Pediatric Dermatology Vol. 21 No.

2 139–145, 2004

Generalized Lentiginosis in Two Children

Blackwell Publishing, Ltd.

Lacking Systemic Associations: Case Report

and Review of the Literature
Wei-Sheng Chong, M.R.C.P., Waraporn Klanwarin, M.D., and
Yoke-Chin Giam, M.Med. (Paed)
National Skin Center, Singapore

Abstract: Generalized lentigines associated with multiple noncutaneous

features, as in the LEOPARD syndrome and the Carney complex, have been
well reported in the literature. Reports of patients with generalized lentigines
without systemic abnormalities (termed “generalized lentiginosis”) are
increasing as well. Despite the lack of systemic features, patients with
generalized lentigines only should be monitored for further development of
other noncutaneous features, especially cardiac anomalies. We present two
patients with generalized lentiginosis and propose a working algorithm in
the approach to a child with this finding.

LEOPARD syndrome (also known as multiple lentig- Jakarta, Indonesia, for evaluation of widespread hyper-
ines syndrome) and the Carney complex (LAMB syndrome pigmented spots appearing within 3 weeks. The spots
and NAME syndrome) have been well described. Patients were noted to be more abundant on sun-exposed areas.
with such syndromes have generalized lentigines associated He was an only child, born to unaffected parents, and
with a variety of physical noncutaneous abnormalities and there was no family history of similar cutaneous lesions.
defects such as cardiac and musculoskeletal anomalies. He was prescribed a sunscreen and was advised to avoid
However, several patients have been described in the excessive sun exposure.
literature with generalized lentigines without associated He had no noteworthy past medical history and his
noncutaneous abnormalities. We report two children seen physical and mental development was normal. Physical
in the last 2 years at the National Skin Center, Singapore, examination revealed a healthy, well-nourished boy with
who presented with generalized lentigines with the absence numerous hyperpigmented macules involving the face,
of associated defined, noncutaneous abnormalities. trunk, extremities, and genitalia (Figs. 1 and 2). The color
of the macules ranged from dark brown to black and they
ranged in size from 1 mm to 1 cm in diameter. Darier sign
CASE REPORTS was negative. The palms, soles, buccal mucosa, and con-
junctiva were spared. The texture of the skin was normal,
Patient 1
with no evidence of actinic damage, scarring, or atrophy.
A 6-year-old Indonesian boy was referred to the He had no facial dysmorphisms, such as ocular hyper-
National Skin Center by a pediatric dermatologist from telorism, low-set ears, or ptosis. Abdominal examination
Address correspondence to Yoke-Chin Giam, M.Med. (Paed), National Skin Center, 1 Mandalay Rd., Singapore 308205, or e-mail: ycgiam@nsc.gov.sg.

Address correspondence to Yoke-Chin Giam, M.Med. (Paed),

National Skin Center, 1 Mandalay Rd., Singapore 308205, or e-mail:
ycgiam@nsc.gov.sg.

139
140 Pediatric Dermatology Vol. 21 No. 2 March/April 2004
Figure 1. Patient 1. Multiple hyperpigmented macules
involving the face.
revealed no abnormal masses. The external genitalia
were normal. There were no skeletal abnormalities such
as kyphoscoliosis. The rest of the examination, including
that of the cardiac system, had normal results.
Electrocardiogram and transthoracic two-dimensional
echocardiography were performed, but revealed no
abnormalities. A biopsy specimen from a typical macule
on the right thigh revealed an increased number of
melanocytes, with an increase in melanin content in
the basal layer. This histology was consistent with a
lentigo.
A diagnosis of generalized lentiginosis (without asso-
ciated defined noncutaneous abnormalities) was made.
He was advised to follow-up, but returned to Indonesia.
Patient 2
A 9-year-old Chinese girl was referred to the National
Skin Center by the School Health Service for gener-
alized hyperpigmented spots. She had hyperpigmented
lesions since the age of 1 year and the lesions were
Figure 2. Patient 1. Multiple hyperpigmented macules
involving the trunk and extremities.
progressively increasing in number. No treatment was
prescribed.
There was nothing of significance in her medical
history and her development was normal. An auditory
screening was done at school and was apparently normal.
She was of normal intelligence. She has a 12-year-old
brother who is unaffected. There was no family history
of generalized hyperpigmented spots.
The physical examination revealed a cheerful girl who
was able to converse fluently. Her height was 148 cm
(90th−97th percentile) and weight was 33.2 kg (75th−
90th percentile). She had multiple light to dark brown
variegated macules, ranging in size from a few millimeters
to 1 cm in diameter (Fig. 3). These were scattered over
her body on the face, trunk, buttocks, and extremities
(Fig. 4). Darier sign was negative. Her buccal mucosa
was unaffected. Clinically these lesions were diagnosed
as lentigines.
There was an absence of dysmorphic features such as
ocular hypertelorism, ptosis, low-set ears, or prognathism.

