Pediatric Dermatology: What we’ve learned that has changed the way we think about and practice medicine

Sheila Friedlander, MD and Ilona Frieden, MD

Part 1: Look What the Wind May Have Blown In

Dr Friedlander began this session with a case study….A child presents to your office with an unusual rash.  The pediatrician called it maculopapular,  others migth call it polymorphous. The rash is papular ,  erythematous and fairly generalized.  Dr Friedlander states that most of the time when a child comes into your office with this type of rash, the history is often not that helpful. Be sure to ask about systemic signs, fever, or anyone else sick in the house.  Obtain a drug exposure history. . What is it reasonable to think about? Most of the time, it is a virus. Enterovirus is a reasonable possibility When in doubt, some physicians will blame EBV, especially if the child has had amoxicillin. Occasionally, it could even be measles with this sort of polymorphous eruption,  so it is important to look for cough, coryza, and conjunctivitis. It could also be Parvo virus so check to see if the  child had “slapped cheeks” appearance at any point, or a lace-like appearance to the body rash. . This particular child has had high  fevers for four days and the family is starting to get anxious.  The patient is fussy and his  lips are cracked. The parents also inform you that the child took amoxicillin two days ago and some NSAIDs yesterday. What do you think this is?  Dr Friedlander again emphasizes that it is important to go through his history of drug exposure;  fortunately  in this case, the rash predates any medications.

When you examine the eyes, you note the conjunctiva are red with a rim or halo of white around the cornea,, which is called limbal sparing—In  the diaper area, there is superficial desquamation that is really faint superimposed on confluent erythema. .  What can cause superficial desquamation in this pattern. What about staph scalded skin? The kids who have staph scalded skin do have intertriginous area involvement, but also often have erythema  in the perioral and periorbital areas along with radiating fissures around the mouth. They may also have blisters or bullae.

When you see a patient like this, you need to think about virus, drug, and staph scalded skin. Remember, this child has a polymorphous rash, has lip and tongue involvement, and a very distinctive diaper-area rash that developed  early in his course. The child also has conjunctivitis with limbal sparing and one enlarged lymph node.

So, what should we be  thinking about? Kawasaki Disease…Dr Friedlander reminds us to consider this whenever we see a child who has had prolonged fever  and a rash.

A 2013 article by Bayers S, et al was published in the JAAD, and is an extremely useful review  for dermatologists interested in  Kawasaki Disease. This disease is a small and medium size artery vasculitis.  One of the diagnostic criteria is fever for more than five days; however, if you have a child that fits all of the criteria at day four, you should move ahead with treatment. The earlier you start intervention, the less likely the child is to develop coronary artery disease. The palms and soles are  often red and swollen, and the aforementioned findings of conjunctival injection along with crusted lips and oral mucous membrane erythema are often present.  Cervical l adenopathy is often present but usually asymmetrical—this is helpful to remember.  If you suspect Kawasaki disease, get an expert in the area to help you manage this patient.

What are other KD  skin findings that are of interest to dermatologists?

  • Micropustular follicular rash (uncommon)
  • Nail discoloration, onychomadesis
  • BCG site rash
  • New onset psoriasis

Kawasaki Disease: Epidemiology

The typical age at presentation is six months to five years of age and the highest incidence of the disease is in Asian countries. In the United States, the highest incidence is among those of Asian ethnicity. If a child has this disease, the risk for a sibling to develop the disease is six to 30 times higher than normal and  for any progeny of KD patients, , the risk for his/her child is two times higher. The recurrence rate is two to four percent.

Why is this disease so important? Coronary artery aneurysms and cardiac disease!

It is extremely important to make the diagnosis because cardiac complications can occur. These include:

  • Coronary ectasia and aneurysms
  • Decreased coronary arterial compliance
  • Myopericarditis
  • Arrhythmias
  • Ischemic heart disease
  • Pericardial effusion
  • Valvular regurgitation
  • Myocardial infarction
  • Sudden cardiac death

Cardiac complications affect 15 to 25 percent of untreated patients.

Treatment for Kawasaki Disease

Again, refer to a specialist to help manage these patients. Treatment can decrease coronary risk by at least a factor of five. Treatment includes IVIG 2gram/kilogram over 12 hours, ASA High (80-100mg) divided qid, then low-dose (3-5mg) around day 14. Corticosteroids may be useful in refractory patients. Biologics, such as infliximab and etanercept, may also be useful. IVIG should be repeated if there is no defervescence at 36 hours.

What causes this disease?

