Pediatric Pearls Perfectly Repolished: Part 1 Molecular Pathways: Towards a Better Understanding of Genetic Disorders Ilona J. Frieden, MD

In this presentation, Dr Frieden discusses molecular pathways and how the science can be applied into clinical practice in order to optimize the outcomes for patients with dermatologic diseases.

 The concept of Molecular Pathways

Dr Frieden’s concept of molecular pathways is described here. Signaling pathways are essential in regulation and growth development. These pathways are the key to understanding of the phenotypic overlap of many genetic disorders because even diseases with distinct genetic causes can show overlap if they involve a molecular pathway because the defect can be present either upstream or downstream of another condition and thus show similar features.  Understanding these pathways can  also help to bring us closer to more rational therapies because if we find things that inhibit overactivity of an element of a pathway, it may work not just for one disease but for several.

 RAS/MAP Kinase Pathway

The RAS/MAP kinase pathway is essential to our central understanding of melanoma genetics, for example melanomas with mutations in NRAS and BRAF. This pathway also plays a major role in NF1 and other genetic syndromes.

 

Collectively germ-line genetic diseases in this pathway can be referred to as “Rasopathies”.  They include Noonan syndrome, cardiofaciocutaneous syndrome, NF1, and Legius syndrome.  All share in common features of developmental delay and most also have café-au-lait macules as a common feature.

 

Geneticists call this group (CFC, Noonan, NF-1, and Costello) of overlapping disorders RASopathies.

Another Important Pathway: PI3K

PI3K stands for phophatidylinositol-3-kinase, and the pathway in which PI3K is involved  is sometimes called the PI3K/AKT/mTOR pathway. This pathway is critical to cell growth and survival. It is intimately involved in normal vascular development and angiogenesis. The mammalian target of Rapamycin (mTOR) integrates signals from the pathway to coordinate cell growth and proliferation both in the fetus and continues to work later in post-natal life as well.

 

PTEN is the most important negative regulator of the cell-survival signaling pathway initiated by P13K. There is also crosstalk between P13K pathways and other tumorigenic signaling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation.

Genetics of Proteus Syndrome

Based on a paper published by Lindhurst et al in 2011, we now know that the cause of Proteus Syndrome is due to mutations in the oncogene AKT1 that is found right in the center of the P13K pathway. The researchers in this study conducted exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome—158 samples from 29 patients. 26 out of the 29 had a somatic activating mutation in the oncogene AKT1. Tissues and cell lines harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Two of the 38 peripheral-blood DNA samples were positive for the mutation compared with affected tissue (75 of 97, P<0.001) and unaffected samples that were positive (13 of 41, P = 0.004). This was a very important breakthrough as it determined that AKT1 was the cause of Proteus syndrome.

PI3K Syndromes: Overgrowth is a Common Motif

  • Cowden and Bannayan syndrome (PTEN)
  • Proteus (ALK)
  • Tuberous Sclerosis
  • Capillary Malformation-AVM and Parkes Weber
  • Familial venous malformations

Diseases Probably in the Pathway (but not proven)

  • Macrocephaly-Capillary Malformation
  • CLOVE syndrome
  • Diffuse capillary malformation with overgrowth
  • Probably others…

Clinical Pearls– Pathways help to explain the overlapping phenotypes of distinct genetic diseases. They help us to think about candidate genes for unknown disorders because they can lead us to look at certain candidate genes to see if they may be the cause of other phenotypically similar conditions. Pathways may also provide important molecular targets for treating previously untreatable diseases.

Inflammatory Diseases in Little Kids: Part 2

Pediatric Psoriasis

Lawrence F. Eichenfield, MD

Obesity appears to be a common comorbidity in pediatric patients with psoriasis.   It is uncertain if the cardiovascular risks seen in adults with psoriasis is fundamentally related to obesity, skin inflammation, or other factors.  It is reasonable to discuss these issues with families of children with psoriasis, though much research is needed about long-term risks and modifying them.

Regarding psoriatic arthritis (PsA) in children, consider asking children with psoriasis about morning stiffness, as this can be a sign of PsA.  Pediatric psoriasis is typically treated with topical corticosteroids and Vitamin-D analogues; however, clinicians should not forget the appropriate placement of light therapy (NB-UVB is the most studied), which can be very effective.  The National Psoriasis Foundation has a pediatric site that is kid-friendly and provides much needed information and resources.

Systemic treatment is appropriate for severe psoriasis in children and adolescents, though it can be much work to have third party payers cover the costs of systemic therapies including biologic agents as there are no specifically approved systemic treatments for children and adolescents with psoriasis.

In summary, there is a fair amount of new information for both Atopic Dermatitis and psoriasis and, in the future, hopefully more treatments will become available for pediatric patients.

