ORIGINAL ARTICLE Pediatric Dermatology 1–6, 2015
Nevus Anemicus: A Distinctive Cutaneous Finding in Neurofibromatosis Type 1 Angela Hern andez-Martın, M.D.,* Francisco Javier Garcıa-Martınez, M.D.,† Anna Duat, M.D.,‡ Inmaculada L opez-Martın, M.D.,§ Lucero Noguera-Morel, M.D.,* and Antonio Torrelo, M.D.* *Department of Dermatology, Hospital Infantil del Ni~ no Jes us, Madrid, Spain, †Department of Dermatology, Hospital del Sureste, Arganda, Madrid, Spain, ‡Department of Neurology, Hospital Infantil del Ni~ no Jes us, Madrid, Spain, §Primary Health Care Centre of Soto del Real, Soto del Real, Madrid, Spain
Abstract: Nevus anemicus (NA) is a cutaneous anomaly characterized by pale, well-defined patches with limited vascularization after rubbing. They are largely known to be associated with neurofibromatosis 1 (NF1) and have received little attention in the literature until recently. We sought to characterize the prevalence and clinical features of patients with NA and NF1. We conducted an observational prospective study of 99 children ~ o Jesu s, Madrid, Spain, from January 1, 2012, with NF1 at the Hospital Nin through July 31, 2013, and reviewed three other series of patients with NF1 and NA recently reported. The prevalence of NA in children with NF1 ranged from 8.8% to 51%, being much more prevalent at younger ages. Prospective studies yielded a higher prevalence than retrospective studies. NA was located most commonly on the trunk, particularly on the anterior chest wall, and was often multiple. Patients with segmental au lait spots rarely had NA, and NA was absent in NF1 or isolated cafe other genodermatoses. The collection of data was not homogeneous in all studies. NA has a high prevalence in individuals with NF1 patients but seems to be absent in connection with other genodermatoses, therefore its presence can assist in the diagnosis of suspected cases of NF1. The subtle clinical appearance of NA makes its detection difficult, and physicians involved in the care of children with NF1 must be aware of its possible presence and significance.
Nevus anemicus (NA) is a pale, round to oval, wellcircumscribed cutaneous macule with a polylobulated contour with limited vascularization after warming or vigorous rubbing of the area. The surrounding skin may become erythematous while the lesional area
stays pale. They can be solitary or multiple and may be isolated or in close proximity to vascular malformations, possibly reflecting a loss of heterozygosity (1). Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by germline
Address correspondence to Angela Hernandez-Martın, M.D., Department of Dermatology, Hospital Infantil del Ni~ no Jes us, Avda. Menendez Pelayo 65, 28009 Madrid, Spain, or e-mail: [email protected]. DOI: 10.1111/pde.12525
© 2015 Wiley Periodicals, Inc.
1
2 Pediatric Dermatology 2015
mutations in the NF1 gene encoding neurofibromin, a negative regulator of the Ras/mitogen-activated protein kinase pathway (2). According to the National Institutes of Health (NIH), NF1 is diagnosed clinically according to the presence of two or more of seven criteria: six or more cafe au lait spots (CALS) larger than 5 mm in diameter in prepuberal children or 15 mm after puberty, skinfold freckling, two or more neurofibromas of any type or one plexiform neurofibroma, optic glioma, two or more Lisch nodules, distinctive osseous lesions, and a first-degree relative with NF1 (3). NIH consensus criteria for NF1 are highly sensitive and specific in adults, but only 45% of children younger than 2 years fulfill NIH clinical criteria (4,5). Therefore the diagnosis may be delayed until additional clinical criteria develop. Additionally, although the so-called typical CALS and skinfold freckling are highly suggestive of NF1 and may satisfy the two clinical NIH consensus criteria mandatory for diagnosis, other Ras pathway anomalies such Noonan syndrome, Noonan syndrome with multiple lentigines (LEOPARD syndrome), and Legius syndrome share these findings (6). Although the association between NA and NF1 is largely known (7), it has received little attention in the literature until recently. We report a series of 34 children with NA and NF1 and review the most recent literature with the aim of further characterizing this association and emphasizing its diagnostic value. METHODS We performed an observational prospective study aimed at detecting NA in patients with suspected or definite NF1 seen in the Department of Neurology of the Hospital Infantil Ni~ no Jes us, Madrid, Spain, from January 1, 2012, to July 31, 2013. Because CALS and freckling are not exclusive of NF1, we defined three groups of patients: group 1 included cases with confirmed NF1 (patients fulfilling NIH criteria of NF1 other than CALS and freckling exclusively unless there were proven germline NF1 mutations) and NA, group 2 included patients with the same diagnostic criteria as group 1 but without NA, and group 3 included patients with generalized and segmental CALS (≥6 CALS >0.5 cm in diameter) with or without freckling but without other clinical criteria of NF1 or confirmatory genetic testing. All patients underwent a complete skin examination, excluding the perineum and genital area in adolescents. Because the study was performed after a routine physical examination, no institutional review board approval was required.
