Vitamin D: A New Promising Therapy for Congenital IchthyosisGomathy Sethuraman, MD,a Raman K Marwaha, MD,b Apoorva Challa, MSc,a Vamsi K Yenamandra, MBBS,a Lakshmy Ramakrishnan, PhD,c Sanjay Thulkar, MD,d Vinod K Sharma, MDa

Departments of aDermatology cCardiac Biochemistry, and dRadiodiagnosis, All India Institute of Medical Sciences,

New Delhi, India; and bDepartment of Endocrinology,

Institute of Nuclear Medicine and Allied Sciences, DRDO,

New Delhi, India

Dr Sethuraman conceptualized and designed

the study, supervised and coordinated the data

collection, drafted the initial manuscript, and

critically revised the manuscript; Dr Marwaha

conceptualized and designed the study, drafted

the initial manuscript, and critically revised

the manuscript; Ms Challa carried out the

biochemical assays; Dr Ramakrishnan supervised

the biochemical assays and critically revised the

manuscript; Dr Yenamandra supervised patient

recruitment and critically revised the manuscript;

Dr Sharma provided technical support; Dr

Thulkar carried out the radiological evaluation;

and all authors approved the fi nal manuscript as

submitted.

Dr Marwaha’s current affi liation is Senior

Consultant Endocrinology and Scientifi c Advisor

(Projects), International Life Sciences Institute

(ILSI), New Delhi, India.

DOI: 10.1542/peds.2015-1313

Accepted for publication Aug 26, 2015

Address correspondence to Gomathy Sethuraman,

MD, Department of Dermatology, All India Institute

of Medical Sciences, New Delhi 110029, India. E-mail:

kgsethu@yahoo.com, aiimsgsr@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,

1098-4275).

Copyright © 2016 by the American Academy of

Pediatrics

FINANCIAL DISCLOSURE: The authors have

indicated they have no fi nancial relationships

relevant to this article to disclose.

FUNDING: No external funding.

REPORT

Congenital ichthyoses are a group of

Mendelian disorders of cornification

that result in abnormal differentiation

and desquamation of the epidermis.

We earlier reported a high prevalence

of vitamin D deficiency and rickets in

children with congenital ichthyosis.1,2

Ichthyosis children with serum levels

of 25-hydroxyvitamin D (25(OH)D)

≤ 8 ng/mL and parathyroid hormone

(PTH) ≥ 75 pg/mL had significantly

higher risk of developing rickets.3 The

earlier practice of treating such cases

in our department was to supplement

with 60 000 IU of oral cholecalciferol

weekly for 6 weeks followed by

60 000 IU once a month. The

compliance to this treatment protocol

was poor because of the inability

of these cases to come for regular

follow-up due to poor socioeconomic

status and residing a long distance

from the clinic. Hence, we decided

to treat congenital ichthyosis and

vitamin D deficiency, with oral

cholecalciferol 60 000 IU daily for 5

days (stoss therapy).4 Incidentally,

we noticed an excellent clinical

response with regard to softening of

skin and reduction in scaling by day

5, and therefore we continued with

the same dose for another 5 days to

observe whether there was further

improvement in the skin.

In this initial observational case

series, we describe our experience

of short-term high-dose vitamin

abstractSevere vitamin D deficiency and rickets are highly prevalent among

children with congenital ichthyosis. We report an incidental observation of

a dramatic and excellent clinical response with regard to skin scaling and

stiffness in children with congenital ichthyosis after short-term high-dose

vitamin D supplementation that has not been previously described. Seven

children with congenital ichthyosis (5 with autosomal recessive congenital

ichthyosis; 2 with epidermolytic ichthyosis) and severe vitamin D deficiency

(and/or rickets) were given 60 000 IU of oral cholecalciferol daily for 10 days

under supervision. All children were subsequently put on recommended

daily allowance of 400 to 600 IU of cholecalciferol. The main outcome

measures observed and studied were reduction in skin scaling and stiffness

of the extremities. All cases had severe vitamin D deficiency (serum

25-hydroxyvitamin D < 4 ng/mL) and secondary hyperparathyroidism.

Six patients had clinical and radiologic evidence of rickets. Significant

improvement in scaling was noticeable by day 5, showing further

improvement by day 10, in 6 of the 7 cases. At 1 month, the skin had become

near normal in all the cases of autosomal recessive congenital ichthyosis.

Remarkable reduction in stiffness was also observed in all children.

