Segmental pigmentation disorder (mosaic hyperpigmentation)

Segmental pigmentation disorder (SPD or mosaic hyperpigmentation, pigmentary mosaicism) refers to a hyperpigmented or hypopigmented patch often with a sharp midline demarcation and a less distinct lateral border, commonly located on the trunk. Lesions are often noted in infancy and are described in a segmental block-like pattern resembling a ‘checkerboard’ or following the lines of Blaschko. Those lesions that less commonly involve non-truncal sites (such as the extremity or neck) usually extend onto the torso, and solitary facial involvement has been described. The majority of patients with SPD have no extracutaneous abnormalities. SPD is thought to be due to somatic mutations resulting in cutaneous mosaicism. Extensive cases can be variably associated with chromosomal anomalies. The natural history of SPD has not been reported, but persistence of the hyperpigmentation is expected. A rare biopsy done on a patient with hyperpigmented SPD showed increase melanin in the basal layer, similar to CALM.

Neurofibromatosis type 1 (NF-1)

CALM are usually the first presenting sign in NF-1, and multiple CALM can be seen in 90% of patients with NF-1 on the trunk, buttocks and legs. In fair-skinned individuals, CALM may be initially overlooked on cutaneous examination. The number of CALM increases over time during the first decade of life and lesions tend to grow in proportion to the child and may darken with sun exposure. Axillary and/or inguinal freckling is usually absent at birth but present by age 3–5 years, although it may be noted earlier. This common feature tends to be the cutaneous sign, along with multiple CALM, that establishes the diagnosis and is felt to be pathognomonic for NF-1. Multiple CALM can be seen in other variants of NF, including neurofibromatosis type 2, segmental NF-1 and hereditary spinal neurofibromatosis. A more extensive discussion of NF can be found in Chapter 29 .

Legius syndrome

Legius syndrome (neurofibromatosis type 1-like syndrome) is a recently identified autosomal dominant disorder caused by a mutation in the SPRED1 gene. The SPRED1 gene is responsible for making spred-1 protein which inhibits the Ras/MAPK pathway. Affected individuals typically have CALM and axillary freckling. However, neurofibromas, typical osseous lesions, Lisch nodules of the iris and central nervous system tumors are characteristically absent. Some patients with Legius syndrome have been described with macrocephaly, a Noonan-like facial appearance, learning disorders, developmental delay and/or attention deficit/hyperactivity disorder in childhood. Several families with Legius syndrome have been described with lipomas as well. Many individuals may meet the NIH diagnostic criteria for NF-1 but gene testing will be negative for mutations in the neurofibromin gene. It is uncertain if there is an increased risk of malignancies. However, some authors have proposed less stringent monitoring in Legius patients as compared to NF-1 patients. Screening for developmental delay and behavioral and learning problems is recommended as well as examination and counseling by a clinical geneticist familiar with Legius syndrome.

Familial (inherited) café-au-lait macules

Multiple familial CALM have been described in several families without the other stigmata of NF-1, including the absence of NF-1 gene mutation. SPRED1 had not been tested in these families. This diagnosis should only be made in an older child without the other stigmata of NF-1 with a clear family history of multiple CALM without other signs of NF-1.

McCune–Albright syndrome

The cardinal features of McCune–Albright syndrome (MAS) include polyostotic fibrous dysplasia, endocrinopathies and precocious puberty as well as CALM. MAS is a rare and sporadic disorder caused by a postzygotic mutation in the gene, GNAS1 . The GNAS1 gene encodes for the alpha subunit of the guanine nucleotide-binding protein, causing loss of GTPase activity and increased stimulation of the adenylate cyclase system, resulting in proliferation and autonomous hyperfunction of hormonally responsive cells. This autosomal dominant mutation is only compatible with life when it occurs in individuals as a postzygotic somatic mutation with resulting mosaicism, which in turn results in marked phenotypic variability.

The CALM seen in MAS are often large, and segmental with favored distribution over the torso and buttocks. They may also follow the lines of Blaschko ( Fig. 24.2 ). The border of the CALM in MAS is often described as ‘jagged’ and irregular. These cutaneous findings may be present at birth or within the first few years of life and have been noted in approximately 53–98% of patients with MAS. Melanotic macules of the oral mucosa have also been reported.

Café-au-lait macules in Blaschkoid distribution in a neonate with McCune–Albright syndrome.

