Congenital and inherited hyperpigmentation disorders

INTRODUCTION — Hyperpigmentation is the darkening or increase in the natural color of the skin, usually due to an increased deposition of melanin (hypermelanosis) in the epidermis and/or dermis. Less frequently, it may be caused by the deposition in the dermis of endogenous or exogenous pigments, such as hemosiderin, iron, or heavy metals.

Hyperpigmentation is a feature of a multitude of clinical conditions, ranging from normal variations of skin color to acquired and inherited syndromes, and is one of the most common reasons for dermatologic consultation, particularly in patients with darkly pigmented skin [1-3]. Although hyperpigmentation is not harmful, it can cause significant cosmetic disfigurement and become a persistent psychosocial burden for the patient, due to the limited efficacy of the available treatments.

This topic will review the approach to the patient with congenital and inherited hyperpigmentation disorders. Incontinentia pigmenti, pigmentary mosaicism, and acquired disorders of pigmentation, including melasma, are discussed separately.

●(See "Incontinentia pigmenti".)

●(See "Pigmentary mosaicism (hypomelanosis of Ito)".)

●(See "Acquired hyperpigmentation disorders".)

●(See "Melasma: Management".)

PATHOPHYSIOLOGY OF SKIN PIGMENTATION

Determinants of skin color — The color of human skin is mainly determined by the two types of melanin, the black-brown eumelanin and the yellow-red pheomelanin, which are present in individuals of all skin colors, though their ratio is highly variable and determines the hue of the skin [4-6]. Melanin is produced by melanocytes, specialized cells of neural crest origin that reside in the basal layer of the epidermis. The biosynthesis of melanin occurs in lysosome-like organelles called melanosomes, which are transported to the cell periphery and transferred from the dendritic tips of the melanocytes to the surrounding keratinocytes [7]. Each melanocyte is associated with up to 40 basal keratinocytes to form the epidermal melanin unit [8].

Differences in the number, size, and aggregation of melanosomes within the melanocytes and keratinocytes, but not in the overall number of melanocytes, contribute to ethnic differences in skin color [9,10]. Darkly pigmented skin has a higher content of melanin, higher eumelanin-to-pheomelanin ratio, nonaggregated and larger melanosomes, and slower melanosome degradation within the keratinocytes [11].

Genetic basis of pigmentary disorders — The biochemical pathway of melanogenesis is under complex genetic control, with hundreds of genes and genetic polymorphisms involved in the modulation of type and distribution of pigmentation [7,12,13]. However, only a few of them have been identified as the cause of specific monogenic hyperpigmentation disorders [13].

Mutations affecting genes involved in the differentiation and migration of melanocyte precursors in the neural crest or in the proliferation and activity of mature melanocytes may be involved in the pathogenesis of hyperpigmentation associated with inherited syndromes [7]. The genetic defects associated with a number of inherited and syndromic hyperpigmentation disorders are summarized in the table (table 1).

PATIENT EVALUATION AND DIAGNOSIS — The diagnosis of hyperpigmentation disorders may be challenging. An algorithmic approach to the diagnosis based upon history and clinical parameters is shown in the figure (algorithm 1). In most cases, the initial patient evaluation involves a detailed personal and family medical history and a complete physical examination, which should include a careful search for additional cutaneous and extracutaneous signs and symptoms.

Questions that may be useful for the evaluation of patients with hyperpigmentation disorders include [1]:

●Is the disorder congenital or acquired?

●Is the disorder isolated or part of a syndrome?

●Is the pigmentation localized or diffuse?

●Is the pigmentation well circumscribed or ill defined?

●Does the pigmentation have a pattern (eg, linear, reticular)?

●Is the pigmentation associated with inflammation and/or prior cutaneous injury?

●Is the pigmentation stable, progressing, or regressing?

History — A detailed family history may be helpful to determine whether the disorder is congenital and isolated or inherited and, in the latter case, what is the probable inheritance pattern [14]. However, although congenital or inherited hyperpigmentation disorders are often present at birth, history may be misleading since parents/caregivers may not have noted it for months or longer.

The course of the disorder is also a useful parameter in the clinical diagnosis of hyperpigmentation disorders. Inherited disorders of hyperpigmentation are often stable, whereas most acquired forms show progression or regression.

