However in children multiple large CAL spots may

However, in children, multiple large CAL spots may be a sign of one of several syndromes. By far, the most common condition is type 1 neurofibromatosis. It is generally assumed that six or more CAL spots, larger than 1.5 cm in diameter, are pathognomonic of this disease. The importance of this finding was demonstrated in a study that showed that 89% of children with more than six CAL macules and no obvious diseases, who were observed for 3 years, eventually developed neurofibromatosis. Children may have CAL spots as the only manifestation until puberty, when other signs begin to appear. Multiple hereditary CAL spots without other features of neurofibromatosis have been ascribed to Legius syndrome, caused by SPRED 1 mutations. A long-term follow-up and repeated evidence of absence of other involved organs are necessary to consider this diagnosis. Children with McCune–Albright syndrome (polyostotic fibrous dysplasia), which is usually caused by mosaicism for a tachykinin receptor in the GNAS1 gene, may also have multiple CAL spots. However, these lesions are characteristically fewer, larger, and darker; have more jagged margins; and supposedly resemble the coast of Maine, as depicted in a classic American paper. Besides the characteristic bony lesions, other findings of this syndrome include endocrinologic abnormalities, especially precocious puberty in girls, thyrotoxicosis, pituitary gigantism, and Cushing syndrome. Watson syndrome, which is known to be allelic to neurofibromatosis-1, is characterized by CAL spots and pulmonary stenosis, low intelligence, dysmorphic facial features, axillary freckling, and pigmented patches without neurofibromas. Overlapping phenotypes, including neurofibromatosis-1 and Noonan, Costello, LEOPARD, and cardio-facio-cutaneous syndromes, are better explained as inherited RAS-MAPK signal transduction disorders, a signaling pathway that activates constitutional melanogenesis, and shares CAL spots and other diffuse/localized pigmentary anomalies. Other rare conditions in which CAL spots arise in the first years of life are listed in Table 1.
Non-Blaschkoid and Blaschkoid segmental hypermelanoses Segmental hypermelanosis is an expression of a cutaneous mosaicism of the pigmentary system that appears as a hyperpigmented macule in a segmental pattern and presents early in life. Histologic features are nonspecific and correspond to a localized increased pigment load, as detected by Fontana Masson stain, without melanocytic hyperplasia. Most cases of segmental hypermelanosis (Figure 4) have their onset at birth or in early childhood, and may continue to enlarge in proportion to skin expansion. They may appear anywhere on the skin and are typically unilateral with a sharp cutoff at the midline. They often follow a dermatome, but may present a checkerboard pattern or affect a large Blaschko\'s line. In most cases, there are no associated dysmorphic features, although there have been a few reported cases of associated neurologic problems. McCune–Albright syndrome and segmental neurofibromatosis should be discussed if bony anomalies and neurofibroma, respectively, coexist. Linear/whorled nevoid hypermelanosis develops at birth or within the first few weeks of life (Figure 5). Affected children develop swirls of macular hyperpigmentation along Blaschko\'s lines. The hyperpigmentation is composed of homogeneous macules that coalesce into reticulated patches. Linear and whorled nevoid hypermelanosis has been associated with serious congenital defects, and a set of investigations, including brain magnetic resonance imaging, should be considered in this setting. Differential diagnoses include the following: other Blaschko linear hyper- and hypomelanoses, such as incontinentia pigmenti that reaches a pigmented stage in childhood, after the typical vesiculobullous and verrucous aspects corresponding to neonatal and infantile stages, respectively; and hypomelanosis of Ito, which is symptomatically a kind of reverse pattern linear/whorled nevoid hypermelanosis.