Figure 3. Patient 2. Close-up of the multiple variegated
macules on the forearm.
No significant kyphoscoliosis, pectus carinatum, or exca-
vatum was noted. Cardiac examination revealed normal
first and second heart sounds with midsystolic click. The
external genitalia were normal.
Further cardiac evaluation by a pediatric cardiologist
showed a normal electrocardiogram. Transthoracic two-
dimensional echocardiography revealed mild prolapse
of the anterior mitral valve leaflet. The pulmonary and
aortic valves were normal.
Her 24-hour urinary free cortisol level was within
normal limits. No biopsy was performed, as her parents
refused consent for the procedure.
She was diagnosed to have generalized lentiginosis
(without associated, defined noncutaneous features, apart
from an incidental finding of mild mitral valve prolapse).
She applied sunscreen daily and avoided excessive sun
exposure. As her multiple lentigines were cosmetically
disfiguring, her parents were eager to have them removed
by neodymium:yttrium-aluminum-garnet (Nd:YAG) laser
by a dermatologic surgeon.
Chong et al: Generalized Lentiginosis 141
Figure 4. Patient 2. Scattered hyperpigmented macules
on the face.
DISCUSSION
A child may present with multiple lentigines distributed
in a localized or generalized fashion (1). Examples of
disorders associated with localized lentigines are Peutz-
Jeghers syndrome and partial unilateral lentiginosis (1,2),
in which lentigines are distributed over the perioral
area/oral mucosa/ hands and in a segmental fashion,
respectively (1). Generalized lentigines reportedly occur
in association with a variety of physical abnormalities
affecting the cardiac, musculoskeletal, neurologic, repro-
ductive, gastrointestinal, and auditory systems. These
anomalies have been categorized into separate syndromes,
notably the LEOPARD syndrome and the Carney com-
plex (LAMB and NAME syndromes) (1–15).
LEOPARD syndrome is also known as multiple
lentigines syndrome, lentiginosis profusa syndrome,
progressive cardiomyopathic lentiginosis, cardiocutaneous
syndrome, and Moynahan syndrome (3–5). Historically
it was first reported in a case by Zeisler and Becker in
1935 (3,6). Subsequently Moynahan and Walther et al
142 Pediatric Dermatology Vol. 21 No. 2 March/April 2004

