Pediatric Dermatology Vol. 31 No. 4 471–476, 2014
Analysis of 36 Cases of Blaschkoid Dyspigmentation: Reading Between the Lines of Blaschko Jared Cohen, III, M.S.,* Katayoon Shahrokh, M.D.,† and Bernard Cohen, M.D.‡,§ *School of Medicine, University of Maryland, Baltimore, Maryland, †Physical Medicine and Rehabilitation, University of California, Irvine, Irvine, California, ‡Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, §Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
Abstract: Genetic mosaicism indicated by lines of Blaschko pigmentary changes has been described under a number of different and confusing terms, including hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, nevus depigmentosus, and cutis tricolor. Moreover, extracutaneous findings, particularly serious neurologic defects, have been reported in a large number of these cases. We reviewed the cutaneous and extracutaneous findings in 36 patients referred to the Harriet Lane Pediatric Dermatology Clinic, Johns Hopkins University, from June 12, 2008, to May 24, 2009, for evaluation of macular lesions along the lines of Blaschko. Patients with dyspigmentation along the lines of Blaschko and no history of preceding inflammatory skin lesions were identified for inclusion in a database at their initial visit. Information on age at presentation; sex; age when first diagnosed; type, pattern, and location of the pigmentary anomaly; and extracutaneous abnormalities noted on a review-of-systems questionnaire and physical examination was recorded for each child. Patients were asked to follow up within 6 to 12 months of the initial visit. Patients included 13 boys and 23 girls ages 3 months to 15 years with lesions noted from birth to 12 years. Lesions were hypopigmented in 21 patients and hyperpigmented in 15. No patients presented with hypopigmented and hyperpigmented lesions. Extracutaneous findings were noted in five children (13.9%). Historically, cases of Blaschkoid hypopigmentation and hyperpigmentation have been associated with a high percentage of extracutaneous manifestations, particularly neurologic and neurodevelopmental defects. In our study, only five patients (13.9%) were noted to have extracutaneous abnormalities, and these findings may have been coincidental. We propose the term ‘Blaschkoid dyspigmentation’ to describe the cutaneous findings. Although serious extracutaneous
Address correspondence to Jared Cohen, M.S., 514 South Durham Street, Baltimore, MD 21231, or e-mail: jared.cohen@ som.umaryland.edu. DOI: 10.1111/pde.12346
© 2014 Wiley Periodicals, Inc.
471
472 Pediatric Dermatology Vol. 31 No. 4 July/August 2014
findings may occur in children with Blaschkoid dyspigmentation and results of careful physical examination and review of systems should direct an evaluation, serious extracutaneous findings occur in a minority of patients.
In the early 1900s, Alfred Blaschko described a unique pattern of dyspigmentation that was distinct from the dermatomes. This pattern of hyperpigmentation or hypopigmentation displayed in a whorled shape on the trunk, a V-shape on the back, and waves on the vertex scalp was later referred to as the lines of Blaschko (1). Rudolf Happle was the first to propose that pigmentary anomalies along the lines of Blaschko were a result of genetic mosaicism (1). It is now well accepted that genetic mosaicism resulting in Blaschko’s lines can arise from a multitude of genetic defects, including chromosomal nondisjunction, lyonization, and chimerism (2). Various terms have been used to describe dyspigmentation distributed along the lines of Blaschko without a preceding inflammatory phase typical of incontinentia pigmenti and with or without associated extracutaneous defects. These include hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, nevus depigmentosus, and cutis tricolor. Reports of extracutaneous defects (e.g., neurologic, ophthalmologic, musculoskeletal) vary from 16% to 100% (2–5). In our experience, extracutaneous anomalies, particularly serious neurologic and neurodevelopmental defects, are rare in children with this pattern of dyspigmentation, and we suspect that previous series have had a major referral bias. Moreover, we propose the term Blaschkoid dyspigmentation to replace the various confusing diagnostic terms that have been used to describe this heterogeneous group of disorders, all of which are markers of genetic mosaicism. Because of the conflicting reports about the prevalence of extracutaneous manifestations in association with Blaschkoid dyspigmentation, we reviewed the charts of 36 children seen at the Harriet Lane Pediatric Dermatology Clinic, Johns Hopkins University, who were described as having hyperpigmentation or hypopigmentation along the lines of Blaschko. One or both full-time pediatric dermatology faculty saw all patients. This chart review was performed in an attempt to better understand the frequency of extracutaneous involvement in children referred to pediatric dermatology for congenital or early childhood Blaschkoid dyspigmentation.
