Birthmarks of Potential Medical Significance by mikeholy

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									                                                                                                                                 Article   dermatology




Birthmarks of Potential Medical
Significance    ´
Jacinto A. Hernandez,
                         Objectives               After completing this article, readers should be able to:
MD*,
Joseph G. Morelli, MD†   1. Describe the clinical manifestations of neurofibromatosis type 1.
                         2.                                    ´
                            List conditions associated with cafe au lait macules.
                         3. Explain the clinical significance of congenital melanocytic nevi.
                         4. Characterize tuberous sclerosis complex.
                         5. List the two syndromes associated with port-wine stains and extracutaneous
                            abnormalities.
                         6. Categorize and describe the three types of hemangiomas.


                         Introduction
                         Birthmarks are common ( 8% to 10%) in newborns. Most birthmarks represent vascular
                         and pigmentary lesions. The natural history of these lesions varies from being transient
                         phenomena and essentially normal variants of no clinical significance to permanent
                         cutaneous abnormalities that may be associated with significant systemic complications or
                         diseases. Table 1 lists some neonatal skin lesions that should be recognized by the clinician
                         as clues to more serious disorders.
                            This review describes some of the most commonly encountered, clinically significant
                         birthmarks, emphasizing those findings that should prompt early assessment, diagnosis,
                         and appropriate treatment and counseling.

                         Hyperpigmented Birthmarks
                         Hyperpigmented lesions are common at birth and in the first few postnatal weeks. They
                         may be macular, papular, plaquelike, evenly colored, or speckled.

                                 ´
                              Cafe Au Lait Macules
                             ´
                         Cafe au lait macules (CALMs) are localized epidermal melanocytic flat lesions that usually
                         are round or oval, evenly colored with light brown pigmentation, have distinct margins,
                         and range in size from a few millimeters to 15 to 20 cm in diameter. They can occur
                         anywhere on the body, most often on the buttocks in newborns (Fig 1). Most CALMs are
                         present at birth or develop in the first few postnatal months. They are seen in 0.3% to 18%
                         of neonates and usually are not associated with specific abnormalities, although they can be
                         markers for some genetic diseases, such as neurofibromatosis type 1 (NF-1). Neonates who
                         have multiple CALMs should be evaluated carefully for stigmata of NF-1, including
                         measuring and counting of lesions. Although solitary lesions are common or nonspecific,
                         more than three CALMs in Caucasian infants and more than five CALMS in infants of
                         other races are uncommon at any age. Six or more CALMs greater than 5 mm in diameter
                         are presumptive evidence of NF-1. The presence of axillary or inguinal freckling in addition
                         to multiple CALMs enhances the possibility of NF-1. Other signs of NF-1 in neonates are
                         extremely rare (eg, Lisch nodules, optic gliomas, osseous lesions, other neural tumors).
                         The clinical manifestations of NF-1 may evolve over time, and neonates at risk or in whom
                         evidence of disease is presumed should be monitored closely. Approximately 75% of infants
                         who have six or more CALMs and are followed for 2 years develop signs of NF-1.
                            Diagnosis is based on the clinical experience. A family history of NF or other syndromes
                         should be investigated, and parents examined when possible. The differential diagnosis of

                         *Professor of Pediatrics, Neonatology Section, Department of Pediatrics.
                         †
                           Professor of Dermatology and Pediatrics, University of Colorado Health Sciences Center, Denver, CO.


