Freckles Mfc

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Freckles Mfc
Volume 32, Issue 4 , December 2014 , Pages 211-216
Special issue articles Recommended articles
Exome sequencing identifies SLC24A5 as a candidate gene for non-syndromic oculocutaneous albinism
J Invest Dermatol , 133 ( 2013 ) , pp. 1834 - 1840
Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4
Am J Hum Genet , 69 ( 2001 ) , pp. 981 - 988
Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis
J Invest Dermatol , 124 ( 2005 ) , pp. 1186 - 1192
Hyperpigmentation of the distal phalanx in healthy Caucasian neonates
Eur J Dermatol , 11 ( 2001 ) , pp. 120 - 121
Transient neonatal pustular melanosis
Actas Dermosifiliogr , 104 ( 2013 ) , pp. 84 - 85
Birthmarks with serious medical significance: nevocellular nevi, sebaceous nevi, and multiple cafe-au-lait spots
J Pediatr , 95 ( 1979 ) , pp. 696 - 700
A clinical, pathological and genetic study of multiple neurofibromatosis
Charles C. Thomas , Springfield, IL ( 1956 )
Diagnostic outcome in children with multiple cafe au lait spots
Pediatrics , 90 ( 1992 ) , pp. 924 - 927
Review and update of SPRED1 mutations causing Legius syndrome
Hum Mutat , 33 ( 2012 ) , pp. 1538 - 1546
Activating mutations of the stimulatory G protein in the McCune–Albright syndrome
N Engl J Med , 325 ( 1991 ) , pp. 1688 - 1695
Melanotic macules in Albright's syndrome and in neurofibromatosis
JAMA , 205 ( 1968 ) , pp. 618 - 628
Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction
Hum Mol Genet , 15 ( Suppl. 2 ) ( 2006 ) , pp. R220 - R226
Hypermelanoses of the newborn and of the infant
Dermatol Clin , 25 ( 2007 ) , pp. 327 - 336
Linear and whorled nevoid hypermelanosis: report of two cases
Arch Pediatr , 5 ( 1998 ) , pp. 1098 - 1102
Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase
Nat Genet , 18 ( 1998 ) , pp. 38 - 43
Carney complex: pathology and molecular genetics
Neuroendocrinology , 83 ( 2006 ) , pp. 189 - 199
Extensive Mongolian spots: a clinical sign merits special attention
Pediatr Neurol , 34 ( 2006 ) , pp. 143 - 145
Orbital melanocytoma completely resected with conservative surgery in association with ipsilateral nevus of Ota: report of a case and review of the literature
Head Neck ( 2014 Jul 3 ) , 10.1002/hed.23828
Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature
Mod Pathol , 27 ( 2014 ) , pp. 1468 - 1478
2019, Indian Journal of Practical Pediatrics
Copyright © 2014 Published by Elsevier Taiwan LLC.
Skin color is an important social and cultural characteristic, which explains why the parents of children with any deviations from normal pigmentation are concerned about this problem. This article discusses selected pigment anomalies present at birth or appearing in the first months of life. They may be transient or permanent, localized (as in café-au-lait spots) or segmental, or more rarely, complex or generalized. As with most pigmentary diseases , a physical examination, including Wood's lamp examination and a detailed history, is usually sufficient for diagnosis. Time of onset, distribution pattern, and associated clinical and sometimes histopathologic or molecular findings are helpful in differentiating these disorders.
Skin color is an important social and cultural characteristic, which explains why the parents of children with any deviations from normal pigmentation are concerned about this problem. Troubles in skin color may raise considerable concern in black and Asian communities. Normal constitutive pigmentation is under the control of myriad genes, but recent studies in humans have attributed a major part of pigmentation variation across races to a limited number of genes. The human equivalent of the mutant golden zebrafish SLC24A5/NCKX5 explains a major part of the shift observed from Negroid to Caucasian phenotypes, and has recently been related to oculocutaneous albinism type 6. 1 Other important human genes include MATP / SLC45A2 , which when mutated is responsible for oculocutaneous albinism type 4, 2 and the MRC-1 gene, several loss of function variants of which have been described to be associated with pale skin and red hair, indicating a skewing of melanin production toward that of pheomelanin . Although recreational sun exposure is contraindicated in babies, examination at birth may be misleading for congenital anomalies , because modifications of pigmentation are frequently revealed after the first outdoor exposures. Normal skin has essentially all its melanin in the epidermis and hairs. The color that one perceives when viewing the skin depends on several factors, especially the depth of pigment deposits. If melanin pigment is present in the dermis , the integument takes on a blue–gray hue that looks bluer as the pigment is deposited deeper. Melanin is not the only natural skin pigment. Diet carotenoids deposit in the epidermis and dermis, and contribute in a minimal way to the yellowish tint of the skin. However, a pronounced yellowing of the integument is common in babies on high carotenoid diets. Red and blue hues are the product of oxyhemoglobin and reduced hemoglobin in capillaries, arteries, and veins in the dermis. They may mix in some areas with abnormalities of the pigmentary system, such as in phakomatosis pigmentovascularis ( Figure 1 ), and variations may depend on the maturation of the skin and its thickness.