MATERIALS AND METHODS This was an institutional review board–approved retrospective chart review of 34 patients referred to the Harriet Lane Pediatric Dermatology Clinic from June 12, 2008, to May 24, 2009, for evaluation of macular lesions of hypopigmentation or hyperpigmentation in a linear, whorled, or V-shape pattern conforming to the lines of Blaschko. Patients were identified for inclusion in a database at their initial visit. Patients with a history of preceding inflammatory lesions were excluded. Information on age at presentation; sex; age when first diagnosed; type, pattern, and location of the pigmentary anomaly; and extracutaneous abnormalities noted on a review-ofsystems questionnaire and physical examination was recorded for each child. Patients were asked to follow up within 6 to 12 months of the initial visit. The review of systems included personal or family history of growth or developmental delay, attention deficit hyperactivity disorder (ADHD), seizures, kidney dysfunction, cardiac disease, vision or ocular abnormalities, gastrointestinal abnormalities, other skin conditions, arthritis, HIV/AIDS, thyroid disorders, hepatitis, hypertension, bleeding disorders, food allergies, depression, tuberculosis, asthma, and diabetes.
Figure 1. Blaschkoid dyspigmentation with hypopigmented patches on the abdomen of an infant.
Cohen et al: Analysis of 36 Cases of Blaschkoid Dyspigmentation
Figure 2. Blaschkoid dyspigmentation with hyperpigmented patches on the lower extremities of an infant.
RESULTS The patients included 13 boys and 23 girls, with ages at the time they were seen in our clinic ranging from 3 months to 15 years. Eighteen patients were noted to have abnormal pigmentation at birth, 15 by 2 years of age, and 3 after 2 years of age. Patterns of pigmentation were seen in the form of swirled, segmental, and linear shapes or in various combinations. All lesions were sharply demarcated. Twenty-one patients had hypopigmentation (Fig. 1), and 15 had hyperpigmentation (Fig. 2). No patients had a mixed presentation. Five patients had diffuse
473
involvement of the skin. The pigmentation was limited to the head and neck in 1 patient, the trunk in 1 patient, and the extremities in 11 patients. Bilateral pigmentation was seen in five patients (Table 1). Extracutaneous findings were noted in five patients (13.9%). Abnormalities of the central nervous system were found in two patients (5.6%). Two patients were found to have isolated abnormalities of the musculoskeletal system (5.6%). Two patients (5.6%) were found to have kidney dysfunction. Only one patient (2.8%) was found to have involvement of more than one organ system. No patients were diagnosed with a distinctive syndrome. No patients were found to have mental retardation or epilepsy (Table 1, Fig. 3). Clinical follow-up data were obtained in the pediatric dermatology clinic in seven patients, none of whom were found to have additional extracutaneous features. DISCUSSION Terms used to describe congenital hypopigmentation and hyperpigmentation along the lines of Blaschko, including nevus depigmentosus, hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, and cutis tricolor, are often confusing and the reported association with extracutaneous findings is variable (Table 2 (1,3,4,6–12). Case series of patients with Blaschkoid
n = 36; ADHD, attention deficit hyperactive disorder. *Orthopedic: 2 children; 1 child had hip dysplasia, 1 child has a shortened right femur
Figure 3. Extracutaneous findings in patients with Blaschkoid dyspigmentation who presented to the Johns Hopkins Pediatric Dermatology Clinic. Only 5 of the 36 children with Blaschkoid dyspigmentation were observed to have extracutaneous manifestations.