Skin examination — In all patients with hyperpigmentation disorders, a complete skin examination should be performed under visible light and Wood's light. Important clinical parameters include:

●Extent of the pigmentary abnormality (localized versus diffuse)

●Color hue (shades of brown/black, slate-gray/blue)

●Morphology of individual lesions

●Distribution (eg, dermatomal, following Blaschko lines)

●Pattern (eg, linear, reticular, nonfigurate)

A careful search for associated cutaneous and extracutaneous signs and symptoms may provide important clues to the diagnosis in patients with hyperpigmentation disorders associated with genetic syndromes.

Wood's light examination — Wood's light, also known as "black light," is ultraviolet A light with a peak emission at 365 nm [15]. The patient is examined in a darkened room with the light source held at 10 to 15 cm from the skin. Wood's light can be helpful in determining disease extent (eg, sun-exposed areas, areas previously involved by inflammatory processes, dermatomal distribution, following Blaschko lines) and whether the pigment deposition is epidermal, dermal, or mixed. However, its effectiveness is limited in patients with darkly pigmented skin [16,17]:

●Epidermal hypermelanosis – Under natural light, epidermal hypermelanosis appears light brown to dark brown in color. The pigmentation, as well as the contrast between involved and uninvolved skin, is enhanced when viewed under a Wood's lamp.

●Dermal hypermelanosis – Under natural light, dermal hypermelanosis has a bluish or ashen gray hue with margins less defined than epidermal hypermelanosis. The pigmentation is not accentuated by the Wood's light.

●Mixed hypermelanosis – Mixed hypermelanosis appears light to dark brown under natural light, whereas Wood's light examination will show enhancement in some areas and none in others.

Dermoscopy — Dermoscopy, also known as dermatoscopy, epiluminescence microscopy, or skin surface microscopy, is a noninvasive in vivo technique that has been traditionally used to evaluate pigmented lesions (ie, nevi). However, it also has a role in helping to identify the depth of melanin deposition, from superficial/epidermal to dermal [18]:

●Epidermal hypermelanosis – Pseudoreticular pigment network

●Dermal hypermelanosis – Gray dots and/or blotches, often perifollicular or periadnexal

●Mixed hypermelanosis – Combination of above patterns

Skin biopsy — A skin biopsy for histopathologic evaluation is not routinely performed for the diagnosis of hyperpigmentation disorders. However, it may be necessary when the clinical diagnosis is uncertain. Standard stains (eg, hematoxylin and eosin, Fontana-Masson silver stain) and histochemical techniques (eg, Mart-1, Melan-A) are used to evaluate the number and localization of melanocytes and melanin granules in the epidermis and dermis. The main histopathologic findings in selected acquired and congenital or inherited hyperpigmentation disorders are summarized in the table (table 2).

CIRCUMSCRIBED HYPERPIGMENTATION

Congenital dermal melanocytosis — Congenital dermal melanocytosis is a group of hyperpigmentation disorders characterized by the presence of melanin-producing melanocytes in the dermis. They are most commonly seen in Asian populations and include the nevus of Ito (picture 1), nevus of Ota (picture 2), and the so-called Mongolian spots (picture 3).

The congenital dermal melanocytoses are discussed separately. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Dermal melanocytoses' and "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis'.)

Café-au-lait macules — Café-au-lait macules are sharply demarcated, hyperpigmented macules or patches that are typically two to three shades darker than the normal, uninvolved skin (picture 4). They vary in size from a few millimeters to more than 10 cm and can occur anywhere on the body. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Café-au-lait macule'.)

Café-au-lait macules are often present at birth or appear in the first months of life. Isolated lesions are common and usually have no clinical significance. In contrast, multiple café-au-lait macules may represent the cutaneous marker of underlying genetic disorders such as neurofibromatosis type 1 and McCune-Albright syndrome. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

Café-au-lait macules are difficult to treat. Partial clearance may be achieved with laser treatment, but recurrence is common [19]. (See "Laser and light therapy for cutaneous hyperpigmentation".)

Nevus spilus — Nevus spilus, also called speckled lentiginous nevus, is a hyperpigmented macule or patch with superimposed darker brown macules and papules (picture 5). The darker macules and papules may consist of junctional, compound, Spitz, atypical, or blue nevi. (See "Congenital melanocytic nevi", section on 'Speckled lentiginous nevus'.)