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                                                              generally develop in the first decade of life and usually are
        Neonatal Skin Lesions
   Table 1.                                                   on the same side as unilateral CALMs, consistent with
                                                              the syndrome being a mosaic disorder. Multiple as-
   That Are Clues to More                                     sociated endocrine abnormalities include precocious
   Serious Disorders                                          puberty, hyperthyroidism, Cushing syndrome, hyperso-
                                                              matotropism, hyperprolactinemia, and hyperparathy-
   Hyperpigmented Birthmarks                                  roidism. This syndrome is more common in females than
       ●      ´
           Cafe au lait macules (CALMs)                       in males and most likely is caused by an autosomal
       ●   Congenital melanocytic nevi (CMN)                  dominant lethal mutation with resulting mosaicism. The
   Hypopigmented Birthmarks (“white spots”)                   responsible defect has been mapped to the alpha subunit
                                                              of the GNAS-1 gene. Close observation and follow-up
   Vascular Birthmarks                                        for endocrine abnormalities and referral for orthopedic
       ●   Vascular Malformations                             evaluation are appropriate.
           —Port-wine stains (PWS)
           —Lymphatic malformations
       ●   Vascular Tumors
                                                                 Congenital Melanocytic Nevi
           —Hemangiomas                                       Congenital melanocytic nevi (CMN) are collections of
                                                              melanocytes in the skin present at birth or appearing in
   Nevus Sebaceous
                                                              the first few months after birth. They are macular, papu-
                                                              lar, or plaquelike pigmented lesions in different shades of
                                                              brown, with black or blue foci. Their texture may be
conditions associated with CALMs is extensive (Table          smooth, nodular, verrucous, or rough cobblestonelike,
2). Watson syndrome presents with multiple CALMs,             with or without hair. Lesions typically grow proportion-
intertriginous freckling, short stature, pulmonary steno-     ally with the individual and typically are classified based
sis, and low intelligence and is believed to be a subset or   on the assumed adult size. Small CMN measure 1.5 cm
allelic form of NF-1. NF-2 is a genetically distinct auto-    or less, intermediate CMN range between 1.5 cm and
somal dominant disorder characterized by CALMs and            20 cm, and large CMN (LCMN), also called “garment
acoustic or central nervous system schwannomas.               or bathing trunk nevi,” are more than 20 cm in diameter
    The McCune-Albright syndrome refers to the triad of       (Figs. 3 and 4). In the neonate, any lesions on the head
CALMs, polyostotic fibrous dysplasia, and endocrine            that are approximately 9 cm in diameter or on the body
dysfunction. CALMs in this syndrome are usually large,        that are 6 cm qualify as LCMN or giant.
linear or segmental, unilateral or bilateral, can follow          CMN are clinically significant because of their associ-
Blaschko lines, and may have an irregular jagged margin       ation with malignant melanoma. Small nevi are seen in
said to resemble the “coast of Maine” (Fig 2). Polyos-        1% to 2% of newborns, intermediate-size lesions in 0.6%,
totic fibrous dysplasia is a disorder in which bone is         and LCMN in no more than 0.02%. The risk of malig-
replaced by fibrous tissue, resulting in asymmetry, bony       nant melanoma arising within small and intermediate
growth, and pathologic fractures. These bony lesions          CMN is very small, usually 2% or less. Consequently, the
                                                              clinical management of these patients remains controver-
                                                              sial. Most require only clinical follow-up. The decision to
       Other Syndromes
   Table 2.                                                   excise the lesions is individualized. Large CMN are most
                                                              common on the posterior trunk, but also may be seen on
   Definitely Linked to Multiple                               the anterior and lateral trunk, head, neck, or extremities.
   CALMs                                                      Multiple small satellite CMN are seen in most patients
                                                              who have LCMN. Although the estimated lifetime risk
   ●   Watson syndrome
                                                              for melanoma in patients who have LCMN ranges be-
   ●   Neurofibromatosis type 2 (NF-2)
   ●   McCune-Albright syndrome                               tween 6% and 8%, the associated death rate is less than
   ●   Tuberous sclerosis complex (TSC)                       1%. Approximately 50% of melanomas occur by 3 to 5
   ●   Ring chromosomes syndromes                             years of age; the greatest risk for malignant transforma-
   ●   Less consistently:                                     tion appears to be in the prepubertal years. LCMN of the
       —Bloom syndrome
                                                              scalp and dorsal axis have been associated with neurocu-
       —Leopard syndrome
       —Silver-Russell syndrome                               taneous melanosis. Large CMN in the lumbosacral area
                                                              may be associated with spinal dysraphism, myelomenin-

