Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by congenital ichthyosis, atopic manifestations, hair shaft abnormalities, immunological dysfunction, and multi-systemic complications. The underlying genetic defect is associated with loss of function mutations in the SPINK 5 gene, located on chromosome 5q32. This leads to impairment of a serine peptidase inhibitor, lympho-epithelial Kazal-type-related inhibitor (LEKTI) [1],[2],[3].

Congenital ichthyoses exist on their own or as part of a syndrome, such as in NS. This disorder of skin keratinization manifests as hyperkeratosis and abnormal skin scaling over the entire body. Congenital ichthyoses have increasingly been linked to the development of non-melanoma skin cancers in the literature, including in NS patients [4],[5],[6],[7],[8],[9],[10]. One review included 28 cases of inherited ichthyoses associated with skin cancer, including three NS patients [6].

This case further adds to the available evidence of the association of Netherton syndrome with the development of non-melanoma skin cancer. This is also the first case of recurrent inguinal squamous cell carcinoma (SCC), with nodal metastasis, in a patient with NS.

A 54-year-old male with a past medical history of NS, multiple squamous cell skin cancers, systemic lupus erythematosus (on hydroxychloroquine) was admitted to an outside hospital with an enlarging left inguinal mass with ulceration and necrosis. Prior to admission, he was treated with cefalexin followed by trimethoprim-sulfamethoxazole by his primary care doctor for a left inguinal soft tissue infection.

On admission, he was started on IV (intravenous) vancomycin and IV piperacillin/tazobactam. Surgery was consulted and he underwent wide local resection, superficial and deep regional lymph node dissection, and resection of the left femoral vein. Biopsy specimens showed moderately differentiated invasive squamous cell carcinoma with involvement of 2/5 regional lymph nodes and invasion of the left femoral vein apex and wall (Figure 1). Computed tomography (CT) without contrast of the chest, abdomen, and pelvis did not show any evidence of metastatic disease. Intraoperative wound cultures were positive for Escherichia coli, Pseudomonas aeurignosa, and Streptococcus viridans. IV vancomycin and IV piperacillin/tazobactam were transitioned to IV aztreonam and IV cefepime for a total of 14 days of antibiotics.

The patient was then transferred to our tertiary care medical center for hematology/oncology and plastic surgery evaluation. Shortly after transfer, he was found to have evidence of a post-surgical wound infection and developed septic shock with 3/3 blood cultures positive for Methicillin-resistant Staphylococcus aureus (MRSA). He was treated with vasopressors and IV daptomycin. His hospital course was further complicated by Clostridium difficile colitis with toxic megacolon requiring total colectomy and end ileostomy. He eventually underwent further wound excision with autograft to the left groin by plastic surgery. His graft did not adhere appropriately in the presence of an enlarging left inguinal mass. He underwent core biopsy of this left inguinal mass which was positive for recurrent squamous cell carcinoma.

After further evaluation by surgery, the tumor was determined to be unresectable. Given his current condition and medical comorbidities, he was felt to be too unstable for inpatient systemic chemotherapy. He was also determined to be a poor radiation candidate due to the extent of his left inguinal wound. After further discussion with the primary team and oncology, the patient decided to pursue transfer to an inpatient hospice facility and eventually passed away from complications of his cancer.

Netherton syndrome is a very rare multi-system disease with both cutaneous and extra-cutaneous manifestations. It is characterized by severe skin manifestations, hair shaft defects, and multi-systemic complications [11].

Squamous cell carcinoma has been reported in only a handful of cases of adults with NS [5],[7],[8]. It is unclear whether these occurrences are incidental, however growing evidence exists for syndromes with inherited ichthyoses and the development of skin cancer. For example, Keratitis–ichthyosis–deafness (KID) syndrome, an autosomal dominant disease characterized by congenital erythrokeratoderma has been associated with skin cancers [6]. Non-melanoma skin cancers have also been reported in congenital ichthyosiform erythroderma and lamellar ichthyosis [5].

Although causation for the development of skin cancer in NS has not been proven, it can be postulated how susceptibility for skin neoplasms could arise in this patient population. At the molecular level, LEKTI activity is evident in many tissue types including epithelia, mucosa, and thymus, and is suggested to play a role in epidermal barrier function and immunity. It is therefore feasible that LEKTI perturbations may impact T cell differentiation and IgE overproduction, ultimately leading to altered epidermal cell growth, proliferation, differentiation, and invasive capacity [12].

Prior studies have suggested that skin cancer in NS patients could also be related to chronic inflammation of the skin, chronic infections, such as human papillomavirus (HPV), or the use of treatments such as ultraviolet (UV) therapy or immunosuppressants. B-cell and natural killer (NK) cell dysfunction also occurs, which could lead to diminished immunosurveillance of the skin. In KID syndrome, congenital ichthyosiform erythroderma and lamellar ichthyosis, it has been hypothesized that epidermal barrier dysfunction may lead to impaired T-cell surveillance due to increased UV radiation penetration [5]. In our patient, it is possible that the use of immunosuppressive medications for his lupus erythematosus could have also contributed to the development of his recurrent squamous cell carcinoma.

Further investigation is needed to better highlight the complexity of factors associated with the development of SCC in patients with NS and other forms of ichthyoses. Genotype/phenotype correlations between LEKTI domain deficiency and clinical manifestations in NS patients have recently been elucidated, thereby hinting at possibilities for eventual targeted therapeutic interventions [13],[14]. At present, studies have strongly recommended routine surveillance for skin malignancies in patients with NS and other types of congenital ichthyoses. Ongoing clinical trials using immunotherapies are also being tested as potential new targets for treatment of NS patients [11].

Netherton syndrome is a rare autosomal recessive disorder consisting of congenital ichthyosis, severe atopic manifestations, hair shaft abnormalities, immunological dysfunction, and multi-systemic complications. This case highlights an adult patient with NS who developed recurrent inguinal squamous cell carcinoma with nodal metastasis. Growing evidence exists for the development of non-melanoma skin cancers in patients with NS and other forms of ichthyoses.