Non-malignant features of cancer predisposition syndromes manifesting in childhood and adolescence: a guide for the general pediatrician

We conducted a comprehensive literature search to identify relevant publications on CPS and their respective non-malignant manifestations in children and adolescents. The primary sources of data were the CCR pediatric oncology series published in 2017, covering the 50 most common CPS with ≥ 5% cancer risk (Supplemental Table 1), as well as ORPHANET and GeneReviews ® [Internet] for information on non-malignant features of these CPS. Additionally, the PubMed database was searched using combinations of the following keywords: "cancer predisposition syndromes", "non-malignant symptoms", "non-neoplastic symptoms", "phenotypic manifestations", and specific syndrome names [e.g., neurofibromatosis type 1 (NF1), Beckwith–Wiedemann syndrome (BWS)]. CPS without non-malignant manifestations, e.g. Li-Fraumeni syndrome, were excluded from this analysis.

Studies were included whenever they met the following criteria:

Studies were excluded if they:

Extracted data included syndrome names, affected organ systems, specific non-malignant signs and symptoms, frequency of signs and symptoms, and age at first occurrence, if applicable (Supplemental Table 2). No further exploration of hematological manifestations was performed. A structured approach was used to categorize the findings by organ system (Fig. 2), ensuring a comprehensive overview relevant to daily clinical practice.

Non-malignant dermatological features (Table 1) are often among the earliest and most apparent indicators of CPS. Café-au-lait spots, frequently associated with NF1 [37‐39] and constitutional mismatch repair deficiency (CMMRD) [15, 40, 41], are light brown skin lesions that vary in size and number (Fig. 3a, b). Patients with NF1 typically have six or more spots, which are crucial for diagnosis [37, 39]. These spots often appear in early childhood and may be accompanied by axillary or inguinal freckling. Facial angiofibromas, common to tuberous sclerosis complex (TSC) [42‐45], present as red or flesh-colored papules primarily on the nose and cheeks (Fig. 3e). Other notable dermatological features include hyperpigmentation and telangiectasias in Bloom syndrome (BS) [46, 47] due to increased sun sensitivity, sebaceous adenomas in Muir–Torre syndrome (MTS) [48, 49], palmar or plantar pits in Gorlin syndrome (GS) [50‐53], and mucocutaneous perioral pigmentation in Peutz–Jeghers syndrome (PJS) [54‐56] (Fig. 3f). Conditions such as xeroderma pigmentosum (XP) [57, 58] and Rothmund–Thomson syndrome [59, 60] are characterized by severe photosensitivity, poikiloderma, and cutaneous atrophy, necessitating strict photoprotection to prevent skin damage and malignancy. Additionally, Birt–Hogg–Dubé syndrome (BHDS) [61] often presents with fibrofolliculomas, trichodiscomas, and acrochordons. Rubinstein–Taybi syndrome (RTS) [62] features keloid formation, while Cowden syndrome, part of PTEN hamartoma tumor syndrome (PHTS) [54, 63, 64], features pigmentation anomalies such as trichilemmomas and papillomatous papules.

Neurological and developmental anomalies (Table 2) are significant indicators of CPS. Cerebellar ataxia, a hallmark of ataxia-telangiectasia (A-T) [65‐67], manifests as a progressive loss of coordination and balance. Patients exhibit oculomotor apraxia, making eye movements difficult. Intellectual and learning disabilities are prevalent in NF1 [37‐39, 68], TSC [42‐45], and PHTS [54, 63, 64], posing substantial challenges during cognitive development. Seizures and autism spectrum disorder are primarily associated with TSC [42‐45], with seizures often being refractory and difficult to manage. Macrocephaly is a common feature in both NF1 [37‐39, 68] and PHTS [54, 63, 64], and in the context of CPS, it often coexists with other dysmorphic features or neurological anomalies. Furthermore, developmental delay, hypotonia, and speech difficulties are common to several syndromes, such as Costello syndrome (CS) [69, 70] and cardiofaciocutaneous (CFC) syndrome [71]. Patients with BS [46, 47] may demonstrate normal intelligence but suffer from speech and drooling issues that can be misinterpreted as intellectual deficiency.

CPS can profoundly affect growth and metabolism (Table 2). BWS [72, 73] is characterized by both prenatal and postnatal overgrowth, as well as associated features such as macroglossia, which can lead to difficulties in feeding and speech. Hyperinsulinism, leading to hypoglycemia, is a common metabolic issue in BWS [72, 73]. BS [46, 47] often presents with failure to thrive due to growth difficulties, proportionate growth deficiency of prenatal onset, and continued growth deficiency throughout life. Growth hormone deficiency, often seen in NF1 [37‐39] and Fanconi anemia (FA) [67, 74, 75], results in short stature and other related complications. Additionally, conditions such as Simpson–Golabi–Behmel syndrome [76‐78] feature prenatal and postnatal overgrowth, macrocephaly, and macroglossia. Patients with CS [69, 70] exhibit severe postnatal feeding difficulties, failure to thrive, and short stature.