Segmental pigmentation disorder — Segmental pigmentation disorder is a form of pigmentary mosaicism characterized by hypo- or hyperpigmented patches with a segmental pattern that has been referred to as block-like, flag-like, or resembling a checkerboard [20]. Any site can be affected, but the trunk is favored. The shape is frequently quadrangular, and the margins may be serrated [21]. The cutaneous findings can be more prominent in individuals with darkly pigmented skin [22]. (See "Pigmentary mosaicism (hypomelanosis of Ito)", section on 'Segmental pigmentation disorder'.)

DIFFUSE LINEAR HYPERPIGMENTATION

Pigmentary demarcation lines — The color of skin normally exhibits variation in hue and intensity at various sites of the body [23]. In all skin types, the dorsal skin surfaces are more pigmented than the ventral surfaces. Pigmentary demarcation lines (also known as Futcher or Voigt lines) are a frequent finding, particularly in individuals with darkly pigmented skin. They are symmetric, bilateral, and are present from infancy to adulthood. Eight types of pigmentary demarcation lines (A to H) have been described [24]:

●Type A – Lateral aspect of upper anterior portion of arms, across the pectoral area (picture 6A-B)

●Type B – Posterior medial portion of lower limb (picture 7)

●Type C – Vertical hypopigmentation line in pre- and parasternal areas

●Type D – Posterior medial area of spine

●Type E – Bilateral aspect of chest, from the mid-third of clavicle to periareolar skin

●Type F – A straight or curved convex line sharply demarcating a relatively darker zone from a light area over the face; a V-shaped hyperpigmented line between the malar prominence and the temple (picture 8)

●Type G – W-shaped hyperpigmented lines between the malar prominence and the temple (picture 9)

●Type H – Linear bands of hyperpigmentation from the angle of the mouth to the lateral aspects of the chin (picture 10)

Type A or Futcher lines are the most common type. They appear as sharp, easily recognizable lines located on the lateral aspect of the anterior portion of the upper arm, delineating the contrast in depth of color between the lateral and medial side of the arm (picture 6A).

Incontinentia pigmenti — Incontinentia pigmenti, also known as Bloch-Sulzberger syndrome (MIM #308300), is an X-linked dominant multisystem disease that is usually lethal in males. It presents in newborns with linear papules and vesicles (picture 11A-B).

Within weeks or months, these lesions progress to verrucous streaks, which typically resolve leaving streaks of hyperpigmentation (picture 12A-B). At three to six months of age, hyperpigmented whorls and swirls appear along Blaschko lines (picture 13).

By the second or third decade of life or sooner, the hyperpigmented whorls may gradually become hypopigmented and may leave subtle atrophy. Incontinentia pigmenti is discussed in greater detail elsewhere. (See "Incontinentia pigmenti".)

Linear and whorled nevoid hypermelanosis — Linear and whorled nevoid hypermelanosis, also called linear nevoid hypo-/hyperpigmentation, is a clinical manifestation of pigmentary mosaicism (previously known as hypomelanosis of Ito) characterized by hyperpigmented macules in a streaky configuration along the lines of Blaschko, mainly located on the trunk and limbs (picture 14A-B) [25,26]. The pigmentation is present at birth or appears in the first few weeks of life, progresses for one to two years, and then stabilizes. In some patients, hypo- and hyperpigmented macules coexist. A quality-switched (Q-switched) 694 nm ruby laser has been used to treat linear and whorled nevoid hypermelanosis in a single case report [27]. (See "Pigmentary mosaicism (hypomelanosis of Ito)".)

There are isolated reports of associated extracutaneous abnormalities, involving mostly the central nervous system, musculoskeletal system, and heart. The presence of genetic mosaicism has been documented in a few patients (mosaic trisomy 7, 14, 18, 20, and X-chromosomal mosaicism) [28-30].

The diagnosis is clinical. Histology is nonspecific and shows increased pigmentation of the basal layer with prominent melanocytes and variable presence of pigmentary incontinence. The differential diagnosis includes the pigmented stage of incontinentia pigmenti and epidermal nevus. (See "Incontinentia pigmenti" and "Epidermal nevus and epidermal nevus syndrome".)