 

 

Inflammatory Diseases in Little Kids: Part 1

Inflammatory Disease in Little Kids

Lawrence F. Eichenfield, MD

 

In this presentation, Dr. Eichenfield discussed inflammatory diseases in children in a clinically relevant manner.  Dr. Eichenfield provided a review of the pathogenesis of atopic dermatitis (AD), the role of filaggrin, and allergies in AD.  He also updated us on new findings in pediatric psoriasis.

Atopic Dermatitis

When reviewing AD, it is important to consider the issues noted below:

  • Barrier dysfunction
  • Infection
  • Inflammation
  • Allergy
  • Itching

PEARL:  The phenotype, associated with ichtyhosis vulgaris, is associated with peanut allergy.  Be careful when you take your atopic child or nephew to a baseball game or circus.

Filaggrin Insufficiency

Filaggrin haploinsufficiency is defined as a 50% reduction in the expression of the filaggrin protein, an important functional protein that influences epidermal function.   Filaggrin mutations are associated with decreased filaggrin production, as well as higher rates of development of associated conditions.  The odds ratios for the risk of peanut allergy, asthma, or atopic dermatitis with Filaggrin mutations are greater as compared to individuals without Filaggrin mutations. The odds ratios for atopic dermatitis and asthma, from meta-analyses involving several thousand patients display that FLG mutations confer an overall risk of asthma of 1.5, but this risk is restricted to patients with atopic dermatitis. The odds ratio for the complex phenotype of asthma plus atopic dermatitis is 3.3. The odds ratio for peanut allergy is 5.3 and is based on data from a single study.  Of interest is that there is no filaggrin in the mucosal surfaces of the mouth or esophagus so it likely that the peanut allergy is the result of epicutaneous sensitization. (Irvine AD, McLean I, Leung DYM. N Engl J Med 2011;365:1315-27)

The question is how does filaggrin deficiency affect the skin barrier?  The answer is a decrease in filaggrin expression increases skin permeability, increases skin pH, decreases natural moisturizing factor and decreases cell-to-cell cohesion impacting barrier function.

Of importance, even in individuals who do not have the filaggrin mutation, there are decreased filaggrin byproducts in actively, inflamed eczema.

Atopic dermatitis can be triggered by the chronic exposure of barrier-disrupted skin to percutaneous antigens due to abnormalities in fillaggrin; however, only 30-50% have FLG mutations and most outgrow AD.  40% of patients with FLG-null alleles do not get AD. Therefore, there are other factors that influence AD development and course other than just filaggrin.

What are some of the traditional approaches and targeted therapies?

  • Moisturizing after bathing
  • Use of emollients
  • Targeted barrier repair products

These measures are part of maintenance care for all patients, and primary intervention for mild AD in infants.

What are some of the things that can be done for the prevention of Atopic Dermatitis? In the past, physicians have considered:

  • Formula
  • Maternal diet
  • Infant diet
  • Allergen avoidance (both environmental and food)
  • Probiotics
  • Prebiotics

So far, none of strategies mentioned above have solid data for their efficacy. Several international studies are currently looking at the role of early intervention in skin care in order to stop AD.

Anti-inflammatory therapy

There are typically two ways that a dermatologist handles a child with AD.

1. “As low as you can go (or just above where they were)”, i.e., the least strong topical steroid that can be used and 2: “Stronger steroids” to start, with tapering to less potent corticosteroids as the AD improves. Both of these approaches are reasonable. Many clinicians tend to “mix and match” the topical corticosteroids with the non-steroid topicals and utilize wet wraps with topical corticosteroids in patients with more difficult remissions.

Over the next few years, dermatologists will be seeing some new agents for the treatment of AD. These therapies include selective glucocoid agonist receptor stimulants, histamine 4 blockers as well as other molecules.

Wet Wrap Dressing with TCS Use: Effective, Rapid Control of Severe AD

Dawn Davis and colleagues conducted a study on wet wrap dressing in 218 patients who were hospitalized. The mean age of application was 6 years (2 months-17 years), the mean duration of hospital stay was 3.61 days (range 1-16) and all patients showed improvement.  45% of the patients showed 75-100% improvement; 38% of patients showed 50-75% improvement and 6% of patients showed a 25-50% improvement.

There are many methods to the use of wet wrap with topical corticosteroids and the benefits are clearly demonstrated.

Another important therapeutic intervention for AD, now recognized internationally, is education.   A struggle that clinicians face is how to educate patients within the limited time of busy office settings, so that patients understand how to utilize their medicines while also managing their fears with respect to the utilization of steroids and medications.

Pediatric Pearls and Conclusions

  • Prescribe specific amounts
  • Assess quantities of time
  • Discuss strengths and safety
  • Use educational and instructional materials
  • Handouts, web-sites, video training modules:  www.eczemacenter.org
  • Follow-up soon!  Studies show that there is more chance that patients will follow their regimen and will have better clinical outcomes

Maintenance Therapy

  • Emollients alone? In 30-40% of infants, this may be sufficient
  • Intermittent corticosteroids
  • TCIs (delicate areas, persistent, frequently recurrent)
  • Targeted-Barrier-repair products
  • BRING THEM BACK while they are still under control

What about the patients who are better, but not great or have persistent, frequent flaring?