We know that cases tend to occur close to each other temporally and there is a prediliction for winter and spring. It occurs mostly in children and is self-limiting. It takes a  course similar to that of  infectious processes  where  immune-mediated response is apparent. Lots of organisms  have been implicated; yet the etiology remains elusive..

Over the last  few years, researchers have found that a correlation exists between wind currents that track from Asia to Japan which  traverse the North Pacific and the occurrence of Kawasaki disease. There have been three epidemics in Japan in May, March, and April, which correlate with times of highest intensity wind currents The belief is that there may be a wind-borne environmental trigger. Investigators are now utilizing  planes and are collecting samples of air in the middle of these wind currents. Many scientists believe that there is a wind-borne agent that is causing this disease. Stay tuned, we may have more information next year.

Part 2: What is a Birthmark?

In the broad sense, a birthmark is a developmental anomaly that is present on the skin. As you know, they do not necessarily need to be present on the day of birth and they can range from common to rare.

Dr Frieden discusses the six questions that you should ask when you see a child with a birthmark.

  • What is the diagnosis? Is this a port wine stain or is this a premonitory mark of an infantile hemangioma. It is extremely important to pin down the diagnosis.
  • Is there a risk of extracutaneous associations?
  • What is the prognosis/natural history?
  • What (if anything) needs to be done? Are there good treatments?
  • Is there a “window of opportunity?”—an example of this would be infantile hemangioma whereby early intervention can really make a difference if treatment is needed
  • What is the cause?

Dr Frieden has been a pediatric dermatologist for a little over thirty years and she states that parents always ask: “what caused this?”  Previously, the answer was “we don’t know”.  Often times, especially for mothers, they ask themselves if they did something wrong during the pregnancy.

So to answer the sixth question, according to Dr Frieden, “2013 has really been a watershed year.”  Researchers are now using deep sequencing of birthmark tissue, not germ-line DNA in order to understand the genes that cause birthmarks. Most of the birthmarks that appear are post-zygotic somatic mutations. Knowing the cause of the birthmark may help to pave the way for newer therapies.

In 2013 Mutations In….

  • GNAQ cause Sturge-Weber
  • KRAS and HRAS causes of nevus sebaceous
  • NRAS cause of giant nevi
  • GTPase BMS1 cause of familial aplasia cutis congenital (germ-line)

What’s exciting about this? New therapies will be developed to address activating mutations because these are also mutations that can cause cancer. We know that researchers are looking for ways to stop activating mutations in these pathways. So you may ask “how does this affect a birthmark?” Dr Frieden provides an example where it may be very important and that is in Sturge-Weber. In Sturge-Weber, children are generally born with Sturge-Weber and they are neurologically normal, there are exceptions to this; however, Sturge-Weber is really a progressive disease. Children will develop heavy paralysis and seizure disorder despite the fact that they are normal at birth. It may be that if we treated these patients with something that inhibited an activated mutation GNAQ only for a couple of years, for example, we may be able to avoid some of the developmental changes that occur. Scientists don’t really know whether or not this is true, but it is an example of where we may be able to halt progression. This is an incredibly exciting time because, as physicians, we may be able to look parents in the eye and provide them with some information about the cause of the birthmark.

Part 3: Drug Reactions in Kids

This section of the presentation focused on drug reactions.,foc. Why is Dr Friedlander cautious when prescribing  minocycline? There is more and more evidence that minocycline is one of the offenders that can cause Drug Reaction Eosinophila and Hypersensitivity Syndrome (DRESS). It’s important to be aware of this disorder and how frequently we can see it.  It  can occur in one in 1,000 to 10,000 drug exposures. DRESS can be distinguished from other drug reactions in that often times the onset is later, approximately two to six weeks after exposure. It presents with a morbilliform rash, significant facial and periorbital edema, and exfoliative changes. Why is it of concernt? DRESS can affect the liver and other organs and has a mortality rate of up to ten percent. This is a good discussion to follow in that of  Kawasaki Disease because they share a similar differential diagnosis. Patients with DRESS have bilateral, significant cervical adenopathy, there may also be significant facial edema, and  often have what looks like an extensive erythematous, sometimes edematous,  confluent eruption. Husain Z, et al published a very useful review in the JAAD in 2013 regarding clinical perspectives and management and therapeutics for DRESS syndrome.

What are the drugs that we need to worry about?