TABLE 1. Criteria for Diagnosis of the Multiple Lentigines Syndrome

Lentiginosis
Other cutaneous abnormalities, such as axillary “freckling” or café au lait spots, dermatoglyphic abnormalities, interdigital webs,
onychodystrophy, multiple granular cell myoblastoma, or schwannoma
Structural cardiac abnormalities
Pulmonary valve stenosis (valvular or infundibular type), aortic valve stenosis, obstructive cardiomyopathy
Electrocardiographic abnormalities
For example, left axis deviation (with or without left anterior fascicular hemiblock), right bundle branch block
Others include abnormal S waves (S I, II, III, or S V1–5), right ventricular hypertrophy and /or left ventricular hypertrophy, right axis deviation and
paroxysmal atrial tachycardia, premature ventricular contractions, complete heart block, low voltage
Cardiac symptoms
Dyspnea on exertion, symptoms of congestive heart failure, or paroxysmal atrial tachycardia, sudden death
Genitourinary abnormalities
May include cryptorchidism, hypospadias, ovarian agenesis or hypoplasia, cystic ovarian disease, delayed puberty, renal agenesis, absence or
duplication of a ureter
Neurologic defects
Sensorineural deafness, mental retardation, oculomotor defects
Others include abnormal electroencephalogram, seizures, hyposmia, slowed peripheral nerve conduction
Cephalofacial dysmorphism
Ocular hypertelorism, mandibular prognathism, broad nasal root
Others include dysmorphic skull, low-set ears, dental abnormalities, high palatal arch, ptosis of the upper lids, epicanthal folds, lateral canthi lower
than the medial canthi, cleft palate
Shortness of stature (usually below the 25th percentile) or low birthweight (under the 25th percentile)
Skeletal anomalies
May include pectus carinatum or excavatum, retarded bone age, kyphoscoliosis, winging of scapulae, hypermobile joints
Others include cubitus valgus, rib anomalies, hypoplastic fifth digit, syndactyly, cervical spine fusion, spina bifida occulta, Madelung deformity of
the wrist, delayed healing of fractures
If the patient has multiple lentigines, features in at least two other categories listed above must be present. If lentigines are absent, a diagnosis of
multiple lentigines syndrome (MLS) may be made if the patient has features in at least three other categories listed above and has an immediate
relative with MLS as defined in the previous statement.
Adapted from Voron et al (3,9).

reported further similar cases (3,6). But it was Gorlin
et al (7), in 1969, who coined the term “LEOPARD
syndrome” as a mnemonic for the central features of the
condition: lentigines, electrocardiogram (ECG) abnormal-
ities, ocular hypertelorism, pulmonary stenosis, abnormal
genitalia, growth retardation, and sensorineural deaf-
ness. These features are not the only ones described in
association with LEOPARD syndrome (5). Many other
cutaneous and noncutaneous abnormalities have been
reported as well (5) (Table 1).
Such protean and diverse manifestations of this
complex syndrome, together with the lack of pathogno-
monic morphologic and biochemical markers, make
defining the LEOPARD syndrome difficult (3). In fact,
not all patients described have all the features (2). Some
features may develop later in life and do not clinically
manifest until puberty (3). In 1984 Colomb and Morel
(8) reviewed 38 reports, as well as two of their own
patients, and found that 100% of the patients had lent-
igines, 80% had ECG abnormalities/cardiac murmurs,
60% had skeletal abnormalities, 50% had hypertelorism,
42% were short, 35% had mental retardation, and
29% had abnormal genitalia (males). The rarest feature
was sensorineural deafness (27%). This illustrates the
extremely variable expressivity of this syndrome (6).
In view of the difficulty in defining this syndrome, in
1976 Voron et al (9) proposed the minimum criteria for
a diagnosis: 1) if the patient has multiple lentigines, then
at least two other clinical criteria are required; or 2) if
lentigines are absent, then features in at least three other
categories plus one immediate relative with LEOPARD
syndrome are required (Table 1).
The pathogenesis remains unknown. There are two
possible mechanisms (3) that have been proposed. First,
LEOPARD syndrome results from a neural crest defect,
leading to hyperactivity of melanocytes in the skin.
This produces lentiginosis with increased activity of β-
adrenergic effectors in cardiac muscle, which produces
cardiomyopathy and ECG changes. Second, LEOPARD
syndrome arises from a basic genetic defect in neuro-
ectoderm whereby the abnormal neural crest cell lines
interact with mesodermal cells, resulting in disease
manifestations.
Clinically lentigines are dark brown, irregularly shaped
macules that range in size from pinpoint to 5 mm in
diameter (5). They are not limited to sun-exposed areas
(2,3,6) and are found primarily on the face, neck, and
upper trunk, with some involvement of the extremities.
Less commonly involved are the palms, soles, and
genitalia; the oral mucosa is typically spared (5,6,11).

