Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant condition caused by mutations of the NF1 gene, located on chromosome 17q11.2 (1). The NF1 gene makes a protein called neurofibromin, which helps prevent tumors by turning off a process that can lead to cell growth, specifically by changing active RAS-GTP into inactive RAS-GDP, which helps control the RAS/MAPK pathway. Neurofibromin is found in high concentrations in melanocytes, Schwann cells, oligodendrocytes, and neurons. It influences how cells develop, how their structure changes, and how they die by working with different signaling pathways, such as PI3K/AKT/mTOR, cAMP/PKA, and Rho/ROCK (2). Loss of neurofibromin function due to defective mRNA or protein expression results in constitutive activation of RAS, leading to uncontrolled cell growth and cancer. Somatic mutations also drive sporadic cancers, including gliomas, neurofibromas, and malignant peripheral nerve sheath tumors (MPNST). Moreover, it can disrupt the mRNA transcript through splicing errors, premature stop codons, or altered coding sequences, leading to loss of functional neurofibromin. The NF1 gene has one of the highest rates of spontaneous mutation in humans; approximately 5,000 pathogenic variations, including large deletions and frameshift, nonsense, missense, and splicing mutations. Both germline and somatic mutations disrupt neurofibromin’s RAS/MAPK regulation, promoting proliferation in NF1-associated tumors (e.g., MPNSTs) and sporadic malignancies (3).

NF1 affects approximately 1 in 2,500 to 3,000 people, making it one of the most prevalent hereditary disorders (4). Clinical manifestations vary significantly among patients due to phenotypic heterogeneity. Despite the frequent identification of NF1 in early childhood, some individuals may not receive a diagnosis until their late 20s, 30s, or even later (5).

The hallmark of NF1 is the development of neurofibromas. They are generally benign and asymptomatic but can cause pain and damage to the surrounding tissues. They start in the cells and tissues of the nervous system and are the defining feature. Additional clinical features include pigmentation changes such as café-au-lait spots on the skin, as well as benign skin tumors or freckles. Brain tumors, anomalies of the bones, and other complications are examples of other clinical features the patients could develop (6).

Therapeutic interventions are determined according to the symptoms that appear on the patient; for example, mitogen-activated protein kinase (MEK) inhibitors (selumetinib, mirdametinib) for plexiform neurofibromas. For malignant peripheral nerve sheath tumors (MPNSTs), complete surgical resection is the only curative treatment for localized MPNST, while radiotherapy is considered for high-grade or incompletely resected tumors, and neoadjuvant chemotherapy with anthracycline and ifosfamide is the standard regimen for high-risk cases despite limited randomized data (7). Management involves annual dermatologic/neurologic exams, blood pressure monitoring, and whole-body MRI for high-risk patients, with women starting breast MRI at 30 due to elevated risk. Emerging therapies include NF1 mRNA replacement, RAS inhibitors, and anti-Transforming Growth Factor-beta (anti-TGF-β) for MPNSTs (8).

Optic nerve gliomas, glioblastomas, paragangliomas, malignant ganglioneuromas of peripheral nerves, breast cancer, leukemia, and rhabdomyosarcoma are among the neoplasms whose NF1 has been linked to an elevated risk (9). One of the most prevalent abdominal cancers associated with NF1 is gastrointestinal stromal tumors (GISTs) (10). Recent case reports have highlighted a connection between gastrointestinal stromal tumors (GISTs) and neurofibromatosis type 1 (NF1), but papillary thyroid carcinoma (PTC) remains rare among NF1 patients, with only three documented cases of large thyroid tumors in the literature.

Here, we present the first reported case of an unusual association of papillary thyroid carcinoma and gastrointestinal stromal tumor in a 30-year-old female patient who was previously diagnosed with NF1.

A 30-year-old Palestinian female patient, diagnosed with NF1 at the age of 10 years, was in her usual state of health until November 2023, when she presented to our center complaining of severe abdominal pain for 2 days. The pain was colicky in nature, localized in the epigastric region and radiating to the mid-gastric region, and was associated with nausea and black tarry stool, with no fresh hematochezia or hematemesis.

Her personal background demonstrates that her parents are first-degree cousins, her father passed away from multiple myeloma, she has three healthy siblings, and none of her family members have a similar condition.

Physical examination showed that the patient was conscious, drowsy, and pale; multiple café au lait spots (more than 6 lesions measured >15 mm) with multiple skin lipomas were noticed all over her body. Abdominal examination showed mild left lower quadrant tenderness with palpable right upper quadrant cystic lesions, while neck examination was normal with no visible or palpable neck masses or lymph nodes; the rest of the physical examination was unremarkable.

The gastrointestinal medical team was consulted, and further evaluation was recommended. For this reason, she underwent two sessions of upper gastroscopy that showed no active bleeding or other abnormalities. Then the patient underwent colonoscopy, and the colon and terminal ileum were full of altered blood. Pushed endoscopy was done, showing about 3–4 cm of rounded submucosal lesion with an ulcer at the tip and minimal bleeding at the proximal jejunum, suggesting GIST. Subsequently, abdominal computed tomography (CT scan) was ordered, which showed a well-defined intraluminal heterogeneous enhancing soft tissue lesion noted within the jejunal loop at the right upper abdomen, measuring about 2.5 x 2 cm, as shown in Figure 1 .

Surgical resection and anastomosis were done for the jejunal mass. The mass was sent to the pathology lab, which confirmed the diagnosis of small bowel GIST in the jejunum. After the operation, the patient was sent back to the Intensive Care Unit (ICU), where she stayed for three days, and then was transferred to the surgical ward for another seven days.