474 Pediatric Dermatology Vol. 31 No. 4 July/August 2014
TABLE 1. Phenotypic Findings in 36 Cases of Blaschkoid Dyspigmentation Age/sex
Type of pigmentation
First noted
Location
Additional features
26 mos/M 4 yrs/M 11 mos/F 5 mos/F 4 mos/M 19 mos/M 4 mos/F 2 yrs/F 3 yrs/F 8 yrs/F 8 mos/F 1 yr/F 6 mos/M 5 yrs/M 15 yrs/M 9 mos/M 3 mos/F 22 mos/F 11 mos/M 3.5 yrs/F 7 mos/F 13 mos/M 5 mos/F 22 mos/F 7 mos/F 2 yrs/F
Hypopigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hyperpigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation
Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth 2 wks 1 mo 1 mo 2 mos 2 mos 4 mos 5 mos 5 mos
Language delay None None None None None None None None None Bilateral vesicoureteral reflux Shortened right femur None None None None None None None Hip dysplasia None None None None None None
18 mos/F 13 mos/F 2 yrs/F 14 mos/M 16 mos/F 3.5 yrs/F 3 yrs/F 7 yrs/M 9 yrs/F
Hypopigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hypopigmentation
6 mos 9 mos 10 mos 11 mos 12 mos 24 mos 24 mos 5 yrs 6 yrs
Back, buttock, posterior thigh Right abdomen and low back Diffuse Left abdomen and groin Right flank, groin, thigh, lower extremity Bilateral lower extremities Left upper extremity Diffuse Posterior thighs and lower extremities Left lateral neck, shoulder, upper extremity Diffuse Anterior and posterior trunk Right upper chest, abdomen, and suprapubic area Diffuse Diffuse Left lower chest, abdomen, and back Left jawline and preauricular region Right lower extremity Right abdomen and face Right abdomen and back Anterior trunk and left breast Left upper back, abdomen, and groin Right abdomen and flank Left upper chest, shoulder, and upper extremity Trunk and extremities Bilateral flexure surfaces of upper and lower extremities Left lower extremity Left back Bilateral forearms and left lower extremity Diffuse Bilateral thighs and knees Right abdomen and posterior back Right abdomen and flank Right lower extremity Left chest and upper extremity
13 yrs/M
Hypopigmentation
12 yrs
Right upper extremity
None None None None None None None None Bilateral vesicoureteral reflux, ADHD None
ADHD, attention deficit hyperactive disorder.
TABLE 2. Descriptions of Current Terms in the Literature for Blaschkoid Dyspigmentation Nevus depigmentosus or achromic nevus (7,8) Stable hypopigmented macules following lines of Blaschko Limited, segmental, patchy, blaschkoid Estimated to occur in 0.5% of healthy newborns Hypomelanosis of Ito (3,6,7,9) Macular hypopigmentation following lines of Blaschko (S-shaped or linear) Strongly associated (40%–100%) with multisystem involvement: mental retardation, epilepsy, musculoskeletal deformities, other neurologic abnormalities Linear and whorled nevoid hypermelanosis (10,11) Hyperpigmentation following lines of Blaschko Swirls, streaks Frequency of extracutaneous abnormalities unknown due to low incidence Cutis tricolor (12,13) Hyper- and hypopigmented macules following lines of Blaschko Limited, segmental, blaschkoid Speculated to be caused by a range of mutations, with the extent of dyspigmentation and extracutaneous anomalies related to earlier timing in fetal development Many of these terms overlap and are discriminated by vague characteristics.
Cohen et al: Analysis of 36 Cases of Blaschkoid Dyspigmentation
dyspigmentation continue to be reported under these presumed distinctive patterns, although there is considerable clinical overlap. We therefore prefer to use to use the term Blaschkoid dyspigmentation. Historically most of these series originated in pediatric neurology divisions in tertiary care academic centers, where many children were referred for evaluation of neurologic findings (1,3–6,9,12,13), and dyspigmentation was usually not the primary reason for referral. As a consequence, the association between neurologic and other potentially serious systemic abnormalities most likely represents an inherent reporting bias. In more recent studies by pediatric dermatologists, serious extracutaneous defects have been reported in 4% to 30% of patients (4,10,14). Patients in our study more closely reflect similar retrospective case studies reported by other dermatology investigators. Although our case series of 36 patients may not allow for an accurate estimate of the prevalence of systemic involvement in these patients, the diagnosis of 36 children with Blaschkoid dyspigmentation in less than a year suggests that the prevalence of Blaschkoid dyspigmentation is significantly higher than previously thought, whereas the incidence of systemic involvement is significantly lower. None of our patients were found to have mental retardation or epilepsy, the two features that have been most strongly associated with these cutaneous findings and have served as a major cause of concern when Blaschkoid dyspigmentation has been identified. Abnormalities in our patients included ADHD, vesicoureteral reflux, language delay, hip dysplasia, and a short right femur. ADHD is found in 3% to 7% of the general pediatric population and vesicoureteral reflux, hip dysplasia, and language delays are found in 2%, 4%, and 5% to 8%, respectively. It is possible that the prevalence of these diagnoses in our patients is unrelated to pigmentary findings. Several factors limit our study. Only 20% of the patients were seen a second time in our pediatric dermatology clinic. Although it is possible that study participants may have developed new complications after their initial visit, the vast majority of serious abnormalities, such as mental retardation, developmental delay, musculoskeletal alterations, and anatomic abnormalities of the heart and kidneys, have been described in early infancy. Furthermore, parents may have declined follow-up because of the lack of new problems or concerns. In one study in which follow-up was sought for 5 to 10 years, no additional abnormalities were detected (4).