  • Ask about feeding practices, atopic history
  • Establish aggressive maintenance plan
    • Intermittent CS and/or TCIs
    • Assess sleep and itching as endpoints
    • Trials of TBRP (targeted barrier repair products) and/or emollients
    • Consider anti-infectives, bleach baths/products
    • Check growth, infection history, differential diagnosis
    • Consider allergy referral

TCI Safety Information

New information has been collected with regards to TCI safety, but the data have not yet been published. The FDA Pediatric Advisory Committee evaluated emerging data as part of a routine evaluation of TCI safety and use.   They looked at the epidemiology studies, the clinical studies, Data Safety Monitoring Boards and Post-marketing surveillance/Adverse Events Reporting System (AERS). The FDA found that there is no evidence of an association between TCIs and B-cell lymphomas but because of the limited data available, one cannot necessarily form conclusions from the published literature. The FDA also said that a literature review suggests a possible association between topical tacrolimus use and an increased risk of T-cell lymphoma.  The T-cell lymphoma association, however, may be due to use of the TCI in individuals reported as having eczema prior to the diagnosis of cutaneous T-cell lymphoma (known as protopathic effect).

It is important to remember that these are retrospective studies; so drawing conclusions can be difficult for the clinician.

An epidemiologic survey published by Tennis and Gelfand came to the same conclusions, i.e., there is little to no evidence of an increased risk of lymphomas overall or specific sub-types of lymphoma with topical TCI use and there is no evidence indicating that melanoma or non-melanoma skin cancer is associated with topical TCI use.

Microbes

Dr Eichenfield posed the following question to the audience…

Staph aureus in patients with atopic dermatitis:

A.  Is more likely to be MRSA than staph in infections in non-atopics

B.  Is less common than streptococcal infection

C.  Is less likely to be MRSA than staph in infections in non-atopics

D.  None of the above

MRSA and Atopic Dermatitis

Dermatologists should be aware that atopics have lower rates of MRSA infection than community-acquired staph infections. From an ecological perspective, the question is “does MSSA protect against MRSA?”

Translation into Clinical Practice

Bleach Baths and Alternatives*

  • ¼ to ½ cup for ½ to full tub of standard bleach (6%).
    • 5 cup for 40 gallon full tub is 0.005% concentration
    • Dilute Na hypochlorite and hypochlorous acid (Aurstat: marketed with HylatopicPlus)*
    • Na Hypochlorite body wash (CLn BodyWash)*

The AD market has responded to this and there are now at least two alternatives currently available to bleach baths. One of which is a tube of sodium hypochlorite and hypochlorous acid and it is paired with a ceramide-containing moisturizer. The other product is available over the internet that is a sodium hypochlorite body wash in a can.ir

Comorbidities and Atopic Dermatitis

Over the last few years atopic dermatitis has been associated with higher rates of attention deficit disorder and other mental health disorders.  Recent evaluation of a large healthcare database displayed higher rates of ADD in individuals with atopic dermatitis as compared to those without atopic dermatitis, with evidence of higher rates proportionate to severity of ADD.   Depression was also higher in teens and adults with AD.  While there is may not be enough evidence to mandate screening of atopic dermatitis patients, clinicians should be aware of the association.

Food Allergy and Eczema

About 17% of children with mild AD and 30-40% of moderate to severe children have at least one clinically relevant food allergy.  Food allergy testing (skin testing and IgE testing), however, yields many false positive tests; in fact, it is estimated that 4 out of 5 positive tests may not be associated with true food allergy, but only with IgE sensitization (e.g. Milk: 238 of 1000 tested will have false + ;  vs. 50 having clinically relevant allergy). 

Highlights from the NIH Food Allergy Guidelines

The current guidelines suggest that children less than 5 years of age with moderate to severe AD be considered for FA evaluation for milk, egg, peanut, wheat, and soy, if at least one of the following conditions is met:

  • The child has persistent AD in spite of optimized management and topical therapy.
  • The child has a reliable history of an immediate reaction after ingestion of a specific food

Dr Eichenfield feels that it is appropriate to ask about food allergies; if a child has had a food allergy, then an EPIPEN or EPIPEN Jr. should be prescribed.

Clinical Pearls for Atopic Dermatitis

  • Great skin care
  • Anti-inflammatory medication as needed, with most care as topical regimens
  • Maintenance care “as needed”
  • Keep regimens simple
  • Educate…in the office, on the net, wherever!
  • If really hard, seek help!

Inflammatory Disease in Little Kids

Lawrence F. Eichenfield, MD

In this presentation, Dr Eichenfield discusses inflammatory diseases in children in a clinically relevant manner.  Dr Eichenfield provides a review of the pathogenesis of atopic dermatitis (AD), the role of filaggrin, and allergies in AD.  He also updated us on new findings in pediatric psoriasis.

