Hum Genet (1992) 90:469-471
human ,. geneucs 9 Springer-Verlag 1992
Clinical case report
Aplasia cutis congenita reminiscent of the lines of Blaschko Raoul C. M. Hennekam Clinical Genetics Center Utrecht, P.O. Box 18009, NL-3501 CA Utrecht, The Netherlands Received: 13 March 1992 / Revised: 6 July 1992
Abstract. A male newborn showing congenital symmetrical abdominal skin defects and an alopecia on the scalp following a spiral pattern is described. The pattern of distribution of both skin anomalies was reminiscent of the lines of Blaschko, indicating that somatic mosaicism is the most probable cause for the defects.
Introduction Aplasia cutis congenity (ACC) is a heterogeneous group of disorders in which localized or widespread areas of the skin are absent at birth (Frieden 1986). The defect is most often solitary: in his review of 331 cases, Demmel (1975) found a single skin defect in 74.9%, and multiple defects in 25.1% of patients. Lesions, both single and
multiple, are most frequently present on the scalp (in 86% and 43% of cases, respectively), but may be found on every part of the skin. On the trunk, a single lesion is found in 6.9% of all reported cases, and multiple lesions in 11.4% (Demmel 1975). Here, a newborn is reported who had congenital symmetrical skin defects of the abdomen, and a spiral pattern of alopecia on the scalp. The pattern of distribution of both was remiscent of the patterns of the lines of Blaschko (Blaschko 1901; Happle 1985). The possible etiologies are briefly discussed.
Case report The boy was the third-born child of young non-consanguineous parents. Both sibs and the parents were healthy; specifically, they showed no skin abnormalities. During the tenth week of pregnancy the mother had cystitis that was treated with amoxicillin. Weight
Fig. 1. Proband as a neonate showing symmetrical, sharply demarcated abdominal skin defects respecting the midline Fig. 2. Proband at 2 years of age, showing alopecia in a spiral pattern converging to the vertex
470 at birth was 2995 g (15th centile). The boy appeared to have bilateral symmetrical skin lesions on both sides of his umbilicus, measuring 2cm by 5cm (Fig. l). The borders of the skin defects showed necrotic areas and areas with re-epithelialization. Furthermore, he had one smaller cafe-au-lait spot (0.3 x 1.5 cm) in front of this right ear. On his scalp, a localized alopecia was present, distributed in a spiral streak converging on the vertex (Fig. 2). The structure of the skin involved was irregular, but did not clearly resemble keloid. During crying, he spiral pattern was much more reddened than the normal scalp. He had no significant dysmorphic features, and no other ectodermal defects. Serological investigations failed to find evidence of intrauterine Herpes simplex or VariceIla infections. Radiography of his hands, thorax, pelvis, vertebral column, and lower extremities showed no anomalies, especially no signs of osteopathia striata. The kidneys were normal at sonography. Chromosomal analysis of peripheral lymphocytes showed a normal male karyotype: no signs of mosaicism were found. The skin lesions re-epithelialized spontaneously after 2 months. The child's psychomotor development has been normal until now (he is 2 years old at present).