We assessed the specificity and characteristics of NA in group 1, analyzing sex and age at the time of examination and the location, number, and size of NA. Because NA is often grouped in clusters, we measured the area involved for NA when lesions were located in close proximity. Lesions located in different body areas or widely separated by normal skin were considered to be multiple. We assessed all NIH consensus criteria of NF1 in all three groups and other associated cutaneous and noncutaneous findings commonly found in these patients (juvenile xanthogranulomas [XG] unidentified bright objects on brain magnetic resonance imaging [MRI], and macrocephaly [defined as cephalic contour greater than the 95th percentile]). We also assessed blood hypertension and systemic vascular anomalies as potential additional manifestations of NF1 vasculopathy. Diagnosis of all of these findings was made on clinical grounds, without performing biopsies or using invasive methods. Although not in accordance with the American Academy of Pediatrics, brain MRI is routinely performed in our center in all children older than 2 years with suspicion of NF1. Statistical analysis was performed using SPSS version 20.0 software (SPSS, Chicago, IL). Quantitative variables were reported as mean, median and mode. We used the Pearson chi-square test to determine the association between qualitative variables. When that was not possible because of small sample sizes, the Yates correction was applied. A p-value ≤0.05 was considered significant. The strength of association was assessed using odds ratios. In addition, we analyzed the same data from three different series of patients with NA and NF1 published on Medline throughout the year 2013: two retrospective studies (8,9) and one prospective study (10). These articles were selected because they focused on the association between NF1 and NA, were written in English, and used current diagnostic NIH consensus criteria of NF1 for diagnosis. RESULTS We collected information on 99 individuals with NF1: 34 patients fulfilled group 1 inclusion criteria, 34 fulfilled group 2 criteria, and 31 fulfilled group 3 criteria. Sixty-eight patients (39 male, 29 female) had a definite diagnosis of NF1 and 34 of these (50%) had one or more NA. The total number of NA in group 1 was 79. Age ranged from 2 months to 17 years (mean 8.4 yrs, median 9 yrs). Most patients had multiple NA (median 2), which were located on the trunk in 51% of cases. NA size was highly variable: 48 lesions were
Hern andez-Martın et al: Nevus anemicus in NF1 3
< 5 cm in diameter, 25 were between 5 and 10 cm, and 6 were > 10 cm (Fig. 1). JXGs were observed in six patients with a definite diagnosis of NF1 (9%), and half of these cases had coexisting NA. In group 3, nine patients were considered to have segmental NF1, and 22 had widespread CALS and skinfold freckling. No patient with segmental NF1 had NA or JXG, and five patients with CALS with or without freckling had NA (22%), three had JXG (10%), and one had NA and JXG (0.4%), meaning that 41% of patients with a suspected diagnosis of NF1 had one or both findings. The short follow-up period prevented us from determining how many patients in this group will eventually be diagnosed with definite NF1. All assessed clinical findings in our series are reported in Table 1. As shown, of all assessed variables, only macrocephaly was statistically significant. In three studies including ours, 784 patients with definite NF1 were assessed, with an estimated prevalence of NA between 8.8% and 51% (Table 2). NA was significantly more prevalent at younger ages in all series (median age 7–10 yrs in three studies) and was shown to be multiple in the majority of patients. Data regarding NA size was available only in our study; we observed that 61% of lesions were < 5 cm, which made the detection of NA difficult. The preferred location was the trunk, particularly the anterior chest wall, but NA involved virtually any part of the body surface. All NF1 diagnostic criteria were assessed in three studies, as shown in Table 3. Other associated findings were nonhomogeneously assessed, preventing us from performing an accurate data analysis. Nevertheless, the presence of JXG was evaluated in all four studies (Table 3). When patients with only CALS or freckling were considered, 35 of 350 had NA (10%), but only 1 of 63 (0.1%) with segmental NF1 did (Table 2). So far, no NA have been found in other genodermatoses with CALS (10). A
B