Extracutaneous findings in MAS include polyostotic fibrous dysplasia, where bone is replaced by fibrous tissue resulting in asymmetry, bony growths and pathologic fractures; this finding is rarely seen at birth and tends to manifest over time, usually within the first decade. In addition, endocrine abnormalities that may occur include precocious puberty, hyperthyroidism, Cushing syndrome, hyperparathyroidism, hyperprolactinemia, and hypersomatotropism. Neonatal cholestasis, acholic stools and jaundice have been described as presenting symptoms in neonates with MAS.

Due to the variable clinical expression and segmental nature, diagnosis of MAS may be difficult in infancy. Cutaneous findings of MAS must be differentiated from NF-1. The CALM found in NF-1 tend to be smaller, lighter in color, and more scattered in distribution. Histologic studies would not be helpful in differentiating these disorders. Radiologic studies for MAS may not reveal bony abnormalities in the neonatal period and CALM often precede the development of bony changes by 3 months to 9 years. When MAS is suspected, close observation for endocrine abnormalities is warranted. In those with known or suspected MAS, a referral to orthopedics and endocrinology is recommended. Prognosis for MAS is generally favorable and the development of malignancy is rare. Extensive osseous dysplasia early in life, however, portends a poorer prognosis.

Congenital dermal melanocytosis (Mongolian spots)

Mongolian spots are common birthmarks present in over 80% of black and Asian infants compared with only up to 10% of Caucasians infants. They present at birth, or early infancy, as blue-gray, blue-green, or blue-black macules most often noted over the sacrum and gluteal regions ( Fig. 24.3 ) and less often on extensor extremities and the posterior shoulder. Size can range from a few millimeters to over 10 cm and single or multiple lesions may be present. The borders of Mongolian spots are ill-defined and tend to fade gradually into the surrounding skin color. The coloration will often stabilize in infancy and fade during the first decade of life. Only a small number of lesions persist (3–4%) after adolescence and it has been suggested that these are likely not distinct entities but analogous to Nevus of Ota or Ito. Clinically, these persistent lesions are often blue-black homogenous or speckled patches present in a segmental distribution.

Mongolian spot on the buttocks.

In the Mongolian spot, elongated, slender and slightly wavy dendritic cells containing melanin granules are found in the mid and deep dermis. These dendritic melanocytes are present in low numbers and scattered between collagen bundles, both of which are orientated parallel to the skin surface. There is an absence of melanophages. The reason for regression of Mongolian spots and failure of regression of other dermal melanocytic lesions such as nevus of Ito or Ota with age is currently unknown.

Mongolian spots are common, and associated abnormalities are rare. Dermal melanocytosis may be associated with certain lysosomal storage diseases, including gangliosidosis type 1 (GM1), Niemann–Pick disease, Hunter syndrome, α-mannosidosis syndrome, and Hurler syndrome. Dermal melanocytosis is generally extensive in distribution often involving the ventral and dorsal aspects of the trunk in addition to the sacrum and extremities. Mongolian spots may also co-exist within CALM in NF-1. Dermal melanocytosis is part of the criteria for a subgroup of neurocristopathies labeled ‘phakomatosis pigmentovascularis’ (PPV), in which vascular malformations of the skin, pigmented nevi and Mongolian spots occur together in the same patient (see below). Cleft lip malformation has been associated with adjacent dermal melanocytosis although the significance of the association is unknown.

Nevus of Ota (nevus fuscoceruleus ophthalmomaxillaris, oculodermal melanocytosis)

Bluish hyperpigmentation of the skin along the ophthalmic and maxillary branches of the trigeminal nerve is known as Nevus of Ota ( Fig. 24.4 ). These patches can be brown, blue-gray or blue-black, gray or purple and have a speckled or mottled appearance with poorly-demarcated borders. Nodular areas similar to blue nevi can be present. Nevus of Ota often affects one side of the face and bilateral involvement is described in only 5–10% of patients. Distribution of Nevus of Ota most commonly involves the ophthalmic and maxillary branches with involvement of all three branches of the trigeminal nerve being the least common distribution. This condition is more commonly seen in Asians and has a female preponderance. They may be present at birth or appear within the first year of life, or later between the ages of 11–20 years; mid-childhood onset is rare. Spontaneous resolution does not occur as seen in Mongolian spots. Pathology of cutaneous lesions shows a greater concentration of elongated, dendritic dermal melanocytes scattered within the collagen bundles in the upper dermis (compared with Mongolian spots).