When considering  DRESS, you want to check to see if the patient has eosinophilia and/or liver involvement because such findings raise the likelihood of life-threatening complications. . The common drugs associated with this problem are outlined below:

Ped 1



We now know that there are some genetic polymorphisms for drug metabolism that DRESS patients may exhibit. For many of these patients, there may be a genetic difference in how these drugs are metabolized which may be a cause of the disease.  There are two enzymes that have been implicated, epoxide hydroxylase and glutathione transferase. Another fascinating discovery is the association between DRESS and  human herpes virus (HHV-6), CMV, or EBV. Researchers are really not sure whether or not this a secondary involvement, but some scientists feel that re-activation may play an important role. In fact, there are some studies that have demonstrated that those who receive amoxicillin are worse prognostically because amoxicillin, at least in vitro, can help encourage activation and replication of HHV-6. This is an interesting combination of environmental and immune reactions. A number of specific genetic markers have been identified: these include  HLA-A 3101 in association with  carbamazapine; HLAB-5801 with  allopurinol; and HLA DR3 and HLADQ2 with  carbamazapine that put certain patients at risk.

What organ is likely to be involved if your patient gets DRESS?

Ped 2


Don’t forget to think about the differential diagnosis. Remember that the interval before onset is longer than Stevens Johnson Syndrome and TEN. Organ involvement is also more common in DRESS. These patients also tend to have more facial swelling and symmetrical nodes as opposed to Kawasaki Disease. If you were to perform a biopsy in these patients, you would see a more predominant  lymphocytic infiltration whereas in  Stevens Johnson Syndrome or TEN you would see a predominance of necrosis.

What can you do if you think your patient has had a reaction to DRESS?

First and foremost, you want to discontinue the drug. . You can also do skin or serum testing; this  provides a positive predictive value; however, it is not widely used. Therapy for DRESS includes supportive care, systemic l corticosteroids if there is liver involvement, and avoiding the use of antibiotics or NSAIDs.

Prednisone 1mg/kg/day  is often utilized, and tapered slowly over three to six months. If there is no response, patients can be given IV methylprednisolone 30mg/kg IV qd for three days. Do not stop these kids abruptly as there  relapse can occur. It is also very important to check thyroid function.


Some experts believe that ysphagia is an early manifestation of DRESS syndrome and it may come before the rash. Why is this important? Many times children will present to  the pediatrician with a sore throat and will be given amoxicillin empirically. With the advent of rapid Strep tests, Dr Friedlander would encourage all pediatricians to utilize these tests before simply prescribing amoxicillin, as we know that there is a suggestion that it may be detrimental to patients with evolving DRESS.. Dr Friedlander also recommends antipyretics with Tylenol versus NSAIDs. Remember to ask if the patient is feeling uncomfortable or having trouble swallowing.

MauiDerm News Editor-Judy Seraphine

Pediatric Dermatology: What we’ve learned that has changed the way we think about and practice medicine (continued…)

Sheila Friedlander, MD and Ilona Frieden, MD

Part 4: Hemangiomas and the Use of Beta-Blockers


In this section, Dr Frieden discusses the use of propranolol for the treatment of infantile hemangiomas. A consensus report, published in the Journal of Pediatrics in January of 2013, discussed the initiation and use of propranolol for infantile hemangiomas. Dr Frieden was a co-author on this publication and believes that it may have an affect on the way in which we practice medicine.  The background to this report is that there was a tremendous amount of diversity among the users of this medication. When there is not a lot of data available, the idea of a consensus is to try to come to a central point with general recommendations.

Is hospitalization needed?

The consensus group, comprised by a variety of specialists, recommended inpatient hospitalization if the patient is less than eight weeks old or less than eight weeks adjusted gestational age, and if the patient has other “high-risk” medical conditions. Patients older than eight weeks should receive outpatient monitoring, using heart rate and blood pressure, with dose escalation. Monitoring should be performed one to two hours after dose escalation as great as 0.5mg/kg/day. In Dr Frieden’s practice, she finds that blood pressure monitoring can be difficult with infants; however, heart rate monitoring is easily doable and just about anyone can do this, including parents.

Is EKG needed?

A consensus was not achieved on the use of ECG for everyone.  One may; however, consider ECG in the following circumstances:

  • HR is below normal for age
    • Newborns (<1 month old), <70 beats per minute,
    • Infants (1–12 months old), <80 beats per minute, and
    • Children (>12 months old): <70 beats per minute.
  • Family history of congenital heart conditions or arrhythmias (eg, heart block, long QT syndrome, sudden death); maternal history of connective tissue disease
  • History of an arrhythmia or an arrhythmia is auscultated during examination

The consensus group developed an algorithm that you can utilize or recommend to your pediatric colleagues regarding the initiation of treatment.

