The parents of a 2-month-old boy return to the office for a well-child visit. The infant has a history of hypotonia and poor head control but is growing normally. His parents noted streaky patterns of hypopigmentation over his trunk and extremities shortly after birth and felt they were likely just “birthmarks.”
Diagnosis: Pigmentary mosaicism
Pigmentary mosaicism, previously often referred to as hypomelanosis of Ito or incontinentia pigmenti achromians, describes abnormal pigmentation patterns in the skin secondary to genetic heterogeneity.1 It is a phenotypic manifestation of genetic mosaicism, or the presence of at least 2 distinct cell populations with differing gene expression. The etiology of skin appearance is attributed to reduced melanin in the epidermis.
Patients present with patterns of hypopigmentation in streaks and/or whorls over the trunk, extremities, and/or head, typically following the lines of Blaschko and sparing mucous membranes, palms, and soles.2 In the vast majority of cases, the cutaneous abnormalities are noted within the first year of life.
Beyond the cutaneous findings, multisystem involvement is uncommon but possible, with the central nervous system (CNS) most frequently affected.2 Central nervous system involvement can include epileptic seizures of many types, intellectual delay, behavioral disturbances, autism spectrum disorder, and cortical visual impairment.1-3
Neuroimaging can reveal hypoplastic corpus callosum, absent septum pellucidum, pachygyria, cerebral atrophy, hamartomas, gray matter heterotopias, and/or hemimegalencephaly, among other abnormalities.2,3 In terms of frequency of these associated abnormalities, a 2014 study of patients with Blaschkoid dyspigmentation at the Harriet Lane Pediatric Dermatology Clinic, Johns Hopkins University, Baltimore, Maryland, found that extracutaneous findings were present in only 13.9%.4
The wide range of names that are used to describe the skin findings can lead to confusion for families, and they may therefore find higher risks of extracutaneous findings when performing their own research. For this reason, it is important for providers to know that, although they certainly can be present, CNS or eye abnormalities occur in a minority of patients.4
Various cutaneous fungal infections, such as tinea versicolor and pityriasis alba, can give the appearance of segmental differences in pigmentation.5 Wood lamp examination can be helpful to differentiate, and pigmentary mosaicism would more closely follow the lines of Blaschko and often be present more diffusely than these fungal rashes. In addition, fine scale may be appreciated on scraping of a fungal lesion.
Other genetic or congenital conditions can present with pigmentation abnormalities as well. McCune-Albright syndrome can be associated with areas of hyperpigmentation, although not typically following lines of Blaschko, and often have more jagged “coast of Maine” edges.6 These patients also are likely to have endocrine manifestations, such as vaginal bleeding and precocious puberty.
Tuberous sclerosis can, like pigmentary mosaicism, present with CNS manifestations such as seizures, but hypopigmented regions are typically elliptical in nature. Similarly, hyperpigmented café au lait spots in neurofibromatosis or Legius syndrome typically do not follow lines of Blaschko.5 In piebaldism, which involves absence of melanocytes in certain areas of skin and hair, patches are entirely unpigmented rather than hypopigmented, and about 90% of patients also will have a white section of hair.7
In addition to a thorough skin examination including the use of a Wood lamp and a complete physical exam by system, Kromann and colleagues, in their 2018 review regarding pigmentary mosaicism, propose genetic testing to evaluate each patient in whom the diagnosis is suspected.1 This ideally entails a chromosomal microarray of uncultured cells, with consideration of exome sequencing as it becomes more available. It is important to note that both peripheral blood lymphocytes and skin fibroblasts should be used, as this increases likelihood of identifying the mosaicism.1,2,8
Neurology evaluation, electroencephalogram (EEG), and brain magnetic resonance imaging (MRI) should be considered based on neurologic and developmental findings, and focus should be on early developmental interventions with the appropriate therapeutic services.
The patient was referred to Clinical Genetics, where a diagnosis of pigmentary mosaicism was suspected, prompting a brain MRI with and without contrast and a Neurology evaluation with EEG, as well as a chromosomal microarray. The MRI was positive for mild enlargement of the subarachnoid spaces and absent right septum pellucidum. Routine EEG was unremarkable, with 24-hour EEG planned in the future.
The initial chromosome microarray also was normal. Because of the patient’s developmental delays, he now receives physical therapy (PT) as well as occupational and speech therapy. Since starting work with PT, he has seen marked improvement in his gross motor development, particularly on the left side that initially was found to be weaker.
1. Kromann AB, Ousager LB, Ali IKM, Aydemir N, Bygum A. Pigmentary mosaicism: a review of original literature and recommendations for future handling. Orphanet J Rare Dis, 2018:13(1):39.
2. Bodemer C. Incontinentia pigmenti and hypomelanosis of Ito. Handb Clin Neurol. 2013;111:341-347.
3. Pavone P, Praticò AD, Ruggieri M, Falsaperla R. Hypomelanosis of Ito: a round on the frequency and type of epileptic complications. Neurol Sci. 2015;36(7):1173-1180.
4. Cohen J 3rd, Shahrokh K, Cohen B. Analysis of 36 cases of Blaschkoid dyspigmentation: reading between the lines of Blaschko. Pediatr Dermatol. 2014;31(4):471-476.
5. Plensdorf S, Livieratos M, Dada N. Pigmentation disorders: diagnosis and management. Am Fam Physician. 2017;96(12):797-804.
6. Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012;7(suppl 1):S4.
7. Oiso N, Fukai K, Kawada A, Suzuki Y. Piebaldism. J Dermatol. 2013;40(5):330-335.
8. Lim YH, Moscato Z, Choate KA. Mosaicism in cutaneous disorders. Ann Rev Genet. 2017;51:123-141.