TABLE 2. Comparison Between LEOPARD Syndrome and Carney Complex
Syndrome LEOPARD syndrome
Inheritance Autosomal dominant
Prenatal diagnosis None
Incidence More than 70 cases reported; M = F
Age at presentation Lentigines begin at birth or first few months of life;
abundant by 4 –5 years old
Pathogenesis Unknown
Key features Generalized lentigines, mucosa spared, ECG
conduction defects, pulmonary stenosis, aortic
stenosis, obstructive cardiomyopathy, ocular
hypertelorism, triangular facies, abnormal
genitalia, hypospadia, cryptorchidism, growth
retardation, pectus excavatum or carinatum,
sensorineural deafness, mild mental retardation (rare)
Management Dermatologic examination with skin biopsy;
cardiology, audiology, and urology referral;
evaluate first-degree relatives
Prognosis Normal life span; main concern is obstructive cardiomyopathy
Adapted and modified from Spitz (10).
Lentiginosis is the most common feature and is usually
the first clinical manifestation to appear (5).
Histologically, under light microscopy, there is an
increase in melanin granules (2,3) throughout the
epidermis, with increased numbers of melanocytes
and elongation of the rete ridges (6). Giant melanosomes
can be demonstrated under electron microscopy, but are
neither a specific nor a constant feature (2). Most
melanosomes are normal.
Laboratory evaluations include an electrocardiogram
(2) to detect any underlying abnormal rhythm and other
clues which may suggest a structural cardiac abnormal-
ity, chest radiograph to detect cardiomegaly or skeletal
anomalies, and echocardiography to evaluate cardiac
lesions (3).
The prognosis is mainly determined by the nature and
severity of the cardiac lesions (3). In fact, the major con-
cern is that of hypertrophic obstructive cardiomyopathy
(6,12) because of its association with arrhythmia and
sudden death. Thus patients with LEOPARD syndrome
should undergo periodic evaluation (15) by a cardiologist
with an ECG and chest radiograph performed every
6 months (3). Echocardiography should be performed
depending on the clinical findings.
The use of lasers, such as the Q-switched Nd:YAG
laser, has been shown to be effective in the treatment
of lentigines (1,11). Noninvasive agents such as tretinoin
cream and hydroquinone cream used in combination
have been shown to lighten lentigines after several months
of application (1,11).
Another complex syndrome associated with general-
ized lentigines is the Carney complex (3,11,13,14). It is
transmitted in a mendelian autosomal dominant fashion
(6,10). First described in 1985 by Carney et al, the
Chong et al: Generalized Lentiginosis 143
Carney complex (LAMB, NAME)
Autosomal dominant
None
Rare; M = F
Birth to first few years of life
Unknown
Lentigines, melanocytic nevi, blue nevi,
ephelides, mucocutaneous myxomas, myxoid
neurofibromatosis, atrial myxomas, secondary
embolization, endocrine neoplasia, pigmented
nodular adrenocortical disease, Cushing syndrome,
pituitary adenoma, acromegaly, testicular tumors,
sexual precocity, psammomatous melanotic schwannoma
Dermatologic examination with skin biopsy;
cardiology and endocrine referral; examination
of first-degree relatives
Complications of cardiac myxomas may shorten life span
syndrome comprises myxomas, spotty pigmentation,
endocrine overactivity, and more recently, psammomat-
ous melanotic schwannoma (14). Two syndromes are
described under the umbrella of Carney complex (5) –
LAMB (11,13) (lentigines, atrial myxomas, mucocuta-
neous myxomas, and blue nevi) and NAME (6,11,13)
(nevi, atrial myxomas, myxoid neurofibromatosis, and
ephelides and endocrine neoplasia). Clinically the
lentigines are very similar to those found in LEOPARD
syndrome. They are distributed diffusely on the body and
are most commonly found on the face, vermilion border
of the lips, eyelids, conjunctiva, nasal bridge, ears, oral
mucosa, neck, and upper trunk (14). The main difference
is that lentigines involve the oral mucosa in Carney
complex (3), whereas in LEOPARD syndrome, the oral
mucosa is typically spared (5,6,11). The other feature
that helps to distinguish the two syndromes is the presence
of dysmorphism (5,6) in LEOPARD syndrome; patients
with Carney complex are not typically dysmorphic.
Myxomas affect the heart, skin, and breasts (14). The
most important component of the complex is atrial
myxoma (14). These cardiac myxomas may be single,
but are usually bilateral. Complications include conges-
tive heart failure, chest pain, pulmonary edema, embolic
phenomenon, and death (5). Cardiac myxomas account
for 20% of the deaths in such patients (5). Thus, for
patients with Carney complex, regular cardiac screening
is mandatory and early surgical resection (5,14) of the
atrial myxoma may be lifesaving. A comparison of the
features of LEOPARD syndrome and Carney complex is
summarized in Table 2.
Arnsmeier and Paller (4) and Uhle and Norvell (15)
reported families who had only generalized lentig-
ines without noncutaneous manifestations. The terms
144 Pediatric Dermatology Vol. 21 No. 2 March/April 2004