DIFFUSE RETICULAR HYPERPIGMENTATION

Dowling-Degos disease — Dowling-Degos disease (DDD), also known as reticulate pigmented anomaly of flexures, is a rare autosomal dominant genodermatosis associated in approximately one-half of cases with loss-of-function mutations in the gene that encodes keratin 5, KRT5 [31]. Mutations in POFUT1 and POGLUT1 (which encode the protein O-fucosyltransferase 1 and O-glucosyltransferase 1, respectively) involved in the Notch signaling pathway, have been found in affected individuals who do not have mutations in KRT5 [32-35]. The disease has been reported worldwide and affects all sexes equally. Onset is typically during the third to fourth decade of life.

DDD is characterized by an acquired reticular hyperpigmentation that begins in the axillae and groin and later involves other body folds, including intergluteal and inframammary folds, neck, and inner aspects of the arms and thighs (picture 15A-B). Generalized forms with more extensive distribution have also been described [36]. Associated features include comedo-like lesions on the back or neck, pitted perioral or facial scars, and epidermoid cysts [37]. Pruritus is a common accompanying symptom.

The diagnosis is based upon the clinical features and the examination of a skin biopsy. Histology shows increased pigmentation of the basal layer and finger-like rete ridges with thinning of the suprapapillary epithelium.

The differential diagnosis includes a group of related genodermatoses with reticular pigmentation, including:

●Haber's syndrome – Haber's syndrome is characterized by a photosensitive rosacea-like facial eruption, keratotic papules, prominent comedones, pitted scars, and reticulate hyperpigmentation on the trunk, proximal extremities, and axillae [38].

●Galli-Galli disease – Galli-Galli disease is a rare autosomal dominant disorder considered to be an allelic variant of DDD [39-41]. It has the same clinical and histologic features of DDD except for the presence of suprabasal nondyskeratotic acantholysis on histopathology.

●Reticulate acropigmentation of Kitamura – (see 'Reticulate acropigmentation of Kitamura' below).

There are no effective treatments for DDD. Topical retinoids, skin-lightening agents, and laser therapy have been used in a limited number of patients with varying success [42,43].

Reticulate acropigmentation of Kitamura — Reticulate acropigmentation of Kitamura (RAK) is a rare genodermatosis characterized by atrophic, hyperpigmented macules with an initial acral distribution. A mutation in the ADAM10 gene encoding a zinc metalloproteinase has been identified in a RAK family [44]. RAK has been reported worldwide, but most cases are from Japan.

The disease presents in childhood or adolescence with hyperpigmented, slightly depressed macules, often in a reticulate pattern, on the dorsum of the hands and feet. The distinguishing element of this disorder is the atrophic appearance of the lesions. During adulthood, the macules may darken and spread to other sites. Associated findings are pits on the palms, soles, and dorsal aspect of phalanges as well as breaks in palm and sole dermatoglyphics. Histologically, the hyperpigmented macules show epidermal atrophy and elongated rete ridges that contain increased melanin.

The differential diagnosis of RAK includes other diseases presenting with reticular or punctate hyperpigmentation, such as dyskeratosis congenita, dyschromatosis universalis hereditaria, Franceschetti-Jadassohn's syndrome, and DDD. Overlapping cases of RAK and DDD have been reported [45].

There are no effective therapies for RAK. Topical azelaic acid has been successfully used in a single case report [46].

X-linked reticulate pigmentary disorder — X-linked reticulate pigmentary disorder with systemic manifestations (XLPDR; MIM #301220) is a very rare genodermatosis caused by mutations in the POLA1 gene, encoding the catalytic subunit of DNA polymerase-alpha, an essential component of the DNA replication machinery and a critical regulator of the type I interferon response [47,48]. Cells derived from patients with the mutation show increased expression of genes involved in type I interferon signaling pathways and other proinflammatory genes [47]. The disorder was first described in a Canadian family in 1981 and initially called familial cutaneous amyloidosis. Only a few families and one sporadic case have been reported.

The affected males have a distinctive facies with upswept frontal hairline and flared eyebrow and present in the first few months of life with recurrent pneumonias, bronchiectasis, chronic diarrhea, and failure to thrive. By early childhood, male patients develop a generalized reticulate hyperpigmentation and hypohidrosis. Additional systemic manifestations include corneal inflammation and scarring, enterocolitis resembling inflammatory bowel disease, and recurrent urethral strictures. These inflammatory manifestations are believed to be autoinflammatory phenomena due to increased production of interferon-alpha and other cytokines [47].