Discussion
The presence of symmetrical congenital skin defects on the a b d o m e n is a rare event. D e m m e l (1975) r e p o r t e d that, in the literature, of 150 cases with A C C on the trunk and extremities, 22 had m o r e than one skin defect on the trunk. T h e defects were localized on the a b d o m e n in 10 patients, and were most often irregularly formed. In 3 patient, A C C was present both on the trunk and the head. The etiology of A C C is h e t e r o g e n e o u s and often remains u n k n o w n . In general, A C C can be considered as a disruption of skin d e v e l o p m e n t in utero. This disruption m a y be caused by t r a u m a , c o m p r o m i s e d vascularization of part of the skin, teratogenic agents, and t h r o u g h Mendelian disorders (Frieden 1986). N o n e of these possible causes was f o u n d p r o b a b l e in the present patient. A n alopecia areata in a spiral pattern on the scalp is an even less often r e p o r t e d anomaly. Its cause remains uncertain, but it is p r o b a b l y the result of an A C C that had healed in utero. This a n o m a l y has also been reported in a patient with oral - facial - digital s y n d r o m e type 1 (Happle et al. 1984) and in two patients with X-linked chondrodysplasia p u n c t a t a ( H a p p l e 1985). As both involved disorders show an X-linked d o m i n a n t pattern of inheritance, it is conceivable that the spiral alopecia reflects lyonization, and, thus, reflects X - c h r o m o s o m e mosaicism. This same mosaic distribution of skin defects in a n o n - r a n d o m linear pattern can be f o u n d elsewhere on the body. Blaschko (1901) was the first to recognize this. H a p p l e (1985) postulated that the localization of the lines of Blaschko m a y be explained by a dorsoventral outgrowth of two functionally different populations of cells during early embryogenesis. X-inactivation seems the most suitable explanation for these different cell populations, but other genetic mechanisms giving rise to somatic mosaicism (Hall 1988), such as somatic mutations and chimerism, m a y p r o d u c e the same defect. The findings in the present patient confirm the t h e o r y that spiral alopecia reflects mosaicism, as the A C C on the a b d o m e n m a y well also follow the lines of Blaschko, although the typical S-figure on the lateral and anterior aspect of the
a b d o m e n was not completely followed. Thus, the present patient may have a somatic mosaicism visible on two different sites of the body, both sites following Blaschko's lines. A t present, there is only one X-linked disorder that shows A C C , i.e. focal dermal hypoplasia. The absence of abnormalities of the extremities, face, eyes, or on radiography rules out this disorder in the present patient. There was also no mosaicism found during cytogenetic investigations. Thus, no signs of an X-linked cause are present. It is uncertain w h e t h e r A C C frequently follows Blaschko's lines. It appears not to have been r e p o r t e d before (Happle, personal communication). In this respect, it should be m e n t i o n e d that multiple congenital skin defects are often located in the midline or are symmetrical to it; if they are symmetrical to the median line, they show no difference in size, shape, or nature of the surface of the defects ( D e m m e l 1975). This is also compatible with defects following the pattern of Blaschko's lines. In clonclusion, it seems justified in patients with A C C to evaluate carefully the configuration of the defects and to search for other skin anomalies following the lines of Blaschko. A C C m a y be added to the growing list of disorders in which somatic mosaicism may be detectable t h r o u g h skin anomalies (Table 1).
Table 1. Disorders in which skin anomalies reflecting somatic
mosaicism may be found (Happle 1985) X-linked mutations
Lethal for males in non-mosaic state Focal dermal hypoplasia Incontinentia pigmenti Oral-facial-digital syndrome type I X-linked chondrodysplasia punctata CHILD syndrome Non-lethal for males in non-mosaic state X-linked hypohidrotic ectodermal dysplasia Cutaneous amyloidosis, Partington type Menkes disease Genomic mosaicism
Following a linear pattern McCune-Albright syndrome Schimmelpenning-Feuerstein-Mims syndrome Proteus syndrome Linear psoriasis Hypomelanosis of Ito Aplasia cutis congenita Following a non-linear pattern, respecting the midline Sturge-Weber angiomatosis Klippel-Trenaunay syndrome Following a non-linear pattern, no respect to midline Oculo-cerebro-cutaneous syndrome Neurocutaneous melanosis Cutis marmorata telangiectatica congenita Maffucci syndrome
471
Acknowledgements. I thank Dr.R.Happle (Munster, Germany) for his suggestions and encouragement.
References Blaschko A (1901) Die Nervenverteilung in der Haut in ihrer Beziehung zu den Erkrankungen der Haut. Braumuller, Wien Leipzig Demmel U (1975) Clinical aspects of congenital skin defects. Eur J Pediatr 121 : 21-50
Frieden IJ (1986) Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14: 646-660 Hall JG (1988) Review and hypotheses: somatic mozaicism: observations related to clinical genetics. Am J Hum Genet 43 : 355363 Happle R (1985) Lyonization and the lines of Blaschko. Hum Genet 70 : 200-206 Happle R, Fuhrmann-Rieger A, Fuhrmann W (1984) Wie verlaufen die Blaschko-Linien am behaarten Kopf? Hautarzt 35: 366-369
human ,. geneucs 9 Springer-Verlag 1992
Clinical case report
Aplasia cutis congenita reminiscent of the lines of Blaschko Raoul C. M. Hennekam Clinical Genetics Center Utrecht, P.O. Box 18009, NL-3501 CA Utrecht, The Netherlands Received: 13 March 1992 / Revised: 6 July 1992
Abstract. A male newborn showing congenital symmetrical abdominal skin defects and an alopecia on the scalp following a spiral pattern is described. The pattern of distribution of both skin anomalies was reminiscent of the lines of Blaschko, indicating that somatic mosaicism is the most probable cause for the defects.