Atopic Dermatitis (AD)

When reviewing AD, it is important to consider the issues noted below:

  • Barrier dysfunction
  • Infection
  • Inflammation
  • Allergy
  • Itching

PEARL:  The phenotype, associated with ichtyhosis vulgaris, is associated with peanut allergy. Be careful when you take your atopic child or nephew to a baseball game or circus.

Filaggrin Insufficiency

Filaggrin haploinsufficiency is defined as a 50% reduction in the expression of the filaggrin protein, an important functional protein that influences epidermal function.   Filaggrin mutations are associated with decreased filaggrin production, as well as higher rates of development of associated conditions.  The odds ratios for the risk of peanut allergy, asthma, or atopic dermatitis with filaggrin mutations are greater as compared to individuals without filaggrin mutations. The odds ratios for atopic dermatitis and asthma, from meta-analyses involving several thousand patients display that FLG mutations confer an overall risk of asthma of 1.5, but this risk is restricted to patients with atopic dermatitis. The odds ratio for the complex phenotype of asthma plus atopic dermatitis is 3.3. The odds ratio for peanut allergy is 5.3 and is based on data from a single study.  Of interest is that there is no filaggrin in the mucosal surfaces of the mouth or esophagus so it likely that the peanut allergy is the result of epicutaneous sensitization. (Irvine AD, McLean I, Leung DYM. N Engl J Med 2011;365:1315-27)

The question is how does filaggrin deficiency affect the skin barrier?  The answer is that decrease in filaggrin expression increases skin permeability, increases skin pH, decreases natural moisturizing factor and decreases cell-to-cell cohesion impacting barrier function.

Of importance, even in individuals who do not have the filaggrin mutation, there is decreased filaggrin byproducts in actively, inflamed eczema.

Atopic dermatitis can be triggered by the chronic exposure of barrier-disrupted skin to percutaneous antigens due to abnormalities in filaggrin; however, only 30-50% have FLG mutations and most outgrow AD. 40% of patients with FLG-null alleles do not get AD. Therefore, there are other factors that influence AD development and course other than just filaggrin.

What are some of the traditional approaches and targeted therapies?

  • Moisturizing after bathing
  • Use of emollients
  • Targeted barrier repair products

These measures are part of maintenance care for all patients, and primary intervention for mild AD in infants

What are some of the things that can be done for the prevention of Atopic Dermatitis? In the past, physicians have considered:

  • Formula
  • Maternal diet
  • Infant diet
  • Allergen avoidance (both environmental and food)
  • Probiotics
  • Prebiotics

So far, none of strategies mentioned above have solid data for their efficacy.

Several international studies are currently looking at the role of early intervention in skin care in order to stop AD.

Anti-inflammatory therapy

There are typically two ways that a dermatologist handles a child with AD.

1. “As low as you can go (or just above where they were)”, i.e., the least strong topical steroid that can be used and 2: “Stronger steroids” to start, with tapering to less potent corticosteroids as the AD improves. Both of these approaches are reasonable. Many clinicians tend to “mix and match” the topical corticosteroids with the non-steroid topicals and utilize wet wraps with topical corticosteroids in patients with more difficult remissions.

Over the next few years, dermatologists will be seeing some new agents for the treatment of AD. These therapies include selective glucocoid agonist receptor stimulants, histamine 4 blockers and other molecules as well.

Wet Wrap Dressing with TCS Use: Effective, Rapid Control of Severe AD

Dawn Davis and colleagues conducted a study on wet wrap dressing in 218 patients who were hospitalized. The mean age of application was 6 years (2 months-17 years), the mean duration of hospital stay was 3.61 days (range 1-16) and all patients showed improvement.  45% of the patients showed 75-100% improvement; 38% of patients showed 50-75% improvement and 6% of patients showed a 25-50% improvement.

There are many methods to the use of wet wrap with topical corticosteroids and the benefits are clearly demonstrated.

Another important therapeutic intervention for AD, now recognized internationally, is education.   A struggle that clinicians face, is how to educate patients within the limited time of busy office settings, so that patients understand how to utilize their medicines, while also managing their fears with respect to the utilization of steroids and medications.

Pediatric Pearls and Conclusions

  • Prescribe specific amounts
  • Assess quantities of time
  • Discuss strengths and safety
  • Use Educational and Instructional materials
  • Handouts, Web-sites, Video training modules www.eczemacenter.org
  • Follow-up soon!  Studies show that there is more chance that they will follow their regimen and will have better clinical outcomes

Maintenance Therapy

  • Emollients alone? In 30-40% of infants, this may be sufficient
  • Intermittent corticosteroids
  • TCIs (delicate areas, persistent, frequently recurrent)
  • Targeted-Barrier-repair products
  • BRING THEM BACK when they’ll still be under control

What about the patients who are better, but not great or have persistent, frequent flaring?