In females, XLPDR is characterized by patchy, linear hyperpigmentation following the lines of Blaschko that resemble stage III incontinentia pigmenti, in the absence of systemic manifestations. (See "Incontinentia pigmenti".)

Naegeli-Franceschetti-Jadassohn syndrome — Naegeli-Franceschetti-Jadassohn syndrome (MIM #161000) is a rare, autosomal dominant form of ectodermal dysplasia caused by heterozygous mutations in the KRT14 gene at 17q21,2 [49,50]. Clinical features include reticular hyperpigmentation of the skin (picture 16), palmoplantar keratoderma, absence of dermatoglyphs (picture 17), hypohidrosis, and heat intolerance. The hyperpigmentation appears in early childhood, increases during the first 10 years of life, and begins to fade around puberty. Dental abnormalities and early tooth loss are common. Nail dystrophy and malalignment can also be seen in these patients.

Dermatopathia pigmentosa reticularis — Dermatopathia pigmentosa reticularis (MIM #125595) is an autosomal dominant disorder closely related to Naegeli-Franceschetti-Jadassohn syndrome [51,52]. It is caused by mutations in the KRT14 gene and characterized by the triad of reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. In contrast with Naegeli-Franceschetti-Jadassohn syndrome, there are no dental abnormalities. Variable features include adermatoglyphia, hypohidrosis or hyperhidrosis, and palmoplantar hyperkeratosis [53]. 

Dyskeratosis congenita — Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and an increased risk of developing several malignancies, in particular, squamous cell carcinoma (especially mucosal), acute myelogenous leukemia, and Hodgkin disease [54].

DC is inherited in an X-linked recessive fashion, but autosomal recessive and dominant forms also have been reported. It is caused by mutations in the DKC1 gene encoding the protein dyskerin, which is involved in telomerase stabilization and maintenance [55]. Telomerase dysfunction leads to chromosome instability and likely plays a role in tumorigenesis.

The mucocutaneous manifestations of DC include (picture 18):

●A lacy, reticulated pattern of hyperpigmentation involving primarily the neck, upper chest, and upper arms, which develops during the first decade of life.

●Nail dystrophy manifesting as longitudinal ridging, splitting, and early pterygium.

●Teeth anomalies, including malformed, missing, or aberrant spacing (picture 19).

●Leukoplakia of the oral mucosa, most often involving the tongue (picture 20).

DC is discussed in detail separately. (See "Dyskeratosis congenita and other telomere biology disorders".)

Dyschromatosis symmetrica hereditaria — Dyschromatosis symmetrica hereditaria is characterized by small, irregular, hyper- and hypopigmented macules on the dorsal aspects of hands and feet (picture 21) [56]. It is caused by over 200 described mutations in the ADAR1 gene encoding an adenosine deaminase and shows an autosomal dominant inheritance pattern [57,58]. Most cases are reported from East Asia (Japan, Korea, China), but the disorder has also been observed in European, Afro-Caribbean, and Indian individuals [59].

Most patients develop hyper- and hypopigmented macules by the age of six. Lesions typically increase in size and number until adolescence and then stabilize and persist indefinitely. The diagnosis is clinical. (See "The dyschromatoses", section on 'Dyschromatosis symmetrica hereditaria'.)

Dyschromatosis universalis hereditaria — Dyschromatosis universalis hereditaria (DUH) is a rare disorder characterized by hypo- and hyperpigmented macules in a generalized distribution [60]. It is most frequently seen in East Asian and South Asian countries, particularly in Japan and India [61]. DUH is caused by mutations in the ABCB6 (ATP-binding cassette subfamily B, member 6) gene and is inherited in an autosomal dominant fashion with variable penetrance [62,63]. Novel mutations of SASH1 have been identified in Chinese families with DUH [64,65].

Hypo- and hyperpigmented macules usually appear in the first years of life on the hands and then extend to the face, trunk, and extremities. The diagnosis is clinical. (See "The dyschromatoses", section on 'Dyschromatosis universalis hereditaria'.)

DIFFUSE HYPERPIGMENTATION, NONFIGURATE

Familial progressive hyperpigmentation — Familial progressive hyperpigmentation (FPH1) is a rare autosomal dominant disorder characterized by irregular patches of cutaneous and mucosal hyperpigmentation that are present either at birth or in early infancy and increase in size and number with age [66]. FPH1 has been mapped to chromosome 19p13.1-pter, although mutations in a specific gene have not been identified [67].