Nevus of Ota involving the forehead, cheek and sclera.

In addition to cutaneous involvement, Nevus of Ota involving the ocular sclera can be seen in two-thirds of patients. Pigmentation of the sclera, conjunctiva, cornea, iris and choroid, and less commonly, the optic nerve, retrobulbar fat, orbital periosteum and extraocular muscles can occur. Oral mucosal pigmentation and pigmentation of the tympanic membrane can occur as well.

Most Nevi of Ota pose a potential cosmetic concern but few may be associated with complications. Open-angle glaucoma occurs in approximately 10% of patients due to proliferation of melanocytes in the anterior chamber angle. The most concerning complication is the development of melanoma within pigmented areas. Malignant degeneration has been reported and may include the eye (choroid, iris, or orbit), skin, and brain. Sturge–Weber syndrome, Klippel–Trenaunay syndrome, neurofibromatosis, inflammatory vascular disease, cerebral arteriovenous malformation, multiple hemangiomas, and spinocerebellar degeneration have been described occurring in association with Nevus of Ota. Rare occurrences of ipsilateral hearing loss with Nevus of Ota have been reported. Nevus of Ota occurring with nevus flammeus is seen in variants of phakomatosis pigmentovascularis. Leptomeningeal melanosis and Nevus of Ota can occur concurrently as well.

Nevus of Ito (nevus fuscoceruleus acromiodeltoideus)

The Nevus of Ito is an analogous lesion to Nevus of Ota with a distribution over the posterior supraclavicular and lateral cutaneous branchial nerves. These blue-gray poorly-demarcated patches may present over the shoulder, supraclavicular neck, upper arm, scapular and deltoid areas ( Fig. 24.5 ). Bilateral nevus of Ito has been reported in a patient with a speckled lentiginous nevus, and bilateral Nevus of Ota with a unilateral Nevus of Ito has been noted. Cutaneous melanoma and malignant cellular blue nevus have been rarely reported in Nevus of Ito and extracutaneous findings are not seen.

Nevus of Ito.

Blue nevi

Blue nevi are dermal melanocytomas that represent benign proliferations of pigment producing dendritic dermal melanocytes ( Fig. 24.6 ). Dermoscopy of common blue nevi reveals uniform blue coloration. Blue nevi are rarely seen at birth, but congenital forms have been described. Most are acquired, with onset in childhood or adolescence, with predilection for the scalp and face, dorsal aspects of the distal extremities and sacral area. Three types of blue nevi have been described: (1) cellular blue nevus, (2) common blue nevus, and (3) the combined nevus.

Typical-appearing blue nevus.

Cellular blue nevi seen at birth are rare and have a predilection for the scalp, sacrococcygeal area and buttocks. They present with blue-gray or blue-black nodules or plaques with a smooth or irregular surface texture. Although most congenital cellular blue nevi are small in size (1–3 cm), larger and ‘giant’ lesions can be seen, most commonly on the scalp. Melanoma has been described particularly in larger lesions on the scalp. Multiple satellite blue nevi in association with a large congenital cellular blue nevus have also been reported. Other related variants of congenital blue nevi include the pauci-melanotic cellular blue nevi, epithelioid blue nevi (also known as pigmented epithelioid melanocytoma), congenital plaque-type blue nevi and neurocristic hamartomas. Multiple blue nevi may be seen in Carney complex (see below) or without associated abnormalities. A rare, congenital, plaque-like type of blue nevus, showing a circumscribed area with numerous macules and papules has been described. Blue nevi may arise within speckled lentiginous nevi as well as within other dermal melanocytoses such as Nevus of Ota.

Blue-black nodules, papules and plaques seen at birth or infancy are suggestive of blue nevi. A biopsy may be needed to confirm the diagnosis and differentiate lesions from melanoma. Common blue nevi will show pigmented dendritic melanocytes singly or in small aggregations in the reticular dermis, surrounded by thickened collagen. Histopathology of cellular blue nevi, in contrast, shows cellular islands of large spindle-shaped or epithelioid cells with little or no melanin, in addition to pigmented dermal dendritic melanocytes. Lesions may penetrate deep into the subcutaneous fat.