Figure 1 . Phakomatosis pigmentovascularis. Note the mix of blue, red, and anemic macules.
This article discusses pigment anomalies present at birth or appearing in the first months of life. They may be transient or permanent, localized [as in café-au-lait (CAL) spots] or segmental, or more rarely, complex or generalized. In most pigmentary diseases , physical examination, including Wood's lamp examination and a detailed history, is usually sufficient. Time of onset, distribution pattern, and associated clinical and sometimes histopathologic findings are helpful in differentiating these disorders. Molecular diagnosis has become available for some rare entities, such as hereditary symmetrical dyschromatoses, 3 but the bulk of nevoid lesions has not yet been understood at the molecular level.
At birth, maturation of the pigmentary system is not completed, and some areas, such as the scrotum in boys or dorsum of fingers (especially the distal phalanx), may look strikingly hyperpigmented in babies with otherwise pale skin. 4 Pigmentation of the genital area is probably influenced by sex hormone impregnation prior to birth, and friction or suction may partly explain finger hyperpigmentation ( Figure 2 ). Some lighter phenotypes can be found with such transient birthmarks , babies belong usually to skin phototypes IV and darker, and this phenotype is normal in Asian and black babies. Transient pustular melanosis (TPM) is characterized by pustules present at birth that evolve into macular pigmentation ( Figure 3 ). The content of the pustules is mostly neutrophilic, and the duration of the rash, especially the pigmentation, is longer. TPM is more common in black neonates, and is probably the cause of the so-called ‘‘freckling’’ or ‘‘lentigines neonatorum’’ noted in 15% of black neonates. The cause of both of these eruption types, which may coexist and are not linked to an infectious agent, is still unclear. Sterile transient neonatal pustulosis , a term that encompasses pustular rashes of erythema toxicum neonatorum and TPM, has been proposed. The fact that TPM is mostly diagnosed in black neonates may correspond to accelerated stimulation of negroid melanocytes caused by cytokines and growth factor release by inflammatory cells of the epidermal infiltrate. An increased amount of melanin in basal and suprabasal layers can be detected with the Fontana–Masson preparation. In pustules, erythema toxicum neonatorum-like features can be seen. Most characteristically, the subcorneal pustule contains polymorphonuclear leucocytes and scattered eosinophils . Keratinous debris, serous fluid , and fragmented hair shafts may also be present. Moderate acanthosis can be associated with this condition. In the dermis , eosinophils and neutrophils may be seen around capillaries and the upper portion of the hair follicle . TPM was originally described to be more frequent in black neonates when residual hyperpigmentation was included in its definition. The eruption is always present at birth. Lesions are located on the chin, neck, nape , upper chest, lower back, and buttocks, and also on the lower abdomen and medial side of the thighs. Rarely, the scalp , palms, and soles are involved. Clusters of pustules occur around the nipples and on pressure areas. In typical cases, pigmented macules coexist initially with flaccid vesiculopustules (1.5–3 mm in diameter) with no surrounding erythema that rupture easily and leave a collarette of fine white scales. Individual pustules dry out and may leave a flat, brownish crust that can be detached easily by gentle scratching. Unscratched crusts may persist for a few weeks, and pigmented freckles may persist for a few months in pigmented patients. Typical erythema toxicum neonatorum lesions occur in most patients in association with TPM in a typical time course. 5
Figure 2 . Physiological finger pigmentation in a newborn.
Figure 3 . Neonatal freckling caused by transient pustular melanosis .