Supplementation with high-dose vitamin D followed by recommended daily

allowance appears to be an effective form of therapy in the management of

congenital ichthyosis with vitamin D deficiency.

CASE REPORTPEDIATRICS Volume 137 , number 1 , January 2016 :e 20151313

To cite: Sethuraman G, Marwaha RK, Challa A, et al.

Vitamin D: A New Promising Therapy for Congenital

Ichthyosis. Pediatrics. 2016;137(1):e20151313

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SETHURAMAN et al

D supplementation in children of

congenital ichthyosis with vitamin D

deficiency and/or rickets.

METHODS

Seven consecutive cases of congenital

ichthyosis with severe vitamin D

deficiency (autosomal recessive

congenital ichthyosis [ARCI] =

5; Epidermolytic ichthyosis [EI]

= 2), aged 9 months to 8 years,

were recruited in the outpatient

dermatology clinic and admitted for

treatment with oral cholecalciferol

60 000 IU daily for 10 days under

supervision, with the exception of

an infant who was given this dose

for 5 days only. All children were

subsequently put on recommended

daily allowance (RDA) of 400 to 600

IU of cholecalciferol. In addition, 40

mg/kg/day of elemental calcium

was given in all the cases. Serum

biochemistry and urinary calcium-

creatinine ratio were evaluated

at baseline, 10 days, 1 month,

and 3 months. Serum 25(OH)

D and PTH were measured by

chemiluminescence assay (Diasorin,

Stillwater, MN). Calcium, phosphate,

and alkaline phosphatase were

estimated by auto-analyzer.

RESULTS

All children had severe vitamin

D deficiency (serum 25(OH)

D < 4 ng/mL) and secondary

hyperparathyroidism. Six patients

had clinical and radiologic

evidence of rickets (mean rickets

radiologic scores 4.2, range 1–10).

Significant improvement in scaling

was noticeable by day 5, showing

further improvement by day 10,

in all the cases except 1 (Figs 1, 2,

3, and 4) (Supplemental Figure 5).

Remarkable reduction in stiffness

was also observed in all children. At

1 month, the skin had become near

normal. The overall response was

significantly better on the face and

trunk than the extremities. The child

who was given only 5 days of oral

vitamin D also showed an excellent

response with normalization of

ectropion by day 5 (Fig 3 A3).

Two of the children with ARCI, who

had completed 6 months of follow-up

with daily allowance of vitamin

D, maintained the same status in

2

FIGURE 1Autosomal recessive congenital ichthyosis in a child. A (1–3), Baseline picture shows dark brown large and thick adherent scales on the face, trunk, and extremities. B (1–4), Reduction in scaling after 5 days of cholecalciferol therapy. C (1–3), Further reduction in scaling after 10 days of oral cholecalciferol therapy. D (1–4), Near normal skin at 1-month follow-up.

FIGURE 2EI in a child. A (1–5), Baseline picture showing hyperkeratotic ridgelike verruciform scaling that is more pronounced on the extremities. B (1–3), Excellent clinical response resulting in clearance of thick hyperkeratotic scaling after 10 days of cholecalciferol supplementation. C (1–4), showing sustained clinical response at 3-month follow-up. D (1–4), showing advanced skeletal changes of rickets.

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PEDIATRICS Volume 137 , number 1 , January 2016

skin condition. However, in 1 of

these cases, the caregiver stopped

the RDA for 4 weeks, resulting in

reappearance of scaling on the trunk,

which subsequently started clearing

within 2 weeks of restarting the RDA

of vitamin D.

In 1 case of EI, the response was not

satisfactory despite adequate levels

of serum 25 (OH) D. Serum 25(OH)

D > 150 ng/mL was observed in

2 cases on day 10, and hence the

RDA was not given until day 30,

after which serum 25(OH)D levels

normalized. No clinically evident

adverse side effects were seen except

for hypercalcemia in 1 case, which

normalized during follow-up.

Serum 25 (OH) D, PTH, calcium,

phosphate, and alkaline phosphatase

levels at different points of time

during follow-up are shown in Tables

1 and 2.

