Congenital Pigmentary Anomalies in Neonates: Clinical Updates and Management

Congenital pigmentary anomalies, or pigmented birthmarks, occur due to genetic changes in the germline with a presumed second milestone in the affected skin or somatic genetic changes in the developing fetus.

They can occur in various distributions along the body, including single versus multiple, focal versus segmental (involving large sections of the body), or curvilinear (e.g., Blaschko-linear, which means following Blaschko lines that represent the path of migration. of keratinocytes in the uterus), and unilateral versus bilateral.

Earlier somatic genetic changes lead to more widespread skin involvement and, if they involve pluripotent progenitor cells, a higher risk of multisystem intervention.

Therefore, multifocal and extensive birthmarks may be more concerning than focal and single birthmarks. The pattern and type of birthmark(s) present, as well as associated cutaneous and extracutaneous findings, will help guide further evaluation and management.

Pigment mosaicism describes the coexistence of 2 genetically and phenotypically different populations of pigmented cells in an individual. This term typically describes extensive hypo- or hyperpigmented patches, archetypal patterns of which have been identified: 

1) narrow linear Blaschko-bands; 
2) wide linear Blaschko-bands; 
3) checkerboard pattern; 
4) phylloid (leaf-shaped) pattern; 
5) irregular pattern without midline demarcation; 
6) lateralization pattern; and 
7) sash-shaped pattern.(1)

Pigmentary mosaicism may be present at birth or may manifest in the first 2 years of age. Extensive pigmentary mosaicism may be limited to the skin or present along with systemic abnormalities.

The most important factor in evaluating pigmentary mosaicism is to analyze the presence of neurological, ophthalmological, musculoskeletal, and cardiac abnormalities in history and clinical examination.

There is no standard screening protocol for pigmentary mosaicism; The evaluation is guided by clinical findings. If the patient has other abnormalities or evidence of neurodevelopmental disorders or seizures, the patient should be referred for genetic evaluation. Multisystem disease is most commonly caused by chromosomal aberrations, microdeletions, and mutations have also been described.(1) In contrast, cases limited to the skin do not warrant further evaluation.

Hypomelanosis of Ito is a term historically used to describe extensive curvilinear hypopigmentation associated with extracutaneous anomalies, including neurological (90%), musculoskeletal (70%), ophthalmological (25%) and cardiac (10%) alterations.(2)

Linear and whorled nevoid hypermelanosis is the historical term used to describe extensive hyperpigmentation with systemic abnormalities. These terms are not preferred since most children with pigmentary mosaicism are neurologically normal and do not have an associated genetic syndrome.

There are other rare cases called pigmentary mosaicism syndromes that are associated with specific genes. For example, a “tricolor cutis” phenotype (concomitant hyper- and hypopigmented whorled patches) has recently been described in 5 patients with megaloencephaly and mutations along the phosphatidylinositol-3-kinase (PI3K) signaling pathway, the protein kinase B (PKB/AKT) and mammalian target of rapamycin (mTOR). It is called Megaloencephaly-polymicrogyria-pigmentary mosaicism syndrome and is a subset of the PIK3CA-related overgrowth spectrum.(3)(4)

Pigmentary mosaicism must be distinguished from extensive epidermal nevi, which present as raised hyperpigmented to pinkish warty, hyperkeratotic, or smooth papules that coalesce into curvilinear plaques.

Epidermal nevi may be thin at birth and must be palpated to distinguish them from pigmentary abnormalities. They have been associated with several mutations in the PI3K/AKT/mTOR signaling pathways and rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). ), as well as with keratin genes.(5)

Epidermal nevus syndrome describes extensive epidermal nevi associated with systemic diseases that vary in presentation depending on the gene involved and, similar to pigmentary mosaicism, may also be associated with neurological, ophthalmological, and musculoskeletal abnormalities.(5)

Congenital melanocytic naevi (CNM) are defined as melanocytic naevi that are present at birth.

NMCs are most commonly classified based on projected adult size as small (<1.5 cm), medium (1.5–19 cm), and large (>20 cm), (6) with some authors including a category of NMCs. giant (projected adult size > 40 cm).

In a newborn, a large/giant NMC (NMCGG) is a lesion that measures 6 cm or more on the body or 9 cm or more on the scalp. (7) Other classification schemes take into account not only the size, but also the number of satellite lesions and the morphological characteristics of the nevus. (8)

Small CMNs are seen in 1% to 2% of the population, have a low risk of malignancy, and do not require routine monitoring. In contrast, NMCGGs are rare, occurring in 1 in 20,000 newborns. (9) Patients with NMCGG or multiple NMC pose management challenges derived from the risk of cutaneous and central nervous system (CNS) melanoma, extracutaneous manifestations (CMN syndrome), and the psychosocial burden due to the appearance of nevi. and therefore these patients will be the focus of discussion in this section.