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Pigmentary mosaicism has been proposed to describe the pathogenesis of pigmentary anomalies along the lines of Blaschko (4). Since 2000, several investigators have speculated that a wide range of mutations can cause the various phenotypic mosaic patterns seen in Blaschkoid dyspigmentation (4,11,12). They have also proposed that the extent of cutaneous involvement and risk of extracutaneous anomalies increases when mutations occur early in fetal development. Therefore practitioners can usually reassure parents that children with Blaschkoid dyspigmentation are unlikely to have or develop serious extracutaneous involvement, especially when lesions are limited and children are developing normally. A careful examination and review of systems should be performed and pertinent clinical findings should direct further evaluation and studies. REFERENCES 1. Happle R. Mosaicism in the human skin. Arch Dermatol 1993;129:1460–1470. 2. Wiss K. Neurocutaneous disorders: tuberous sclerosis, incontinentia pigmenti, and hypomelanosis of Ito. Semin Neurol 1992;12:364–373. 3. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A et al. Hypomelanosis of Ito. A study of 76 infantile cases. Brain Dev 1998;20:36–43. 4. Di Lernia V. Linear and whorled hypermelanosis. Pediatr Dermatol 2007;24:205–210. 5. Hara M, Saito K, Yajima K et al. Clinico-pathological study of hypomelanosis of Ito—a neurocutaneous syndrome. Brain Dev 1987;9:141. 6. Gomez-Lado C, Eiris-Punal J, Blanco-Barco O et al. Hypomelanosis of Ito: a possibly under-diagnosed heterogeneous neurocutaneous syndrome. Rev Neurol 2004;38:223–228. 7. Ito M. Studies of melanin XI. Incontinentia pigmenti achromians: a singular case of nevus depigmentosus systematicus bilateralis. Tohoku J Exp Med 1952;55 (Suppl):57–59. 8. Lee HS, Chun YS, Hann SK. Nevus depigmentosus: clinical features and histopathologic characteristics in 67 patients. J Am Acad Dermatol 1999;40:21–26. 9. Ruiz-Maldonado R, Toussaint S, Tamayo L et al. Hypomelanosis of Ito: diagnostic criteria and report of 41 cases. Pediatr Dermatol 1992;9:1–10. 10. Maruani A, Khallouf R, Machet MC et al. Diffuse linear and whorled nevoid hypermelanosis in a newborn. J Pediatr 2012;160:171. 11. Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000;159:745– 749. 12. Ruggieri M, Roggini M, Kennerknecht I et al. Cutis tricolor (Ruggieri-Happle syndrome). In: PascualCastroviejo I, Di Rocco C, Ruggieri M, eds.
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Neurocutaneous disorders. Phakomatoses and hamartoneoplastic syndromes. New York: Springer-Verlag, 2008:461–471. 13. Berker M, Oruckaptan HH, Oge HK et al. Neurocutaneous melanosis associated with Dandy-Walker
malformation. Case report and review of the literature. Pediatr Neurosurg 2000;33:270–273. 14. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 cases of hypopigmentation and hyperpigmentation along lines of Blaschko. Arch Dermatol 1996;132:1167–1170.
