Disorders of Pigmentation

For diagnosis

Clinical evaluation

Biopsy rarely needed for confirmation

Genetic screen for mucopolysaccharidoses in extensive cases

For treatment

Tincture of time—most lesions resolve by age 6 years

The most common hyperpigmentation is the Mongolian spot (Fig. 11.1), which can be noted at birth or shortly thereafter [3]. The Mongolian spot is a bluish coloration noted with immature pigment cell placement in the skin, usually in infants of color who are full term and full-size. The bluish color comes from the Tyndall effect, an optical alteration noted when melanocytes are in the dermis. The leading location is the sacrum and gluteal region, but eccentric placement can be seen anywhere on the body. The Mongolian spot is seen in 9.5–18.9 % of Caucasian infants, 46 % of Hispanic/Latino infants, 62.2 % of Indian infants, 83.6 % of East Asians, and 96 % of Black newborns [4, 5]. Extensive lesions can be associated with mucopolysaccharidoses and may need genetic screen [6].

Fig. 11.1

Mongolian spot on the lower back of an 8-year-old Asian boy with a solitary café au lait macule off to the right side of the back

Most Mongolian spots will disappear with time, and no therapy is needed [7].

Café au Lait Macules

Café au lait macules (Fig. 11.1) are common localized areas of excess pigmentation that are generally round or oval, but may follow a segmental pattern. Although the classic lesion seen in light-skinned individuals or in association with neurofibromatosis is the color of light coffee, lesions can vary from nearly imperceptible in Caucasian infants to dark brown in Black children. It is estimated that 22 % of Black children and 11 % of Caucasian children have a solitary lesion. The lesions are most concerning when found in larger number [8].

The presence of six or more café au lait macules of 5 mm or greater in childhood or 1.5 cm in adulthood is a criterion for the diagnosis of neurofibromatosis type I, a multi-system autosomal dominant genetic disorder associated with tumor development [9]. Of 44 children in a neurofibromatosis type I clinic who had 6 or more café au lait at presentation, 34 went on to meet criteria for the disease—32 of whom met criteria by 72 months [10]. The vast majority of patients will be diagnosed by age 8 years, and 46 % of spontaneous cases by age 1 year [9].

Large segmental café au lait over the trunk may be associated with McCune Albright Disease seen with macrocephaly and precocious puberty. In the setting of multiple café au lait macules, clinical evaluation for the other criteria of neurofibromatosis includes an ophthalmology examination every 6 months, dermatologic evaluation every 6 months, and neurological, orthopedic and/or genetic screen where appropriate. Criteria for neurofibromatosis type 1 and the average timing of onset are listed in Table 11.1 [9].

Table 11.1

Diagnostic criteria for neurofibromatosis type I

Criterion	Clinical appearance	Timing of onset
Café au lait	Six or more tan to brown ovoid macules and patches	Most children will meet this criteria by age 6 years
	>5 mm childhood
	>1.5 cm adulthood
Optic nerve gliomas	Tumor of the optic nerve visualized on dilated examination	10 % by age 3 years
Lisch nodules (smooth muscle hamartomas of the iris)	Pigmented papules on the iris visualized with slit lamp examination	Age 6 or later; 68 % by age 10 years
Osseous lesions	Pseudoarthrosis, sphenoid wing dysplasia, and dysplastic vertebrae seen on x-rays	30 % at birth
Relative	First degree relative with neurofibromatosis	About half are sporadic and half have a first-degree relative
Neurofibromas	Two or more neurofibromas, which are soft tumors that indent with pressure, or plexiform neuroma, which is described as a bag of worms	Meet criteria:
		10 % at birth
		48 % by age 10 years
		84 % of 20 year olds
Freckling	Pinpoint tan macules of the axillary and or inguinal folds	90 % by age 6 years; rare after age 7 years

For diagnosis

Clinical confirmation/ examination (benign vs. in the setting of a systemic genetic syndrome)

Biopsy in atypical lesions may help

Full body skin examination every 6 months

Ophthalmology examination every 6 months

For treatment

Laser may reduce appearance in some cases

Excision of tumors that are causing functional impairment in the setting of neurofibromatosis type 1

Developmental and neurological evaluation in multiple lesions

Nevus Depigmentosus (Fig. 11.2)

Fig. 11.2

Nevus depigmentosus on the lower abdomen in a Hispanic male infant

This misnomer represents a localized reduction in pigmentation seen at birth in children of Asian, Indian, and Hispanic/Latino descent [11]. The areas represent a localized increase in the ratio of pheomelanin to eumelanin and reduced melanosomes (melanin storage organelles). Fifty percent will be seen at birth and almost all lesions are noted by age 1 year.

