Research

Original Investigation

Juvenile Xanthogranuloma and Nevus Anemicus

in the Diagnosis of Neurofibromatosis Type 1
Faustine Ferrari, MD; Alice Masurel, MD; Laurence Olivier-Faivre, MD, PhD; Pierre Vabres, MD

IMPORTANCE The diagnosis of neurofibromatosis type 1 (NF1) is based on 7 clinical criteria.

However, they are of limited value before the age of 2 years. Juvenile xanthogranuloma (JXG)
and nevus anemicus (NA) are commonly observed in children with NF1 and may be useful
diagnostic clues.
OBJECTIVES To evaluate the frequency of JXG and NA, to describe their clinical features, and
to determine their diagnostic value in patients with NF1.
DESIGN, SETTING, AND PARTICIPANTS Retrospective medical record review of outpatients
seen between January 1, 2005, and December 31, 2011. University hospital dermatology
department affiliated with the French NF1 referral center network. Patients with NF1
diagnosed by at least 2 National Institutes of Health criteria and examined at our department.
MAIN OUTCOMES AND MEASURES Percentage of patients with NF1 who had JXG or NA

categorized into 4 age groups.

RESULTS Among 72 patients with NF1 (median age, 15.4 years), 23 had JXG (10%) or NA
(25%). Both lesions were more frequent (55%) in those younger than 2 years (JXG, 30%; NA,
35%). Most JXG lesions were multiple and resolved spontaneously. Cephalic and genital
involvement was frequent. No patient with JXG developed chronic myelomonocytic
leukemia. Nevus anemicus was present on the neck and upper chest in 72% of cases. Among
10 patients (14%) who had only 1 diagnostic criterion at first visit, including 9 younger than 2
years, JXG or NA was present in 8 (80%).
CONCLUSIONS AND RELEVANCE We found a high frequency of JXG and NA in patients with
NF1, especially in children younger than 2 years with fewer than 2 diagnostic criteria. Hence,
JXG and NA appear helpful in improving early diagnosis of NF1 in young children and infants.
JAMA Dermatol. 2014;150(1):42-46. doi:10.1001/jamadermatol.2013.6434
Published online November 20, 2013.

eurofibromatosis type 1 (NF1) is a hereditary autosomal

dominant condition with an estimated incidence of 1 in
3500 births. About half the cases are sporadic. According to the National Institutes of Health (NIH) consensus
conference,1 a diagnosis of NF1 in children is established by the
presence of at least 2 of 7 clinical criteria: 6 or more caf au lait
macules larger than 0.5 cm, 2 neurofibromas or 1 plexiform neurofibroma, axillary or inguinal freckling, optic glioma, at least 2
iris Lisch nodules, a characteristic bone lesion (pseudarthrosis
or sphenoid dysplasia), or a first-degree relative with NF1. It later
appeared that the presence of T2 unidentified bright objects on
brain magnetic resonance imaging also has good diagnostic
value.2-4 Indeed, NIH diagnostic criteria allow a diagnosis of NF1
in most children at the age of 5 years5,6 but are of limited value
for earlier diagnosis. Actually, before the age of 2 years, 50% of
children with sporadic NF1 have been reported to harbor only 1
NIH criterion, resulting in delayed diagnosis. In this age group,
42

Author Affiliations: Dermatology,

Centre Hospitalier Universitaire de
Dijon (Ferrari, Vabres); Medical
Genetics, Centre Hospitalier
Universitaire de Dijon (Masurel,
Olivier-Faivre); Research Unit EA 4271
Gntique des Anomalies du
Dveloppement, Universit de
Bourgogne, PRES
Bourgogne-Franche Comt, France
(Olivier-Faivre, Vabres); Centre de
Comptence Maladies Rares
Neurofibromatose 1, Dijon, France
(Ferrari, Masurel, Olivier-Faivre,
Vabres).
Corresponding Author: Pierre
Vabres, MD, Service de Dermatologie,
Centre Hospitalier Universitaire,
Hpital du Bocage, 14 rue Paul
Gaffarel, BP77908, 21079 Dijon
CEDEX, France
(pierre.vabres@chu-dijon.fr).

NF1 usually manifests as isolated multiple caf au lait spots,

which are highly suggestive but not specific for NF1.7-9 Additional
cutaneous manifestations may occur in children with NF1: juvenile xanthogranulomas (JXG) and nevus anemicus (NA).
Juvenile xanthogranuloma10 is the most common non-Langerhans cell histiocytosis. It consists of an asymptomatic yellowbrown papule or nodule, usually solitary, preferentially localized
on the head and neck. It appears in the early years of life, may
be present from birth, and resolves spontaneously.11 Its association with NF1 was first reported in 1937 by Lamb and Lain.12 Since
then, multiple additional cases have been reported.13-20 The presence of JXG in patients with NF1 is considered a warning sign for
juvenile chronic myelomonocytic leukemia (JCMML).21-27 Patients
with NF1 and multiple JXG lesions have a 20- to 30-fold higher
risk of developing JCMML than those without JXG lesions.25,28,29
However, in at least 2 retrospective series of JXG in patients with
NF1,30,31 no increased incidence of JCMML was reported.