Key Take Home Points

In March of 2014, propranolol was approved for the treatment of infantile hemangiomas at a dosage of 3mg/kg/day. A randomized trial demonstrated a 60 percent clearance; however, in systematic reviews, the response rate of propranolol is in the range of 90 to 97 percent, although not everyone achieved clearance. Significant uncertainty and divergence of opinion still exist regarding the safety, monitoring, and dose escalation of propranolol. If the child is at risk for PHACE, at the minimum, you should perform an echocardiogram before considering initiating propranolol. Remember that the peak effect of the medication, in terms of cardiovascular effects, occur one to three hours after administration. The dose response is most pronounced after the first dose and it is extremely important to recheck the heart rate with dose escalation greater than 0.5 percent mg/kg/day. Hypoglycemia is the most common, serious complication. You should discontinue the medication during intercurrent illness, especially with decreased oral intake.

Topical Beta-Blockers

If you are concerned about hypoglycemia and other potential side effects, topical therapy may be a viable option.

What’s the evidence with regards to timolol? There are many citations supporting the safety of  timolol with minimal to no toxicity reported. Most dermatologists have found it useful for thin facial and hand lesions; however, there are some data that support its use in focal, deep facial lesions. A randomized controlled trial demonstrated that timolol 0.5 percent gel twice a day  was a safe and effective option for small superficial infantile hemangiomas that have not ulcerated and are not on mucosal surfaces.

There have been some recent concerns regarding potential toxicity of  timolol when utilized on ulcerated lesions, mucous membranes, or when used extensively in small premature infants.  as it may be absorbed and lead to  systemic levels of drug that could be problematic. Dr Friedlander and her colleagues are currently conducting a study at UCSD investigating  this issue.

Many experts suggest utilizing the drug sparingly, not more than  one to two drops twice a day, particularly in  micropreemies.

Part 5: Vascular Birthmarks and Overgrowth

A 2013 article by Lee MS, et al published in the JAAD reconfirmed Dr Frieden’s approach to the management of vascular birthmarks and overgrowth. Vascular stain and overgrowth were previously lumped together as “Klippel-Trenaunay.” As far back as 2004, Dr Frieden and her colleagues were able to report that the geographic stains had much higher morbidity and a much poorer prognosis. Many cases that were previously diagnosed as CMTC actually reticulate port wine stain. So, how do we give accurate prognostic information to patients and families?

It is important, as clinicians, to distinguish geographic from blotchy/reticulate stains. Conduct serial leg measurements if stains involve the lower extremity and measure head circumference. It is also imperative to look for dysmorphic features, e.g, syndactyly and facila dysmorphism. If dysmorphic features are present, you should consider rare Vascular Stain/Overgrowth syndromes.

Pediatric Dermatology Summary

  • Don’t forget about Kawasaki Disease—maybe the wind blew it in??
  • Birthmarks aren’t necessarily present at birth- and we now sometimes know the associated mutation
  • Dysphagia is an early symptom in DRESS
  • Propranolol is the drug of choice for most problematic infantile hemangiomas and treatment guidelines exist
  • Timolol for children is A-OK


Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases

Amy Paller, MS, MD

Our great progress in understanding the underlying basis for immune-mediated and genetic diseases has led to breakthroughs in therapy beyond prenatal and preimplantation diagnosis. Newer technology, ranging from next-generation sequencing to microarrays to proteomics, has facilitated these breakthroughs. Gene replacement through skin grafts has been initiated for treating recessive dystrophic epidermolysis bullosa based on early mouse studies and our knowledge of the deficiency of collagen VII and stem cell therapy to replenish cells with collagen VII- or laminin 332-producing skin cells at wounds has been modified to decrease risk and increase efficiency.

The availability of technology to create induced pluripotent stem cells and direct their differentiation into skin cells means designable sources of both stem cells and skin cells for grafts. New technology, such as use of microneedles or topically applied interfering RNA, is being studied as well to suppress the abnormal protein product and correct dominant-negative skin disorders, such as epidermolysis bullosa simplex and dominant dystrophic epidermolysis bullosa. Laboratory-based technology has also delineated the alterations in RNA and protein expression that define cutaneous immune-mediated disorders and tumors.