  • Ask about feeding practices, atopic history
  • Establish aggressive maintenance plan
    • Intermittent CS and/or TCIs
    • Assess sleep and itching as endpoints
    • Trials of TBRP (targeted barrier repair products) and/or emollients
    • Consider anti-infectives, bleach baths/products
    • Check growth, infection history, differential diagnosis
    • Consider allergy referral

TCI Safety Information

There has been new information collected with regards to TCI safety, but the data have not yet been published. The FDA Pediatric Advisory Committee evaluated emerging data as part of a routine evaluation of TCI safety and use.   They looked at the epidemiology studies, the clinical studies, Data Safety Monitoring Boards and Post-marketing surveillance/Adverse Events Reporting System (AERS). The FDA found that there is no evidence of an association between TCIs and B-cell lymphomas but because of the limited data available, one cannot necessarily form conclusions from the published literature. The FDA also said that a literature review suggests a possible association between topical tacrolimus use and an increased risk of T-cell lymphoma.  The T-cell lymphoma association, however, may be due to use of the TCI in individuals reported as having eczema prior to the diagnosis of cutaneous T-cell lymphoma (known as protopathic effect).

It is important to remember that these are retrospective studies; so drawing conclusions can be difficult for the clinician.

An epidemiologic survey published by Tennis and Gelfand came to the same conclusions, i.e., there is little to no evidence of an increased risk of lymphomas overall or specific sub-types of lymphoma with topical TCI use and there is no evidence indicating that melanoma or non-melanoma skin cancer is associated with topical TCI use.

Microbes

Dr Eichenfield poses the following question to the audience…

Staph aureus in patients with atopic dermatitis:

A.Is more likely to be MRSA than staph in infections in non-atopics

B.is less common than streptococcal infection

C.Is less likely to be MRSA than staph in infections in non-atopics

D.None of the above

MRSA and Atopic Dermatitis

Dermatologists should be aware that atopics have lower rates of MRSA infection than community-acquired staph infections. From an ecological perspective, the question is “does MSSA protect against MRSA?”

Translation into Clinical Practice

Bleach Baths and Alternatives*

  • ¼ to ½ cup for ½ to full tub of standard bleach (6%).
    • 5 cup for 40 gallon full tub is 0.005% concentration
    • Dilute Na hypochlorite and hypochlorous acid (Aurstat: marketed with HylatopicPlus)*
    • Na Hypochlorite body wash (CLn BodyWash)*

The AD market has responded to this and there are now at least two alternatives currently available to bleach baths. One of which is a tube of sodium hypochlorite and hypochlorous acid and it is paired with a ceramide-containing moisturizer. The other product is available over the internet that is a sodium hypochlorite body wash in a can.

Comorbidities and Atopic Dermatitis

Over the last few years the information available on attention deficit disorder has become much stronger as it relates to AD. Clinicians should know that behavioral disorders have been talked about in patients with AD for over 20 years. According to a recent publication in JAMA, as well as an unpublished large database survey study, ADD was seen more in younger children with AD and it was dose-dependent, in that, it correlated with the AD, the higher the severity, the more the risk of ADD. Depression was also higher in teens and adults. While there is no evidence to mandate screening, it should be considered.

Food Allergy and Eczema

About a17% of children with mild AD and 30-40% of moderate to severe children have at least one clinically relevant food allergy. However, food allergy testing (skin testing and IgE testing) can create a lot of false positives; in fact, 4 out of 5 tests may give a positive food allergy test yet there is no clinical relevance to the positive test.

(e.g. Milk: 238 of 1000 tested will have false +;  vs. 50 having clinically relevant allergy)

Consider Food allergy testing for moderate to severe, <5 yr old, with food reaction and/or disease resistant to standard topical regimens

Highlights from the Guidelines

The current guidelines suggest that children less than 5 years of age with moderate to severe AD be considered for FA evaluation for milk, egg, peanut, wheat, and soy, if at least one of the following conditions is met:

  • The child has persistent AD in spite of optimized management and topical therapy.
  • The child has a reliable history of an immediate reaction after ingestion of a specific food

Dr Eichenfield feels that it is appropriate to ask about food allergies and if a child has had a food allergy then an EPIPEN or EPIPEN Jr. should be prescribed.

Clinical Pearls for Atopic Dermatitis

  • Great skin care
  • Anti-inflammatory medication as needed, with most care as topical regimens
  • Maintenance care “as needed”
  • Keep regimens simple
  • Educate…in the office, on the net, wherever!
  • If really hard, seek help!