DISCUSSION NA is rare in the general population (2,9) but seems to have a much higher prevalence in patients with NF1. An association between NF1 and NA was first suggested in 1915 (7) and was later confirmed (11,12). According to these older references, NA can appear in up to 15% of individuals with NF1. NA did not receive further attention in the literature until 2013, when we and three other groups assessed large series of individuals with NF1 and associated NA (8– 10). Not surprisingly, retrospective studies (8,9) yielded much lower estimates than prospective assessments (10), probably because NA is clinically subtle and may be easily overlooked unless purposely searched for (Fig. 2). The two prospective studies yielded similar figures, supporting that the real prevalence of NA in NF1 is probably closer to 50%. NA appears equally in both sexes. The exact age of presentation is difficult to assess, because the majority of our patients’ parents were not aware that their children had NA. We now routinely rub the anterior chest wall in infants even if NA is unapparent. Some of our patients’ parents noted that the NA was particularly evident when the child had a fever, blushed, or was having a warm bath. It is unclear why adults have a lower prevalence of NA. It may be because children allow easier complete physical examination and have fewer NF1 marks that would obscure NA detection. In addition, some studies may be biased because they involve pediatric clinical settings, and although NA is considered stable throughout life, their spontaneous regression with age cannot be excluded since it has been documented (8). Review of the series determined that NA are most commonly located on the trunk, particularly on the anterior chest wall and sternal area, but can be present in any location. NA is often multiple and the size is C
Figure 1. Clinical findings. Nevi anemicus was of variable size and was most often located on the anterior chest wall. There were lesions (A) < 5 cm, (B) between 5 and 10 cm, and (C) > 10 cm.
4 Pediatric Dermatology 2015
TABLE 1. All Assessed Findings in Our Series of 68 Patients with Definite Diagnosis of Neurofibromatosis 1 Finding
With NA
Without NA
Age, median, years NA, n (%) Juvenile xanthogranuloma, n (%) Macrocephaly, n (%) Unidentified bright objects, n (%) High blood pressure, n (%) Vascular anomalies, n (%)
8.5 34 (50) 3 (8.8) 19 (55.9) 30 (88.2) 2 (5.9) 4 (11.8)
7.5 34 (50) 3 (8.8) 3 (8.8) 27 (79.4) 1 (2.9) 3 (8.8)
p-Value
Odds ratio (95% CI)
– –
– – 1 (0.18, 5.34) 13.08 (3.34, 51.24) 1.94 (0.51, 7.38) 2.06 (0.17, 23.82) 1.37 (0.28, 6.68)
1*
Nevus Anemicus: A Distinctive Cutaneous Finding in Neurofibromatosis Type 1 Angela Hern andez-Martın, M.D.,* Francisco Javier Garcıa-Martınez, M.D.,† Anna Duat, M.D.,‡ Inmaculada L opez-Martın, M.D.,§ Lucero Noguera-Morel, M.D.,* and Antonio Torrelo, M.D.* *Department of Dermatology, Hospital Infantil del Ni~ no Jes us, Madrid, Spain, †Department of Dermatology, Hospital del Sureste, Arganda, Madrid, Spain, ‡Department of Neurology, Hospital Infantil del Ni~ no Jes us, Madrid, Spain, §Primary Health Care Centre of Soto del Real, Soto del Real, Madrid, Spain
Abstract: Nevus anemicus (NA) is a cutaneous anomaly characterized by pale, well-defined patches with limited vascularization after rubbing. They are largely known to be associated with neurofibromatosis 1 (NF1) and have received little attention in the literature until recently. We sought to characterize the prevalence and clinical features of patients with NA and NF1. We conducted an observational prospective study of 99 children ~ o Jesu s, Madrid, Spain, from January 1, 2012, with NF1 at the Hospital Nin through July 31, 2013, and reviewed three other series of patients with NF1 and NA recently reported. The prevalence of NA in children with NF1 ranged from 8.8% to 51%, being much more prevalent at younger ages. Prospective studies yielded a higher prevalence than retrospective studies. NA was located most commonly on the trunk, particularly on the anterior chest wall, and was often multiple. Patients with segmental au lait spots rarely had NA, and NA was absent in NF1 or isolated cafe other genodermatoses. The collection of data was not homogeneous in all studies. NA has a high prevalence in individuals with NF1 patients but seems to be absent in connection with other genodermatoses, therefore its presence can assist in the diagnosis of suspected cases of NF1. The subtle clinical appearance of NA makes its detection difficult, and physicians involved in the care of children with NF1 must be aware of its possible presence and significance.