Wood’s lamp examination will demonstrate partial highlighting and better define lesions. Nevus depigmentosus needs no therapy, but judicious sun protection to avoid enhancement of the color differential from normal skin is cosmetically beneficial [12].

For diagnosis

Wood’s lamp equivocal

Biopsy for hematoxylin and eosin stain or electron microscopy

In cases of multiple lesions, full-body exam every 6 months with Wood’s lamp for highlighting

Ophthalmic examination every 6 months

For treatment

No therapy needed. Most cases cause limited cosmetic disfigurement

Cosmetic camouflage

Tuberous Sclerosis

Multiple areas of hypopigmentation can be noted in systemic genetic disease such as tuberous sclerosis, presenting early on with confetti macules and thumbprint macules, and later with the botanically reminiscent ash leaf macules. The current criteria for tuberous sclerosis are listed in Table 11.2. Diagnosis requires ophthalmologic, neurologic, and genetic screens accompanied by frequent dermatologic follow-up (every 6 months) and imaging of the head, which may identify UBOs (unidentified bright objects) or intracranial tubers [13–16].

Table 11.2

Diagnostic criteria for tuberous sclerosis (two major or one major and two minor)

Criteria	Dermatologic clinical appearance	Frequency
Major
Angiofibromas or Fibrous forehead plaque	Flesh-colored papules perinasal	32.1–100 %
Angiofibromas or Fibrous forehead plaque	Similar to Shagreen but facial forehead localization (Both begin in toddler to early childhood years)	2.5–55 %
Hypomelanotic macules (≥3, at least 5-mm diameter)	Ovoid hypopigmented lesions, usually truncal	55.5–95 %
Ungual fibromas (> or =2)	Flesh-colored to brown narrow spicules of skin originating in the cuticle and overhanging the nail	20 % overall; 80 % of older patients
Shagreen patch	Thick or indurated flesh-colored plaque, usually lower back; onset first decade	12.3–83 %
Multiple retinal hamartoma	Noted on ophthalmology exam	30–50 %
Cortical dysplasias	Tubers and cerebral white matter migration lines
Subependymal Nodules	Noted on brain scans; tubers and cerebral white matter migration lines
Subependymal giant cell astrocytoma	Noted on brain scans
Cardiac Rhabdomyoma	Noted in utero/at birth on ultrasound/echocardiography; self-resolving	12 % have cardiac issues as a result
Lymphangioleiomyomatosis (LAM)	Noted within the bones and lungs of the chest cavity with imaging	38 % adults
Angiomyolipomas	Noted mostly within the kidneys on imaging
Minor “Confetti” skin lesions	Scattered hypopigmented areas a few mm wide across the back	3–58 %
Dental enamel pits (>3)	Noted on dental evaluation	100 %
Intraoral fibromas (> or =2)	Noted on dental evaluation	20–50 %
Retinal achromic patch		1.2–15 %
Multiple renal cysts		6.2–28 %
Non renal hamartomas

For diagnosis of tuberous sclerosis
Criteria evaluation, coordinated multidisciplinary evaluation—ophthalmology, dermatology, neurology, renal, pulmonary, genetics, dental, and cardiology
Skin and oral evaluation every 3–6 months
Biopsy for confirmation of growths which are not clinically typical, including fibrous forehead plaque
In cases of multiple lesions, full-body exam every 6 months with Wood’s lamp for highlighting
Chest X ray, EKG, echocardiography, abdominal ultrasound, CT scan head, MRI abdomen
Ophthalmic examination every 6 months
For treatment
	Level of evidence
Coordinated multidisciplinary care—ophthalmology, dermatology, neurology, renal, pulmonary, genetics
Cosmetic camouflage
Cosmetic therapies are available to reduce facial lesions, including topical rapamycin	C
Topical rapamycin for facial angiofibromas	C
MTOR inhibitors (e.g. sirolimus)	A

Nevoid Melanosis or Blaschkoid Pigmentation

Nevoid hypermelanosis or hypomelanosis (Fig. 11.3) (synonyms hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, nevus depigmentosus, cutis tricolor or Blaschkoid dyspigmentation) is the appearance of tan to brown (slightly hypopigmented to hyperpigmented) lesions in a Blaschkoid pattern, usually on limbs with trunk and abdomen trailing as locations [17]. A Blaschkoid pattern means they follow the Lines of Blaschko, which are noted at birth or within the first 2 years of life, and represent localized cutaneous mosaicism in association with either a normal child (majority of cases) or neurologic (e.g. seizure and mental retardation), skeletal and multi-system abnormalities. When hypopigmented streaks are paired with neurologic abnormalities, the complex is often termed hypomelanosis of Ito. In two chart reviews, of 36 patients and 54 patients, only 13.9 % and 30 % of patients had extracutaneous manifestations, respectively [17, 18]. The majority of patients with Blaschkoid pigmentation were otherwise normal.

