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Year : 2017  |  Volume : 3  |  Issue : 1  |  Page : 124-131

Part 1: Café-au-lait macule – Presentation and genesis

1 Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
2 Department of Family Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
3 Department of Internal Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
4 Department of Pathology, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA

Date of Web Publication7-Jul-2017

Correspondence Address:
Sudip Nanda
Department of Internal Medicine, St. Luke's University Hospital Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2455-5568.209836

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Café-au-lait macules (CALMs) are clinically significant presentations of isolated hyperpigmentation whose mechanism evades discovery. While not always of pathogenic origin, CALMs manifest in a number of diseases, implying a diversely regulated and interconnected developmental pathway. In this paper, we highlight a patient presenting with an undiagnosed, systemic condition and multiple CALMs as a backdrop for approaching the pathogenesis of hyperpigmentation. We underscore the key players in melanogenesis with the goal of better elucidating the mechanisms involved in pathogenic CALMs.
The following core competencies are addressed in this article: Patient care, Medical knowledge.

Keywords: Café-au-lait macules, melanogenesis, transforming growth factor beta, microphthalmia-associated transcription factor

How to cite this article:
Stone LE, Fegley MW, Duarte-Chavez R, Singh A, Longo S, Nanda S. Part 1: Café-au-lait macule – Presentation and genesis. Int J Acad Med 2017;3:124-31

How to cite this URL:
Stone LE, Fegley MW, Duarte-Chavez R, Singh A, Longo S, Nanda S. Part 1: Café-au-lait macule – Presentation and genesis. Int J Acad Med [serial online] 2017 [cited 2022 Jan 25];3:124-31. Available from: https://www.ijam-web.org/text.asp?2017/3/1/124/209836

  Introduction Top

As with most disorders of hyperpigmentation, café-au-lait macule identification is based on a diagnosis of multiple, pre-determined classification criteria. CALMs are cited for their clearly demarcated, uniformly darkened color and variable size between 1 mm and 20 cm (average <0.5 cm). They normally appear on the torso, buttocks, axilla, or lower extremities. The temporal manifestation of these macules is variable, with most present at birth and others manifesting or even disappearing throughout development and into adulthood.[1]

While these described definitions yield a diagnostic picture more variable than consistent, the unique presentation of an individual's CALMs can lend valuable information in the diagnosis of an underlying pathophysiology.

  Case Report Top

The patient is a pleasant 26-year-old male who presented to our clinic with an upper gastrointestinal bleed. He has multiple CALMs over his torso ([Figure 1]). His history revealed a very complex medical course including a vertebral artery aneurysm coiling in 1996, splenic aneurysm coiling in 2003, and splenectomy and aortic aneurysm repair in 2003. In addition, he also described multiple episodes of pneumothorax and both upper and lower gastrointestinal bleeds, aside from his presenting episode. Since his original presentation, he has also suffered spontaneous esophageal tears, Dieulafoy's lesions, and additional intestinal bleeds. A comprehensive evaluation with genetic testing at a prestigious national center of excellence, University Hospital, has failed to identify a known disease at the root of these symptoms.
Figure 1: Patient with multiple café-au-lait macules

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  Discussion Top

Without having an algorithmic approach to this patient's unknown condition, we decided to look at the mechanism of café-au-lait macule formation as a reference for this patient's pathology. It should be noted, however, that the presence of CALMs is not necessarily indicative of a serious pathology. Non-pathogenic CALMs are actually quite common, often being termed “birthmarks” by the common population. However, despite being thoroughly studied, the actual incidence of CALMs is contested, with some papers reporting 26% prevalence and others <1%. These inconsistencies are not necessarily mutually exclusive. The number of CALMs tends to increase in childhood and decrease in adulthood, therefore adjusting the baseline incidence according to the average age of the studied cohort. What does seem to be consistent, though, is a preferential manifestation of CALMs among certain populations.[2] In one combined race study, the estimated prevalence of café-au-lait macules in the black population was 18.3% with 1.8% having more than three CALMs versus a 0.3% prevalence in the Caucasian population with 0% having more than three.[3] The reason for variance in racial presentation is unknown and offers a tantalizing niche for future research.