Introduction Aplasia cutis congenity (ACC) is a heterogeneous group of disorders in which localized or widespread areas of the skin are absent at birth (Frieden 1986). The defect is most often solitary: in his review of 331 cases, Demmel (1975) found a single skin defect in 74.9%, and multiple defects in 25.1% of patients. Lesions, both single and
multiple, are most frequently present on the scalp (in 86% and 43% of cases, respectively), but may be found on every part of the skin. On the trunk, a single lesion is found in 6.9% of all reported cases, and multiple lesions in 11.4% (Demmel 1975). Here, a newborn is reported who had congenital symmetrical skin defects of the abdomen, and a spiral pattern of alopecia on the scalp. The pattern of distribution of both was remiscent of the patterns of the lines of Blaschko (Blaschko 1901; Happle 1985). The possible etiologies are briefly discussed.
Case report The boy was the third-born child of young non-consanguineous parents. Both sibs and the parents were healthy; specifically, they showed no skin abnormalities. During the tenth week of pregnancy the mother had cystitis that was treated with amoxicillin. Weight
Fig. 1. Proband as a neonate showing symmetrical, sharply demarcated abdominal skin defects respecting the midline Fig. 2. Proband at 2 years of age, showing alopecia in a spiral pattern converging to the vertex
470 at birth was 2995 g (15th centile). The boy appeared to have bilateral symmetrical skin lesions on both sides of his umbilicus, measuring 2cm by 5cm (Fig. l). The borders of the skin defects showed necrotic areas and areas with re-epithelialization. Furthermore, he had one smaller cafe-au-lait spot (0.3 x 1.5 cm) in front of this right ear. On his scalp, a localized alopecia was present, distributed in a spiral streak converging on the vertex (Fig. 2). The structure of the skin involved was irregular, but did not clearly resemble keloid. During crying, he spiral pattern was much more reddened than the normal scalp. He had no significant dysmorphic features, and no other ectodermal defects. Serological investigations failed to find evidence of intrauterine Herpes simplex or VariceIla infections. Radiography of his hands, thorax, pelvis, vertebral column, and lower extremities showed no anomalies, especially no signs of osteopathia striata. The kidneys were normal at sonography. Chromosomal analysis of peripheral lymphocytes showed a normal male karyotype: no signs of mosaicism were found. The skin lesions re-epithelialized spontaneously after 2 months. The child's psychomotor development has been normal until now (he is 2 years old at present).