Fig. 11.3

Congenital hypopigmentation along the lines of Blaschko

Neurologic and ophthalmologic screen is indicated [19]. Gross skeletal evaluation of children with Blaschkoid dyspigmentation and limb measurement (assessment for symmetry or anomaly) and appropriate orthopedic evaluation where indicated. Genetic testing for chimerism is reasonable, with cutaneous genotyping of the two different tones of skin (from biopsy) being an optional screen for mosaicism, though unnecessary in the general setting. Where the underlying diagnosis is hard to establish, biopsy can be performed.

For diagnosis of syndromic cases

Repeat cutaneous evaluation every 6–12 months in the first few years of life with Wood’s lamp for highlighting looking for anomalies, localized alterations in hair growth, overgrowth or atrophy of limb and associated cutaneous changes (e.g. palmoplantar keratoderma)

Referrals to ophthalmology, neurology and genetics

Biopsy for confirmation of diagnosis where uncertain

Limb lengths and widths to identify underlying skeletal abnormalities

For treatment

Coordinated multidisciplinary care—ophthalmology, dermatology, neurology, genetics

Cosmetic camouflage is available for visible lesions

Laser therapies may be tried for hyperpigmented lesions similar to those used in the setting of café au lait

Becker’s Nevus

The Becker’s Nevus (Fig. 11.4) is an organoid nevus that appears in a checkerboard mosaic pattern [20]. A smooth muscle hamartoma is usually accompanied by overlying hyperpigmentation, appearing like a café au lait and hypertrichosis. The constellation of findings can be seen in the infantile smooth muscle hamartoma, or appear around puberty on the trunk or proximal extremities, at which time it is usually termed a Becker’s Nevus. The younger the child, the less likely it is that hypertrichosis will be noted [21]. The Becker’s Nevus is felt to have estrogen receptors. It may be familial in nature [20]. When it is accompanied by hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings, it is termed the HATS association [22]. A rare association with neurofibromatosis type I has been reported [23]. Becker’s Nevus Syndrome is the presence of the Becker’s Nevus with unilateral breast hypoplasia and skin, muscle, or skeletal abnormalities. Mental retardation may be noted [24].

Fig. 11.4

Becker’s nevus on the shoulder in an African American male

The Becker’s Nevus can be diagnosed clinically in most cases. Confirmatory tests include Wood’s lamp to define the extent of pigmentation (especially needed for light-skinned patients or females with minimal, light body hair). Confirmatory biopsy can be performed demonstrating typical histology [21]. Imaging, dental, and orthopedic evaluations can aid in the defining of associated structural abnormalities, if suspected. A solitary report of a melanoma in a Becker’s Nevus has appeared in the literature, therefore biopsy of changing lesions or for the appearance of new lumps or bumps is needed [25]. Removal of hair or pigmentation overlying a Becker’s nevus has been described, with variable success, using variable lasers, as well as fractional resurfacing laser [26, 27].

For diagnosis

Clinical evaluation

Biopsy for confirmation

Chest X-ray, Dental X-rays, and MRI can define underlying defects

For treatment

Biopsy of alterations in pigmentation, lumps, bumps, or nodules

Cosmetic camouflage

Laser therapies have been described including hair removal, pigment removal lasers, and fractional resurfacing

Nevus of Ito and Nevus of Ota

These melanocytic nevi are named based upon their localization in the skin [28]. Presenting in grey-blue sheet of color in the first year of life, they may affect any place in the head and neck region. The Nevus of Ota (Fig. 11.5) usually appears in the first or second trigeminal distribution, with associated ocular component in some cases, while Nevus of Ito appears in the shoulder girdle. In these cases, ongoing ocular assessment is needed to identify associated glaucoma and/or melanoma of the eye. In the skin, palpation for lumps and bumps and ongoing cutaneous evaluation is recommended. Because of the rare association with meningeal melanocytomas which need to be excised, observation for neurologic changes (e.g. headaches) is needed [29, 30]. The lesions are more common in Asians and may cause stigma [28]. A variety of laser techniques for removal are available with variable success [31]. These lesions, in contrast to the Mongolian Spot, do not fade with time.

