CASE REPORT Pediatric Dermatology Vol. 32 No. 4 e145–e147, 2015
CHILD Syndrome: Successful Treatment of Skin Lesions with Topical Simvastatin/ Cholesterol Ointment—A Case Report Alexios Alexopoulos, M.D., and Talia Kakourou, M.D., Ph.D. First Department of Pediatrics, University of Athens and Aghia Sofia Children’s Hospital, Athens, Greece
Abstract: CHILD syndrome is a rare X-linked dominant condition that presents with congenital hemidysplasia, Ichthyosiform erythroderma, and limb defects in affected patients. We report the case of a 10-year-old girl treated with topical simvastatin and cholesterol ointment, after which her skin lesions significantly improved within the first 30 days of treatment.
CHILD syndrome (congenital hemidysplasia, Ichthyosiform erythroderma, and limb defects) is a syndromic disorder of distal cholesterol metabolism; its cutaneous and extracutaneous findings reflect the deficiency of the pathway end product and the accumulation of toxic metabolic intermediates upstream from the pathway block (1,2). Paller et al (3) reported two patients diagnosed with CHILD syndrome in whom the topical coapplication of lovastatin and cholesterol was an effective treatment for ichthyosiform dermatitis. We subsequently used the same pathogenesis-based therapy for our patient. CASE REPORT A 10-year-old girl presented with the existing diagnosis of CHILD syndrome confirmed by molecular analysis of the NSDHL gene (a missense mutation was identified: c.314 C>T; p A105V). She was born with a severely malformed upper right extremity, including a markedly underdeveloped arm and fore-
arm and only three distorted fingers on the affected limb with significant onychodystrophy. In addition to the skeletal malformations, our patient had ichthyosiform erythrodermic plaques on the dorsal surface of her rudimentary right hand; over the surface of her right axilla; over her right inguinal area, extending to the inner thigh and the genital area, sharply demarcated at the midline (4); and over her right popliteal fossa. Because there was no improvement of our patient’s itchy ichthyosiform skin lesions with topical applications of emollients, keratolytics, retinoids, or calcineurin inhibitors, treatment was initiated with topical coapplication of simvastatin and cholesterol after obtaining parental informed consent (Fig. 1). She was observed at 1, 2, and 4 weeks, at 3 months, and then at 3-month intervals after treatment commenced for a total of 8 months until this report was written. A maintenance schedule consisting of treatment twice a week was planned thereafter. Full blood counts, urea, electrolytes, liver function
Address correspondence to Alex Alexopoulos, M.D., Children’s Hospital ‘Agia Sofia’ Thivon and Papadiamantopoulou Street, Goudi, Athens 11527, Greece, or e-mail: [email protected]. uk. DOI: 10.1111/pde.12587
© 2015 Wiley Periodicals, Inc.
e145
e146 Pediatric Dermatology Vol. 32 No. 4 July/August 2015
Simvastatin 0.5% /Cholesterol Bland emollients ointment twice daily
0 Months 1
2
Simvastatin 2% / Cholesterol ointment twice daily for three months
3
4
Simvastatin 2% / Cholesterol ointment twice daily, every other day
5
6
7
8
Figure 1. Treatment timeline.
A
B
C
D
Figure 2. (A, B) Before treatment started and (C, D) 2 months after treatment started
tests, cholesterol, and triglycerides were measured every 2 months and were found within normal limits throughout the treatment regimen. The itchiness
subsided by the end of the first week after initiation of treatment, the erythema and the scaling of the skin showed signs of significant improvement by the end of
Alexopoulos and Kakourou: CHILD Syndrome Topical Treatment
the second week, the thickening of the skin due to lichenification was reduced after the fourth week, and residual postinflammatory hypopigmentation was the only cutaneous manifestation 2 months after the treatment started (Fig. 2A, B).
e147
Furthermore, simvastatin and cholesterol have a well-known safety profile, are low in cost, and are lipid soluble, and their therapeutic effect can be visually observed without difficulty. REFERENCES
DISCUSSION Topical treatment with simvastatin and cholesterol and subsequent correction of the cutaneous phenotype is an excellent example of targeting therapy to the pathogenesis of an inherited disorder of lipid metabolism. Topical treatment with simvastatin bypasses the first-pass hepatic metabolism of statins, enhancing the effective delivery of the drug to the target organ. Similarly, its topical application directly onto the skin prevents intrahepatic incorporation of cholesterol into lipoprotein particles.
1. Cooper MK, Wassif CA, Krakowiak PA et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 2003;33:508–513. 2. Elias PM, Williams ML, Holleran WM et al. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res 2008;49:697–714. 3. Paller AS, van Steensel MA, Rodriguez-Martin M et al. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol 2011;131:2242–2248. 4. Happle R. X-chromosome inactivation: role in skin disease expression. Acta Paediatr Suppl 2006;95:16–23.