By understanding pathways that are activated, new therapy has been developed to target specifically these pathways and suppress the overactive immune system or growth and survival pathways. Recognition of the key roles of TNF, IL-23, and IL-17 in psoriasis has revolutionized our intervention through the development of targeted biologics.  The promising ongoing trials of IL-4 receptor antagonist and other blockers of Th2/Th22 pathways suggest that severe atopic dermatitis will similarly be treated with effective biologics. Already small molecules that target the activated signaling pathways in basal cell carcinomas (vismodegib), neurofibromatosis (imatinib for mast cells), and tuberous sclerosis (rapamycin) have suppressed tumor growth. Rapamycin is currently being applied to other disorders in which Akt/mTOR signaling is activated, such as venous malformations and could be considered for the subset of epidermal nevi with Akt pathway activation.

The other pathway leading to growth is the MAP kinase pathway, including through Ras and Raf activation. While a classic example of successful pathway suppression includes vemurafenib for Braf activation/ the Braf V600E mutation in melanoma, this MAP kinase pathway also plays a role in pediatric skin disorders of keratinocytes  (e.g., epidermal nevi), melanocytes (e.g., several forms of pigmented nevi), and endothelial cells (e.g., portwine stains). Finally, protein or lipid replacement therapy is an option used for several noncutaneous genetic disorders and is finding its way to dermatology. Injected recombinant collagen VII protein is now in trials for adults with recessive dystrophic EB and the combination of a statin to suppress the accumulation of cholesterol pathway precursors and cholesterol to replete the deficiency from pathway blockade has been used topically to reverse the skin changes of CHILD syndrome (Congenital Hemidysplasia with Ichthyosis and Limb Defects), which results from an enzyme deficiency in cholesterol biosynthesis.

These examples are just the beginning of what laboratory breakthroughs can yield for our patients. The next frontier is epigenetics and scientists are now unraveling the mechanisms that control cell- and tissue-specific gene expression. We can only imagine what scientists will discover in the future to transform medicine through personalized mutation-based gene and pharmacologic therapy.


Pediatric Dermatology: Nail Diseases

Ilona Frieden, MD
Sheila Friedlander, MD

In this section, Drs Frieden and Friedlander reviewed  coxsackie onychomadesis, the treatment of onychomycosis in children and a how to best obtain nail specimens in kids.

Healthcare providers should be aware that onychomadesis is a sequela of HFMD and fairly commonly seen after  coxsackie A-6 infection. With onychomadesis, you typically see shedding of the fingernails and toenails within one to two months after HFMD. Onychomadesis can appear in the form of exaggerated Beau’s lines. It is not surprising that this happens with infection, but why can it occur with mild disease? Osterback R et al obtained shed nails from two siblings with onychomadesis who had HFMD eight weeks before the nail shedding. The nail clippings were enterovirus positive by RT-PCR and one case was identified as CVA6. Dr Frieden believes that this may, in fact, be an infection of the nail matrix and not merely a physiological response of stopping nail growth.


Fungal nail infections are more common in adults; however, they DO affect children (0.16%). The incidence of fungal nail infections in children may be increasing due to occlusive foot lifestyle. While families want their children to be “perfect”, they are reluctant to put their children on prolonged systemic therapy, and do they want their children to undergo lab studies. It is important to keep in mind that children have thinner nails and; therefore, grow faster.

How do we best approach fungal nail infections in children? A study by Lawry MA, et al. showed that the best approach to diagnosing fungal nail infections is through PAS and culture and the second best approach is PAS.

Clinical Pearl: Dr Frieden comments that one of the best ways to get a diagnosis of onychomycosis in a small child is by using a disposable curette. Kids are not as afraid of this versus a scalpel because this instrument is blunt and looks more like a spoon. This is a great technique for a KOH or culture specimen.

How do we treat children?
  • Benign neglect (this is certainly still a reasonable approach)
  • Ciclopirox, amorolfine lacquer, bifonazole-urea
  • Griseofulvin 20/kg for at least 6 months; don’t exceed 1 gram (compliance can be difficult as well as side effects)
  • Terbinafine 5mg/kg/d  don’t exceed 250mg; FN 6 wks; TN 12 wks (Families can get a month supply for $3-$6)
  • Fluconazole 6mg/kg/week once a week; FN 12 weeks; TN 26 wks
  • Itraconazole caps 5mg/kg/d  pulse therapy; FN 2 pulses; TN 3 pulses

Dermatologists should know that onychomycosis does not always require systemic treatment for a cure. Dr Friedlander and her colleagues conducted a prospective trial of forty children with non-matrix nail disease. 30 patients  (25 male and 15 female with a median age of 9.8) were placed on active topical ciclopirox lacquer and 10 patients on vehicle. The lacquer was applied daily and nails were trimmed weekly for 32 weeks. If the patients had a poor response, they were rolled over to active treatment at week 12. The only known AE was a transient discoloration of the nail.