Mosaic conditions

Mosaicism is the presence of two or more genetically distinct cell lines in a single individual, which may arise from a variety of genetic defects from separate single mutations, groups of mutations or chromosomal differences. Cutaneous mosaicism is associated with diverse pigmentary patterns along the lines of Blaschko or in segmental or block-like patterns, such as the pigmentary anomalies found with hypomelanosis of Ito and McCune–Albright syndrome. Many hyperpigmented conditions present in segmental or Blaschko-linear patterns and may be isolated skin findings or coincide with systemic manifestations ( Box 24.1 ).

Chimerism

A chimera refers to an individual with cells derived from two separate zygotes that can be demonstrated by molecular analysis. Human chimerism is rare. Nevoid hyperpigmentation patterns described in human chimeras have included a flag-like rectangular pattern, a pattern of rounded units (café-au-lait-like patches) and a striated pattern.

Linear and whorled nevoid hypermelanosis

The term ‘linear and whorled nevoid hypermelanosis’ (LWNH) is generally used to describe a sporadic disorder of hyperpigmentation in swirls and streaks following a Blaschkoid distribution. Classically, the hyperpigmentation consists of homogenous 1–5 mm macules forming a reticulated configuration and sparing the palms, soles, mucous membranes and eyes. Segmental, linear or swirled hyperpigmentation or a combination of these with a sharp midline demarcation is seen over the trunk and less commonly involving the extremities ( Fig. 24.7 ). LWNH appears at birth or during the first few weeks to months of life without any preceding inflammatory eruption. The pigmentation may progress for the first 1–2 years of life and then stabilize, possibly becoming less prominent over time. Biopsy of the hyperpigmented macules shows basilar hyperpigmentation with no pigment incontinence or dermal melanophages.

Localized, whorled hyperpigmentation, considered a sign of cutaneous mosaicism.

This child was clinically well.

Systemic abnormalities seen in association with LWNH include neurologic, developmental, musculoskeletal, and cardiac abnormalities that often arise early in life; LWNH has been described as akin to hypomelanosis of Ito (HI) with cutaneous hyperpigmentation instead of hypopigmentation. No large study exists to define the incidence of systemic features in patients with LWNH. However, systemic comorbidities are described much less frequently in association with LWNH as compared with HI.

LWNH is believed to result from somatic mosaicism of neuroectodermal cells deriving from neural crest, with normal and hyperpigmented skin a result of two distinct populations of cells. Chromosomal mosaicism has also been described. Although thought to be a sporadic disorder, rare familial occurrences of LWNH have been reported, suggesting an undescribed gene abnormality.

LWNH is usually diagnosed clinically and should be distinguished from other conditions with Blaschkoid hyperpigmentation ( Box 24.1 ). With diffuse skin disease, it can be difficult to deem which coloration represents the patient’s normal skin and whether the affected areas are represented by hyper- or hypopigmentation. Skin biopsy will enable differentiation from some conditions such as incontinentia pigmenti (IP) and early (macular) epidermal nevus.

Incontinentia pigmenti

Incontinentia pigmenti (IP; see also Chapter 29 ) is an X-linked dominant hereditary disorder found predominantly in females, manifesting with characteristic skin findings, various tooth, eye and nail abnormalities, and neurologic and immunologic impairment. Incontinentia pigmenti is due to a mutation in the IKK-gamma (NEMO) gene.

The cutaneous findings of the IP syndrome are evident at birth or shortly thereafter and have been classically defined by four stages: (1) vesiculobullous, (2) verrucous, (3) hyperpigmented and (4) hypopigmented. However, all four stages may not be seen over time, or they may overlap throughout life. The first inflammatory vesiculobullous stage presents with streaks of eosinophil-filled epidermal vesicles in a geometric fashion, mainly on the extremities, followed by verrucous or lichenoid lesions, and papules and pustules within 2–6 weeks ( Fig. 24.8 ). This stage may persist for several months. Once resolved, widely disseminated hyperpigmentation in a whirled or linear fashion arises, mainly on the trunk. The third stage generally resolves over years and may completely disappear. A fourth stage of atrophy and hypopigmentation, commonly over the lower extremities, may replace the hyperpigmented areas. This stage may be subtle and faint and can be easily overlooked in adult females.

Overlapping hyperpigmented and verrucous stages of incontinentia pigmenti in a newborn.

The differential diagnosis of the hyperpigmented stage of IP includes linear and whorled nevoid hypermelanosis, macular epidermal nevi and other disorders with Blaschkoid pigmentation.