Nevus anemicus (NA) is a pale, round to oval, wellcircumscribed cutaneous macule with a polylobulated contour with limited vascularization after warming or vigorous rubbing of the area. The surrounding skin may become erythematous while the lesional area
stays pale. They can be solitary or multiple and may be isolated or in close proximity to vascular malformations, possibly reflecting a loss of heterozygosity (1). Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by germline
Address correspondence to Angela Hernandez-Martın, M.D., Department of Dermatology, Hospital Infantil del Ni~ no Jes us, Avda. Menendez Pelayo 65, 28009 Madrid, Spain, or e-mail: [email protected]. DOI: 10.1111/pde.12525
© 2015 Wiley Periodicals, Inc.
1
2 Pediatric Dermatology 2015
mutations in the NF1 gene encoding neurofibromin, a negative regulator of the Ras/mitogen-activated protein kinase pathway (2). According to the National Institutes of Health (NIH), NF1 is diagnosed clinically according to the presence of two or more of seven criteria: six or more cafe au lait spots (CALS) larger than 5 mm in diameter in prepuberal children or 15 mm after puberty, skinfold freckling, two or more neurofibromas of any type or one plexiform neurofibroma, optic glioma, two or more Lisch nodules, distinctive osseous lesions, and a first-degree relative with NF1 (3). NIH consensus criteria for NF1 are highly sensitive and specific in adults, but only 45% of children younger than 2 years fulfill NIH clinical criteria (4,5). Therefore the diagnosis may be delayed until additional clinical criteria develop. Additionally, although the so-called typical CALS and skinfold freckling are highly suggestive of NF1 and may satisfy the two clinical NIH consensus criteria mandatory for diagnosis, other Ras pathway anomalies such Noonan syndrome, Noonan syndrome with multiple lentigines (LEOPARD syndrome), and Legius syndrome share these findings (6). Although the association between NA and NF1 is largely known (7), it has received little attention in the literature until recently. We report a series of 34 children with NA and NF1 and review the most recent literature with the aim of further characterizing this association and emphasizing its diagnostic value. METHODS We performed an observational prospective study aimed at detecting NA in patients with suspected or definite NF1 seen in the Department of Neurology of the Hospital Infantil Ni~ no Jes us, Madrid, Spain, from January 1, 2012, to July 31, 2013. Because CALS and freckling are not exclusive of NF1, we defined three groups of patients: group 1 included cases with confirmed NF1 (patients fulfilling NIH criteria of NF1 other than CALS and freckling exclusively unless there were proven germline NF1 mutations) and NA, group 2 included patients with the same diagnostic criteria as group 1 but without NA, and group 3 included patients with generalized and segmental CALS (≥6 CALS >0.5 cm in diameter) with or without freckling but without other clinical criteria of NF1 or confirmatory genetic testing. All patients underwent a complete skin examination, excluding the perineum and genital area in adolescents. Because the study was performed after a routine physical examination, no institutional review board approval was required.
We assessed the specificity and characteristics of NA in group 1, analyzing sex and age at the time of examination and the location, number, and size of NA. Because NA is often grouped in clusters, we measured the area involved for NA when lesions were located in close proximity. Lesions located in different body areas or widely separated by normal skin were considered to be multiple. We assessed all NIH consensus criteria of NF1 in all three groups and other associated cutaneous and noncutaneous findings commonly found in these patients (juvenile xanthogranulomas [XG] unidentified bright objects on brain magnetic resonance imaging [MRI], and macrocephaly [defined as cephalic contour greater than the 95th percentile]). We also assessed blood hypertension and systemic vascular anomalies as potential additional manifestations of NF1 vasculopathy. Diagnosis of all of these findings was made on clinical grounds, without performing biopsies or using invasive methods. Although not in accordance with the American Academy of Pediatrics, brain MRI is routinely performed in our center in all children older than 2 years with suspicion of NF1. Statistical analysis was performed using SPSS version 20.0 software (SPSS, Chicago, IL). Quantitative variables were reported as mean, median and mode. We used the Pearson chi-square test to determine the association between qualitative variables. When that was not possible because of small sample sizes, the Yates correction was applied. A p-value ≤0.05 was considered significant. The strength of association was assessed using odds ratios. In addition, we analyzed the same data from three different series of patients with NA and NF1 published on Medline throughout the year 2013: two retrospective studies (8,9) and one prospective study (10). These articles were selected because they focused on the association between NF1 and NA, were written in English, and used current diagnostic NIH consensus criteria of NF1 for diagnosis. RESULTS We collected information on 99 individuals with NF1: 34 patients fulfilled group 1 inclusion criteria, 34 fulfilled group 2 criteria, and 31 fulfilled group 3 criteria. Sixty-eight patients (39 male, 29 female) had a definite diagnosis of NF1 and 34 of these (50%) had one or more NA. The total number of NA in group 1 was 79. Age ranged from 2 months to 17 years (mean 8.4 yrs, median 9 yrs). Most patients had multiple NA (median 2), which were located on the trunk in 51% of cases. NA size was highly variable: 48 lesions were