The graph above shows that 77 percent of these patients had mycologic cure, 71 percent had effective treatment and 34 percent had a complete cure. These numbers are much higher than what we see in adults. These patients were followed over one year and the vast majority of them did not relapse.  When asked about quality of life and whether or not the patients would undergo this treatment again, over 90 percent responded “definitely yes” or “probably yes.” (Friedlander SF et al. Ped Dermatology. 2012;Dec28)

This trial was just a a small pilot study, and thus  needs to be repeated.  Non-lunula nail disease can remit without medication (n =2); and topical therapy appears to work better in young nails than in adult nails.  This data suggests that topical therapy may be a reasonable option as first-line therapy for some children with fungal nail disease.

There are new products currently being studied for the treatment of nail disease. Nuvail, for example, is an innovative approach in that it is a poly-urethane vapor permeable substance. It is currently marketed for dystrophic/brittle nails. A small prospective study of Nuvail in 62 patients demonstrated 60 percent improvement in six months and a 62 percent mycologic cure in six months. Stay tuned for more information….





Pediatric Dermatology: Hand-Foot-Mouth and Beyond

Ilona Frieden, MD
Sheila Freidlander, MD

Dr Frieden discusses the new manifestations of an old disease. Classic HFMD presents with exanthem (skin) and (enanthem) mouth symptoms. Skin symptoms include grey-white vesicles on the palms and soles and occasionally  on the buttocks, diaper area, knees and elbows. Mouth symptoms include vesicles and erosions on anterior oral mucosa and are very painful.

From November of 2010 to February 2011, 63 cases of atypical HFMD were reported to the CDC. 34 cases had vesicle, stool, blood, and/or respiratory samples. 74 percent of these cases were PCR positive for coxsackie A6, whereas in the past in North American most cases were due to coxsackie A16.  These patients differ from those with classic HFMD in that there was a wider age range, greater than ten percent of the body surface area was involved, these patients had fevers and a rash that appeared “severe”, and they had findings of “locus minoris resistentiae.”

Mathes E and colleagues published a report on coxsackie exanthems characterizing the 2011 outbreak of the emerging viral type, A6. There were 64 children and 18 and ot 19 were positive for PCR enterovirus. 58 percent of the children had atopic dermatitis, 56 percent had ecema herpeticum-like eruptions which were termed “eczema coxsackium”.  Additionally 22 percent had findings of locus minoris, 35 perecent had Gianotti-Crosti-like eruptions and 18 percent had hemorrhagic purpuric or petechial skin lesions. (Mathes E, et al. Pediatrics. 2013;132(1):e149-157.) This virus can also affect adults.  An important sequellae is  onychomadesis which can develop two to four weeks after infection.

New Ways to Diagnose Viruses

Traditionally, it was difficult and expensive to find out which/whether a specific virus was pathogen. Viral cultures are expensive and the question remained as to what to look for. Acute and convalescent titers were the “gold standard”, but follow-up studies were required so you didn’t receive the answers you were looking for right away.  Dr Friedlander comments that we are now lucky enough to have commercially available multiplex PCR diagnostic panels for viruses. These panels are available in some labs or hospitals. They can typically detect influenza A and B, adenovirus, parainfluenza 1-3, respiratory syncytial virus A and B, human metapneomovirus and human rhinovirus. Other panels can detect coronavirus, coxsackie/echo virus, bocavirus, adenoviruses, parainfluenza and seasonal influenzas.  This is a positive step as it provides clinicians with the ability to have answers more rapidly than previously.


Pediatric Dermatology: Infantile Hemangiomas

Sheila Freidlander, MD
Ilona Frieden, MD

In this presentation, Drs Frieden and Friedlander discuss infantile hemagiomas, coxsackie and beyond, and nail disease.

Infantile Hemangiomas (IH): What We’ve Learned

At USC, Dr Friedlander and her colleagues followed 500 babies in a prospective study looking at the incidence and risk factors for IH.  They found that overall 4.5 percent of infants were affected. The risk factors included placental anomalies (35 percent of IH deliveries) and gestational age (extreme prematurity). One of the unexpected findings was that of location (53 percent were located on trunk, only 12 percent on the head and neck), this would make sense with what one would expect as the trunk is a larger body surface area. They also found that 91 percent of the hemangiomas were focal and 23 percent were abortive/telangiectatic.  The most important thing that was discovered was that only one of the 34 lesions discovered on the 500 babies needed intervention. This is reassuring information and can help guide clinicians to “worry less” about small truncal lesions:  however facial and larger lesions should be evaluated early to determine if intervention would be appropriate.  .