“generalized lentiginosis” and “lentiginosis profusa” are

often reserved for such patients who have widespread
lentigines without associated noncutaneous abnormal-
ities, and “LEOPARD syndrome” is reserved for patients
with systemic anomalies (4). Our two cases fit the
description of “generalized lentiginosis” – evidence of
generalized cutaneous lentigines without mucosal in-
volvement and lack of defined noncutaneous features
based on criteria proposed by Voron et al (9) (patient 2
has mitral valve prolapse; probably an incidental finding).
A 24-hour urine free cortisol level (3) was determined
for patient 2 to screen for Cushing syndrome (associated
with Carney complex) and this was normal. The lack
of a positive family history of generalized lentigines
in both patients suggests the possibility of sporadic (12)
mutations occurring in the involved genes, although
such genes have yet to be identified.
Therefore, is generalized lentiginosis an entity distinct
from LEOPARD syndrome? Arnsmeier and Paller (4)
believe that generalized lentiginosis is a distinct entity
and patients are not at risk for developing noncutaneous
abnormalities. On the other hand, McKusick et al and
other authors do not consider the two syndromes as
separate. In fact, a literature review has provided
evidence of considerable heterogeneity in families with
LEOPARD syndrome, including some members with
only cutaneous manifestations (4). We believe that gen-
eralized lentiginosis and LEOPARD syndrome represent
a spectrum of the disease process and are not distinct
entities.
Until further reports of affected families, linkage Figure 5. Proposed algorithm in approach to a child with
analysis, identification of gene mutations, and other more generalized lentigines.
conclusive information about transmission are estab-
lished, screening and full evaluation for systemic abnor-
malities, especially cardiac lesions, should be performed disorders as the LEOPARD syndrome and Carney com-
on all patients with generalized lentigines. It has been plex (LAMB and NAME syndrome). However, there
suggested that patients with generalized lentiginosis have been reports of patients with generalized lentigines
(without associated abnormalities) require evaluation without systemic features, including the two children
annually, with particular emphasis on the cardiovascular described here – the term “generalized lentiginosis”
system (13), as noncutaneous abnormalities may develop lacking systemic associations is preferred to “LEOPARD
later. First-degree family members should be fully eval- syndrome,” as it denotes the absence of noncutaneous
uated and genetic counseling offered to all individuals abnormalities. On the other hand, generalized lentig-
who have this disorder to explain the risk of having off- inosis and LEOPARD syndrome may be viewed as a
spring with LEOPARD syndrome (4). spectrum of the same disease process rather than separate
Finally, we would like to propose a working algorithm disease entities, as patients with multiple lentigines may
in the approach to a child with generalized lentigines develop defined noncutaneous abnormalities later (5).
(Fig. 5) and suggest follow-up to rule out systemic Hence the presence of generalized lentigines may be
involvement. viewed as a clinical marker for possible systemic abnor-
malities (5), and patients with this disorder should be
thoroughly evaluated, particularly for cardiac and auditory
CONCLUSION
abnormalities, at the first presentation and at subsequent
Associations of generalized lentigines with noncutane- regular intervals. Genetic counseling should be offered
ous abnormalities have been well described in such to all individuals who have generalized lentigines.

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