Analysis of 36 Cases of Blaschkoid Dyspigmentation: Reading Between the Lines of Blaschko Jared Cohen, III, M.S.,* Katayoon Shahrokh, M.D.,† and Bernard Cohen, M.D.‡,§ *School of Medicine, University of Maryland, Baltimore, Maryland, †Physical Medicine and Rehabilitation, University of California, Irvine, Irvine, California, ‡Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, §Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
Abstract: Genetic mosaicism indicated by lines of Blaschko pigmentary changes has been described under a number of different and confusing terms, including hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, nevus depigmentosus, and cutis tricolor. Moreover, extracutaneous findings, particularly serious neurologic defects, have been reported in a large number of these cases. We reviewed the cutaneous and extracutaneous findings in 36 patients referred to the Harriet Lane Pediatric Dermatology Clinic, Johns Hopkins University, from June 12, 2008, to May 24, 2009, for evaluation of macular lesions along the lines of Blaschko. Patients with dyspigmentation along the lines of Blaschko and no history of preceding inflammatory skin lesions were identified for inclusion in a database at their initial visit. Information on age at presentation; sex; age when first diagnosed; type, pattern, and location of the pigmentary anomaly; and extracutaneous abnormalities noted on a review-of-systems questionnaire and physical examination was recorded for each child. Patients were asked to follow up within 6 to 12 months of the initial visit. Patients included 13 boys and 23 girls ages 3 months to 15 years with lesions noted from birth to 12 years. Lesions were hypopigmented in 21 patients and hyperpigmented in 15. No patients presented with hypopigmented and hyperpigmented lesions. Extracutaneous findings were noted in five children (13.9%). Historically, cases of Blaschkoid hypopigmentation and hyperpigmentation have been associated with a high percentage of extracutaneous manifestations, particularly neurologic and neurodevelopmental defects. In our study, only five patients (13.9%) were noted to have extracutaneous abnormalities, and these findings may have been coincidental. We propose the term ‘Blaschkoid dyspigmentation’ to describe the cutaneous findings. Although serious extracutaneous
Address correspondence to Jared Cohen, M.S., 514 South Durham Street, Baltimore, MD 21231, or e-mail: jared.cohen@ som.umaryland.edu. DOI: 10.1111/pde.12346
© 2014 Wiley Periodicals, Inc.
471
472 Pediatric Dermatology Vol. 31 No. 4 July/August 2014
findings may occur in children with Blaschkoid dyspigmentation and results of careful physical examination and review of systems should direct an evaluation, serious extracutaneous findings occur in a minority of patients.
In the early 1900s, Alfred Blaschko described a unique pattern of dyspigmentation that was distinct from the dermatomes. This pattern of hyperpigmentation or hypopigmentation displayed in a whorled shape on the trunk, a V-shape on the back, and waves on the vertex scalp was later referred to as the lines of Blaschko (1). Rudolf Happle was the first to propose that pigmentary anomalies along the lines of Blaschko were a result of genetic mosaicism (1). It is now well accepted that genetic mosaicism resulting in Blaschko’s lines can arise from a multitude of genetic defects, including chromosomal nondisjunction, lyonization, and chimerism (2). Various terms have been used to describe dyspigmentation distributed along the lines of Blaschko without a preceding inflammatory phase typical of incontinentia pigmenti and with or without associated extracutaneous defects. These include hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, nevus depigmentosus, and cutis tricolor. Reports of extracutaneous defects (e.g., neurologic, ophthalmologic, musculoskeletal) vary from 16% to 100% (2–5). In our experience, extracutaneous anomalies, particularly serious neurologic and neurodevelopmental defects, are rare in children with this pattern of dyspigmentation, and we suspect that previous series have had a major referral bias. Moreover, we propose the term Blaschkoid dyspigmentation to replace the various confusing diagnostic terms that have been used to describe this heterogeneous group of disorders, all of which are markers of genetic mosaicism. Because of the conflicting reports about the prevalence of extracutaneous manifestations in association with Blaschkoid dyspigmentation, we reviewed the charts of 36 children seen at the Harriet Lane Pediatric Dermatology Clinic, Johns Hopkins University, who were described as having hyperpigmentation or hypopigmentation along the lines of Blaschko. One or both full-time pediatric dermatology faculty saw all patients. This chart review was performed in an attempt to better understand the frequency of extracutaneous involvement in children referred to pediatric dermatology for congenital or early childhood Blaschkoid dyspigmentation.