NMC results from post-zygotic somatic mutations in genes such as NRAS ,(10) BRAF ,(11) and other rarer mutations. NMCGG genotyping is not standard practice but has become more important given the potential for molecularly targeted treatments for cutaneous symptoms such as pain and pruritus (12) or for palliation of CNS melanoma (13) with drugs such as trametinib, an inhibitor. MEK. Currently, these treatments are experimental but provide hope for the future.

NMC can vary in color from pink to dark brown and can be located anywhere on the skin. Small NMCs are typically homogeneous light brown or dark brown macules or patches at birth. In contrast, NMCGG may have thick, rough plaques or deep nodules with homogeneous or variegated color. Hypertrichosis (excessive hair growth) may be seen at birth or may develop in childhood.

Some NMCs, especially scalp NMCs, can spontaneously lighten over time.(14)

NMCGGs are commonly associated with numerous smaller “satellite” nevi. The NMCGG are distributed in typical patterns (in "cape", in "swimsuit", or in "motorcyclist glove") (15) that in theory reflect the migration of a proposed new population of melanocytic precursors that arise at the time of gastrulation. .(16) NMC can be associated with itching and fragility of the skin and special care should be taken in the newborn to avoid adhesives or irritants on the skin of the nevus.

Neonates with NMCGG or multiple NMC of any size should be referred at birth for expert management by specialists with experience in NMC. Patients in this group may have extracutaneous manifestations that reflect early somatic mutations of a presumed pluripotent cell leading to the phenotype called “NMC syndrome.” (17) These extracutaneous findings include: 

1) congenital neurological disease, 
2) typical facial features, 
3) underdevelopment of fat or muscle in the nevoid areas, and 
4) endocrinological alterations.

Congenital neurological disease deserves special discussion. The term neurocutaneous melanosis is used in many publications to describe the presence of melanocytic lesions in the brain parenchyma or leptomeninges of the brain or spinal cord. However, neurocutaneous melanosis is a nonspecific term that does not distinguish between benign or malignant CNS disease.

Patients with congenital neurological disease are at risk for CNS melanoma, which is universally fatal, as well as hydrocephalus, developmental delay, and seizures. Therefore, patients with NMCGG or 2 NMC of any size should undergo screening with gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and spinal cord, ideally before 6 months of age before complete myelination occurs. of the brain.

If performed during the neonatal period, an MRI can be obtained without sedation. If the initial MRI is normal, then further evaluation is not recommended. If MRI shows abnormalities, management requires specialized evaluation at a center with experience in NMC.(18)

All children with NMCGG who present with neurological findings in later childhood should undergo imaging to exclude CNS melanoma.

Cutaneous melanoma in NMCGG is rare and usually occurs early in childhood. Melanomas in this context most commonly present as a rapidly growing nodule that often sits deep in the subcutaneous tissue of the nevus.

Any rapidly changing nodule in a CMN should be biopsied and the histopathological findings reviewed by pathologists with experience in pediatric nevi.(18)(19)

Current NMC treatment focuses primarily on excellent skin care to maintain its integrity and prevent infection. Patients often suffer from significant pruritus, which can be difficult to treat. Prophylactic excision is not effective in preventing melanoma and removal of the entire nevus is often unrealistic in NMCGG.

The decision to undergo surgery versus observation is nuanced and should be guided by the realistic expectation of the cosmetic outcome and the impact of multiple surgeries on the child (20). In all of these discussions, it is exceptionally helpful to refer patients to intervention groups. support such as Nevus Outreach (www.nevus.org). As mentioned before, new molecular targeted therapies may change the face of NMCGG treatment and are currently the subject of intense research.

Nevus spilus (NS), also known as mottled lentiginous nevus, refers to a tan patch dotted with pigmented macules (macular type) or papules (papular type).

The macular type tends to be more stable over time with a more uniform pigmentation pattern, while the papular type is more dynamic with different types of nevi developing over time in a random configuration. (21) As such, some authors have described NS as “melanocytic gardens.” (22) NS is a less common congenital anomaly, present in 0.2% to 2.2% of the general population. (23)

Some experts believe it may represent an attenuated NMC. (22) Most NS do not require further evaluation or routine monitoring. Although NSs are typically not problematic, cases of melanoma developing within an NS have been reported, (23) so any rapid change or atypical lesion warrants further evaluation.

