Vogt et al. Journal of Medical Case Reports 2011, 5:577 http://www.jmedicalcasereports.com/content/5/1/577 well as an increased risk of MPNSTs (Table 1). These features were also noted in our second patient. He had an extremely high internal tumor load (Figure 4), indica- tive of the severe disease manifestations resulting from the type-2 NF1 deletion. Our patient died of the compli- cations associated with a secondary, therapy-resistant MPNST at the age of 18 years. Patients with large NF1 deletions have been reported to have a substantially higher risk of development of MPNSTs as compared with NF1 individuals lacking large NF1 deletions. Whereas the lifetime risk of an MPNST in all patients with NF1 is 8% to 13%, patients with NF1 deletion have an estimated lifetime risk of an MPNST of 16% to 26% [7]. In the study of Mautner et al. [5], 21% of the patients with molecularly ascertained type-1 NF1 dele- tions had an MPNST, thereby confirming the increased risk with respect to this malignant tumor experienced by patients with type-1 NF1 deletions. Our study sug- gests that patients with type-2 NF1 deletions may also be subject to an increased risk of MPNSTs. Conse- quently, patients with this type of deletion should also receive intensive medical care in order to guarantee early detection of the malignant transformation of tumors. The clinical phenotype observed in our first patient was milder than the phenotype observed in our second patient. However, our first patient was only 13 years old at the time of examination and therefore the load of age-dependent symptoms (such as number of Page 6 of 7 neurofibromas) cannot yet be fully assessed. Further- more, NF1 is generally associated with high variability in terms of its clinical expression. Hence, some degree of variability in clinical expression is to be expected in patients with large deletions. Regardless, our first patient also exhibited several symptoms known to be associated with type-1 NF1 deletions such as dysmorphic facial fea- tures, macrocephaly, large hands and feet, hyperflexibil- ity of the joints, mild motor and cognitive developmental delay and T2 hyperintensities. Addition- ally, she had a congenital heart defect (patent foramen ovale). Congenital heart defects certainly belong to the NF1 deletion-associated phenotype as they were also observed in 21% of patients with type-1 NF1 deletion [5]. Our second patient also had a pulmonary valve insufficiency (grade I). The clinical phenotype observed in our two patients with putative germline type-2 NF1 deletions reported in this study is broadly similar to those associated with type-1 NF1 deletions [5,6]. Also in one of our previous studies, severe clinical phenotypes were observed in two patients with germline type-2 NF1 deletions [11]. How- ever, the patients reported in that study could not be investigated by us in great detail with respect to their clinical manifestations; therefore, further conclusions were not possible [11]. The severe clinical phenotype often associated with large NF1 deletions has been suggested to represent a contiguous gene syndrome [6]. Accordingly, the clinical Table 1 Comparison of the prevalence of clinical features observed in patients with type 1 NF1 deletions as reported by Mautner et al. [5] with the clinical features noted in our two patients with non-mosaic type-2 NF1 deletions Clinical features of patients with type-1 NF1 deletions (percentage of patients with this feature)a Presence or absence of this feature in our patients by breakpoint Patient 2429 Patient 2358 Facial dysmorphism (90%) Tall stature (46%)b Large hands and feet (46%) Macrocephaly (39%)c Learning disabilities (48%) Attention deficits (33%) Scoliosis (43%) Hyperflexibility of the joints (72%) Plexiform neurofibromas (76%) Subcutaneous neurofibromas (76%) Cutaneous neurofibromas (86%) MPNST (21%) T2 hyperintensities (45%) Muscular hypotonia (45%) Congenital heart defects (21%) aAccording to the analysis of 29 patients with type-1 NF1 deletion [5]. bTall stature was denoted if height measurements were at or above the 94th percentile. cMacrocephaly was denoted if the head circumference was at or above the 97th percentile. -, absent; +, present; MPNST, malignant peripheral nerve sheath tumor; NA, not assessed. + - + + + + - + + (multiple) + (multiple) + (multiple) + - + + - + + + (mild) + + + + - - + + +