Pediatric Psoriasis

Obesity is a common comorbidity in pediatric patients with psoriasis. This is an important consideration for clinicians and counseling is important; however, this is being studied as to how this will correlate to adult risk. Regarding psoriatic arthritis in children, the most important screening test that dermatologists should remember to ask is about morning stiffness, i.e., arthritis. Pediatric psoriasis is typically treated with topical corticosteroids and Vitamin-D analogues; however, clinicians should not forget the appropriate placement of light therapy (NB-UVB is the most studied), which can be very effective. There are also combination products currently being studied such as Clobetasol/VitD. The National Psoriasis Foundation has a pediatric site that is kid-friendly and provides much needed information and resources.

Systemic treatment is still an ongoing battle with payors. There are no approved systemic treatments for children and adolescents with psoriasis.

In summary, there is a fair amount of new information for both AD and psoriasis and, in the future, hopefully more treatments will become available for pediatric patients.

 

 

Pediatric Pearls Restrung: Part 2

Sheila Friedlander, Ilona Freiden

Diaper Rashes

1984 was the introduction of a superabsorbent polymer, sodium polyacrylate. It absorbs a lot of water and converts from powder to gel. These diapers also buffer pH, they have a polyethylene film surface, are less irritant, and are better at containing fecal bacteria.

The lesions for diaper rash tend to appear as kissing lesions; in children with more chronic fecal or urinary exposure, the lesions can spread out.

When managing these children, try to address underlying cause of constant exposure to liquid stool. Barrier pastes e.g. Triple paste, Desitin, etc are often helpful. Clinicians should also consider adding an anti-yeast medication e.g. miconazole-zinc oxide paste or nystatin-HC ointment combination. If the child is not responding, re-think the diagnosis.

Pseudoverrucous Papules and Nodules

These are also known as “Granuloma gluteal infantum”. The papulo-nodular eruption is due to chronic irritation, usually with severe chronic fecal or urinary exposure. They can be difficult to treat so clinicians need to address underlying cause, if possible.

Pampers Dry-Max® are a 2010 product and claim to be two times drier and 20% thinner in order to “let them play on!” However, there was a widespread social media outburst (~12,000 members) among mothers who claimed that the diapers caused rashes and even “chemical burns”. A Consumer product safety commission investigated the issues and found that from April through August 2010, CPSC received nearly 4,700 incident reports about diaper rash. Nearly 85 percent of these complaints came in May and then dropped off significantly. The report from September 2010 stated: To date, the review has not identified any specific cause linking Dry Max diapers to diaper rash. However, if parents think Pampers DryMax are causing their child to have a rash, consult the doctor and change to a different diaper.

Vitamin D Delirium and Sunscreen Phobia

Patients are inundated with conflicting information regarding the benefits of the sun and the role of Vitamin D. Obviously, there are clear risks of the sun and there are also risks regarding the agents used for sun protection. Clearly, patients and parents are confused. It is important, as a clinician, to have a cogent message in mind. It’s important to explain the controversies and provide patients/parents with direction.

The sun is a source of Vitamin D; yet, it is also a source of harmful radiation. The spectrums for these two actions overlap and there is no way to separate them.
The AAD & AAP remain steadfast in their recommendations, i.e., vitamin D should be obtained via diet /supplements.

Vitamin D Requirements—IOM Recommendations
Assume no solar production component!

• Babies 0-1 400IU
• Adults 1-70 600 IU
• Adults 70+ 800 IU
• Safe upper limit – 4000 IU
• Why not more? Stones!

Take Home Message:

• Only clear benefit of Vitamin D relates to bone health
• Get your required amount through diet/supplements
• Things are not as bad as we thought in terms of how many people are deficient (IOM)
• There are risks to too much Vitamin D

Sunscreens

Patients are confronted with several different choices when choosing a sunscreen product. The Environmental Working Group – Watchdog has continuing concerns regarding sunscreen ingredients. Organic sunscreens have a hormonal effect and physical sunscreens have a penetration, persistence via ultramicronized nanoparticles. Their newest concern is Retinyl palmitate, a Vitamin A derivative found in many sunscreens. It is a vitamin A relative (retinyl ester) used to fortify food products such as milk, dairy, cereal. In sunscreens, it acts as antioxidant + aesthetic optimizer. In animal models, RP can generate free radicals. The National Toxicology Program selected RP for study, along with aloe vera, nano-titanium dioxide and zinc oxide.

Regarding baby sunscreen, it’s really an effort of trial and error. It is probably best that the baby is not exposed.

It is important to work with your patients and really weigh the benefits against the risks. The projected risk of melanoma in the US in 2015 is one out of fifty. One American dies of melanoma every hour. Clearly, we know that UB radiation exposure plays a role in this. If sunscreen were applied appropriately, we would be better off.

A study in Australia (Green AC, et al.) looked at patients 25 to 75 years of age to measure the effect of five years of sunscreen application and betacarotene on the incidence of BCC and SCC. The group that used the sunscreen had a lower incidence of melanoma (22 versus 11). There was some controversies around this study; however, an editorial in the Journal of Clinical Oncology stated that the P values were of borderline significance, but the hazard ratios showed a 50% reduction—in situ compared to invasive malignant melanoma and a 73% reduction in hazard related to melanoma alone.