Fig. 11.5

Nevus of Ota in an Asian male infant

Congenital Widespread Alterations in Pigmentation

Oculocutaneous Albinism

Clinical Features

Oculocutaneous albinism (OCA) results from gene defects in the melanin synthesis pathway and affects 1:20,000 [32]. The specific defective gene determines if patients will have either decreased melanin synthesis or complete absence of melanin synthesis [32–34]. The adverse effect on melanin is manifested in hair follicles, ocular structures, and the skin. OCA types 1 through 4 have normally structured melanocytes, but the melanocytes are unable to make pigment. Patients with OCA Type I have pink nevi, severe nystagmus, and increased risk of squamous cell carcinomas. OCA Type 1A has completely absent tyrosinase, and thus begets the most severe clinical manifestations and highest skin cancer risk. In OCA Type 1B, the tyrosinase is present, but decreased, producing clinical variants such as yellow mutant. OCA Type 2 results from a defect in P protein, and results in the brown variant where those afflicted have nystagmus, light brown hair, and pigmented nevi, and may make more pigment as they get older. OCA Type 3 is due to a defect in tyrosine-related protein resulting in the Rufous subtype, where patients have nystagmus, blue or brown iris, light brown to red hair, and light brown-red-bronze skin. OCA Type 4 is due to mutation in membrane-associated transporter protein (MATP), a melanosome membrane transporter (Table 11.3). There are other hypomelanosis disorders that have oculocutaneous manifestations along with systemic manifestations, including Hermansky-Pudlak syndrome, Chediak-Higashi syndrome and Griscelli syndrome.

Table 11.3

Types of oculocutaneous albinism (OCA)

Type of OCA	Inheritance	Gene defect and pathogenesis	Distinguishing clinical features
Type 1a (Tyrosine-negative)	AR	TYR, tyrosinase enzyme deficiency; absence of tyrosinase activity or inability tyrosinase to transport to melanosomes	Absence of melanin in skin, hair, and eyes
			White hair may become slightly yellow over time
			Severe nystagmus
			Amelanotic nevi (pink nevi)
			Blue-gray eyes, decreased visual acuity, prominent red reflex throughout life
			Increased risk of squamous cell carcinomas
Type 1b (yellow mutant)	AR	TYR, tyrosinase is present but decreased	Develops some pigment over time
Type 2 (Tyrosinase positive) (brown variant)	AR	P gene, defect in P protein, decreased eumelanin synthesis, normal number of melanocytes	Brown variant is most common form of albinism in those of African descent
			Light brown hair
			Pigmented nevi
			Eye symptoms may improve with age
			May get more pigment with increased age
Type 3 (Rufous)	AR	TYRP-1, Tyrosinase-related protein 1	Nystagmus
			Decreased visual acuity
			Blue-brown iris
			Light brown-red-bronze skin
Type 4		MATP, Mutation in membrane-associated transporter protein, a melanosomes membrane transporter	Similar to OCA type 2

Investigations Recommended

For diagnosis

Biopsy to determine presence of melanocytes or not (may be required)

Family history (required)

Genetic testing

Ophthalmologic examination for nystagmus, strabismus, photophobia, poor vision

For on-going management

Dermatology follow up to biopsy any suspicious lesions to rule out skin cancer (Basal cell carcinoma, Squamous cell carcinoma, melanoma)

Ophthalmologic follow-up

Sun avoidance, sunscreen, eye protection, protective clothing

Phenylketonuria

Clinical Features

Phenylketonuria (PKU) results from a deficiency of phenylalanine hydroxylase (PAH) or tetrahydrobiopterin, the phenylalanine hydroxylase co-factor [35, 36]. PKU is inherited via autosomal recessive pattern and affects 1:10,000–15,000 Caucasian newborns. The PAH gene is found on chromosome 12q23.1, but there are over 600 reported mutations. Patients with similar PAH defects may have different phenotypes. Without functioning PAH, the pathway of phenylalanine-to-tyrosine-to-dopamine-to-melanin does not occur. Tyrosine is needed for production of melanin, which is necessary for hair and skin color.

In addition to skin hypopigmentation, mental retardation, dermatitis, photosensitivity, and seizures may occur. Most patients have fair skin, blonde hair, and blue eyes. A musty odor is often noted from the by-products (phenylacetic acid) of the failed metabolic pathway. Patients with high levels of phenylalanine may have atopic dermatitis-like dermatitis and sclerodermoid-like skin changes, which improve with lowered phenylalanine levels.

Screening for PKU is a component of many state-mandated newborn screening programs [35–38]. If recognized early, a phenylalanine-free formula can be instituted, and later a low-phenylalanine diet. The dietary restrictions are instituted to prevent the most severe adverse events and clinical features that result from high phenylalanine levels. Despite these strict diet-control efforts, neurodevelopmental and psychological problems may still emerge.