The patient received two units of packed red blood cells (PRBCs) on admission due to a drop in hemoglobin from 8.9 to 5.5, and an additional five units over the next four days. She was also given six units of fresh frozen plasma (FFP) and two units of platelets before her operation.

A whole-body CT scan with intravenous contrast was performed during her hospital stay, and the results were as follows: Brain CT Scan: A suspected small hypodense lesion was seen in the hypothalamic area measuring about 1 cm in diameter as shown in Figure 2 .

Non-enhanced Axial CT scan shows a hypodense lesion (red arrows).

Neurofibromatosis type 1 is a multisystem disorder that affects 1 in 3,000s (11). The primary cause of NF1 is a mutation of the NF1 gene on chromosome 17q11. 2 (1). Numerous clinical traits that might manifest at any age are linked to NF1. Every racial and ethnic group is affected, and both sexes are equally affected (12). Neurofibromatosis type 1 is characterized by several café-au-lait macules (CALMs), cutaneous neurofibromas (CNs) (12), plexiform neurofibromas, deep or subcutaneous nodular neurofibromas, and distinctive ocular symptoms. Individuals with NF1 are more likely to experience difficulties with behavior, learning, and social adaptation. Optic or non-optic brain tumors occur far more frequently; however, the majority of these tumors have a benign course. People with NF1, particularly those with large numbers or big-size plexiform or deep nodular neurofibromas, are more likely to develop malignant peripheral nerve sheath tumors that tend to emerge at a much younger age and have a poorer prognosis than in the general population (13).

NF1 can be diagnosed by applying the diagnostic criteria established by the National Institutes of Health (NIH). To make the diagnosis of NF1, an individual must meet a minimum of two of the following requirements: (a) possessing six or more café-au-lait spots measuring more than 5mm in the prepubertal period and more than 15 mm in the post-pubertal period, (b) a growing plexiform neurofibroma or several other neurofibromas, (c) freckling in the groin area or armpits, (d) having an optic glioma, (e) at least two growing Lisch nodules (hamartomas), (f) displaying specific skeletal abnormalities, or (g) having a first-degree relative with NF1 (14). Based on the initial two diagnostic criteria, our patient was identified as having NF1. The patient developed GIST after being diagnosed with NF1. A period of time later, the patient was then diagnosed with PTC.

It is well established that NF1 predisposes to cancers (15). Patients with NF1 have an increased risk of various tumors. The most common are non-neurofibroma neoplasms (28.1%), followed by low-grade gliomas (22.3%), particularly optic pathway gliomas (16.5%). Sarcomas, such as malignant peripheral nerve sheath tumors (4.5%) and breast cancer (1.9%), and Gastrointestinal stromal tumors (0.6%) also occur. Less frequent tumors include endocrine neoplasms (pheochromocytoma, neuroendocrine tumors), skin cancers (basal cell carcinoma), leukemias, genitourinary cancers, lymphomas, and rare cases of lung cancer, meningioma, and others. This diverse tumor spectrum underscores the need for vigilant monitoring in NF1 patients (16).

GIST is one of the most prevalent non-neurological malignancies compared to the general population; NF1 individuals had a 45 times greater incidence of GIST (17). Which is a mesenchymal tumor typically originating in the stomach or small intestine (18). In contrast to sporadic GIST, NF1-associated GIST is more frequent in women and manifests at a younger age (19). Our patient has one tumor in the jejunum. Our patient’s gastroscopy showed no abnormalities or active bleeding. Therefore, abdominal CT or magnetic resonance imaging should be performed on middle-aged and elderly NF1 patients who have gastrointestinal symptoms to rule out GIST in the intestines. A CT scan of the abdomen can reveal tumors and provide details about their size, location, edges, and how they interact with nearby tissues. Capsule endoscopy and small intestinal endoscopy are also commonly used to diagnose GISTs (19). The diagnosis for our patient was confirmed by conducting an abdominal CT scan and capsule endoscopy. On the other hand, the case took an unexpected turn when a thyroid nodule with hypermetabolic uptake was subsequently discovered on a PET scan. Additional tests, which included ultrasound-guided biopsy and FNA, revealed PTC, demonstrating the complex nature of the patient’s medical condition. Endocrine tumors, like pheochromocytomas, are more common in people with NF1, with a percentage of 0.1% to 5.7% of NF1 individuals (20), but PTC appears to be quite uncommon in NF1 patients (21). The literature currently has very few instances demonstrating NF1 with PTC, but none of them showed the co-existence of GIST and PTC with NF1.

No family history of NF1 was present in the patient, except for her father, who passed away from multiple myeloma (MM). The association between MM and NF1 is very rarely described in the literature. The data did not support a direct link between NF1 and MM pathogenesis (22). This study has potential limitations; one of the patient’s case limitations was the lack of a childhood neurofibromatosis diagnosis. Furthermore, the diagnosis procedure would have been delayed, and significant expenditures associated with genetic testing.

To the best of our knowledge, this case is the first case combining GIST, PTC, and NF1 in one patient, and that’s what makes our case report unique.

The fact that GIST occurs together with PTC in this NF1 case draws attention to the intimate connection between genetics and the formation of tumors. Physicians should always bear in mind that there are many forms of cancer in people suffering from NF1, like in this patient’s case. The point also emphasizes the care taken during genetic testing when making treatment strategies, indicating a probable relationship between genes and the development of tumors among patients suffering from NF1. Research is needed to understand the complex mechanisms behind the different manifestations and tumors that occur in individuals with NF1.