Differential diagnosis of café-au-lait macules

When diagnosing CALMs, one should be aware not only of variation in café-au-lait presentation itself but also with other possible classifications of hyperpigmentation.[4] It should first be noted that CALMs are not a diffuse hyperpigmentation, as might be seen in Addison's disease, hemochromatosis, or a phototoxic allergic reaction. These mentioned conditions do not contain the demarcated, round borders we would expect to see in a macular condition, but rather show gradations of skin pigmentation across the entire body. A phototoxic allergic reaction, for example, presents as a sort of diffuse sunburn whereas hemochromatosis creates a uniform, slate gray appearance over the body surface.[5]

The more difficult diagnostic considerations concern CALMs versus other isolated forms of hyperpigmentation. Removing these other possibilities from the differential requires attention to the unique criteria of CALM diagnosis. First, CALMs occur independently of sun exposure, whereas freckles or lentigines are sun-dependent. Melasma, as well, is sun-dependent, but also shows strong linkage to oral contraceptive or anticonvulsant use as well as pregnancy.[6] Neither of these associations exists for CALM manifestation. Furthermore, the presence of newly appearing regions of hyperpigmentation around the neck, elbow, or axilla in a patient with insulin resistance bears more clinical suspect as acanthosis nigricans.[6] Such a suspicion can be verified with metabolic testing. A detailed look at a hyperpigmentation differential is presented in [Table 1] and [Table 2].[5],[6],[7],[8]
Table 1: Differential for isolated hyperpigmentatio

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Table 2: Differential for diffuse hyperpigmentation

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Café-au-lait macules as indicators of disease

When determining whether or not to investigate CALMs as a sign of systemic disease, it is generally agreed that the more CALMs an individual has, the greater the suggestion of underlying pathology versus isolated, non-disease-related presentations. In particular, >6 CALMs is one of the stronger diagnostic criteria for neurofibromatosis type 1 (NF-1). Patients with NF-1 are in fact often diagnosed by their macule presentation, with some estimates suggesting that 99% of patients who will later be diagnosed with NF-1 fulfill the CALM criteria by age 1.[9] In addition to NF-1, CALMs are also considered a diagnostic criteria for McCune–Albright syndrome, Fanconi anemia, and multiple lentigines syndrome, underscoring the vast, and seemingly disconnected, manifestation of these macules.[1]

It is important to underscore that CALMs are merely part of the diagnostic algorithm for these conditions rather than a conclusive indicator of a specific disease. Indeed, the difference between CALM presentation by disease has yet to be rigorously explored. It is notable that some authors suggest that the type of macule border is diagnostically useful, with “coast of California” smooth-edged CALMs more common in NF-1 and “coast of Maine” ragged-edged CALMs seen in McCune–Albright syndrome. In general, however, CALMs without additional symptomology are considered non-pathological.[1] A list of conditions associated with prominent CALMs is shown in [Table 3].[1],[10] [Figure 2] depicts a CALM-associated disease differential algorithm.
Table 3: Café-au-lait macules manifestation in disease

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Figure 2: Café-au-lait macule differential by craniofacial examination. Many of the conditions associated with bodily café-au-lait macules have unique findings focused at the head and face. These features can be exploited to construct a differential for pursuing additional signs and symptoms.

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Our brief analysis of the widespread clinical relevance of CALMs grants us a glimpse of the complicated, multifaceted, far-reaching pathways necessarily intrinsic to CALM development. It is no surprise, then, that despite its function in diagnosis, the mechanism of café-au-lait formation is still unclear. This bears challenges concerning our patient, whose pathology, we assert, originates in molecular deregulation. Given his systemic symptoms, we hypothesize that he carries a defect in one or a combination of factors affecting early fetal development. If correct, such a pathogenic factors necessarily links the processes of melanogenesis to the integrity of system-wide organ structure and function.

Overview of melanogenesis

To discuss the molecular foundation of CALMs, it is necessary to provide a brief overview of melanogenesis and melanin transport. This understanding is critical, as histologic studies of CALMs demonstrate that both the involved melanocytes and keratinocytes show heightened melanin concentrations.[11] [Figure 3] and [Table 4] are presented as an appendix to the following text.[12],[13],[14],[15],[16]
Figure 3: Overview of melanogenesis and notable mediators. MITF = Microphthalmia-associated transcription factor, PAX3 = Paired box 3, TGF-β = Transforming growth factor beta, SPRED1 = Sprouty-related, EVH1 domain-containing protein 1, KIT = Tyrosine kinase receptor, KIT-L = KIT-ligand (also known as SCF = stem cell factor), Ras/rab = Ra(t) s(arcoma) (referring to original identification/isolation procedure), MAPK = Mitogen activated protein kinase (MAPK system)