Rarely, a large NS may represent several rare neurocutaneous disorders and should prompt further examination for other cutaneous, neurological, and musculoskeletal abnormalities. NS may be a component of phacomatosis pigmentovascularis (discussed in the dermal melanocytosis section) or phacomatosis pigmentokeratotic, which involves a large checkerboard pattern of NS with concomitant capillary malformation and extensive linear epidermal naevi or sebaceous nevi with or without systemic abnormalities.(24)

An activating HRAS mutation (c.37G->C, p.Gly13Arg) has recently been described in isolated NS as well as in 2 cases of pigmentokeratotic phacomatosis,(24) supporting the concept that the timing of the somatic mutation in development can have a great impact on clinical outcome.

There is also a recently described papular SN syndrome, in which a large block-shaped SN is associated with ipsilateral neurological or skeletal abnormalities, including hyperhidrosis, motor neuropathy, and sensory neuropathy.(25) If any of these syndromes are suspected , the patient should be referred for genetic evaluation.

Café au lait spots (MCL) are very common in the healthy population, affecting 2% to 3% of newborns and approximately one third of young children,(26) and are more common in darker-skinned individuals. .

They present as well-defined hyperpigmented patches, either with smooth regular edges (typical MCL) or with jagged, irregular edges (atypical MCL). The presence of 3 or more MCLs should increase concern for neurofibromatosis type 1 (NF1), especially in children younger than 1 year.(27) On the other hand, multiple MCLs are less of a concern in healthy older children, as 97 % of people with NF1 will meet clinical criteria by the age of 8 years.(28)

NF1 occurs due to inactivating germline mutations in the NF1 gene , which encodes the tumor suppressor protein neurofibromin. NF1 can affect almost all organ systems, giving rise to numerous skin, neurological, ocular, and skeletal abnormalities; tumors and malignancies such as optic gliomas, rhabdomyosarcoma, juvenile myelomonocytic leukemia and malignant peripheral nerve sheath tumors; learning and behavioral disorders and seizures; and vasculopathies, among others.(29)(30)

Patients with NF1 should be followed by a specialized clinic or an experienced doctor given the multitude of possible complications; Screening and follow-up guidelines have been proposed.(30)(31) Diagnosis is based on the 1988 National Institutes of Health consensus criteria for NF1, which requires compliance with 2 relevant clinical and historical findings.(32)

MCLs are the earliest cutaneous manifestation of NF1 and therefore it is essential to recognize them. The presence of 6 or more MCLs greater than or equal to 0.5 cm in their largest diameter in prepubertal patients, and greater than or equal to 1.5 cm in postpubertal individuals meets 1 diagnostic criterion for NF1. However, MCLs can also be associated with several rare genetic disorders, such as RAS-associated pathologies or disorders with mutations along the RAS/RAF/MEK/ERK signaling pathway.

The clinical findings that underlie NF1 diagnoses are dynamic and develop over time. For example, intertriginous freckles or small brown macules develop in the armpit, inguinal folds, or neck later in early childhood, and cutaneous neurofibromas do not develop until late childhood or adolescence.

Genetic testing in patients with multiple MCL may lead to an earlier and more accurate diagnosis than clinical criteria(33) and therefore, suspected cases should be referred early for genetic evaluation. Early identification of NF1 allows the implementation of detection of optic gliomas and learning disabilities.(31)

MCLs can also occur with a segmental (mosaic) distribution due to post-zygotic mutations in NF1 or SPRED1 . (26) Case reports have described fully developed NF1 in the offspring of patients with segmental NF1, but the exact risk in a particular patient cannot be determined, (34) although it is probably low.

Giant segmented MCLs may be an isolated finding or a component of McCune-Albright syndrome, which occurs due to post-zygotic mutations in the GNAS gene and is characterized by large MCLs with irregular “Maine coast” borders, precocious puberty (85 % of girls, 10%-15% of boys), testicular anomalies in 85% of boys, other endocrinopathies and skeletal fibrous dysplasia, which can lead to fractures and bone pain.(26)(35)

Plexiform neurofibromas (PN), which meet diagnostic criteria for NF1, can be confused with NMC or MCL.(36) NPs are congenital cutaneous or extracutaneous tumors that can grow and become disfiguring or disabling and have up to a 10% risk of degeneration to malignant tumors of the peripheral nerve sheath, particularly the internal NPs. (37)

However, this risk may be an overestimate determined largely by clinically evident NPs before the widespread availability of MRI. Cutaneous NPs are often described as flaccid masses with a “bag of worms” texture but may resemble MCLs when they are flatter and more pigmented. Several clues distinguish NPs from MCLs.