MATERIALS AND METHODS This was an institutional review board–approved retrospective chart review of 34 patients referred to the Harriet Lane Pediatric Dermatology Clinic from June 12, 2008, to May 24, 2009, for evaluation of macular lesions of hypopigmentation or hyperpigmentation in a linear, whorled, or V-shape pattern conforming to the lines of Blaschko. Patients were identified for inclusion in a database at their initial visit. Patients with a history of preceding inflammatory lesions were excluded. Information on age at presentation; sex; age when first diagnosed; type, pattern, and location of the pigmentary anomaly; and extracutaneous abnormalities noted on a review-ofsystems questionnaire and physical examination was recorded for each child. Patients were asked to follow up within 6 to 12 months of the initial visit. The review of systems included personal or family history of growth or developmental delay, attention deficit hyperactivity disorder (ADHD), seizures, kidney dysfunction, cardiac disease, vision or ocular abnormalities, gastrointestinal abnormalities, other skin conditions, arthritis, HIV/AIDS, thyroid disorders, hepatitis, hypertension, bleeding disorders, food allergies, depression, tuberculosis, asthma, and diabetes.
Figure 1. Blaschkoid dyspigmentation with hypopigmented patches on the abdomen of an infant.
Cohen et al: Analysis of 36 Cases of Blaschkoid Dyspigmentation
Figure 2. Blaschkoid dyspigmentation with hyperpigmented patches on the lower extremities of an infant.
RESULTS The patients included 13 boys and 23 girls, with ages at the time they were seen in our clinic ranging from 3 months to 15 years. Eighteen patients were noted to have abnormal pigmentation at birth, 15 by 2 years of age, and 3 after 2 years of age. Patterns of pigmentation were seen in the form of swirled, segmental, and linear shapes or in various combinations. All lesions were sharply demarcated. Twenty-one patients had hypopigmentation (Fig. 1), and 15 had hyperpigmentation (Fig. 2). No patients had a mixed presentation. Five patients had diffuse
473
involvement of the skin. The pigmentation was limited to the head and neck in 1 patient, the trunk in 1 patient, and the extremities in 11 patients. Bilateral pigmentation was seen in five patients (Table 1). Extracutaneous findings were noted in five patients (13.9%). Abnormalities of the central nervous system were found in two patients (5.6%). Two patients were found to have isolated abnormalities of the musculoskeletal system (5.6%). Two patients (5.6%) were found to have kidney dysfunction. Only one patient (2.8%) was found to have involvement of more than one organ system. No patients were diagnosed with a distinctive syndrome. No patients were found to have mental retardation or epilepsy (Table 1, Fig. 3). Clinical follow-up data were obtained in the pediatric dermatology clinic in seven patients, none of whom were found to have additional extracutaneous features. DISCUSSION Terms used to describe congenital hypopigmentation and hyperpigmentation along the lines of Blaschko, including nevus depigmentosus, hypomelanosis of Ito, linear and whorled nevoid hypermelanosis, and cutis tricolor, are often confusing and the reported association with extracutaneous findings is variable (Table 2 (1,3,4,6–12). Case series of patients with Blaschkoid
n = 36; ADHD, attention deficit hyperactive disorder. *Orthopedic: 2 children; 1 child had hip dysplasia, 1 child has a shortened right femur
Figure 3. Extracutaneous findings in patients with Blaschkoid dyspigmentation who presented to the Johns Hopkins Pediatric Dermatology Clinic. Only 5 of the 36 children with Blaschkoid dyspigmentation were observed to have extracutaneous manifestations.