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JXG and NA

Original Investigation Research

Nevus anemicus32 is a pale macular skin area, often with

polycyclic borders, caused by permanent vasoconstriction in
the superficial dermis, which may be relieved on injection of
an -blocking agent.33-39 It is unassociated with impaired melanization or sensitivity. Nevus anemicus is considered stable
throughout life. It appears at birth or during childhood, predominantly on the trunk. It is sometimes associated with an
adjacent port wine stain,40 which is thought to result from a
twin spotting phenomenon.41 Association with NF1 was first
suggested in 1915 by Naegeli.42 It was later reported by Schmidt
in 192943 and Fleisher and Zeligman36 in 1969.
Because both signs are present in children, they may represent early diagnostic criteria for NF1. However, no studies
have addressed their diagnostic value in NF1. Hence, our objectives were to evaluate the frequency of JXG and NA, to describe their clinical features, and to determine their diagnostic value in patients with NF1.

Methods
Clinical medical records and photographs from patients with
NF1 who underwent detailed skin examination at the DepartFigure 1. Age Distribution of Juvenile Xanthogranuloma (JXG) and Nevus
Anemicus (NA)
50

NA
JXG

Patients, %

40

30

20

10

<2 (n = 20)

2-9 (n = 10)

10-19 (n = 10)

20 (n = 32)

Age, y

The JXG lesions were exclusively observed in younger patients, whereas the NA
lesions were also present in adult patients, albeit with lower frequency.

ment of Dermatology, Dijon University Hospital, Dijon, France,

between January 1, 2005, and December 31, 2011, were reviewed. Because the study was performed retrospectively, institutional review board approval was not required. Recorded clinical data were age at first diagnosis of JXG or NA;
age at diagnosis of NF1; NIH criteria at first and last visits; sex;
personal and family history; mode of inheritance of NF1; type,
number, and localization of skin lesions; evolution; and any
other associated clinical or laboratory anomalies. Diagnoses
of NF1, JXG, and NA were made on a clinical basis. Neurofibromatosis type 1 was defined as the presence of at least 2 NIH
criteria. Juvenile xanthogranuloma was defined as asymptomatic yellow-brown papules or nodules, without Darier sign
(swelling or redness on rubbing). Nevus anemicus was defined as hypochromic macules devoid of vasodilation on friction. No skin biopsies were performed. The frequency, median age at diagnosis, and sex ratio for each sign (JXG and NA)
were calculated in our whole population divided into 4 age
groups (<2 years, 2-9 years, 10-19 years, and 20 years). Association of JXG and NA with age group, sex, mode of inheritance of NF1, and number of NIH criteria at first visit was determined using the Fisher exact test, with P < .05 considered
statistically significant.

Results
Among all 72 medical records of patients with NF1 (33 males
and 39 females) seen at the Department of Dermatology, Dijon University Hospital, Dijon, France, between January 1, 2005,
and December 31, 2011, a diagnosis of JXG or NA was found in
23 patients (32%). Most patients were children, with the median age at first visit being 15.4 years (range, 1 week to 67.8
years). Seven patients (10%) had JXG (5 males and 2 females),
and 18 patients (25%) had NA (11 males and 7 females). Two
patients (3%) had both NA and JXG. Among patients younger
than 2 years, 11 (55%) had either JXG (30%) or NA (35%). Frequencies in older age groups are shown in Figure 1. Neurofibromatosis type 1 occurred de novo in 38 patients (53%). No
significant association was observed between the presence of
JXG or NA and the mode of inheritance (inherited vs spo-

Table 1. Characteristics of Juvenile Xanthogranuloma (JXG) and Nevus Anemicus (NA)

No. (%)
Site
Scalp and face

JXG Lesions
45 (80)

Patients With JXG

6 (86)

NA Lesions
2 (4)

Patients With NA
2 (11)

Neck and upper chest

1 (2)

1 (14)

33 (72)

Lower and upper back

2 (4)

2 (28)

8 (17)

13 (72)
6 (33)

Abdomen

Groin and genitalia

4 (7)

4 (57)

Upper limbs

2 (4)

2 (29)

1 (2)

1 (6)

Lower limbs
Total
No. of lesions per patient, median
(range)
Solitary

1 (14)

2 (4)

2 (11)

56 (100)

2 (4)

7a (100)

46 (100)

18a (100)

2 (1-28)

Not applicable

2 (1-7)

Not applicable

Not applicable

2 (29)

Not applicable

6 (33)

Multiple

Not applicable

5 (71)

Not applicable

12 (67)

Clustered

Not applicable

Not applicable

10 (56)

jamadermatology.com

Not applicable

Patients could harbor lesions in

more than one site.