NPs are darker than surrounding MCLs, have poorly defined borders and subtle textural changes and superimposed hypertrichosis, while MCLs are completely fluid and may not be detected by palpation alone.

Multiple molecular targeted therapies are being studied to reduce the morbidity of NPs(38). The drug selumetinib was approved by the Food and Drug Administration (FDA) in April 2020 for patients ≥ 2 years of age with NF1 who have symptomatic, inoperable NPs. .(39)

Other pigmentary abnormalities may be an early clue to NF1. Anemic nevus (AN) is a congenital anomaly resulting from constitutive local cutaneous vasoconstriction. NA can be an isolated finding or can be seen in association with NF1 and less frequently with other pathologies associated with RAS.(40)

Clinically, NA presents as an intense “paint splatter” patch with peripheral round macules that fail to become erythematous on rubbing, in contrast to the surrounding normal skin, most commonly located on the chest. Hypomelanotic macules may also be associated with NF1, although tuberous sclerosis (TS) is the prototypical hypomelanotic macule (MH) disorder.(41)

MH are a relatively common birthmark present in 4.7% of the general population.(42)

They appear as macules or flat white patches of different sizes and shapes and are benign. However, the presence of 3 or more MH greater than 3 mm in diameter should raise concern for ET and meets 1 of the main diagnostic criteria for the disorder (≥ 2 major criteria are necessary).(43)

ET is a neurocutaneous disorder caused by pathogenic variants in the TSC1 or TSC2 genes involved in the mTOR cell proliferation pathway that lead to hamartomas or multisystem cysts, seizures, and developmental delay. Seizures may be present as early as 4 to 6 months of age, and childhood seizures are a major risk factor for developmental delay and autism spectrum disorder in patients with ET.(44)

Preventive antiepileptic medication can improve cognitive outcomes, so early diagnosis is imperative.(44) MH are among the first clues for ET, present in 94% of cases at initial evaluation.(43) (Four. Five)

“Confetti” MHs (multiple smaller, scattered MHs) and ash leaf macula or spot (lancet-shaped, conical at 1 end) are more specific for ET (43) and should prompt further examination. Infants suspected of having ET should receive genetic, neurological, and cardiological evaluations.

Brain MRI and echocardiography in infants can facilitate the diagnosis when genetic evaluation is not available and can potentially reveal subependymal nodules, cortical dysplasia, or cardiac rhabdomyomas, each of which meets 1 main diagnostic criterion.(43)(44)

The differential diagnosis of MH includes nevus depigmentosus, which tends to be larger and solitary and is not associated with syndromes, and post-inflammatory hypopigmentation, which is often more poorly defined and may have a border of hyperpigmentation and a known history of skin injury or inflammation.

Dermal melanocytosis (MD) is extremely common in black neonates, affecting mostly Asian (81%–100%) and black (95.5%–96%) infants, as well as a significant portion of Hispanic infants. (46.3%–70.1%) and a minority of whites (9.6%).(46) MD reflects the retention of melanocytes in the dermis, which is deeper than their typical location in the basal layer of the epidermis. During development, melanocytes migrate from the neuroectoderm on the dorsal side of the body to the ventral side.

If melanocytes do not migrate completely or are not removed, they are retained in the dermis. This leads to ill-defined blue, blue-gray, or blue-green macules and patches without overlying texture changes, typically in the lumbosacral region and extending to the buttocks.

These patches gradually fade throughout childhood. Other common locations include the shoulders, ankles, and the dorsal aspects of the hands and feet, where they are less likely to fade but do not cause medical problems. It is important to recognize that classic MD is extremely common and benign and to provide peace of mind to families. MD should not be confused with hematomas or non-accidental trauma.(47)

Unlike classical MD, less common subtypes may occasionally be associated with complications. Nevus of Ota, or oculodermal melanocytosis, refers to MD with periocular distribution, often involving the sclera, and occurs most commonly in female patients of Asian descent.(48) Nevus of Ota can be treated for improvement aesthetics with Q-switched alexandrite lasers.