474 Pediatric Dermatology Vol. 31 No. 4 July/August 2014
TABLE 1. Phenotypic Findings in 36 Cases of Blaschkoid Dyspigmentation Age/sex
Type of pigmentation
First noted
Location
Additional features
26 mos/M 4 yrs/M 11 mos/F 5 mos/F 4 mos/M 19 mos/M 4 mos/F 2 yrs/F 3 yrs/F 8 yrs/F 8 mos/F 1 yr/F 6 mos/M 5 yrs/M 15 yrs/M 9 mos/M 3 mos/F 22 mos/F 11 mos/M 3.5 yrs/F 7 mos/F 13 mos/M 5 mos/F 22 mos/F 7 mos/F 2 yrs/F
Hypopigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hyperpigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hyperpigmentation Hypopigmentation
Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth Birth 2 wks 1 mo 1 mo 2 mos 2 mos 4 mos 5 mos 5 mos
Language delay None None None None None None None None None Bilateral vesicoureteral reflux Shortened right femur None None None None None None None Hip dysplasia None None None None None None
18 mos/F 13 mos/F 2 yrs/F 14 mos/M 16 mos/F 3.5 yrs/F 3 yrs/F 7 yrs/M 9 yrs/F
Hypopigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hyperpigmentation Hypopigmentation Hypopigmentation Hypopigmentation Hypopigmentation
6 mos 9 mos 10 mos 11 mos 12 mos 24 mos 24 mos 5 yrs 6 yrs
Back, buttock, posterior thigh Right abdomen and low back Diffuse Left abdomen and groin Right flank, groin, thigh, lower extremity Bilateral lower extremities Left upper extremity Diffuse Posterior thighs and lower extremities Left lateral neck, shoulder, upper extremity Diffuse Anterior and posterior trunk Right upper chest, abdomen, and suprapubic area Diffuse Diffuse Left lower chest, abdomen, and back Left jawline and preauricular region Right lower extremity Right abdomen and face Right abdomen and back Anterior trunk and left breast Left upper back, abdomen, and groin Right abdomen and flank Left upper chest, shoulder, and upper extremity Trunk and extremities Bilateral flexure surfaces of upper and lower extremities Left lower extremity Left back Bilateral forearms and left lower extremity Diffuse Bilateral thighs and knees Right abdomen and posterior back Right abdomen and flank Right lower extremity Left chest and upper extremity
13 yrs/M
Hypopigmentation
12 yrs
Right upper extremity
None None None None None None None None Bilateral vesicoureteral reflux, ADHD None
ADHD, attention deficit hyperactive disorder.
TABLE 2. Descriptions of Current Terms in the Literature for Blaschkoid Dyspigmentation Nevus depigmentosus or achromic nevus (7,8) Stable hypopigmented macules following lines of Blaschko Limited, segmental, patchy, blaschkoid Estimated to occur in 0.5% of healthy newborns Hypomelanosis of Ito (3,6,7,9) Macular hypopigmentation following lines of Blaschko (S-shaped or linear) Strongly associated (40%–100%) with multisystem involvement: mental retardation, epilepsy, musculoskeletal deformities, other neurologic abnormalities Linear and whorled nevoid hypermelanosis (10,11) Hyperpigmentation following lines of Blaschko Swirls, streaks Frequency of extracutaneous abnormalities unknown due to low incidence Cutis tricolor (12,13) Hyper- and hypopigmented macules following lines of Blaschko Limited, segmental, blaschkoid Speculated to be caused by a range of mutations, with the extent of dyspigmentation and extracutaneous anomalies related to earlier timing in fetal development Many of these terms overlap and are discriminated by vague characteristics.
Cohen et al: Analysis of 36 Cases of Blaschkoid Dyspigmentation
dyspigmentation continue to be reported under these presumed distinctive patterns, although there is considerable clinical overlap. We therefore prefer to use to use the term Blaschkoid dyspigmentation. Historically most of these series originated in pediatric neurology divisions in tertiary care academic centers, where many children were referred for evaluation of neurologic findings (1,3–6,9,12,13), and dyspigmentation was usually not the primary reason for referral. As a consequence, the association between neurologic and other potentially serious systemic abnormalities most likely represents an inherent reporting bias. In more recent studies by pediatric dermatologists, serious extracutaneous defects have been reported in 4% to 30% of patients (4,10,14). Patients in our study more closely reflect similar retrospective case studies reported by other dermatology investigators. Although our case series of 36 patients may not allow for an accurate estimate of the prevalence of systemic involvement in these patients, the diagnosis of 36 children with Blaschkoid dyspigmentation in less than a year suggests that the prevalence of Blaschkoid dyspigmentation is significantly higher than previously thought, whereas the incidence of systemic involvement is significantly lower. None of our patients were found to have mental retardation or epilepsy, the two features that have been most strongly associated with these cutaneous findings and have served as a major cause of concern when Blaschkoid dyspigmentation has been identified. Abnormalities in our patients included ADHD, vesicoureteral reflux, language delay, hip dysplasia, and a short right femur. ADHD is found in 3% to 7% of the general pediatric population and vesicoureteral reflux, hip dysplasia, and language delays are found in 2%, 4%, and 5% to 8%, respectively. It is possible that the prevalence of these diagnoses in our patients is unrelated to pigmentary findings. Several factors limit our study. Only 20% of the patients were seen a second time in our pediatric dermatology clinic. Although it is possible that study participants may have developed new complications after their initial visit, the vast majority of serious abnormalities, such as mental retardation, developmental delay, musculoskeletal alterations, and anatomic abnormalities of the heart and kidneys, have been described in early infancy. Furthermore, parents may have declined follow-up because of the lack of new problems or concerns. In one study in which follow-up was sought for 5 to 10 years, no additional abnormalities were detected (4).