Facial anomalies (Supplemental Table 3) are common non-malignant indicators of many CPS and can serve as important diagnostic clues. Proteus syndrome (PS) [54, 79, 80] can result in asymmetric overgrowth of facial features, contributing to a distinctive facial appearance. In multiple endocrine neoplasia type 2B (MEN2B) [17, 81, 82], mucosal neuromas (Fig. 3d) cause bumpy, often enlarged lips and tongue.

A broad or prominent forehead is observed in several CPS. For instance, patients with Noonan syndrome (NS) [83, 84] typically present with a broad forehead, while those with CFC syndrome [71] exhibit a large forehead. Bohring–Opitz syndrome (BOS) [85] also includes a prominent forehead with glabellar nevus flammeus. RTS [62] is characterized by highly arched eyebrows and long eyelashes. Patients with NS [83, 84] may present with hypertelorism and ptosis, as well as downslanting palpebral fissures. In CS [69, 70], ptosis and full cheeks are common, while BOS [85] features synophrys, proptosis, and hypertelorism. A convex nasal ridge is typical in RTS [62], whereas patients with CFC syndrome [71] often present with a short nose with a depressed nasal bridge. BOS [85] can feature a depressed, wide nasal bridge and anteverted nares. NS [83, 84] patients frequently have a short nose with a depressed nasal bridge as well. Patients with CS [69, 70] often have a large mouth with prominent lips and thickened ear helices. Ear anomalies are also notable in several CPS; low-set, posteriorly rotated ears are common in NS [83, 84], while patients with CFC syndrome [71] may exhibit low-set ears as well.

Non-malignant ocular symptoms (Table 3) include retinal hamartomas in TSC [42‐45] and Lisch nodules, which are pigmented iris hamartomas, in NF1 [37‐39]. Patients with Wilms tumor-aniridia-genitourinary anomalies-intellectual disability (WAGR) syndrome [86, 87] frequently exhibit aniridia, which can be associated with other eye anomalies such as cataract, glaucoma, and optic nerve hypoplasia. Additionally, conditions like BOS [85] can present with retinal and optic nerve anomalies, high myopia, and other vision issues.

Hearing loss (Table 3), both sensorineural and conductive, is associated with neurofibromatosis type 2 (NF2) [88‐90]. Patients with NF2 often develop bilateral vestibular schwannomas, leading to progressive hearing loss.

Thyroid anomalies (Table 3) are prevalent in several CPS. For example, PHTS [54, 63, 64] often presents with thyroid nodules and a predisposition to thyroid cancer. DICER1 syndrome [64, 91, 92] is associated with multinodular goiter and differentiated thyroid cancer.

Pulmonary cysts leading to spontaneous pneumothorax are characteristic of BHDS [61]. In DICER1 syndrome [64, 91, 92], cystic lesions in terms of pleuropulmonary blastoma (PPB) type I may precede the more aggressive malignant types II and III. Chronic respiratory infections due to immunodeficiency are common in A-T [65‐67], and pulmonary fibrosis is a significant concern in dyskeratosis congenita [93, 94]. Patients with TSC [42‐45] may develop lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia.

Congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy are associated with NS [83, 84] and CS [69, 70]. Patients with CFC syndrome [71] often present with valvular pulmonary stenosis and hypertrophic cardiomyopathy. Vascular anomalies, including arterial stenosis and aneurysms, are notable in NF1 [37‐39, 68] and BS [46, 47], whereas cardiac fibromas are typical in GS [50‐53]. Vascular malformations are also significant, with conditions like Bannayan–Riley–Ruvalcaba syndrome [54, 63, 95] presenting with hemangiomas and vascular anomalies, and PS [54, 79, 80] featuring vascular malformations, which may be capillary, venous, or lymphatic in nature.

Hepatomegaly and nephromegaly are frequent findings in BWS [72, 73], while splenomegaly is common in FA [67, 74, 75]. Additionally, gastrointestinal anomalies such as esophageal and duodenal atresia may occur in individuals with FA, contributing to feeding difficulties and requiring surgical interventions early in life. Cystic nephromas, which are benign kidney tumors, are often seen in DICER1 syndrome [64, 91, 92]. PJS [54‐56] presents with gastrointestinal polyps, which may be detected at any site within the GI tract, most frequently in the small intestine, and may lead to complications such as intussusception.

Renal cysts and tumors are prevalent in Von Hippel-Lindau (VHL) disease [96‐98] and BHDS [61]. Ambiguous genitalia and disorders of sex development are indicative of WAGR syndrome [86, 87]. Denys–Drash syndrome [99] features nephropathy that progresses to end-stage renal disease, along with genital anomalies such as ambiguous genitalia.

Musculoskeletal anomalies (Table 4) include scoliosis and bone dysplasia in NF1 [37‐39], and jaw cysts along with bifid ribs in GS [50‐53]. MEN2B [17, 81, 82] is characterized by marfanoid habitus, pes cavus, pectus excavatum, and joint hyperextensibility. RTS [62] features joint hypermobility and skeletal dysplasia.

