Within the cohort of 200 patients with FA, 12 individuals presented with at least one NMSC (SCC or BCC), while 25 patients had at least one BT. Though BT were detected at an earlier age than NMSCs (median 17.5 vs. 31.3, years respectively), patients with FA with skin cancers had them at a younger age compared with the general population. Patients had NMSCs in various locations. Topology information was unavailable for some diagnoses, but many occurred in sun-exposed areas, including the scalp and face. NMSC is known as the most common type of cancer in the general population, but usually does not occur until later in life. For individuals of European ancestry, incidence of NMSC peaks at around 70 years of age and is highly unusual in the teenage years, but were observed at these ages in patients with FA [11]. In a recent study that analyzed statistical associations between clinical parameters in NMSC occurrences, researchers found that the mean diagnostic age was 70.1 years for BCC and 74.2 years for SCC [12]. Patients with FA may be at increased risk of developing an NMSC due to their FA diagnosis (a DNA repair disorder). Additionally, patients with FA may be exposed to radiation or long periods of immunosuppression, which could further increase their likelihood of developing an NMSC.

A prior study on NMSC in individuals with FA yielded results consistent with our findings [13]. In this study, all 8 patients with NMSCs had them at early ages compared to the general population, mirroring our observations. One of their patients had 12 occurrences, while one of our patients had 26. Additionally their youngest patient diagnosed with an NMSC was 10 years old, whereas our youngest patient was 11. These findings are in line with our findings, as well as existing literature, and undercore the importance of proactive monitoring through regular consultations with dermatologists.

A greater proportion of female patients had at least one NMSC event compared to male counterparts. In the general population, several studies found a higher incidence of NMSC in males than in females [14,15,16]. However, when Evans et al. stratified their analysis based on patient age, they found that in the 10 to 49 year old age cohort, the majority of BCC patients were females, constituting 60.4% of the cases. Conversely, among individuals 50 to 99 years, females accounted for only 36.0% of the BCC cases [14]. This difference in age groups may be due to hormonal effects. Although many women with FA experience early ovarian failure and early menopause, only three women in our cohort had a diagnosis of primary ovarian failure. However, data was unavailable for some women. Taking in consideration the lower survival probability of FA patients compared to the general population, the Evans et al. study could explain the sex distribution found in our NMSC cohort. To further elucidate the potential factors influencing this unusual sex distribution of NMSC in our FA patient group, it is essential to consider unique aspects related to FA, specifically factors that affect sun exposure, health protection behaviors, and lifestyle choices.

The anatomical locations and pathogenesis mechanisms of benign tumors in this group were extremely diverse. This group included both rare and common growths, occurring at various ages, both pre-transplant and following transplant. We did not identify any clear patterns in the distribution of benign tumors. Due to the lack of information in the literature on benign tumors in the general population, we cannot determine whether FA is characterized by an increased risk of benign tumors.

In this case series, one patient (FANCA) demonstrated 26 occurrences of NMSC. Most of these instances occurred post-HCT, which was performed at the age of 33, following their diagnosis of FA at 32. This patient also presented with an unspecified immunodeficiency, potentially contributing to the heightened susceptibility to multiple skin cancers. Interestingly, this patient is also heterozygous for two of the seven known BCC risk single nucleotide polymorphisms (SNPs)- rs7538876 (AG) and rs157935 (GT). This patient had the reference allele at rs801114 and rs11170164. No information on SNPs rs401681, rs2151280, and rs78378222 were available for this patient. Collins et al. conducted an investigation on malignancies post-organ transplant which highlighted the increased aggressiveness of NMSC in recipients due to immunosuppression [17]. Although this patient did not undergo organ transplantation specifically, it is possible that a long period of immunosuppression played a role in their many occurrences of NMSC.

One patient experienced all three events studied: SCC, BCC, and benign tumors. The patient had the FANCA genotype, and like the patient with 26 NMSC occurrences, received her diagnosis and underwent transplant later in life, at 38 years of age. Prior to the transplant, she was diagnosed with BT and BCC, and subsequently experienced both BCC and SCC post-transplant.