Phakomatosis pigmentovascularis

Phakomatosis pigmentovascularis (PPV) is defined by the presence of a widespread vascular malformation, in particular a capillary malformation (port-wine stain), with cutaneous pigmented lesions such as dermal melanocytosis (usually slate-gray or blue melanosis or Mongolian spot-like) or nevus spilus with various other cutaneous nevi (nevus anemicus, epidermal nevus, cutis marmorata telangiectatica) and possible extracutaneous alterations. Pigmentation in PPV is often diffuse (>50% of the skin) and persistent and does not correlate with the typical locations for Mongolian spots ( Fig. 24.9 ).

Phakomatosis pigmentovascularis type II.

Extensive dermal melanocytosis (Mongolian spot) and port wine stain.

A classification system based upon dominant pigmentary anomalies and subdivisions with extracutaneous findings categorizes four prominent types of PPV ( Table 24.3 ), with type II the most common. The pathogenesis of PPV has been proposed as a phenomenon called ‘twin spotting’.

Numerous extracutaneous abnormalities may be seen, the most common being an overlap with Sturge–Weber syndrome, as well as Klippel–Trenaunay syndrome and melanosis oculi.

The differential diagnosis of PPV includes capillary malformation-macrocephaly syndrome and Beckwith–Wiedemann syndrome. Proteus syndrome may also be considered and is distinguished by the presence of overgrowth, asymmetry and gigantism. Treatment for certain birthmarks, with the aim of improving aesthetics, such as the port wine stain and dermal melanocytosis, can be accomplished with laser therapy.

Phakomatosis pigmentokeratotica

Phakomatosis pigmentokeratotica (PPK) describes the sporadic concurrence of a Blaschkoid epidermal nevus (organoid or sebaceous differentiation) with a cutaneous pigmentary anomaly such as nevus spilus. The name rightly suggests an analogy with PPV and may occur due to the twin spotting genetic mechanism, and/or multilineage somatic mosaicism. In neonates and infants, the speckled lentiginous nevus may appear as a large CALM, prior to the development of ‘speckles’ and papules. Extracutaneous findings are usually present, including neurologic abnormalities (seizures, mental deficiency, hemiparesis and muscular weakness, dysesthesias), skeletal problems (including vitamin D-resistant rickets), and ophthalmologic alterations. Basal cell carcinoma and melanoma have been reported to arise in the nevus sebaceus and nevus spilus, respectively, and emphasizes the importance for long-term surveillance in these patients.

Naegeli–Franceschetti–Jadassohn syndrome

Naegeli–Franceschetti–Jadassohn syndrome is an autosomal dominant subtype of ectodermal dysplasia syndrome characterized by the development of brown-gray reticulated pigmentation in early childhood without preceding inflammation. Pigmentation is localized on the abdomen in most cases but may be periorbital or perioral, or on the neck, flexures, groin or proximal extremities in some cases. Pigmentation gradually increases over the first decade of life and begins to fade after puberty. Sweating is markedly decreased in affected individuals, dermatoglyphics are often absent, and keratoderma of the palms and soles and dental anomalies can be seen. The syndrome is due to a mutation in the KRT14 gene located on 17q11.2-q21 and is allelic to dermatopathia pigmentosa reticularis.

Striated hyperpigmentation of the torso

Horizontal thin stripes of hyperpigmentation (see Chapter 7 ) over the creases of the abdomen and extremities can be observed in the neonatal period. This finding is typically transient and likely to result from shedding of hyperkeratotic skin after birth.

Congenital curvilinear palpable hyperpigmentation (sock-line bands, sock-line hyperpigmentation)

Congenital curvilinear palpable hyperpigmentation is a relatively recently described clinical finding on the posterior legs (usually bilateral posterior calves) of infants (see Fig. 8.27 ). Involvement of the arms (‘mitten-line hyperpigmentation’) and heels (‘heel-line hyperpigmentation’) has also been described. The hyperpigmented to slightly erythematous plaques are often symmetric, palpable, curvilinear and semicircumferential. Macular hyperpigmentation is also common. The etiology of these lesions is unknown but trauma from tight socks or mittens has been proposed. The pigmentation resolves spontaneously over months to years. Because of the strikingly linear configuration of the lesions, this disorder can be confused with child abuse.