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Table 4: Melanogenesis pathway mediators and their interactions

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Skin pigment is derived from melanin, which is produced from melanocytes located in the stratum basale of the epidermis. Derived from several populations of neural crest cells, progenitor melanoblasts must migrate to the epidermis and differentiate, developing specialized melanin-producing organelles called melanosomes - a lysosomal family organelle. Differentiation also includes the development of melanocyte-specific membrane markers, including microphthalmia-associated transcription factor (MITF), the “master” of melanin synthesis linking to other important downstream regulators, such as several members of the Rab family.[17]

Once settled at the epidermis, melanocytes couple to keratinocytes in a roughly 1:30 ratio. The manufactured melanin inside the melanosome (now termed the “melanocore”) is then trafficked via microtubules to the dendritic edge of the melanocyte, awaiting transport to one of the overlying keratinocytes. Theories for the melanocore-keratinocyte inductive process vary, including one study suggesting an exocytotic/endocytotic pathway of the melanocore mediated by various members of the Rab family, including Rab11b.[18]

A satisfactory understanding of melanogenesis must also take into account external moderating factors. Local fibroblasts in particular play a key role in the melanocyte-keratinocyte interaction, supplying several cytokines that influence melanocyte growth, adhesion, shape, and other factors.[19]

In this broad overview, we note the main players in the currently established pigmentation model: The melanocyte, melanosomes, keratinocytes, fibroblasts, and all associated signaling mediators and pathways. It is no surprise, then, that various aberrations in this diffusely linked network can result in the same phenotypic abnormality that we call CALMs. However, these small differences sometimes manifests at a level visible to microscopic observation. In particular, histologic studies indicate that those CALMs arising from NF-1 have increased melanocyte density whereas CALMs without NF-1 diagnosis rather show increased melanosome size. Furthermore, NF-1 CALMs have shown to have higher concentrations of stem cell factor (SCF) (from fibroblasts) versus sporadic, non-pathogenic CALMS, also suggesting the variability in this hyperpigmentation pathogenesis.[20] Despite this variability, we will continue to discuss CALMs as a general category in efforts to elucidate possible players in common to all CALM manifestation.

Notable melanogenesis mediators

Microphthalmia-associated transcription factor and transforming growth factor beta

MITF is considered the “master” regulator of pigmentation due to its responsiveness to the environment, keratinocyte signaling, fibroblasts, and other cells. Among other things, it controls the initiation of melanogenesis as well as the regulation and differentiation of melanocytes.[21] Overexpression of MITF has been noted in cancers such as melanoma, lending support to MITF's role in the control of melanocyte activity.[22] However, it has also been shown to have a role in freckling and lentigines, suggesting that non-pathologic changes in the regulation of MITF can result in isolated hyperpigmentation.[23] Furthermore, MITF is indicated in non-pigment related disorders, including mastocytosis and autoimmune conditions, lending credence to its potential role in systemic disease.[24]

While the individual pathways of MITF are too numerous to discuss here, we would like to draw attention to the transforming growth factor beta (TGF-β)/paired box 3 (PAX3) signaling pathway in MITF activation. This pathway is known to be important in melanogenesis, with overexpression of PAX3 leading to melanomas – possibly due to an over-activation of MITF. Thus, inhibition of the PAX3 pathway is essential to avoid abnormal melanocyte function. It is known that TGF-β binds to a TGF-beta heterodimer receptor, activating the SMAD2/3 pathway that directly inhibits PAX3 expression.[25] This, in turn, decreases MITF expression. We can, therefore, surmise that a lack of TGF-β or a mutation inhibiting the SMAD2/3 pathways would increase PAX3 action, causing an increase in MITF that could lead to pigmentation defects.