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43

Research Original Investigation

JXG and NA

radic) (odds ratio [OR], 1.22; P > .99; and OR, 2.15; P = .28, respectively) or with sex of the transmitting parent (OR, 0.67;
P > .99 for NA, not assessable for JXG).
Juvenile xanthogranuloma was more frequent in males,
albeit not significantly (OR, 3.30; P = .23). The median age of
the patients at first diagnosis was 1.3 years (range, 0.5-3.1 years).
Lesions were present mainly on the scalp or face (86%) and the
groin or genitalia (57%) (Table 1 and Figure 2). They were more
often multiple than solitary, with a median number of 2 (range,
1-28) (Table 1). The median follow-up of patients with JXG was
2.2 years (range, 0-13.2 years). Spontaneous resolution of JXG
was observed in 5 patients, before the age of 5 years in 4 of them
(Table 2). None of our patients with NF1 and JXG developed
hematologic malignant tumors, particularly chronic myelomonocytic leukemia (CMML). Three patients had thrombocytosis (maximum platelet count, 855 103/L [to convert to
109/L, multiply by 1]). In all cases, it was associated with sideropenic anemia and resolved after iron supplementation.
Nevus anemicus was more frequent in males, albeit not
significantly (OR, 2.29; P = .18). The median age of patients at
diagnosis was 7 years (range, 7 weeks to 57.2 years). Nevus anemicus lesions were asymptomatic, hypochromic, round or elliptoid macules that ranged from 0.5 to 6.0 cm in diameter,
rarely noticed by patients or parents before examination by a
dermatologist. Most NA is visible only after elicitation of vasodilation in surrounding skin by gentle friction during examination, which enhances color contrast, although some NA
is also detectable without friction. In rare instances, NA has
been noticed by parents as local absence of redness on skin va-

Figure 2. Juvenile Xanthogranuloma in a Child With Neurofibromatosis

Type 1

Genital involvement in a 1-year-old boy.

sodilation after a warm bath. These lesions mainly involve the

neck and upper chest (72%) (Table 1 and Figure 3) and are more
often multiple and clustered than solitary (Table 1). The median number of lesions was 2 (range, 1-7). In 3 patients aged
0.1, 1.0, and 15.4 years, NA was associated with an underlying
neurofibroma (2 plexiform neurofibromas on the trunk and 1
superficial neurofibroma on the forehead). Evolution of NA
with age could not be accurately determined because follow-up was available for only 9 patients, with a median duration of 0.6 year (range, 0-20.7 years). Regression of NA was
noted in 1 patient only, at the age of 1 year.
Ten patients (14%) had only 1 NIH diagnostic criterion at
the first visit. Eight of these patients had de novo cases and 9
were younger than 2 years (45.0% in this age group). However, JXG or NA was present in 8 patients (80%), raising high
suspicion for the diagnosis of NF1, which was subsequently
confirmed on follow-up. In addition, JXG was significantly
more frequent in patients with only 1 NIH criterion for NF1 (OR,
30; P < .001) than in patients with NF1 who have a definite diagnosis based on 2 or more NIH criteria. However, NA was not
significantly more frequent in patients with only 1 NIH criterion for NF1 (OR, 3.77; P = .11). Prevalence of JXG and NA in patients with NF1 who have a definite diagnosis at the first visit
was lower. Sixty-two patients (86%) had 2 or more NIH diagnostic criteria at the first visit. Either JXG or NA was present
in 15 patients (24%).

Discussion
We found a high frequency of NA and JXG in patients with NF1.
These conditions were present in more than half the children
with NF1 younger than 2 years. Prevalence of JXG and NA in
the general population is not precisely known.40,44 However,
they are certainly much less frequent. Thus, both cutaneous
signs appear as good criteria for NF1 diagnosis in infancy and
early childhood. In a pediatric series, prevalence of JXG was
reported as 3.9% in a series of 357 patients younger than 17
years45 and 18.2% in a series of 77 patients younger than 3
years.31 In contrast, in the adult series of Huson et al,30 prevalence of JXG was only 0.7%. The intermediate prevalence found
in our study (10%) reflects a mixed adult and (mostly) pediatric population. Most clinical characteristics of JXG in our study
were identical to those previously reported in the general
population11,13,44: predominant cephalic involvement, young

Table 2. Evolution of Juvenile Xanthogranuloma (JXG) on Follow-up

No. of JXG Lesions
at the Initial
Diagnosis

Age at the Initial

Diagnosis, y

3
4

Maximal No. of
JXG Lesions

Age at Maximal
No. of Lesions, y

0.5

1.4

2.8

0.9

28

2.0

Not applicable

12

0.9

19

1.4

4.7

1.3

1.3

2.9

1.5

1.5

2.5

1.9

1.9

15.3

3.1

2.0

Not applicable

Patient No.