Post-inflammatory hyperpigmentation

Post-inflammatory hyperpigmentation (PIH) refers to the term used to describe brown, blue or grayish macules and patches after an exogenous or endogenous insult. PIH can be seen at birth and early on in life. Common exogenous causes in hospitalized infants include the use of tape, adhesive from monitoring leads, and mechanical trauma, which forms distinct patterns. More indistinct forms may result from endogenous inflammatory processes seen in neonates, such as seborrheic dermatitis and atopic dermatitis. In certain skin diseases such as morphea and lichen planus, PIH presents as a definitive morphological feature; however, almost all skin disease which results in inflammation can cause PIH. Those infants with darker skin types tend to be at higher risk for developing hyperpigmentation as compared to those with lighter skin.

A history of contact, trauma, or previous inflammatory process may be the clue to diagnosis. Epidermal melanocytes increase in size, number and melanin production following stimuli, including certain inflammatory diseases. When biopsied, the dermoepidermal junction and basal layer are disrupted by epidermal injury and melanin passes from its usual epidermal position to the dermis, subsequently engulfed by macrophages to form melanophages. PIH takes time to resolve, as dermal melanin is slow to break down.

A premature infant with an ecchymotic plaque of the forehead due to pressure from the strap of a continuous positive airway pressure mask. This resulted in anetoderma.

The differential diagnosis of PIH tends to be one of exclusion; certain patterns due to a particular contact are suggestive. Preceding history of an inflammatory event is helpful. A Wood’s light may aid in determining the extent of pigment alteration as it accentuates epidermal melanin. In rare cases, a biopsy may be indicated and shows melanophages in the superficial dermis and basal layer along with a variable infiltrate of lymphohistiocytes around superficial blood vessels and in dermal papillae. PIH may also be seen as a part of transient neonatal pustular melanosis (see Chapter 7 ) but, interestingly, a biopsy will not show dermal melanophages. Lesions of anetoderma of prematurity have been described to display ecchymotic-like blue-brown discoloration prior to the atrophic stage of these iatrogenic lesions. Hyperpigmentation usually fades over time especially when pigment is epidermal.

Universal melanosis and progressive familial hyperpigmentation

A case of a healthy infant, born with white skin to Mexican parents, was described to develop progressive black pigmentation at 15 days of age that became diffuse by the age of 21 months, involving a portion of the palms and soles, nails, and oral and ocular mucosa. The infant was otherwise well and developmentally normal. A skin biopsy revealed heavy hyperpigmentation of all epidermal layers and pigment-loaded histiocytes in the dermis. This condition was thought by the authors to be due to an overproduction of melanin and termed ‘universal acquired melanosis’ or ‘carbon baby’. Other similar reports in the literature occurring in families have been termed, ‘melanosis universalis hereditaria’, ‘melanosis diffusa congenita’, ‘universal acquired melanosis’, ‘familial progressive hyperpigmentation’, ‘familial universal melanocytosis’, or ‘diffuse melanosis’. It is unclear whether these cases represent the same entity or different disorders. In general, these progressive conditions tend to describe the onset of hyperpigmentation at birth or during early infancy that progresses in extent with age. Familial progressive hyperpigmentation was originally described as hyperpigmentation in a variety of variably sized dots, whirls, streaks, and patches, in contrast to universal acquired melanosis where the entire integument becomes black. Inheritance has been described in many of these similar disorders as autosomal dominant, possibly due to a heterozygous gain of function mutation in the KIT ligand gene. Systemic manifestations do not occur, but irregular pigmentation of nails, oral and ocular mucosa and palms and soles have be seen. Histopathology of reported cases showed epidermal hypermelanosis with dispersed and widely distributed melanosomes within keratinocytes. The clinical features as well as the histologic absence of melanin incontinence should differentiate these conditions from IP, Naegeli–Franceschetti–Jadassohn syndrome and LWNH.

Poikiloderma

Poikiloderma describes the cutaneous findings of atrophy, hyper- and hypopigmentation and telangiectasias that characterize several genetic disorders ( Table 24.5 , Fig 24.12 ). This clinical finding may be present at birth, during infancy, or develop in the first few years of life. Poikiloderma may present as a later finding in xeroderma pigmentosum, connective tissue disorders, Cockayne syndrome and Faconi anemia.

A Native American girl with poikiloderma with neutropenia syndrome.