IH: Where do they come?

Dr Friedlander comments that the worrisome cases are those where the potential for  functional deformity or cosmetic disfigurement exist.  There are three major theories that most experts are comfortable with regarding the pathogenesis of IH. The first  is placental embolization; supporting evidence for this includes the following:  IH share surface characteristics with placental tissue (glut-1, HPL). In addition, placental markers (hCG and hPL) are  expressed on endothelium of proliferating, but not involuting IH tissue. Other similarities between placental and IH tissue have been  identified through DNA profile clustering analysis.

The second theory concerns a somatic mutation in a gene mediating endothelial cell proliferation (VEGF receptor). VGEF (vascular endothelial growth factor) can be likened to a  stimulus package for endothelial cells. Most of the time VEGF will complex  with an inhibitory receptor. If there is not enough of the inhibitory receptor (VEGF 1) around,  then VEGF will complex  with other “more stimulatory type” VEGF receptors and  proliferation then results. Angiogenesis is a tightly regulated balance of promoting and inhibitory factors.  In the simplified model below, complexing of VEGFR2 with VEGF activates EC proliferation.



The third theory, which is the most popular right now, is that IH may result from a combination of factors, including the presence of an area of localized hypoxia  Vascular cells in this area of low oxygen tension produce  hypoxia inducible factor (HIF). HIF sends a message to endothelial progenitor cells in the bone marrow, which then “home” to the hypoxic area and proliferate there.

Why do the endothelial progenitor cells (EPCs) misbehave in the first place?  Perhaps they possess a mutation such as mentioned in theory 2, perhaps it is just the hypoxic endothelial cells, in a particular area, expressing  “recruitment” factor for EPCs. . It has been found that infants with IH have an increased number of circulating EPCs, supporting this latter theory.

The general belief is that all of these theories could be involved with IH.

Therapy for IH

Dr Frieden comments that extrapolating from the data from Dr. Friedlander’s study,  about one in every thousand infants will need an intervention for a hemangioma.  For several years, beta-blockers have been studied as a treatment for IH. There are more than 240 articles published. Dr Frieden and her colleagues conducted a systematic review of 41 case series, with greater than ten patients, looked at a total of 1264 patients. 28 percent of the patients received prior treatment, most commonly oral prednisolone. Propranolol was initiated at the mean age of 6.6 months at a mean dose of 2.1 mg/kg/day. The mean duration of treatment was 6.4 months.  The results of this systematic review demonstrated a response rate of 98 percent (range 82-100 percent). The response rates were comparable irrespective of anatomic sites. There was rebound growth in 17 percent. Adverse events occurred in about three to five percent, with sleep changes and acrocyanosis being the most common. Serious AEs were rare. (Marqueling et al. Pediatr Dermatol. 2013; 30(2):182-91.

In Dr Frieden’s experience, this response rate really parallels that of isotretinoin, i.e. it works so well that  you don’t really need statistics to prove that it works. Dr Frieden also comments that in her practice, they have been treating IH with propranolol for several years and have seen remarkable results.

Steroids versus Propranolol

Another systematic review compared steroids to propranolol. The review of literature was conducted from studies from 1965-2012; 16 studies (2,629 patients) versus 25 studies (795 patients). The overall efficacy rate for systemic steroids was 71 percent compared to 97 percent for propranolol.  AEs for steroids were 17.6 percent versus 13.7 percent in propranolol. This review concluded that propranolol has greater efficacy and acceptable AEs for the treatment of IH. (Izadpanah A, et al. Plast Reconstr Surg. 2013;131(3):601-613.)

Propranolol Consensus Guidelines

Dr Frieden and her colleagues developed guidelines in order to come up with best practices for treating these patients. It is important that dermatologists understand whether patients should be treated inpatient or outpatient. Inpatient hospitalization is suggested for infants younger than eight weeks of age including  gestationally-corrected age for preterm infants, any infant with inadequate social support, and any age infant with comorbid conditions affecting the cardiovascular or respiratory systems. Outpatient treatment with monitoring can be considered for infants/toddlers over eight weeks of age with adequate social support and no significant comorbid conditions.