Benign tumors (Table 4), including lipomas, hamartomas, and adenomas, are commonly observed in MEN syndromes and PJS [54‐56]. MTS [48, 49] features sebaceous adenomas and epitheliomas, while PHTS [54, 63, 64] presents with mucocutaneous hamartomas and thyroid pathology.

Polyhydramnios and preterm birth represent obstetric complications associated with BWS [72, 73] and TSC [42‐45]. BWS [72, 73] may be associated with abdominal wall defects.

The non-malignant features of CPS affect nearly every organ system, necessitating comprehensive and continued evaluation (Fig. 2). For instance, dermatological manifestations such as café-au-lait spots, facial angiofibromas, and sebaceous adenomas serve as critical early indicators that should prompt further genetic evaluation (Fig. 1) [16, 19, 37, 44, 45, 49, 100]. These features are not merely cosmetic concerns but are pivotal in the early diagnosis of CPS, facilitating timely intervention and management [68, 101].

Neurological and developmental symptoms, such as intellectual disabilities, learning challenges, and cerebellar ataxia, significantly impact the quality of life and developmental trajectory of affected individuals. For instance, cerebellar ataxia in A-T leads to progressive loss of coordination and balance, severely affecting daily functioning [65, 66]. Intellectual disabilities in NF1 and TSC result in substantial cognitive challenges, highlighting the need for continuous monitoring and specialized educational support [45, 68, 100].

Growth and metabolic anomalies, including prenatal and postnatal overgrowth seen in BWS and growth hormone deficiency in various CPS, require close collaboration between endocrinologists, geneticists, and nutritionists [73, 102]. Effective management of these conditions has the potential to prevent severe complications and improve overall outcomes. For instance, hyperinsulinism in BWS can lead to life-threatening hypoglycemia, highlighting the need for vigilant metabolic monitoring and management.

The multi-system involvement characteristic of CPS underscores the necessity for interdisciplinary care [37, 96, 103, 104]. This approach ensures comprehensive management of both the non-malignant and malignant aspects of these syndromes. Pediatricians, dermatologists, neurologists, endocrinologists, cardiologists, geneticists, and other specialists must collaborate closely to provide holistic care tailored to the individual needs of each patient.

For instance, the management of NF1 requires regular assessments to monitor neurofibroma, alongside neurological evaluations to address cognitive and developmental issues [37, 39, 68, 100]. Similarly, patients with A-T benefit from coordinated care involving immunologists for immunodeficiency management and infection prophylaxis, neurologists for monitoring neurological symptoms, and oncologists for ongoing tumor surveillance [65‐67].

Moreover, genetic counseling plays a crucial role in the care of families affected by CPS [20]. It helps in understanding the hereditary nature of these syndromes, provides risk assessments for family members, and informs reproductive decisions. Genetic counselors help navigate families through the complexities of genetic testing and the implications of the results.

Early identification and regular surveillance are essential in managing CPS [105‐107]. These measures enable the early detection of complications and help prevent the progression of symptoms. For example, regular MRI scans are essential for detecting and monitoring brain tumors in patients with SUFU-associated GS, while ultrasound screenings are vital for identifying abdominal tumors in BWS [23, 51, 73].

Preventive measures, including strict photoprotection in conditions like BS and XP, are vital in reducing the risk of skin cancers [67]. Additionally, prophylactic interventions such as thyroidectomy in MEN2 to prevent medullary thyroid carcinoma, exemplify proactive management strategies necessary in CPS care [14, 33].

The psychosocial impact of CPS on patients and their families is significant [108]. Chronic conditions and the potential for malignancies pose substantial emotional and psychological challenges [109, 110]. Providing comprehensive psychosocial support, including counseling and access to support groups, is crucial in helping patients and their families cope with the stress and uncertainties associated with CPS [110, 111].

Transitioning from pediatric to adult care is a critical period for children and adolescents with CPS [112, 113]. This transition must be meticulously planned and managed to ensure continuity of care, adherence to surveillance protocols, and psychosocial support. Adolescents with CPS often face unique challenges due to the lifelong nature of their conditions, the complexity of their medical needs, and the potential for both malignant and non-malignant manifestations. Effective transition planning should start early, involving a multidisciplinary team that includes pediatricians, oncologists, and adult care providers. This ensures that all aspects of the patient’s health are considered and addressed. Education about the genetic nature of CPS, potential health risks, and the importance of continued surveillance empowers patients to understand their condition better, promoting self-management and adherence to medical recommendations. A well-structured transition program can significantly improve health outcomes and quality of life for adolescents with CPS, fostering a smooth and effective shift from pediatric to adult healthcare systems.

In conclusion, this comprehensive overview highlights the diverse range of non-malignant manifestations associated with CPS, emphasizing the critical importance of early detection and multidisciplinary management. By recognizing these features, pediatricians and other healthcare providers facilitate timely diagnosis, genetic counselling, and appropriate surveillance. This proactive approach ultimately improves medical outcomes and the well-being of affected children, adolescents, and those at risk of CPS.