The pathogenesis and etiology of poikiloderma are unknown, but commonly associated with UV exposure. The diagnosis is made by the typical clinical appearance of the reticulated eruption of telangiectasias and hypo- and hyperpigmentation. Histologic features depend on the severity and stage and include varying degrees of epidermal atrophy with hyperkeratosis, dilated vessels, hydropic degeneration of the basal layer, pigment-laden macrophages, and a dermal band-like or perivascular infiltrate of lymphocytes. The prognosis is dependant on the underlying associated disorder, and prompt recognition will aid in early diagnosis, monitoring and implementation of sun-avoidance behaviors.

Addison disease and adrenocortical-unresponsiveness syndrome

Addison disease is adrenocorticoid deficiency resulting from dysfunction or destruction of the adrenal cortex. Glucocorticoid and mineralocorticoid production is affected. Although onset is usually in adulthood it may present earlier in congenital adrenal hyperplasia, due to a disorder of long-chain fatty acid metabolism, or polyglandular autoimmune syndromes.

Hyperpigmentation of skin and mucous membranes often precedes symptoms and is due to the stimulant effect of excess ACTH (adrenocorticotrophic hormone) and MSH (melanocyte-stimulating hormone) on melanocytes. Pigmentation may present as diffuse tan, brown, or bronze darkening of skin surfaces, especially on sun-exposed areas, including nails and palmar creases, and blue-back patches on mucosal surfaces (including oral and anogenital mucosa). Associated signs and symptoms include weakness, weight loss, hypotension, hyponatremia, hyperkalemia, hypoglycemia and eosinophilia.

ACTH-insensitivity syndrome (or adrenocortical-unresponsiveness syndrome), a congenital insensitivity to functionally normal ACTH secretion, causes diffuse hyperpigmentation in the neonatal period and may precede systemic symptoms. Histologic findings of the hyperpigmentation are nondiagnostic and include increased epidermal melanin in keratinocytes and no increase in melanocytes.

LEOPARD syndrome (multiple lentigines syndrome, Moynahan syndrome)

The acronym LEOPARD was proposed by Gorlin to describe a heterogeneous syndrome that includes cutaneous lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth and sensorineural deafness. This rare autosomal dominant condition with variable expressivity involves cutaneous features as well as multiple organ systems. The originally described mutation responsible for LEOPARD syndrome (LS) was found on the gene PTPN 11, which has a dominant negative effect, interfering with growth factor/Erk-MAPK signaling. Additional mutations in BRAF and RAF1 have now been described and found to be associated with LS. LS is allelic to Noonan syndrome with many overlapping findings.

Lentigines can be noted during infancy as flat black-brown macules that increase in number until puberty, being generalized, with a predominance on the face, neck and upper trunk and usually sparing the mucous membranes. Lesions may not appear until childhood and the total number may be in the thousands; however, cases without lentigines have been reported. When biopsied the pigmented lesions reveal features of typical lentigines, displaying elongation of rete ridges, an increase in the concentration of melanocytes in the basal layer (without nests) with an increase in the amount of melanin in melanocytes and keratinocytes, as well as melanophages in the upper dermis. Café-au-lait macules are also seen in up to 70–80% of patients with LS and can predate the appearance of lentigines.

In addition to lentigines, the majority (85%) of those with LS have heart defects, such as hypertrophic cardiomyopathy and pulmonary valve stenosis. Congenital heart disease is often the most urgent medical issue during the first months of life and remains the leading medical issue for those patients that will eventually carry the diagnosis of LS. Facial anomalies (mild or marked) are also invariably present in many patients with LS, although they are not diagnostically specific for the disorder. Postnatal growth retardation, sensorineural hearing deficit and intellectual disability are less common associations but they are part of the classically described syndrome. Genital anomalies are seen predominantly in males and include gonadal hypoplasia, hypospadias, and delayed puberty. Various craniofacial and skeletal anomalies have been described including short stature, pectus excavatum, kyphosis, ocular hypertelorism, and mandibular prognathism.

The diagnosis of LS is based on the cutaneous and systemic findings. Diagnostic criteria have been suggested: (1) if lentigines are present, at least two of the six other features are needed to make the diagnosis; (2) if lentigines are absent, an affected first-degree family member with LS and three of the six other features are needed for diagnosis. The differential diagnosis includes both generalized and patterned lentiginosis, namely Carney complex and Peutz–Jeghers syndrome (see below). The lentigines seen in XP can be widespread but are not present at birth and occur after UV exposure. In LS, the presence of lentigines is independent of UV exposure.