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Table 3.   Vascular Malformations                                                     and size ranges from 1 to several
                                                                                      centimeters. Poliosis on the scalp
   Flow Type              Tissue Type               Disease Example                   (white patches of the hair) or in the
                                                                                      eyebrows and eyelashes also can be
   Slow flow               Capillary                 Port-wine stain (PWS)
                          Venous                    Klippel-Trenaunay syndrome
                                                              ´                       seen. It is rare for newborns to have
                          Lymphatic                 Cystic hygroma                    other cutaneous signs of TSC.
   Fast flow               Arterial                  Aneurysm and stenosis             Shagreen patches (sometimes
                          Arteriovenous             Arteriovenous malformations       present at birth) and angiofibromas
   Complex                Mixed tissues             Hemolymphatic angiodysplasia
                                                                                      usually become apparent in early
                                                                                      childhood, and periungual fibro-
                                                                                      mas tend to occur in adulthood.
gocele, and sometimes limb hypoplasia. The manage-                  Lesions that should be distinguished from the cuta-
ment of large CMN should be individualized, but con-             neous hypopigmented macules of TSC include nevus
sidering the early age of development of melanomas and           anemicus, nevus depigmentosus, postinflammatory hy-
the poor prognosis, early partial or complete prophylac-         popigmentation, piebaldism, and vitiligo. Criteria for the
tic excision is supported by many specialists. In addition       diagnosis of TSC are very well defined in the standard
to melanoma, LCMN can be associated with other ma-               textbooks of pediatrics and dermatology.
lignant tumors (eg, rhabdomyosarcomas, liposarcomas).
                                                                Vascular Birthmarks
Hypopigmented Birthmarks                                        Vascular birthmarks are cutaneous anomalies of angio-
Localized forms of hypopigmentation (“white spots”)             genesis and vasculogenesis resulting in various clinical
are relatively common and may be present at birth or            presentations and often heralding other disease states or
manifest later in infancy or early childhood (Fig. 5).          anomalies. Two major groups of vascular birthmarks are
These hypopigmented macules are the result of impaired          recognized: vascular malformations, which are com-
melanocyte function. Because infants have lighter skin          posed of dysplastic vessels, and vascular tumors that
color at birth than later in life, focal forms of hypo-         demonstrate cellular hyperplasia (hemangiomas).
pigmentation may be less obvious or completely missed
at birth. Examination under a Wood lamp may be nec-                 Vascular Malformations
essary to detect subtle lesions in fair-skinned infants.        Vascular malformations are errors in morphogenesis that
    The clinical significance of these localized forms of        may affect any branch of the neonatal vasculature. They
hypopigmentation is their potential association with the        are subcategorized according to flow characteristics and
tuberous sclerosis complex (TSC). Although isolated             predominant anomalous channels (Table 3). Capillary,
hypopigmented macules may be a variant of normal in             venous, lymphatic, arterial, and arteriovenous malforma-
neonates, the presence of three or more white spots or          tions occur either alone or in combination. They are
isolated hypopigmented macules in the setting of suspi-         present at birth and often are localized and circum-
cious signs or symptoms or a family history should              scribed, although they can present in a segmental, sys-
prompt evaluation for TSC. Examination of the parents           tematized pattern or in a diffuse, disseminated form.
and other family members may be indicated.                      Some are part of a more complex syndrome pathology.
    TSC, an autosomal dominant disorder that is charac-         Although they grow proportionately with affected chil-
terized by cutaneous and neurologic abnormalities as            dren’s development, they do not have a proliferative
well as multiple visceral hamartomas. The classic triad for     phase or tendency to spontaneous involution. This re-
TSC consists of multiple angiofibromas, seizures, and            view focuses only on the clinical significance of the
mental retardation. Estimates of the prevalence of TSC          capillary malformations.
range from 1:10,000 to 1:40,000, and spontaneous mu-                Salmon patch is the most common capillary malfor-
tations account for 50% to 75% of cases. Hypomelanotic          mation. It is present at birth as a pink blanching patch
macules can be one of the earliest indicators of the            most commonly located on the forehead (“angel kiss”)
disease. They occur in approximately 80% of patients            and nape (“stork bite”). Other involved sites include the
who have TSC and generally are present at birth. These          glabella, nose, upper eyelids, and upper lip, where the
hypopigmented macules appear polygonal (“thumb-                 lesions simply are referred to as vascular stains or nevus
print”), lance-ovate (“ash leaf spot”), and guttate-like        simplex. Salmon patches occur in nearly 50% of new-
(“confetti”). The margins may be regular or irregular,          borns and affect males and females equally. They are