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Pigmentary mosaicism has been proposed to describe the pathogenesis of pigmentary anomalies along the lines of Blaschko (4). Since 2000, several investigators have speculated that a wide range of mutations can cause the various phenotypic mosaic patterns seen in Blaschkoid dyspigmentation (4,11,12). They have also proposed that the extent of cutaneous involvement and risk of extracutaneous anomalies increases when mutations occur early in fetal development. Therefore practitioners can usually reassure parents that children with Blaschkoid dyspigmentation are unlikely to have or develop serious extracutaneous involvement, especially when lesions are limited and children are developing normally. A careful examination and review of systems should be performed and pertinent clinical findings should direct further evaluation and studies. REFERENCES 1. Happle R. Mosaicism in the human skin. Arch Dermatol 1993;129:1460–1470. 2. Wiss K. Neurocutaneous disorders: tuberous sclerosis, incontinentia pigmenti, and hypomelanosis of Ito. Semin Neurol 1992;12:364–373. 3. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A et al. Hypomelanosis of Ito. A study of 76 infantile cases. Brain Dev 1998;20:36–43. 4. Di Lernia V. Linear and whorled hypermelanosis. Pediatr Dermatol 2007;24:205–210. 5. Hara M, Saito K, Yajima K et al. Clinico-pathological study of hypomelanosis of Ito—a neurocutaneous syndrome. Brain Dev 1987;9:141. 6. Gomez-Lado C, Eiris-Punal J, Blanco-Barco O et al. Hypomelanosis of Ito: a possibly under-diagnosed heterogeneous neurocutaneous syndrome. Rev Neurol 2004;38:223–228. 7. Ito M. Studies of melanin XI. Incontinentia pigmenti achromians: a singular case of nevus depigmentosus systematicus bilateralis. Tohoku J Exp Med 1952;55 (Suppl):57–59. 8. Lee HS, Chun YS, Hann SK. Nevus depigmentosus: clinical features and histopathologic characteristics in 67 patients. J Am Acad Dermatol 1999;40:21–26. 9. Ruiz-Maldonado R, Toussaint S, Tamayo L et al. Hypomelanosis of Ito: diagnostic criteria and report of 41 cases. Pediatr Dermatol 1992;9:1–10. 10. Maruani A, Khallouf R, Machet MC et al. Diffuse linear and whorled nevoid hypermelanosis in a newborn. J Pediatr 2012;160:171. 11. Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000;159:745– 749. 12. Ruggieri M, Roggini M, Kennerknecht I et al. Cutis tricolor (Ruggieri-Happle syndrome). In: PascualCastroviejo I, Di Rocco C, Ruggieri M, eds.
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Neurocutaneous disorders. Phakomatoses and hamartoneoplastic syndromes. New York: Springer-Verlag, 2008:461–471. 13. Berker M, Oruckaptan HH, Oge HK et al. Neurocutaneous melanosis associated with Dandy-Walker
malformation. Case report and review of the literature. Pediatr Neurosurg 2000;33:270–273. 14. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 cases of hypopigmentation and hyperpigmentation along lines of Blaschko. Arch Dermatol 1996;132:1167–1170.