DISCUSSION

Our report clearly shows that

correction of severe vitamin D

deficiency with short-term high-

dose cholecalciferol (vitamin

D3) in children with congenital

ichthyosis (ARCI and EI) results

in significant reduction in skin

scaling. Keratinocytes possess

the entire vitamin D metabolic

pathway, including the 25(OH)

D-1α- hydroxylase resulting in

production of 1,25 dihydroxy

vitamin D3, which is responsible

for the autocrine or paracrine

functions. It may be hypothesized

that correcting vitamin D deficiency

with high-dose vitamin D3 might have

resulted in an increased keratinocyte

production of 1,25(OH)2D3,

which has antiproliferative and

prodifferentiating actions leading

to normalization of keratinization

and clearance in skin scaling.6,7 This

hypothesis has been supported

by the in vitro observation by Lu

et al,8 who have shown that 1,25

dihydroxy vitamin D3 regulates

the expression of a number of

genes that are involved in the

terminal differentiation and

desquamation of keratinocytes.

These are collectively called as

vitamin D–responsive genes, which

include involucrin (that is involved

in cornified envelope formation),

peptidylarginine deiminase (a family

3

FIGURE 3ARCI in an infant. A1, Baseline picture showing thick hyperkeratotic platelike scales on the face with ectropion. A2, Remarkable improvement in scaling with normalization of ectropion after 5 days of oral cholecalciferol. A3, Sustained clinical response at 3 weeks after vitamin D supplementation.

FIGURE 4ARCI in a male patient. A1, Thick tilelike scales on the legs. A2, Beginning of clearing of scales. A3, Near normal skin at 3 months after vitamin D supplementation.

TABLE 1 Biochemical Profi le of Ichthyosis Children: 25(OH)D and PTH

Pt Age (y) Gender Diagnosis Radiologic

Rickets Scoresa

25(OH)D (ng/mL)b PTH (pg/mL)c

Day 0 Day 10 Day 30 3 mo Day 0 Day 10 Day 30 3 mo

1 3 M ARCI 4 <4.0 47 31.8 239 26.1 20.3

2 8 F ARCI 8 <4.0 23.3 635 90.1

3 2.5 M ARCI 1 <4.0 35.3 37.4 13.1 152 23.8 11.2 18.8

4 3 M EI 10 <4.0 >150 67.7 36.7 398 70 166 41.3

5 1.5 M ARCI 4 <4.0 119 37.2 38.4 584 34.2 45.3 64.7

6 3.5 F EI Normal <4.0 101 63.6 55.6 22 26.5

7 0.75 M ARCI 2.5 >150 75 38.4 144 6.52 20.8 21.6

a From Thatcher et al.5. Pt, patient number.b Normal: 30–100 ng/mL.c Normal: 15- 65 pg/mL.

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SETHURAMAN et al

of calcium-dependent enzymes

required for protein deimination

during the final stages of epidermal

differentiation), transglutaminase

1 (that is involved in cross linking

of cornified envelope proteins

with keratins), kallikrein (serine

proteases that helps in shedding of

old corneocytes), serine proteinase

inhibitors B (important for negative

feedback regulation of stratum

corneum serine protease activity),

cystatin EM, small proline rich

protein 1 B, Kruppel-like factor 4 and

c-fos. The excellent clinical response

to vitamin D in our series might be

related to the vitamin D-mediated

epidermal differentiation network.

We changed the regular treatment

protocol of weekly dose of

vitamin D followed by monthly

maintenance to a short-term high-

dose supplementation, owing to

poor compliance associated with

staggered regular protocol. Several

investigators have evaluated the

safety of high-dose vitamin D.

Hackman et al9 used similar high-

dose therapy (oral cholecalciferol

50 000 IU daily for 10 days) for

vitamin D–deficient population

without significant adverse effects.

They concluded that the high-dose

regimen might be an effective

and cheap alternative for patients

with vitamin D deficiency. Mondal

et al,10 in their randomized trial,

compared the safety and efficacy

of cholecalciferol 600 000 IU single

intramuscular high dose with

staggered oral dose in children with

rickets and concluded that both are

safe and effective. The short-term

high-dose therapy in our series

seems to work well in congenital

ichthyosis. This is in contrast to

the observation by Thacher et

al,5 who despite treating a case of

lamellar ichthyosis and rickets with

intramuscular vitamin D3 600 000

IU showed no improvement in skin

scaling. The same study also showed

no improvement after 6 weeks of

topical calcipotriene. Okano et al11

also reported ineffectiveness of oral

1 α hydroxyvitamin D3 in ichthyosis.

