Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.

Pallister-Hall-like syndrome (PHLS) is a pleiotropic autosomal recessive disorder characterized by phenotypic variability. Patients exhibit postaxial polydactyly as well as hypothalamic hamartoma, cardiac and skeletal anomalies, and craniofacial dysmorphisms. Hirschsprung disease has also been observed (Rubino et al., 2018; Le et al., 2020). Pallister-Hall syndrome (146510) is an autosomal dominant disorder with features overlapping those of PHLS, caused by mutation in the GLI3 gene (165240).

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma).

CHEK2-related cancer predisposition is predominantly characterized by an increased risk of female breast cancer. To a lesser extent there is an association with increased risk of prostate cancer. Associations for other cancers are less well established or conflicting. Cancer risks in those with CHEK2-related cancer predisposition can vary considerably depending on modifying factors such as family history.