Sunscreen Phobia-Summary

• Sun exposure – Modifiable risk factor
• Many studies – positive effect of sunscreen on mole number, some now show direct protective effect for melanoma
• Concerns raised by EWG re: ingredients; all theoretical re: humans
• If you tell people to avoid sun, they may ask you re: Vit D…. be prepared!

Pediatric Pearls Restrung (Part 1)

 

Sheila Friedlander, MD and Ilona Frieden, MD

What’s really new in pediatric dermatology?  In this presentation, Drs. Friedlander and Frieden discussed the latest and greatest in pediatric dermatology.

Beta Blockers & Hemangiomas

Do hemangiomas go away?  Before 2008 and to this day, many treatments can provide modest efficacy, and are best used in growth phase. These treatments include corticosteroids: systemic, intralesional and topical; other systemic agents such as interferon alpha and vincristine; pulsed dye laser and other treatments such as cryotherapy and imiquimod.

A somewhat recent breakthrough was the discovery of the use of propranolol for the treatment of hemangiomas. These data were published in 2008 in The New England Journal of Medicine.  The general consensus among pediatric dermatologists is that this truly is a breakthrough, along the lines of isotretinoin for severe acne and other major treatment breakthroughs.

Propranolol Q & As

Does it work?

There are more than 75 articles published since original report. It has impressive efficacy with more shrinkage of Infantile Hemangiomas (IH) than with prior treatments

Does it ever not work?

Occasionally; Based on the literature, there seems to be about a 5 to 10% failure rate

What is the usual dose?

1-3 mg/k/day divided BID or TID usually 6-12 months

What is the duration of treatment?

That depends on many factors – usually 6-12 months, sometimes longer

Can rebound occur?

YES!  Literature says about 20-25% of time

Can it be efficacious in older children with a fully-grown hemangioma?

There is some evidence for efficacy in older children up to age 3 to 4

What about for other vascular tumors or malformations (Kasabach-Merritt, Lymphatic Malformations)?

Probably NOT

Safety

Regarding the safety of propranolol, there are potential effects on cardiovascular system but bradycardia and hypotension are usually not an issue. There have been some reports of hypoglycemia, which can happen after weeks to months, mostly in the setting of decreased eating/fasting (anticipatory guidance), this is truly a risk that needs to be monitored. Nightmares, GI upset, asthma exacerbation have also been reported. There is a special concern for children with PHACE syndrome regarding arteriopathy/ “demand related potential ischemia”, which could cause a stroke.

There is really no consensus regarding how to best monitor patients on propranolol; however, there is a randomized control trial underway (sponsored by Pierre Favre). Here is how propranolol is used in Dr. Frieden’s practice at UCSF:

  • Less than 3 months hospitalized for 2 days
  • Over 3 months titrate dose up to 2 mg/k/day over 10 days as out-patient with HR measured for beta-blocker effect
  • Detailed instructions to avoid hypoglycemia

How does Propranolol work?

CD34+ EPCs in proliferative stage express angiotensin converting enzyme and angiotensin II receptor-2. An explant model shows EPCs form proliferative blast-like structures in the presence of angiotensin II. The authors hypothesize that the renin-angiotensin system may account for the response to propranolol. (Itinteang et al. J Plast Reconstr Aesthetic Surg 2010; Online early)

Topical Beta Blockers

There are three recent articles regarding the use of Timolol 0.5%. Timolol Gel-Forming Solution BID may be helpful for some superficial IH.  (Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. 2010 May;146:564-5.; Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010 Feb;128:255-6.; Khunger N,  Pahwa M. Dramatic response of a large hemifacial infantile hemangioma associated with PHACE syndrome to timolol lotion. Br J Dermatol Dec 15, 2010) The use of topical Timolol can be monitored by looking at systemic effects and the heart rate.

Treating Hemangiomas Current Status

  • A Randomized Control Trial is underway (for the use of propranolol)
  • Physicians must stay in their own comfort zone
  • Currently many are “drifting toward” propranolol as 1st line:
  • Use local consultants to determine the best approach
  • Frank discussion with parents – still use steroids for some patients early in the course
  • Hospitalize (usually 2 days) to initiate propranolol    if < 3 months of age

Warts and Molluscum

Warts and molluscum can be seen as a very important part of the dermatology practice as they are both extremely common. They are often physically benign; however, they can be extremely psychologically debilitating. Parents may become overly invested in a “clean slate”, and parents can really do damage to the child because of the messages they are giving. You, as the dermatologist, must act as the child’s advocate, as not all warts need to be treated because the risk of the treatment may be worse than the psychological damage that it is going on. It is important to consider what the parent feels because that is what the child is hearing.

