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Penetrance is complete, though expressivity is quite variable even among the family members. Given that NF1 is a common hereditary condition, existence of a second genetic disorder in NF1 patients is not unexpected. During comprehensive evaluations of individuals with NF1, we encountered 11 patients with dual diagnosis who contributed to phenotypic complexity and challenges for long\u2010term management. Examples include Prader\u2013Willi Syndrome, Autosomal Dominant Polycystic Kidney Disease, Down syndrome, infantile myofibromatosis, Craniosynostosis, cleft lip and palate, 47,XYY, 22q11.2 duplication, 15q13.3 deletion syndrome, and <jats:italic>BRCA2\u2010<\/jats:italic> and <jats:italic>ATM\u2010<\/jats:italic> related cancer predisposition syndromes. Presence of dysmorphism, developmental delay, atypical tumors, and family history of other genetic disorders including cancers appears as determinants to consider a second genetic etiology and helps to differentiate from an extreme phenotypic spectrum of NF1. Clinicians should have high index of suspicion to exclude coexisting disorders, as apart from providing comprehensive medical care. This also has potential implications in genetic counseling. Long\u2010term effects of the synergistic mechanisms leading to phenotypic complexity and patient outcomes are yet to be characterized, with follow\u2010up needed.<\/jats:p>","DOI":"10.1002\/ajmg.a.62575","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T13:02:14Z","timestamp":1637326934000},"page":"911-918","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neurofibromatosis 1 in the setting of dual diagnosis: Diagnostic and management conundrums"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-6555","authenticated-orcid":false,"given":"Karthik","family":"Muthusamy","sequence":"first","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aseel","family":"El\u2010Jabali","sequence":"additional","affiliation":[{"name":"Alfaisal University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Ongie","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radhika","family":"Dhamija","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Phoenix Arizona USA"},{"name":"Department of Neurology Mayo Clinic  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dusica","family":"Babovic\u2010Vuksanovic","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Pediatric and Adolescent Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"StatPearls","author":"Akhtar F.","year":"2020"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00446.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.6.e82"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx081"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12987"},{"issue":"3","key":"e_1_2_9_7_1","first-page":"307","article-title":"Coexistence of neurofibromatosis type 1 and mosaic trisomy 8 in the same patient","volume":"21","author":"Basaran S. 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