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asymptomatic, pose minimal cosmetic problems, and              representing a milder form of the disease. KTS is com-
usually disappear within 2 years, although nape lesions        monly unilateral (95%) and usually involves the lower
usually persist.                                               extremity (95%), upper extremity (5%), or both. When
    Port-wine stains (PWSs) are slow-flow capillary mal-        the predominant vascular malformation is multiple arte-
formations that may occur anywhere on the body and             riovenous shunts, the syndrome is called Parkes-Weber
almost always are present at birth. These pink or red          syndrome; when the limb abnormality is undergrowth,
patches grow proportionately with the child and persist        the syndrome is Servelle-Martorell syndrome. The diag-
throughout life. Usually, PWSs, like hemangiomas, do           nosis usually is made clinically, but modern vascular
not involute (Fig. 6). They have been associated with          imaging techniques help delineate the vascular defect.
other cutaneous lesions and with extracutaneous abnor-         MRI angiography and Doppler ultrasonography are nec-
malities. When associated with a pigmented lesion, such        essary to evaluate flow characteristics and rule out an
as mongolian spot, nevus spilus, or hyperpigmented nevi,       arteriovenous fistula.
the condition is known as phakomatosis pigmento vas-
cularis. If a PWS is found midline over the spine or scalp,       Vascular Tumors (Hemangiomas)
it may be a marker for an occult spinal or cranial dysra-      Hemangiomas represent the most common vascular tu-
phism. Two syndromes associated with PWSs and extra-           mor encountered during the neonatal period, occurring
cutaneous abnormalities are Sturge-Weber syndrome              in 1.0% to 2.6% of newborns. Approximately 25% of the
                        ´
(SWS) and Klippel-Trenaunay syndrome (KTS).                    tumors are present at birth; the remainder develop in the
    Also known as encephalotrigeminal angiomatosis,            first few postnatal weeks. Rarely, they appear as fully
SWS occurs sporadically in the general population and is       grown tumors at birth (congenital hemangioma) that
characterized by the classic triad of facial PWS in the        resolve rapidly, often leaving pronounced atrophic skin
ophthalmic (V1) distribution of the trigeminal nerve, eye      changes. True hemangiomas are benign vascular tumors
abnormalities, and leptomeningeal and brain abnormal-          produced by proliferation of endothelial cells that un-
ities. Facial PWS associated with SWS may involve the          dergo a phase of rapid growth followed by spontaneous
maxillary (V2) or mandibular (V3) distribution of the          slow involution. Approximately 30% of hemangiomas
trigeminal nerve. Patients who have V2 and V3 PWS              spontaneously involute by age 3 years, 50% by age 5
alone without involvement of V1 are not at risk for SWS.       years, and 80% to 90% by age 9 to 10 years. Hemangio-
Eye abnormalities include choroidal vascular anomalies         mas are clinically heterogenous, with their appearance
and glaucoma in about 30% of cases with secondary              dictated by the depth, location, and stage of evolution.
buphthalmus and visual loss. Among the brain abnor-            They are classified as superficial hemangiomas ( 60%),
malities are leptomeningeal vascular abnormalities, calci-     deep hemangiomas ( 15%), and mixed-type hemangio-
fications, enlarged choroidal plexus, cerebral atrophy,         mas ( 25%), which have features of both.
and developmental venous anomalies, resulting in sei-             Superficial hemangiomas (strawberry hemangioma)
zures, mental retardation, and sometimes hemiparesis.          are usually present at birth or develop within the next few
SWS occurs in 10% of neonates who have V1 PWS and              weeks. In the newborn, a pale macule that has threadlike
can pose significant medical and ophthalmologic prob-           telangiectases and a bruiselike macule represent a com-
lems. Imaging of the central nervous system is best            mon precursor lesion. As the tumor proliferates, it as-
performed after 6 months of age, with magnetic reso-           sumes its most recognizable form: a bright red, slightly
nance imaging (MRI) used to find vascular anomaly and           elevated, noncompressible plaque. Its surface texture is
atrophic changes.                                              finely lobulated, resembling strawberries (Fig. 8). Hem-
    KTS also is known as angio-osteohypertrophy syn-           angiomas that lie deeper in the skin are soft, warm masses
drome and is a complex-combined vascular malforma-             that have a slightly bluish discoloration. They range from
tion of the limbs that is visible at birth and grows signif-   a few millimeters to several centimeters in diameter and
icantly. It is characterized by a capillary malformation       usually are solitary, although up to 20% of infants have
(PWS) associated with limb hypertrophy (overgrowth of          multiple lesions. A female predominance (3:1) and an
the soft tissue and bone), varicose veins, lymphedema,         increased incidence among preterm infants have been
and phleboliths (Fig. 7). Sometimes a significant lym-          documented. Generally, superficial hemangiomas reach
phatic or venous malformation may be present. The limb         their maximal size by 6 to 8 months of age, but deep
hypertrophy often increases progressively and dispropor-       hemangiomas may proliferate for 12 to 14 months or
tionately to the child’s growth, but in some cases the         longer. The involuting phase begins with changes in the
soft-tissue hypertrophy shows proportionate growth,            surface color and texture, usually in the center of the