Familial progressive hyperpigmentation 2 (FPH2; MIM #145250), also called familial progressive hyperpigmentation with or without hypopigmentation or melanosis universalis hereditaria, is rare autosomal dominant disorder with variable penetrance caused by mutations in the KITLG gene on chromosome 12q21.32, encoding the C-Kit ligand [68]. FPH2 is characterized by patches of cutaneous hyperpigmentation, café-au-lait macules, and larger, hypopigmented, ash-leaf macules that are present either at birth or in early infancy and increase in size and number with age.

Carbon baby — Universal acquired melanosis or "carbon baby" syndrome is an exceedingly rare type of progressive hyperpigmentation of unknown etiology occurring in children [69,70]. The darkening of the skin starts in the first few months of life on the face and limbs and gradually progresses to involve the entire body surface. On histopathology, there is heavy melanin deposition in the basal and suprabasal layers of the epidermis and presence of melanophages in the dermis [69].

H syndrome — H syndrome (MIM #602782) is a rare, multisystem, autoinflammatory disorder mainly affecting patients of Arab and, less commonly, Indian descent [71]. First described in 2008, H syndrome is characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, and short stature [72,73].

H syndrome is part of the histiocytosis-lymphadenopathy plus syndrome, which includes three other histiocytic disorders once thought to be separate entities:

●Faisalabad histiocytosis

●Sinus histiocytosis with massive lymphadenopathy (familial Rosai-Dorfman disease)

●Pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome

This group of diseases is caused by homozygous or compound heterozygous mutation in the SLC29A3 gene on chromosome 10q22, encoding the solute carrier family 29 member 3, also called the equilibrative nucleoside transporter 3, which mediates the uptake of precursors for nucleotide synthesis by salvage pathways. (See "Peripheral lymphadenopathy in children: Etiology", section on 'Rosai-Dorfman disease'.)

The clinical manifestations of H syndrome are widely variable. Its hallmark is cutaneous hyperpigmentation, which becomes apparent during childhood and is associated with sclerodermatous skin induration and hypertrichosis (picture 22) [74]. The hyperpigmented and hypertrichotic plaques are located on the middle and lower part of the body.

Extracutaneous manifestations may include sensorineural hearing loss, hepatosplenomegaly, short stature, cardiac anomalies (atrial septal defect, ventricular septal defect, mitral valve prolapse, and cardiomegaly), varicose veins, dilated lateral scleral vessels, facial telangiectasias, hallux valgus and fixed flexion contractures of fingers and toes, scrotal masses, and gynecomastia. Membranous nephropathy has been reported in one family [75]. Lymphadenopathy, which may be generalized or localized, has been reported in 24 percent of patients and insulin-dependent diabetes mellitus in 23 percent [74].

Laboratory abnormalities include mild microcytic anemia, elevated erythrocyte sedimentation rate, elevated liver enzymes, growth hormone deficiency, high gonadotropin levels, and low to normal testosterone levels. A biopsy of the involved skin shows hyperkeratosis, acanthosis, and increased melanin deposition in basal keratinocytes; widespread fibrosis of the dermis and subcutis; and an interstitial inflammatory infiltrate composed of small to medium-sized histiocytes, dendrocytes, plasma cells, lymphocytes, and mast cells (picture 23) [76].

The diagnosis of H syndrome is suspected based upon the clinical findings. Mutational analysis will confirm the diagnosis when there is uncertainty or in patients with mild or incomplete phenotypes. There is no established treatment for H syndrome. Therapies that have been attempted include systemic corticosteroids, immunosuppressive agents, interferon-alpha, adalimumab, and radiotherapy [74].

GENETIC SYNDROMES ASSOCIATED WITH LENTIGINOSIS — Genetic syndromes associated with lentiginosis are summarized in the table (table 3) [77].

Carney complex — Carney complex (MIM #160980), previously called LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) or NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelides) (table 3), is a clinically heterogeneous autosomal dominant disorder characterized by the presence of atrial myxomas, lentigines, skin tumors, and endocrine overactivity. They are caused by mutations in the PRKAR1A gene, encoding the protein kinase regulatory subunit 1A, located at 17q22-24.