Hern andez-Martın et al: Nevus anemicus in NF1 3
< 5 cm in diameter, 25 were between 5 and 10 cm, and 6 were > 10 cm (Fig. 1). JXGs were observed in six patients with a definite diagnosis of NF1 (9%), and half of these cases had coexisting NA. In group 3, nine patients were considered to have segmental NF1, and 22 had widespread CALS and skinfold freckling. No patient with segmental NF1 had NA or JXG, and five patients with CALS with or without freckling had NA (22%), three had JXG (10%), and one had NA and JXG (0.4%), meaning that 41% of patients with a suspected diagnosis of NF1 had one or both findings. The short follow-up period prevented us from determining how many patients in this group will eventually be diagnosed with definite NF1. All assessed clinical findings in our series are reported in Table 1. As shown, of all assessed variables, only macrocephaly was statistically significant. In three studies including ours, 784 patients with definite NF1 were assessed, with an estimated prevalence of NA between 8.8% and 51% (Table 2). NA was significantly more prevalent at younger ages in all series (median age 7–10 yrs in three studies) and was shown to be multiple in the majority of patients. Data regarding NA size was available only in our study; we observed that 61% of lesions were < 5 cm, which made the detection of NA difficult. The preferred location was the trunk, particularly the anterior chest wall, but NA involved virtually any part of the body surface. All NF1 diagnostic criteria were assessed in three studies, as shown in Table 3. Other associated findings were nonhomogeneously assessed, preventing us from performing an accurate data analysis. Nevertheless, the presence of JXG was evaluated in all four studies (Table 3). When patients with only CALS or freckling were considered, 35 of 350 had NA (10%), but only 1 of 63 (0.1%) with segmental NF1 did (Table 2). So far, no NA have been found in other genodermatoses with CALS (10). A
B
DISCUSSION NA is rare in the general population (2,9) but seems to have a much higher prevalence in patients with NF1. An association between NF1 and NA was first suggested in 1915 (7) and was later confirmed (11,12). According to these older references, NA can appear in up to 15% of individuals with NF1. NA did not receive further attention in the literature until 2013, when we and three other groups assessed large series of individuals with NF1 and associated NA (8– 10). Not surprisingly, retrospective studies (8,9) yielded much lower estimates than prospective assessments (10), probably because NA is clinically subtle and may be easily overlooked unless purposely searched for (Fig. 2). The two prospective studies yielded similar figures, supporting that the real prevalence of NA in NF1 is probably closer to 50%. NA appears equally in both sexes. The exact age of presentation is difficult to assess, because the majority of our patients’ parents were not aware that their children had NA. We now routinely rub the anterior chest wall in infants even if NA is unapparent. Some of our patients’ parents noted that the NA was particularly evident when the child had a fever, blushed, or was having a warm bath. It is unclear why adults have a lower prevalence of NA. It may be because children allow easier complete physical examination and have fewer NF1 marks that would obscure NA detection. In addition, some studies may be biased because they involve pediatric clinical settings, and although NA is considered stable throughout life, their spontaneous regression with age cannot be excluded since it has been documented (8). Review of the series determined that NA are most commonly located on the trunk, particularly on the anterior chest wall and sternal area, but can be present in any location. NA is often multiple and the size is C
Figure 1. Clinical findings. Nevi anemicus was of variable size and was most often located on the anterior chest wall. There were lesions (A) < 5 cm, (B) between 5 and 10 cm, and (C) > 10 cm.
4 Pediatric Dermatology 2015
TABLE 1. All Assessed Findings in Our Series of 68 Patients with Definite Diagnosis of Neurofibromatosis 1 Finding
With NA
Without NA
Age, median, years NA, n (%) Juvenile xanthogranuloma, n (%) Macrocephaly, n (%) Unidentified bright objects, n (%) High blood pressure, n (%) Vascular anomalies, n (%)
8.5 34 (50) 3 (8.8) 19 (55.9) 30 (88.2) 2 (5.9) 4 (11.8)
7.5 34 (50) 3 (8.8) 3 (8.8) 27 (79.4) 1 (2.9) 3 (8.8)
p-Value
Odds ratio (95% CI)
– –
– – 1 (0.18, 5.34) 13.08 (3.34, 51.24) 1.94 (0.51, 7.38) 2.06 (0.17, 23.82) 1.37 (0.28, 6.68)
1*