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hemangiomas. It is important to realize that not all            icance is the potential association with visceral
hemangiomas look like strawberries, and not all                 hemangiomatosis. If these lesions are limited only to the
strawberry-like lesions are hemangiomas.                        skin, the entity is termed benign neonatal hemangioma-
    Despite the benign nature of most cutaneous heman-          tosis. If evidence shows systemic visceral involvement,
giomas, a significant number cause functional compro-            the term diffuse neonatal hemangiomatosis (DNH) is
mise, residual skin changes, or permanent disfigurement.         used. NH appears early in the neonatal period, and girls
Ulceration, the most frequent complication, can be ex-          are affected more commonly. The cutaneous lesions may
cruciatingly painful and carries the risk of infection, hem-    range from a few millimeters to more than several centi-
orrhage, and scarring. In addition, hemangiomas may be          meters in diameter. There is no consensus regarding the
associated with extracutaneous abnormalities and dys-           number of cutaneous hemangiomas and the risk of vis-
morphogenesis. Periorbital hemangiomas pose consider-           ceral involvement. The gastrointestinal tract (bowel and
able risk to vision and should be monitored carefully.          liver), lungs, and central nervous system are involved in
Infants who have extensive facial hemangiomas, particu-         more than 50% of cases of DNH. The oral mucosa and
larly those in the “beard distribution,” may have associ-       eyes also commonly are affected. Additional complica-
ated subglottic hemangiomas ( 60%) and warrant direct           tions include high-output congestive heart failure, vis-
visualization of the airway. Lumbosacral hemangiomas            ceral hemorrhage, hydrocephalus, and ocular abnormal-
may be markers for occult spinal dysraphism and anorec-         ities. Untreated patients have a high mortality rate
tal and urogenital anomalies. Imaging of the spine is           ( 80%). With current treatment regimens, the mortality
indicated in all patients who have midline hemangiomas          rate can be as low as 29%. Serial physical examinations,
in this region.                                                 visceral ultrasonography, and MRI should be performed
    PHACE(S) syndrome applies to the association of             in neonates who have DNH.
large facial hemangiomas with multiple extracutaneous               Kasabach-Merritt syndrome (KMS) refers to the con-
structural abnormalities, such as cardiovascular, neuro-        sumption (trapping) of platelets and coagulation factors
logic, and ophthalmologic anomalies (Fig. 9). The term          within a congenital or neonatal vascular neoplasm, re-
PHACE(S) refers to: Posterior fossa brain malforma-             sulting in thrombocytopenia, microangiopathic hemo-
tions, Hemangiomas, Arterial anomalies, Coarctation of          lytic anemia, hemorrhage, and purpura from dissemi-
the aorta and cardiac anomalies, Eye abnormalities (and         nated intravascular coagulation (Fig. 11). KMS most
sometimes Sternal clefting/supraumbilical raphe). This          commonly occurs with tumors such as kaposiform he-
syndrome has a marked female predominance (9:1) and             mangioendotheliomas and tufted angiomas. KMS is a
is believed to represent a developmental defect that oc-        rare and distinctive syndrome or phenomenon that has
curs during the 8th to 10th week of gestation.                  no gender predilection and presents at birth as a tumoral
    Management and treatment of hemangiomas must be             mass of variable size and location that subsequently
approached on a case-by-case basis according to the             develops a deep red or purple mass that grows rapidly.
number of lesions, their location and size, and the pres-       This syndrome is a medical/dermatologic emergency
ence of any associated clinical abnormalities. Most hem-        that requires aggressive, often multimodality treatment
angiomas involute spontaneously, requiring no treat-            by a team of specialists and carries a significant mortality
ment. Early treatment of superficial hemangiomas with            rate (20% to 30%). Thrombocytopenia may persist for a
flash lamp-pulsed dye laser therapy may reduce the extent        few years, but more commonly resolves with treatment
of vascular proliferation and induce earlier involution. If     by 12 to 18 months. Current therapies of reported
complications arise and treatment is warranted, oral sys-       success include corticosteroids, interferon-alpha, vincris-
temic corticosteroids are the mainstay of therapy. Re-          tine, and ticlopidine plus aspirin. Surgical excision and
combinant interferon-alpha, an inhibitor of angiogene-          arterial embolization may also benefit some patients.
sis, has been used successfully in treating life-threatening
hemangiomas. However, because 10% of treated patients
develop spastic diplegia, it should not be a primary            Suggested Reading
therapy. Overly aggressive surgical procedures generally        Achaeuer BM, Chang C, Vander VM. Management of hemangio-
should be avoided, but sometimes they are the last alter-          mas of infancy: review of 245 patients. Plast Reconstr Surg.
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    Neonatal hemangiomatosis (NH) refers to the pres-              cohort of 4,641 newborns. Pediatr Dermatol. 1983;1:58 – 68
ence of numerous small, superficial hemangiomas scat-            Berry SA, Peterson C, Mize W, et al. Klippel-Trenaunay syndrome.
tered across the skin surface (Fig. 10). Its clinical signif-      Am J Med Genet. 1998;79:319 –326