Algorithm to Approaching Warts

  • Age
  • Extent
  • Cosmetic impact
  • Child’s concern
  • Parent’s concern
  • Prior therapy
  • Topicals (risk/benefit is often the best treatment)
  • Duct tape (with/without salicylic acid)
  • Triple “whammy”
    • Duofilm
    • Transversal
    • Duct tape
  • No success
    • Liquid N2

It is important to provide a handout for these patients detailing a clear description of the products and an explanation as to how to apply the products. It is important to be sure that patients/parents get the sequence right and that they are warned of any potential adverse effects, i.e. blisters, ring wart, scarring, and terror upon your entering the room.

What else can be done?

  • Topical retinoids
    • Beware of irritation and koebnerization
  • Imiquimod – money/insurance coverage & significant irritation
    • Innoculation may improve efficacy
  • 5-fluorouracil – less money, ? more irritation
    • Concerns re blood levels
  • Laser – a really big gun for lots of money
  • Bleomycin – we just don’t use it much in pediatric dermatology

Other Potential Treatments

According to Dr. Friedlander, Cimetidine can be used to buy you some time. There are some positive reports regarding the use of cimetidine. It appears to work better in children, atopics and in conjunction with topicals. The maximum dose is not really known, Dr. Friedlander generally uses up to 1200 mg, occasionally 1600 mg. It is very important to be aware of drug interactions and parents need to be aware of any other therapies that the child is on or prescribed. Some children don’t like the taste of cimetidine and others have experienced nausea while on the therapy. Dr. Friedlander has found that cimetidine works in about 30% of patients.

Candida, the mighty antigen, is currently a favorite. Candida is a highly immunogenic antigen. It augments the immune response and there is empiric and academic data supporting its use (note that in the first studies many of the patients were also on interferon and; therefore, some patients got sick). Candida is used in a variety of ways; many of the experts adhere to the following:

  • Inject undiluted antigen 0.1-0.3 cc per wart, using 30 gauge needle & tuberculin syringe
  • Inject both intradermally & intralesionally
    Maximum dose:  1 cc per session
  • Repeat in 3-4 weeks, generally 3-4 sessions

Candida does have an effect and it is important to beware of the “painful purple digit”. Do not overdo the injections in the periungual distal finger area.  Candin® the brand name for a candida antigen suspension may be obtained from Allermed Laboratories and a generic Candida antigen is also available.

Molluscum

Molluscum is a large brick-shaped virus. A renewed interest in the virus was came about recently due to the threats of biological warfare. The molluscipoxvirus belongs to the group of Poxviruses. It shares with the true Smallpox virus part of its genome, its specific pathogenicity to humans and its classic “brick-shape”. However, the Molluscipoxvirus is strictly localized to the epidermis and invokes a weak immune response compared to the deadly potential of the Orthopoxvirus.

Who gets molluscum?

The vast majority of people who have molluscum in the pediatric dermatology office are less than eight years of age. Most kids will have less than fifteen lesions, generally on the trunk extremities. A question remains as to whether atopic dermatitis patients have more trouble getting rid of the virus…

We know that molluscum will eventually go away, so why would we treat? There are occasional studies in the literature of molluscum spreading in pools and waterparks, so many physicians advise parents not to let their patients bathe with other children. Spread is a big issue. With molluscum, often times you can see infection and pseudo-infection, along with social stigma so there is a problem in having this disease; therefore, it should be treated.

Options for Treatment of Molluscum

Physical treatment includes curettage (mainly in Canada), cryotherapy and the use of keratolytic agents like salicylic acid. Immunotherapy includes candida, imiquimod, cimetidine and cantharidin. Cantharidin is referred to as “a blistering defense of an ancient medicine.”  It used to be a “Beetle-extract” vesicant and can cause intra-epidermal acantholysis.  Lesions treated with cantharidin heal without scarring and the treatment  is mostly painless. There has been a long history in both folk and traditional medicine regarding its use. In 1962, cantharidin lost FDA approval due to failure of its manufacturers to submit data attesting to its efficacy. The FDA interim policy: Cantharidin on “Bulk Substances List” most commonly used as 0.7% proprietary formulation: ‘topical use in the professional office setting only’

It is also important to conduct test sites and be sure that the family is aware of the blistering. Do not use cantharidin on the face.

A retrospective study on cantharidin looked at 537 children with MCV. Cantharidin treatment was used in 300 children with a follow-up phone interview. The results showed 90% clearing and 8% improvement. The average number of treatments was 2.1. There were blistering sites in 92% of the patients. Temporary burning, pain, erythema, and pruritus were seen in 6-37%. Overall, 95% of the parents reported that they would proceed with the treatment again.

Cantharidin is an excellent treatment for molluscum, but usually needs to be purchased from Canada. (www.ABCpharmacy.com)

Summary Warts & Molluscum

  • Candida antigen really is useful for warts
  • You can purchase it easily
  • Molluscum responds nicely to Cantharidin
  • Use the right formulation in the right places
  • Warn the families of risk of blisters & “marks”