acanthosis should be considered as pathognomonic for CS [7]. The majority of patients present with mucocutaneous manifestations, with trichilemmomas being considered pathognomonic, alongside other features like papillomatous papules, acral keratosis, and lipomas. Benign thyroid nodules and goiter occur in 70 to 80% of cases. Dysplastic cerebellar gangliocytomas, also known as Lhermitte-Duclos disease, are recognized as a diagnostic marker of CS.

Diagnosing this rare but potentially malignant syndrome requires a high level of clinical suspicion. The International Cowden Syndrome Consortium diagnostic criteria are employed for diagnosing CS (Table 1).

Table 1 The International Cowden Syndrome Consortium criteria [8]
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Operational diagnosis of CS in an individual is considered if as follows:

  1. 1.

    At least three major criteria are present, with at least one of these being macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas

  2. 2.

    A combination of two major criteria and three minor criteria are met.

Given the genetic etiology of CS, there is currently no curative treatment available. However, due to the increased risk of malignancies in the breast, thyroid, and other organs associated with this syndrome, proactive and regular screening is pivotal for early detection and management of potential malignancies.

For breast cancer surveillance, regular self-examinations and annual mammography or magnetic resonance imaging (MRI) are recommended, particularly if there is any clinical suspicion or risk factors present. An annual physical examination by a healthcare provider, with a particular focus on the thyroid and breasts, is also advised.

For the early detection of thyroid malignancies, baseline and subsequent annual thyroid ultrasounds are recommended. Any lesions that are deemed suspicious upon ultrasound examination should undergo biopsy for further evaluation.

Furthermore, in cases where a family history of malignancy is present, it is advisable for the suspected proband (the first affected family member seeking medical attention for a genetic disorder) to commence participation in a screening program at least 5 to 10 years prior to the age at which the cancer was diagnosed in the affected relative. This proactive approach aims to facilitate earlier detection and intervention, potentially improving clinical outcomes.

Why is this a noteworthy case report?

This case report merits attention due to its contribution to the heightened awareness and understanding of CS. CS is a multifaceted disorder presenting with a diverse array of symptoms. Notably, early-life neurological changes, distinctive mucocutaneous lesions, and the endoscopic findings of diffuse glycogenic acanthosis coupled with intestinal polyps are pivotal in raising clinical suspicion for CS. Early recognition of these signs is crucial for the timely screening and potential intervention of associated malignancies, particularly in the breast and thyroid.

In essence, CS, which is a rare autosomal dominant condition with a propensity for malignancy, necessitates a heightened level of vigilance from physicians. The presence of the characteristic features delineated in this case report should prompt clinicians to consider a differential diagnosis of CS. This approach is vital in facilitating early diagnosis and appropriate management, potentially improving patient outcomes in the context of this complex and multifarious disease.