Discussion
The presence of symmetrical congenital skin defects on the a b d o m e n is a rare event. D e m m e l (1975) r e p o r t e d that, in the literature, of 150 cases with A C C on the trunk and extremities, 22 had m o r e than one skin defect on the trunk. T h e defects were localized on the a b d o m e n in 10 patients, and were most often irregularly formed. In 3 patient, A C C was present both on the trunk and the head. The etiology of A C C is h e t e r o g e n e o u s and often remains u n k n o w n . In general, A C C can be considered as a disruption of skin d e v e l o p m e n t in utero. This disruption m a y be caused by t r a u m a , c o m p r o m i s e d vascularization of part of the skin, teratogenic agents, and t h r o u g h Mendelian disorders (Frieden 1986). N o n e of these possible causes was f o u n d p r o b a b l e in the present patient. A n alopecia areata in a spiral pattern on the scalp is an even less often r e p o r t e d anomaly. Its cause remains uncertain, but it is p r o b a b l y the result of an A C C that had healed in utero. This a n o m a l y has also been reported in a patient with oral - facial - digital s y n d r o m e type 1 (Happle et al. 1984) and in two patients with X-linked chondrodysplasia p u n c t a t a ( H a p p l e 1985). As both involved disorders show an X-linked d o m i n a n t pattern of inheritance, it is conceivable that the spiral alopecia reflects lyonization, and, thus, reflects X - c h r o m o s o m e mosaicism. This same mosaic distribution of skin defects in a n o n - r a n d o m linear pattern can be f o u n d elsewhere on the body. Blaschko (1901) was the first to recognize this. H a p p l e (1985) postulated that the localization of the lines of Blaschko m a y be explained by a dorsoventral outgrowth of two functionally different populations of cells during early embryogenesis. X-inactivation seems the most suitable explanation for these different cell populations, but other genetic mechanisms giving rise to somatic mosaicism (Hall 1988), such as somatic mutations and chimerism, m a y p r o d u c e the same defect. The findings in the present patient confirm the t h e o r y that spiral alopecia reflects mosaicism, as the A C C on the a b d o m e n m a y well also follow the lines of Blaschko, although the typical S-figure on the lateral and anterior aspect of the
a b d o m e n was not completely followed. Thus, the present patient may have a somatic mosaicism visible on two different sites of the body, both sites following Blaschko's lines. A t present, there is only one X-linked disorder that shows A C C , i.e. focal dermal hypoplasia. The absence of abnormalities of the extremities, face, eyes, or on radiography rules out this disorder in the present patient. There was also no mosaicism found during cytogenetic investigations. Thus, no signs of an X-linked cause are present. It is uncertain w h e t h e r A C C frequently follows Blaschko's lines. It appears not to have been r e p o r t e d before (Happle, personal communication). In this respect, it should be m e n t i o n e d that multiple congenital skin defects are often located in the midline or are symmetrical to it; if they are symmetrical to the median line, they show no difference in size, shape, or nature of the surface of the defects ( D e m m e l 1975). This is also compatible with defects following the pattern of Blaschko's lines. In clonclusion, it seems justified in patients with A C C to evaluate carefully the configuration of the defects and to search for other skin anomalies following the lines of Blaschko. A C C m a y be added to the growing list of disorders in which somatic mosaicism may be detectable t h r o u g h skin anomalies (Table 1).
Table 1. Disorders in which skin anomalies reflecting somatic
mosaicism may be found (Happle 1985) X-linked mutations
Lethal for males in non-mosaic state Focal dermal hypoplasia Incontinentia pigmenti Oral-facial-digital syndrome type I X-linked chondrodysplasia punctata CHILD syndrome Non-lethal for males in non-mosaic state X-linked hypohidrotic ectodermal dysplasia Cutaneous amyloidosis, Partington type Menkes disease Genomic mosaicism
Following a linear pattern McCune-Albright syndrome Schimmelpenning-Feuerstein-Mims syndrome Proteus syndrome Linear psoriasis Hypomelanosis of Ito Aplasia cutis congenita Following a non-linear pattern, respecting the midline Sturge-Weber angiomatosis Klippel-Trenaunay syndrome Following a non-linear pattern, no respect to midline Oculo-cerebro-cutaneous syndrome Neurocutaneous melanosis Cutis marmorata telangiectatica congenita Maffucci syndrome
471
Acknowledgements. I thank Dr.R.Happle (Munster, Germany) for his suggestions and encouragement.
References Blaschko A (1901) Die Nervenverteilung in der Haut in ihrer Beziehung zu den Erkrankungen der Haut. Braumuller, Wien Leipzig Demmel U (1975) Clinical aspects of congenital skin defects. Eur J Pediatr 121 : 21-50
Frieden IJ (1986) Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14: 646-660 Hall JG (1988) Review and hypotheses: somatic mozaicism: observations related to clinical genetics. Am J Hum Genet 43 : 355363 Happle R (1985) Lyonization and the lines of Blaschko. Hum Genet 70 : 200-206 Happle R, Fuhrmann-Rieger A, Fuhrmann W (1984) Wie verlaufen die Blaschko-Linien am behaarten Kopf? Hautarzt 35: 366-369