Lentigines occur most commonly on the face, especially on the lips, eyelids, conjunctiva, and oral mucosa (picture 24), but may be widespread and involve the trunk, extremities, and genitalia [78]. Other skin lesions include junctional and compound nevi, blue nevi, and cutaneous myxomas.

The diagnostic criteria of Carney complex are summarized in the table (table 4). Given the rarity of this disorder, patients with suspected Carney complex (and their family members) should be referred to specialized centers with expertise in this area for diagnosis and genetic testing [79].

Carney complex is discussed in detail elsewhere. (See "Carney complex".)

LEOPARD syndrome — LEOPARD syndrome (MIM #151100), also called Noonan syndrome with multiple lentigines, is a rare, autosomal dominant disorder caused by mutations in the protein tyrosine phosphatase, PTPN11 gene [80]. LEOPARD is an acronym for the major features of this disorder, including multiple lentigines, electrocardiogram (ECG) conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.

LEOPARD syndrome belongs to a group of developmental disorders called RAS/MAPK pathway syndromes, which include Noonan syndrome, neurofibromatosis type 1, neurofibromatosis type 1-like syndrome (Legius syndrome), cardiofaciocutaneous syndrome, Costello syndrome, and capillary malformation-arteriovenous malformation syndrome [81,82]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Capillary malformations (port wine birthmarks) and associated syndromes", section on 'Capillary malformation-arteriovenous malformation syndrome'.)

Multiple lentigines are the most prominent manifestation of LEOPARD syndrome and are present in more than 90 percent of the patients. They appear during infancy and early childhood and increase in number over time to involve a large portion of the skin, including the face (picture 25), neck, and upper trunk (picture 25). Lentigines may also occur on the palms, soles, and sclerae. Café-au-lait macules like those found in neurofibromatosis type 1 occur in approximately one-half of the patients.

The diagnosis of LEOPARD syndrome is difficult, given the highly variable expressivity of the syndrome. In the first year of life, before the appearance of lentigines, the diagnosis can be clinically suspected in infants presenting with three main features: characteristic facial features, hypertrophic cardiomyopathy, and café-au-lait macules [83]. The diagnosis can be confirmed by molecular screening for PTPN11 mutations.

The management of patients with LEOPARD syndrome requires a multidisciplinary approach involving dermatology, cardiology, endocrinology, and other appropriate specialists. Genetic counseling is indicated and involves clinical and cardiologic examination of parents and molecular analysis if appropriate.

Peutz-Jeghers syndrome — Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by mucocutaneous lentigines with intestinal polyposis. It is caused by heterozygous mutations in the STK11/LKB1 tumor suppressor gene, encoding serine/threonine kinase 11.

The lentigines are typically present at birth or appear during childhood. They predominantly affect the perioral and periorbital areas but may involve the volar and dorsal aspects of the hands and feet (picture 26A-D).

Mucosal lesions may affect the palate, tongue, buccal mucosa, and conjunctivae. This syndrome is associated with pancreatic carcinoma and ovarian and testicular tumors. The main entity in the differential diagnosis is Laugier-Hunziker syndrome. The diagnosis and management of Peutz-Jeghers syndrome is discussed in detail separately. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management" and "Juvenile polyposis syndrome".)

Bannayan-Riley-Ruvalcaba syndrome — Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare, autosomal dominant, gastrointestinal hamartomatous polyposis syndrome caused by germline mutations in the PTEN tumor suppressor gene [84]. It is part of Cowden syndrome-1, also called PTEN hamartoma tumor syndrome or multiple hamartoma syndrome (MIM #158350).

The clinical manifestations of BRRS arise early in childhood and include hypotonia, delayed psychomotor development, seizures, diarrhea, intussusception, and anemia. Cutaneous manifestations include genital lentigines, facial verrucae, vascular malformations, lipomas, acanthosis nigricans, and multiple acrochordons. Hyperpigmented macules involving the glans penis (picture 27) or vulva are the most specific finding related to the syndrome.

The diagnosis and management of BRRS are discussed in more detail elsewhere. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Bannayan-Riley-Ruvalcaba syndrome'.)

GENETIC SYNDROMES ASSOCIATED WITH CAFÉ-AU-LAIT MACULES — Genetic syndromes associated with café-au-lait macules are summarized in the table (table 5).