CAL spots present as uniform tan–brown round or oval macules with distinct margins and variable border contour. These lesions tend to enlarge in proportion to general body growth during the first several years of life and then stabilize. They do not regress in later years. Histologically, CAL spots have increased epidermal melanin without melanocytic proliferation . Ultrastructural examination reveals giant pigment granules (macromelanosomes) in lesions of patients with neurofibromatosis . CAL spots are commonly seen at birth or in early infancy and have been noted in up to 25% of children, particularly in black children. 6 Most children with CAL spots have no other associated abnormalities.
However, in children, multiple large CAL spots may be a sign of one of several syndromes. By far, the most common condition is type 1 neurofibromatosis . It is generally assumed that six or more CAL spots, larger than 1.5 cm in diameter, are pathognomonic of this disease. 7 The importance of this finding was demonstrated in a study that showed that 89% of children with more than six CAL macules and no obvious diseases, who were observed for 3 years, eventually developed neurofibromatosis. 8 Children may have CAL spots as the only manifestation until puberty, when other signs begin to appear. Multiple hereditary CAL spots without other features of neurofibromatosis have been ascribed to Legius syndrome , caused by SPRED 1 mutations. 9 A long-term follow-up and repeated evidence of absence of other involved organs are necessary to consider this diagnosis. Children with McCune–Albright syndrome (polyostotic fibrous dysplasia), which is usually caused by mosaicism for a mutation in the GNAS1 gene, 10 may also have multiple CAL spots. However, these lesions are characteristically fewer, larger, and darker; have more jagged margins; and supposedly resemble the coast of Maine, as depicted in a classic American paper. 11 Besides the characteristic bony lesions, other findings of this syndrome include endocrinologic abnormalities, especially precocious puberty in girls, thyrotoxicosis , pituitary gigantism , and Cushing syndrome . Watson syndrome, which is known to be allelic to neurofibromatosis-1, is characterized by CAL spots and pulmonary stenosis , low intelligence, dysmorphic facial features , axillary freckling, and pigmented patches without neurofibromas . Overlapping phenotypes, including neurofibromatosis-1 and Noonan, Costello, LEOPARD, and cardio-facio-cutaneous syndromes, are better explained as inherited RAS-MAPK signal transduction disorders, a signaling pathway that activates constitutional melanogenesis , and shares CAL spots and other diffuse/localized pigmentary anomalies. 12 Other rare conditions in which CAL spots arise in the first years of life are listed in Table 1 . 13
Table 1 . Diseases associated with multiple café-au-lait spots.
Note . Adapted from “Hypermelanoses of the newborn and of the infant” by A. Taïeb and F. Boralevi, 2007, Dermatol Clin, 25 , p. 327–36.
OMIM = online Mendelian inheritance in man.
Segmental hypermelanosis is an expression of a cutaneous mosaicism of the pigmentary system that appears as a hyperpigmented macule in a segmental pattern and presents early in life. Histologic features are nonspecific and correspond to a localized increased pigment load, as detected by Fontana Masson stain, without melanocytic hyperplasia . Most cases of segmental hypermelanosis ( Figure 4 ) have their onset at birth or in early childhood, and may continue to enlarge in proportion to skin expansion. They may appear anywhere on the skin and are typically unilateral with a sharp cutoff at the midline. They often follow a dermatome , but may present a checkerboard pattern or affect a large Blaschko's line. In most cases, there are no associated dysmorphic features , although there have been a few reported cases of associated neurologic problems. McCune–Albright syndrome and segmental neurofibromatosis should be discussed if bony anomalies and neurofibroma , respectively, coexist. Linear/whorled nevoid hypermelanosis develops at birth or within the first few weeks of life ( Figure 5 ). Affected children develop swirls of macular hyperpigmentation along Blaschko's lines. The hyperpigmentation is composed of homogeneous macules that coalesce into reticulated patches. Linear and whorled nevoid hypermelanosis has been associated with serious congenital defects, and a set of investigations, including brain magnetic resonance imaging, should be considered in this setting. Differential diagnoses include the following: other Blaschko linear hyper- and hypomelanoses , such as incontinentia pigmenti that reaches a pigmented stage in childhood, after the typical vesiculobullous and verrucous aspects corresponding to neonatal and infantile stages, respectively; and hypomelanosis of Ito, which is symptomatically a kind of reverse pattern linear/whorled nevoid hypermelanosis. 14
Figure 4 . Segmental block-like nonsyndromic hypermelanosis.
Figure 5 . Linear and whorled pattern of hypermelanosis (dorsum).