Among the 12 patients diagnosed with SCC or BCC, the majority belonged to the FANCA group (9 patients), with one patient in the FANCC category and two patients with unknown genotypes (Supplemental Fig. 3). Conversely, in the cohort of 25 patients with BT, FANCA remained the predominant genotype, accompanied by two FANCC cases. However, this group displayed a more diverse genotype distribution, encompassing FANCI, FANCJ (BRIP1), FANCG, FANCD1 (BRCA2), and FANCR (RAD51).

Notably, two patients with the rare FANCI genotype presented with BT—one with a colloid cyst of the thyroid and the other with a pineal brain cyst. Additionally, a patient with the rare FANCR genotype manifested a BT in the central nervous system, a spinal lipoma. None of these patients underwent HCT, and none experienced SCC or BCC occurrences. All three patients were diagnosed with FA before the age of 6 months.

The single patient with the FANCD1 genotype presented with both a benign kidney tumor and a parietal lobe tumor in the central nervous system. Additionally, this patient was diagnosed and treated for medulloblastoma at approximately 3 years of age. These occurrences align with existing literature, which indicates that patients with the FANCD1 genotype tend to develop solid tumors at early ages and have a predisposition to developing brain tumors before 6 years of age [18].

Individuals with either BT or NMSC exhibited a noteworthy increase in survival probability at age 30 compared to the control group, (ns, p = 0.0930) (Fig. 1). While the median age at transplant for patients with NMSC was higher than that of patients with BT and controls (30.5, 9.0, 9.1 years, respectively), the median age for patients who developed NMSCs was also greater compared to benign tumor and control groups (33, 17.5, and 15.4 years). Considering these observations, we hypothesize that individuals with FA who develop NMSCs, or BT may have a modifying factor that improved their survival estimates up to age 30, which possibly allowed for the acquisition of DNA damage and subsequent NMSCs. Further investigations into the underlying mechanisms and contributing factors to these tumors and potential modifying factors will be instrumental in determining the nature of these and refining prognostic assessments for individuals with FA.

In 2014, a study characterized the incidence of NMSC in patients enrolled in commercial or Medicare health insurance plans. They found that in United States, NMSC incidence was less than 1% in patients aged 0 to 24, 1% in patients aged 25 to 34, 6% in patients aged 35 to 44 and 17% in patients aged 45 to 54 [14]. For the patients with FA described here, the cumulative incidence of NMSC had a large increase from 4.5% at 30 years to 28% at 50 years (Fig. 1). This jump in incidence emphasizes that age is an important factor in the development of NMSC, and potentially reflects the interplay of genetic and environmental factors in patients with FA. It also highlights the unusual findings of patients with NMSC in their teens/early 20s.

The findings presented in this case series are limited by the relatively small size of the patient cohort, which consisted of 30 individuals with FA and either NMSC or BT. The sample size and ancestry homogeneity of this cohort (86% white), limit the generalizability of our results. Additionally, since most patients with benign tumors were evaluated at the NIH, they were likely evaluated more thoroughly compared to patients for which only medical records review was conducted. This may have increased their likelihood of receiving a benign tumor diagnosis and also limited the generalizability of benign tumor prevalence for this population. However, this cohort of 200 patients with FA is relatively large for this rare disorder. Conducting small case series studies, like the one presented here, becomes imperative to highlight diverse patient profiles and abnormalities within this limited population, even though the results may not be readily generalizable. Another notable limitation is the absence of pathology records for a considerable number of tumors. The lack of these records hinders the comprehensive characterization of the tumors, potentially limiting the depth of insights into their specific nature and behavior. The unavailability of detailed information from pathology reports, including histological subtypes and molecular characteristics, makes it difficult for us to identify patterns in the etiology and progression of the tumors.

In summary, this case study provides a detailed exploration of non-melanoma skin cancers and benign tumors in patients with FA, shedding light on clinical features and factors associated with these events. The findings, consistent with existing literature, underscore the significance of early detection and surveillance of patients with FA, even in cases with milder disease presentations, and highlight the necessity for tailored screening and management strategies for this patient population.