Carney complex (NAME/LAMB syndrome)

Several previous descriptions of the syndromes now consolidated under the term Carney complex represent various manifestations of this complex. These include NAME syndrome (nevi, atrial myxoma, myxoid neurofibromata, ephelides) and LAMB syndrome (lentigines, atrial myxoma, myxoid tumors, blue nevi). Carney complex is an autosomal dominant multiple endocrine neoplasia disorder characterized by lentigines, endocrine hyperactivity, cardiac myxomas and schwannomas.

The cutaneous findings in Carney complex include lentigines, café-au-lait macules, and blue nevi. Lentigines occur shortly after birth and are concentrated over the central facial area and can involve the mucosa. They can also extend to the neck, trunk, extremities and genitalia. Associated nevi can be congenital or arise later in infancy. Nontender dermal nodules, or cutaneous myxomas, do not often develop until the second decade of life and are typically located on the head and neck. Associated noncutaneous findings in Carney complex include cardiac myxoma, endocrine diseases and tumors (Cushing syndrome, acromegaly), testicular tumors (in particular, Sertoli cell tumor), psammomatous melanotic schwannomas and possibly other benign and malignant neoplasms such as ductal adenoma of the breast.

Carney complex is due to a mutation in the PRKAR1A gene on chromosome 17q23. This gene encodes the regulatory subunit of protein kinase A and functions as a tumor-suppressor gene. Linkage to the short arm of chromosome 2 has also been described in 11 kindreds with clinical findings of Carney complex, indicating genetic heterogeneity.

Other multiple lentigines syndromes need to be differentiated from Carney complex, including LEOPARD and Peutz–Jeghers syndromes. If a neonate has skin findings suggestive of Carney complex, evaluation by cardiology, endocrinology, and urology is warranted, and genetic counseling should be offered.

Centrofacial lentiginosis

Lentigines with involvement of the central face without further extension to other areas of the skin or mucosa have been termed ‘centrofacial lentiginosis’. Onset is usually in infancy and autosomal dominant inheritance is suggested. In adulthood, the lentigines often fade. Centrofacial lentiginosis may be associated with skeletal and bony abnormalities, neurologic manifestations, developmental and psychiatric symptoms and endocrine dysfunction.

Segmental lentiginosis (partial unilateral lentiginosis, lentiginous mosaicism)

Asymmetric segmental distribution of lentigines in large numbers usually designated to one side of the body has been termed segmental lentiginosis (also reported as partial lentiginosis, unilateral lentigines or agminated lentiginosis). It has been suggested that some of these cases may actually represent a speckled lentiginous nevi, epidermal nevus or LWNH.

Another term, ‘partial unilateral lentiginosis’ (PUL), has been coined to describe small clustered hyperpigmented macules distributed in a unilateral limited area of the body (sometimes in a segmental pattern), usually involving the face, neck, and upper trunk. These macules overlie normal skin and they have a sharp midline demarcation. Histologically lesions show features of lentigo simplex without nevus cells being present, although small nests of melanocytes have been described at the tips of the rete ridges, forming a ‘jentigo’ pattern. Lesions appear in childhood, as early as one year of age, but are rarely seen at birth. PUL has been associated rarely with central nervous system diseases (epilepsy, mental retardation, intracranial vascular malformations). Familial inheritance has not been described.

Segmental lentiginosis should be differentiated from other segmental disorders including speckled lentiginous nevus, segmental NF and agminated Spitz nevi. Wood’s light examination and skin biopsy may be helpful in these cases. Destruction of lentigines via laser or cryotherapy can be performed if desired.

Peutz–Jeghers syndrome

Peutz–Jeghers syndrome (PJS) is one of the most well-known familial lentiginosis syndromes. It is dominantly inherited and caries a risk of solid tumor malignancy. A key cutaneous diagnostic feature of PJS is dark brown-blue macules on the oral mucosa (buccal mucosa, palate, gingival), border of the lips ( Fig. 24.13 ), and palms/soles, eyes, nares and perianal region. Pigmented bands in the nail plates can also be seen. The macules typically appear in childhood but can be present at birth and may fade in late adulthood. Mucosal lentigines tend not to fade. In addition, patients with PJS can have pigmented macules of the bowel mucosa, intestinal hamartomatous and adenomatous polyps (found in the jejunum, ileum, colon, rectum, stomach and duodenum). There is also an increased susceptibility to benign and malignant tumors including benign ovarian sex cord tumors, calcifying Sertoli tumors of the testes, cervical, breast, pancreatic, endometrial and gastrointestinal cancer.

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