Lentigines may be exceptionally present at birth. The typical lentigine (lentigo simplex) is a discrete, small, tan/brown/black, oval or circular macule that may occur on any cutaneous surface or on mucous membranes . Exposure to sunlight does not darken it, and it does not disappear spontaneously. Histologic changes in lentigines are limited to an increased activity of basal epidermal melanocytes , without nesting of melanocytes, but the number of melanocytes can be increased. The multiple lentigines syndrome or LEOPARD syndrome is rarely diagnosed at birth. The acronym LEOPARD describes the following features: lentigines, lesions noted most prominently on the face and trunk that increase in number with age; electrocardiographic abnormalities ; ocular hypertelorism ; pulmonary stenosis ; abnormal genitalia, particularly undescended testicles ; retarded growth; and deafness (sensory). Another multisystemic disease associated with lentigines is Peutz–Jeghers syndrome ( Figure 6 ), an autosomal-dominant disorder that consists of multiple lentigines clustered in the perioral area and elsewhere and gastrointestinal hamartomas situated most densely in the jejunum . Lesions may occur in infancy. Unlike other lentiginoses, lesions may remit completely during adolescence. Germline mutations in STK11, a serine/threonine kinase with a wide tissue distribution, probably in conjunction with acquired genetic defects of the second allele in somatic cells , cause the manifestations of Peutz–Jeghers syndrome. 15 STK11 is a tumor suppressor gene that acts as an early gatekeeper and regulates the development of hamartomas in Peutz–Jeghers syndrome, which may be pathogenetic precursors of adenocarcinoma. Additional somatic mutation events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in most colorectal carcinomas .
Figure 6 . Typical labial lentiginosis associated with Peutz–Jeghers syndrome.
The complex of myxomas , spotty pigmentation, and endocrine overactivity is a condition currently known as Carney complex and is caused by mutation in the protein kinase A regulatory subunit-1-alpha gene ( PRKAR1A ) on chromosome 17q 16 ; however, genetic heterogeneity occurs within this phenotype. A typical patient with this syndrome has at least two of the following findings: cardiac myxomas ; hyperpigmentation of the skin, including lentigines, ephelides, and nevi (although histologically almost all these lesions are lentigines); cutaneous myxomas ; myxoid mammary fibroadenomas ; testicular tumors ; pigmented nodular adrenocortical disease; and pituitary adenomas with gigantism or acromegaly . Multiple pigmented macules are distributed diffusely but are concentrated most heavily on the central face, including the lips, neck, and upper trunk. Skin lesions are present at birth and frequently increase in number at puberty. Multiple subcutaneous myxomas occur in approximately 50% of cases and usually appear in the periorbital and postauricular areas. Early recognition of this syndrome is important because surgical correction of cardiac myxomas may prevent the potentially fatal complication of embolism of tumor fragments.
Freckles are common in light-skinned, red-haired people and seem to be inherited as an autosomal-dominant trait. On histologic examination, ephelides show increased melanin in the epidermis without the melanocytic proliferation or epidermal elongation noted in lentigines. They are not present at birth but arise in infancy or early childhood, mainly on sun-exposed skin. They darken in summer and tend to fade during the winter months, which indicates that sunlight exposure is necessary for their induction. These lesions become less noticeable in adult life. Typically, freckles are well-circumscribed, red–tan macules that occur most commonly on the face, back, and upper shoulders, and spare the mucous membranes . Xeroderma pigmentosum ( Figure 7 ) may be diagnosed as a benign freckling condition in sun-exposed areas. Severe forms, such as xeroderma pigmentosum-C, manifest early in life. The diagnosis is usually made in the first 2 years of life, with a diagnostic delay because of the rarity of the disease in western countries. Photosensitivity with a prolonged erythema helps make a diagnosis, which needs a confirmation using fibroblast cultures to perform an in vitro study of unscheduled DNA synthesis .
Figure 7 . Facial freckling in xeroderma pigmentosum .
Melanocytes move from the neural crest to the skin during early embryonic life, and stem cell factor and endothelin 3 are the major pilot growth factors targeting C-Kit and ED3R, respectively. Failure of complete melanocyte migration into the epidermis prior to birth with ensuing dermal nesting and melanin production produces characteristic blue patches. The Mongolian spot is a hyperpigmented macule or patch present at birth or shortly thereafter with a predilection for Asian
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