Neurofibromatosis type 1 — Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by a mutation in the NF1 gene, encoding the protein neurofibromin, a tumor suppressor expressed in many human cells, primarily in neurons, glial, and Schwann cells [85]. Neurofibromin belongs to a family of GTPase-activating proteins (GAPs) that downregulate the cellular proto-oncogenes p21-ras, an important determinant of cell growth and regulation.

The presence of six or more café-au-lait macules (picture 28) (>5 mm in prepubertal individuals and >15 mm in postpubertal individuals), cutaneous neurofibromas (picture 29A-B), and axillary or inguinal freckling (picture 30) are the hallmark of NF1. Other manifestations of NF1 include plexiform neurofibromas, optic pathway gliomas, and other central and peripheral nervous system tumors.

The clinical manifestations, diagnosis, and management of NF1 are discussed separately. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)

Neurofibromatosis type 1-like syndrome (Legius syndrome) — Neurofibromatosis type 1-like syndrome or Legius syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in SPRED1, encoding a protein that downregulates the RAS/mitogen activated protein kinase (RAS/MAPK) pathway [86,87].

Clinical features include multiple café-au-lait macules, with or without flexural freckling. Importantly, Legius syndrome lacks neurofibromas and central nervous system tumors. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Legius syndrome'.)

McCune-Albright syndrome — McCune-Albright syndrome is a rare mosaic disorder caused by postzygotic activating mutations of the GNAS1 gene, encoding the alpha subunit of the stimulatory G protein [88]. The syndrome is characterized by the triad of polyostotic fibrous dysplasia, café-au-lait macules, and endocrine hyperactivity, classically causing precocious puberty [89]. (See "Definition, etiology, and evaluation of precocious puberty".)

The café-au-lait macules appear at birth or shortly after and are the first manifestation of the disease. They have an irregular border described as a "coast of Maine" border and are often unilateral, with midline demarcation and a tendency to follow the Blaschko lines (picture 31 and picture 32). Later in life, some patients may develop oral mucosal lentigines [90].

There are no effective treatments for hyperpigmented patches associated with McCune-Albright syndrome. The quality-switched (Q-switched) ruby laser has been successfully used in a single patient with facial hyperpigmentation [91].

SUMMARY AND RECOMMENDATIONS

●Determinants of skin color – The color of human skin is mainly determined by the two types of melanin, the black-brown eumelanin and the yellow-red pheomelanin, which are present in individuals of all skin colors, though their ratio is highly variable and determines the hue of the skin. Hyperpigmentation is the darkening or increase in the natural color of the skin, usually due to an increased deposition of melanin (hypermelanosis) in the epidermis and/or dermis. It is a feature of a multitude of clinical conditions, ranging from normal variations of skin color to acquired and inherited syndromes. (See 'Pathophysiology of skin pigmentation' above.)

●Evaluation and diagnosis – Diagnosis of most hyperpigmentation disorders is made on clinical grounds. The initial patient evaluation involves a detailed medical and family history and a complete skin examination. Important clinical parameters include the extent of the pigmentary abnormality, color hue and morphology of individual lesions, distribution, and pattern. An algorithmic approach to the diagnosis based upon history and clinical parameters is shown in the figure (algorithm 1). (See 'Patient evaluation and diagnosis' above.)

●Localized versus diffuse hyperpigmentation – Congenital and inherited hyperpigmentation disorders may be localized (eg, congenital dermal melanocytosis, café-au-lait macule) or diffuse. The latter often show a linear configuration that follows the lines of Blaschko (eg, incontinentia pigmenti, linear and whorled nevoid hypermelanosis) or a reticular pattern (eg, Dowling-Degos disease, reticulate acropigmentation of Kitamura, dyskeratosis congenita). (See 'Circumscribed hyperpigmentation' above and 'Diffuse linear hyperpigmentation' above and 'Diffuse reticular hyperpigmentation' above.)

●Genetic syndromes associated with lentiginosis and café-au-lait macules – Multiple lentigines and café-au-lait macules are the hallmark of several genetic syndromes. Carney complex, LEOPARD (multiple lentigines, electrocardiogram [ECG] conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome, and Peutz-Jeghers syndrome are associated with lentiginosis. Genetic syndromes associated with café-au-lait macules include neurofibromatosis type 1, Legius syndrome, and McCune-Albright syndrome. (See 'Genetic syndromes associated with lentiginosis' above.)