Rare complications include cutaneous, uveal, and intracranial melanoma and glaucoma, although the exact risk is unknown.(48) Any change in the appearance of the nevus, such as the development of papules or nodules or focal color changes, or new cutaneous, ocular symptoms or neurological should lead to prompt evaluation. Nevus of Ito refers to a large segment of MD involving the shoulder. There are some published case reports of melanoma arising from a nevus of Ito, so any change in appearance or texture should suggest prompt dermatological evaluation.(49)

Rarely, diffuse or atypical MD may be associated with genetic disorders, including phacomatosis pigmentovascularis or lysosomal storage diseases. Phacomatosis pigmentovascularis refers to syndromes with concomitant extensive pigmented (MD, NS) and vascular (port wine stain, nevus anemicus) abnormalities with or without systemic complications.

Possible complications include musculoskeletal, neurological, and ophthalmological abnormalities(50) so patients should be evaluated accordingly.

Extensive MD, often involving atypical locations such as the ventral body, has been associated with lysosomal storage disorders, including mucopolysaccharidosis type 1 (i.e., Hurler syndrome) and GM1 gangliosidosis.(51) In these patients, MD It usually becomes more extensive and darkens over time rather than fading. These patients usually present because of neurological degeneration, hepatosplenomegaly, and other signs of their underlying disorders rather than because of cutaneous findings.

Incontinentia pigmenti (IP) is an X-linked dominant disorder associated with mutations in the IKBKG gene .(52) It predominantly affects female patients, as germline mutations are typically lethal in XY males. Male patients with IP reported in the literature generally have post-zygotic mutations or XXY genotype.(52)

The IKBKG gene encodes the activation of nuclear factor-k B, whose normal function is to protect against apoptosis mediated by tumor necrosis factor α.(53)(54) IP is associated with multisystem abnormalities and can cause developmental delay , seizures and blindness. The largest pediatric cohort to date described extracutaneous abnormalities in hair (31%; most commonly alopecia and abnormal texture), dentition (50%; delayed dentition, conical teeth, hypodontia), eyes (31%; retinal problems, including detachment) and nervous system (26%; intellectual delay, seizures).(53)

Infants with suspected PI should be evaluated by ophthalmology immediately as early intervention in those with retinal abnormalities may help prevent retinal detachment and blindness. (55)

The cutaneous manifestations of IP can be the first clue to the diagnosis and present in 4 characteristic stages: 

stage 1 : vesicles on an erythematous base; 
stage 2: warty papules; 
stage 3: hyperpigmented patches; and 
stage 4: atrophic/hypopigmented papules with absent skin annexes (hair follicles and sweat glands). These stages may appear sequentially or together. 

The vesicular stage may reappear spontaneously or in response to fever, systemic diseases, or vaccines.(54) While cutaneous findings at birth and in the neonatal period are typically vesicular and verrucous, hyperpigmented striae have rarely been described as the first manifestation in the skin,(56)possibly due to the prenatal occurrence of the previous stages.

Additionally, older infants presenting for evaluation may have progressed to the hyperpigmentation stage, so it is important to obtain a history of the progression of skin findings. A family history of skin lesions, abnormal dentition, or recurrent miscarriages (of male fetuses) in the patient’s mother may also support the diagnosis.

It is important to recognize common pigmented birthmarks and be familiar with potential cutaneous and systemic complications. NMCGG, NS, and specific MD subtypes are associated with a small increased risk of melanoma, although the exact risk is not known. Patients with NMCGG should be followed by a dermatologist due to the risk of melanoma.(18)(19)

Pigmentary mosaicism is occasionally associated with neurological, ophthalmological, and musculoskeletal abnormalities; The evaluation should be guided by clinical findings. Patients with NMCGG or 2 NMC of any size should undergo MRI of the brain and spinal cord, ideally before 6 months of age, to evaluate neural involvement. If the baseline MRI findings are normal, then no further testing is necessary. If abnormalities are found on MRI, management requires specialized evaluation at a center with experience in NMC.(18)

All children with NMCGG who present with neurological findings in late childhood should undergo imaging to exclude CNS melanoma. The presence of 3 or more MCLs should prompt the detection of NF1. (27)

The presence of 3 or more MH should determine the rapid detection of ET.(43) Skin findings can facilitate the early diagnosis of PI, which requires prompt evaluation by ophthalmology and neurology. NS and MD are usually benign findings with rare syndromic associations.

Congenital pigment anomalies occur due to genetic changes in the germline or somatic genetic changes in the developing fetus. They can present with diverse distribution throughout the body, and in some cases be accompanied by cutaneous and extracutaneous manifestations that can generate morbidity and affect quality of life. Knowing the pattern and type of birthmark, as well as the associated clinical findings, will help in everyday medical practice to guide the evaluation and subsequent management of affected patients.