CHILD Syndrome: Successful Treatment of Skin Lesions with Topical Simvastatin/ Cholesterol Ointment—A Case Report Alexios Alexopoulos, M.D., and Talia Kakourou, M.D., Ph.D. First Department of Pediatrics, University of Athens and Aghia Sofia Children’s Hospital, Athens, Greece
Abstract: CHILD syndrome is a rare X-linked dominant condition that presents with congenital hemidysplasia, Ichthyosiform erythroderma, and limb defects in affected patients. We report the case of a 10-year-old girl treated with topical simvastatin and cholesterol ointment, after which her skin lesions significantly improved within the first 30 days of treatment.
CHILD syndrome (congenital hemidysplasia, Ichthyosiform erythroderma, and limb defects) is a syndromic disorder of distal cholesterol metabolism; its cutaneous and extracutaneous findings reflect the deficiency of the pathway end product and the accumulation of toxic metabolic intermediates upstream from the pathway block (1,2). Paller et al (3) reported two patients diagnosed with CHILD syndrome in whom the topical coapplication of lovastatin and cholesterol was an effective treatment for ichthyosiform dermatitis. We subsequently used the same pathogenesis-based therapy for our patient. CASE REPORT A 10-year-old girl presented with the existing diagnosis of CHILD syndrome confirmed by molecular analysis of the NSDHL gene (a missense mutation was identified: c.314 C>T; p A105V). She was born with a severely malformed upper right extremity, including a markedly underdeveloped arm and fore-
arm and only three distorted fingers on the affected limb with significant onychodystrophy. In addition to the skeletal malformations, our patient had ichthyosiform erythrodermic plaques on the dorsal surface of her rudimentary right hand; over the surface of her right axilla; over her right inguinal area, extending to the inner thigh and the genital area, sharply demarcated at the midline (4); and over her right popliteal fossa. Because there was no improvement of our patient’s itchy ichthyosiform skin lesions with topical applications of emollients, keratolytics, retinoids, or calcineurin inhibitors, treatment was initiated with topical coapplication of simvastatin and cholesterol after obtaining parental informed consent (Fig. 1). She was observed at 1, 2, and 4 weeks, at 3 months, and then at 3-month intervals after treatment commenced for a total of 8 months until this report was written. A maintenance schedule consisting of treatment twice a week was planned thereafter. Full blood counts, urea, electrolytes, liver function
Address correspondence to Alex Alexopoulos, M.D., Children’s Hospital ‘Agia Sofia’ Thivon and Papadiamantopoulou Street, Goudi, Athens 11527, Greece, or e-mail: [email protected]. uk. DOI: 10.1111/pde.12587
© 2015 Wiley Periodicals, Inc.
e145
e146 Pediatric Dermatology Vol. 32 No. 4 July/August 2015
Simvastatin 0.5% /Cholesterol Bland emollients ointment twice daily
0 Months 1
2
Simvastatin 2% / Cholesterol ointment twice daily for three months
3
4
Simvastatin 2% / Cholesterol ointment twice daily, every other day
5
6
7
8
Figure 1. Treatment timeline.
A
B
C
D
Figure 2. (A, B) Before treatment started and (C, D) 2 months after treatment started
tests, cholesterol, and triglycerides were measured every 2 months and were found within normal limits throughout the treatment regimen. The itchiness
subsided by the end of the first week after initiation of treatment, the erythema and the scaling of the skin showed signs of significant improvement by the end of
Alexopoulos and Kakourou: CHILD Syndrome Topical Treatment
the second week, the thickening of the skin due to lichenification was reduced after the fourth week, and residual postinflammatory hypopigmentation was the only cutaneous manifestation 2 months after the treatment started (Fig. 2A, B).
e147
Furthermore, simvastatin and cholesterol have a well-known safety profile, are low in cost, and are lipid soluble, and their therapeutic effect can be visually observed without difficulty. REFERENCES
DISCUSSION Topical treatment with simvastatin and cholesterol and subsequent correction of the cutaneous phenotype is an excellent example of targeting therapy to the pathogenesis of an inherited disorder of lipid metabolism. Topical treatment with simvastatin bypasses the first-pass hepatic metabolism of statins, enhancing the effective delivery of the drug to the target organ. Similarly, its topical application directly onto the skin prevents intrahepatic incorporation of cholesterol into lipoprotein particles.
1. Cooper MK, Wassif CA, Krakowiak PA et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 2003;33:508–513. 2. Elias PM, Williams ML, Holleran WM et al. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res 2008;49:697–714. 3. Paller AS, van Steensel MA, Rodriguez-Martin M et al. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol 2011;131:2242–2248. 4. Happle R. X-chromosome inactivation: role in skin disease expression. Acta Paediatr Suppl 2006;95:16–23.