44

Age at the First

Visit With
Complete
Resolution, y

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JXG and NA

Original Investigation Research

Figure 3. Nevus Anemicus in a Child With Neurofibromatosis Type 1

Multiple clustered nevus anemicus of the neck and chest in an 8-year-old child.

age (<2 years), and tendency to resolve early in childhood.

Male predominance was also found (sex ratio, 2.5). In contrast, 72% of our patients with NF1 had multiple lesions,
whereas JXG lesions are usually solitary papulonodules in
patients without NF1. Likewise, genital involvement was
frequent (57%), and although our small sample precludes
definitive conclusion, it could be a clinical feature of NF1related JXG. No patients presented with CMML at the time
of JXG diagnosis or during follow-up. Most patients (5 of 7)
were older than 3 years at their last visit. Hence, because the
mean age at diagnosis of CMML in NF1 is 3 years, 28 it is
unlikely that any of them developed CMML later. The
absence of JCMML in our series and others suggests that
previous articles about JXG associated with JCMML may
have included patients with NF1 features who may have
actually been affected with cancer predisposition syndromes associated with deficiency of mismatch repair
genes.46,47 An association between JXG and internal neurofibromas has recently been found in a study of 357 children
with NF1.45 We did not search for this association because

we did not routinely perform magnetic resonance imaging

in asymptomatic children.
The high prevalence of NA in NF1 patients (25%) found
in our study is difficult to compare with previous results
because no series of NA in patients with NF1 or in the general population have recently been published, to our knowledge. In addition, NA may have been overlooked in patients
with NF1 because NA is barely visible or invisible unless elicited on skin stroking. However, in the series by Schmidt,43 a
prevalence of 11.04% was reported in 462 patients having a
diagnosis of neurofibromatosis, although it can be argued
that not all of these patients may have had NF1 because
diagnostic criteria have evolved over time. In this publication, a study by Fischer is cited, in which a prevalence of
2.36% among 466 patients is reported. Nevertheless, the
clinical features of NA in our study agreed with previous
articles.33,35,36,39,40,48 These lesions were mostly present on
the neck and upper chest. They first occurred during childhood, and although long-term follow-up data were unavailable, they remained stable at follow-up visits despite lower
observed frequency in older age groups. In patients with
NA, 67% had multiple lesions, whereas they are usually
described as solitary lesions. In addition, previously
reported female predominance36,40 was not found in our
series of patients with NF1 (sex ratio, 1.57). A link between
NA and neurofibromas is likely because many NA lesions
were overlying neurofibromas, especially of the plexiform
type. However, most NA diagnosed in childhood does not
seem to evolve into neurofibromas.
In keeping with results of a study from DeBella et al,5 45%
of our population only had 1 NIH criterion (usually multiple
caf au lait macules) when the first visit occurred at younger
than 2 years. Indeed, at this young age, diagnosis of NF1 is often difficult. Because NA and JXG were present in most children with NF1 aged younger than 2 years and were diagnosed
in 80% of patients with insufficient criteria for diagnosis at that
time, their interest as minor criteria in addition to the previously established NIH criteria could be addressed. Their sensitivity, specificity, and predictive values should be prospectively assessed in a childhood case-control study.

ARTICLE INFORMATION

REFERENCES

Accepted for Publication: June 27, 2013.

1. National Institutes of Health Consensus

Development Conference. Neurofibromatosis:
conference statement. Arch Neurol.
1988;45(5):575-578.

Published Online: November 20, 2013.

doi:10.1001/jamadermatol.2013.6434.
Author Contributions: Drs Vabres and Ferrari had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Vabres, Ferrari.
Acquisition of data: Vabres, Ferrari, Masurel,
Olivier-Faivre.
Analysis and interpretation of data: Vabres, Ferrari.
Drafting of the manuscript: Vabres, Ferrari.
Critical revision of the manuscript for important
intellectual content: Vabres, Masurel, Olivier-Faivre.
Statistical analysis: Vabres, Ferrari.
Study supervision: Vabres.
Conflict of Interest Disclosures: None reported.

jamadermatology.com

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