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Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma:                    terial anomalies, coarctation of the aorta and cardiac defects, and
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NeoReviews Quiz
        ´
 1. Cafe au lait macules (CALMs) are localized epidermal melanocytic flat lesions that have a light brown
    pigment. Six or more CALMs that are greater than 5 mm in diameter each are markers for certain genetic
    diseases. Of the following, the finding of pulmonary stenosis in addition to multiple CALMs is most
    consistent with the diagnosis of:
    A.   Leopard syndrome.
    B.   McCune-Albright syndrome.
    C.   Neurofibromatosis type 2.
    D.   Tuberous sclerosis complex.
    E.   Watson syndrome.

 2. Hypopigmented macules resulting from impaired melanocyte development are significant because of their
    potential association with the tuberous sclerosis complex (TSC). Of the following, the clinical sign of TSC
    that is most likely to be present at birth is:
    A.   Adenoma sebaceum.
    B.   Ash leaf spot.
    C.   Periungual fibroma.
    D.   Scalp poliosis.
    E.   Shagreen patch.

 3. Port-wine stains (PWSs) are slow-flow capillary malformations that often are associated with other
    cutaneous lesions and extracutaneous abnormalities. Of the following, the finding of limb undergrowth in
    association with PWSs is most consistent with the syndrome of:
    A.             ´
         Klippel-Trenaunay.
    B.   Parkes-Weber.
    C.   Servelle-Martorell.
    D.   Silver-Russell.
    E.   Sturge-Weber.

 4. Strawberry hemangiomas are benign vascular tumors produced by proliferation of endothelial cells. They
    undergo an initial phase of rapid growth followed by a phase of spontaneous involution. Of the following,
    strawberry hemangiomas are most likely to:
    A.   Be solitary.
    B.   Have a reduced incidence among preterm infants.
    C.   Involute in most infants by age 3 years.
    D.   Involve both superficial and deep tissues.
    E.   Show male predominance.




                                                                                       NeoReviews Vol.4 No.10 October 2003 e269

								
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