In our series, we did not observe

any noticeable improvement in skin

scaling in 1 case of EI. Two other

reports have observed a beneficial

effect of topical calcipotriol

in various types of congenital

ichthyosis.12,13

Retinoids have been the mainstay

of treatment in moderate to severe

ichthyosis but should be used with

caution, particularly in younger

children, due to their potential

side effects, especially skeletal

toxicity. With retinoid therapy, the

improvement in skin thickness and

scaling begins in ∼1–2 weeks of

starting the treatment in ARCI.14

The response, however, is variable

and does not lead to near complete

clearance of scaling (personal

observation), as reported in the

present case series with vitamin D

supplementation. In all our cases,

the parents noticed reduction in

stiffness within 2 to 3 days of vitamin

D supplementation, indicating an

immediate response. Importantly,

the sustained near-normal skin was

observed in 2 children with ARCI,

who were on RDA for 6 months. In

1 of the cases of EI, even the thick,

scaly plaques significantly cleared

by the 10th day. Because this child

had serum 25(OH)D > 150 ng/mL,

on day 10, we stopped all treatment

for the next 3 weeks, and sustained

clinical response was noticed even at

1 month. Later, at 3-month follow-up,

he continued to have good clinical

response, but with reappearance of

minimal scaling, which significantly

cleared on resuming the RDA of

vitamin D 800 IU.

Our observations suggest that

vitamin D may be considered as

an alternative therapy in younger

children with congenital ichthyosis

and vitamin D deficiency, especially

in pigmented skin types. In view of

widely reported vitamin D deficiency

across the globe, vitamin D therapy

could possibly be used in other skin

types with ichthyosis, even in the

absence of rickets.

In view of 1 case developing

hypercalcemia after 10 days of

therapy and good response with

normalization of ectropion even after

5 days of therapy in another child,

we feel cholecalciferol 60 000 IU

per day for 5 days followed by RDA

may be adequate for good clinical

response. Additional long-term

4

TABLE 2 Additional Biochemical Profi le

Pt Calcium (mg %)a Phosphate (mg %)b Alkaline Phosphatase (IU)c Urinary Calcium/Creatinine Ratio

(Spot)

Day 0 Day 10 Day 30 3 mo Day 0 Day 10 Day 30 3 mo Day 0 Day 10 Day 30 3 mo Day 0 Day 10 Day 30 3 mo

1 10.3 10 10.4 3.72 4.8 5.2 393.5 524 220 0.11

2 10 9.9 6.1 4.8 494 402 0.037 0.053

3 8.97 10.82 11.2 10.2 2.43 6.33 7 4 285.3 334.8 814 262 0.208

4 6.7 9.6 9.7 10.2 3.6 5.7 5.6 4.4 2998 991 492 271 0.061 0.063 0.031 0.071

5 9.12 9.3 9.5 9.8 2.6 4.8 4.7 4.2 649.8 654 439 340 0.05 0.077 0.016 0.17

6 9.1 9.2 9.7 5.1 5.5 4.7 268 238 196 0.045 0.28 0.160

7 10.5 10 9.3 10.4 4.6 3.5 4.3 6.6 446 87 173 247 0.167

a Normal: 8.1–10.4 mg %.b Normal: 2.5–4.5 mg %.c Normal: 240–840 IU.

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PEDIATRICS Volume 137 , number 1 , January 2016

follow-up and randomized controlled

studies are needed to understand the

efficacy of varying dosing schedules,

safety, and duration of therapy

in different types of congenital

ichthyosis with or without rickets.

In addition, molecular studies with

gene expression profile will be an

important step in delineating the role

of vitamin D in congenital ichthyosis.

The limitations in this study were poor

follow-up for clinical and biochemical

evaluation after 1 month of starting

supplementation with vitamin D.

ACKNOWLEDGMENTS

We gratefully acknowledge the faculty

and residents of the department for

their help and support.

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et al. Ichthyosiform erythroderma

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3. Sethuraman G, Sreenivas V,

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levels of 25-hydroxyvitamin D and

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5

ABBREVIATIONS

25(OH)D:  25-hydroxyvitamin D

ARCI:  autosomal recessive

congenital ichthyosis

EI:  epidermolytic ichthyosis

PTH:  parathyroid hormone

RDA:  Recommended Daily

Allowance

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

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DOI: 10.1542/peds.2015-1313 originally published online December 31, 2015; 2016;137;Pediatrics 

Lakshmy Ramakrishnan, Sanjay Thulkar and Vinod K SharmaGomathy Sethuraman, Raman K Marwaha, Apoorva Challa, Vamsi K Yenamandra,

Vitamin D: A New Promising Therapy for Congenital Ichthyosis

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