TGF-β's connection to melanogenesis has been tentatively studied on a few occasions, yielding compelling results that deserve discussion. Proper TGF-β regulation has been linked to maintaining the quiescence and maturity of the melanocyte stem cell population.[26] From this, we can surmise that irregular signaling would cause an upset in the natural stem cell-derived melanocyte maintenance process. It is also interesting to note that TGF-β deregulation is associated with symptoms akin to Loeys–Dietz and Marfan syndrome, lending support to its role in the multi-organ symptomology seen in our patient.[27],[28]

Rab family

One of the key processes in melanogenesis concerns the transport of the melanocore to the keratinocyte receiver. We begin by noting the Rab family in this process, which observably bears some of its regulation from pathways connected to MITF expression.[17] While much research remains to elucidate the functional significance of the Rab network, it is notable for our purposes that a deregulation of Rab5a has been associated with a form of the connective tissue disease - Ehlers–Danlos - yielding the possibility of Rab involvement in this patient's pathology.[29] Our search within the Rab family is further narrowed due to the necessity that the Rab protein play a role in the pigmentation process. One of the most studied Rab pathways in melanogenesis is Rab27a. However, while knockout models are shown to demonstrate Griscelli syndrome, a form of hypopigmentation, overexpression of Rab27a seems to have no role in hyperpigmentation.[30]

Additional studies looking at other Rab signaling pathways have yielded more fruitful possibilities. Studies uncovering the role of Rab11a and b in melanogenesis have yielded preliminary results indicating that Rab11 knockout models exhibit heightened melanosome accumulation and subsequent cell coloration.[31] Another study suggests that Rab11 plays a role in endosomal trafficking, implying that an up-regulation in this process might contribute to increased melanin movement and deposition.[18] While the current connection between these two studies has yet to be elucidated, we can hypothesize that a pathological mechanism increasing melanocore transport would contribute to increased melanin deposition in keratinocytes. This possibility provides an incentive for future study into the role of Rab11 as well as its downstream and upstream regulators as a cause of CALM formation.

KIT and fibroblasts

The KIT receptor tyrosine kinase on melanocytes, when bound by ligand, triggers activation of sprouty-related, EVH1 domain-containing protein 1, a potent Ras/Mitogen-activated protein kinase suppressor known to inhibit melanogenesis.[32] Given these details, it is possible that a mutation of the KIT receptor could generate uncontrolled melanin production. Indeed, a gain-of-function polymorphism in the KIT receptor has already been linked to isolated hyperpigmentation in familial progressive hyperpigmentation, elucidating the importance of the KIT pathway in normal pigmenting patterns.[10] In addition, KIT de-regulation is also noted to be involved in systemic sclerosis, an aberration in collagen deposition, yielding promise to its effect in systemic connective tissue abnormalities.[33] Given this relevance to the patient's pathology, further inquiries into the regulation and/or inhibitors of the KIT/Ras pathway might reveal unknown contributors in the pathogenesis of CALMs.

Looking outside of the coupled melanocyte-keratinocyte interactions draws our attention to the role of fibroblasts in melanogenesis. One area receiving attention is the role of the fibroblast-induced action on melanocytes, specifically through SCF and hepatocyte growth factor (HGF). It has been observed that fibroblasts from NF-1 CALMs secrete excessive levels of these two factors (although levels are normal in sporadic CALMs).[20] This pattern suggests suspicion regarding the fibroblast influence on hyperpigmentation pathogenesis.

However, due to the isolation of elevated SCF/HGF levels to NF-1 macules, a mechanism of pathogenesis for all CALMs might best be studied by looking at downstream players in this pathway. In this line of thought, while increased SCF/HGF levels might up-regulate some unknown factor in NF-1, the up-regulation of that same factor in its own right might also be a legitimate source of pathogenesis in non-NF-1 CALMs. The viability of fibroblast involvement in these pathways is a tempting lead to follow, given that SCF is a known ligand for the KIT receptor mentioned above.[34]

  Conclusion Top

Considering the multitude of factors that can affect melanogenesis, and our own lack of comprehensive knowledge as a medical community, this topic leaves us susceptible to speculation. We surmise that one or a combination of factors involved in melanogenesis also affect the structure of muscular arteries, lung, and intestinal parenchyma, thus accounting for our patient's other symptoms. This notion is given credence when noted that each of the factors discussed – MITF, Rab family, TGF-β, KIT, and fibroblasts – have at least been tentatively linked to systemic connective tissue disease abnormalities. A more rigorous analysis of these factors may help uncover a thus unknown contributor to the constellation of symptoms in this patient's systemic condition. Nonetheless, due to the well-established link between TGF-b signaling and common connective tissue diseases, we hypothesize the TGF-β/PAX3 signaling pathway in MITF activation has the highest likelihood of carrying the causative abnormality in our patient. If correct, such an abnormality would yield not only CALM manifestation but also systemic symptoms, largely due to aberrant TGF-β signaling.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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