Regarding monitoring, the peak effect of oral propranolol on HR and BP is one to three hours after administration. Patients should be monitored with HR and BP measurement at baseline and at one and two hours after receiving the initial dose. This should be repeated with significant dose increases, i.e., greater than 0.5 mg/kg/day, including at least one set of measurements after the target dose has been achieved. If HR and BP are abnormal, then the child should be monitored until the vitals signs normalize and if necessary the dosage adjusted. The cardiovascular effects are usually most pronounced  after the first dose so there is no need to repeat monitoring  for the same dose again unless the patient is very young or has comorbid conditions. Of note, HR is usually easier to accurately obtain than BP.

With regards to hypoglycemia, routine glucose testing is not recommended. The risk of hypoglycemia is age-dependent and is related to the effects of propranolol on gluconeogenesis and glycogenolysis.  Hypoglycemia ia more likely to occur if a child has had a prolonged period of time without oral intake and is age dependent. Infants less than six weeks of age should be fed at least every four hours, infants six weeks to four months should be fed every five hours and infants greater than four months every six to eight hours. Propranolol should be temporarily discontinued during intercurrent illness, especially in the setting of restricted oral intake.

Providers must remember that these guidelines are based on current knowledge and should be considered provisional. Martin. et al have written an article providing written instructions re: propranolol therapyr  for parents and caregivers.  It is a  useful educational tool and resource for these parents and includes extremely helpful information. (Martin K, et al. Pediatr Dermatol. 2013;30(1):155-159.

How do beta blockers work?

Both speakers agree that  we don’t fully understand how this class of medications works for IH. One of the theories is that they decrease rennin production. The second theory is the regression via HIF-1-alpha-mediated inhibitor of VEGF-A and the third theory is the inhibition of “homing” of endothelieal progenitor cells to hemangioma sites, as Dr Friedlander previously discussed.

Topical Beta Blockers

Sometimes the risk-benefit ratio of propranolol is of concern. We now have an option with the  topical beta blocker, timolol, which has been  previously approved  for adult and pediatric glaucoma. There have been at least twenty articles since February 2010 with approximately 175 patients evaluated. Nearly all of these studies were retrospective with the largest series being of 73 patients. Most of the studies utilized timolol ophthalmic solution but two reports used compounded propranolol. There were varied concentrations and frequency, however timolol 0.5% gel-forming solution is most commonly used, typically with a – duration of three months or more.

Collectively, reports in the past two and a half years have shown encouraging results with topical beta blockers. Lesions on the eyelid tend to do particularly well, as do hemangiomas which are more superficial and smaller in size. Preliminary reports suggest that timolol is well tolerated, in that there have been no significant toxicity reports to date. The drug is also relatively inexpensive. It is important; however, to remember that timolol has a relatively higher potency and there is a risk of achieving significant blood levels, particularly in small premature infants. The quantity used should be limited; some healthcare providers use a maximum of one drop two times per day.

Multimodal Therapy

We have seen beneficial effects of early pulsed dye laser (PDL) therapy in individuals with infantile hemangiomas. (Admani S et al. Dermatologic Surgery. 2012;1-7)  Multiple cases have demonstrated that in some cases you can do better with combination therapy, such as steroid use and PDL or beta blockers and PDL. Mixing and matching with regards to treating IH is a reasonable approach.


Pediatric Dermatology

Our expert panel of pediatric dermatologists reviewed various topics in the field of pediatric dermatology including, hemangiomas, nail diseases, atopic dermatitis, inflammatory disorders, and skin lesions.

Drs Friedlander and Frieden began the pediatric dermatology session with a discussion on infantile hemangiomas (IH). Dermatologists need to continue to understand the incidence and pathogenesis of IH and when to recognize when intervention is required. A large prospective study showed that overall 4.5% of infants were affected by IH. Where do infantile hemangiomas come from? There are three theories: 1. Placenta embolization; 2. Somatic mutation in gene mediating endothelial cells (VEGF); 3. A hypoxic location elicits production of HIF.

How do we treat IH?

Over the last four years, Beta Blockers have emerged as a novel therapy for the treatment of IH. Guidelines were recently published for the use of propranolol in patients with IH. (Drolet et al. Pediatrics 2012 December 24. Epub ahead of print) A recent systematic review compared the improvement of IH with propranolol versus steroids and the results were 98 percent and 71 percent, respectively. The adverse events were also higher in the steroid group versus the propranolol group. All patient vital signs should be monitored when given propranolol; the most frequent side effect is hypoglycemia.

What if propranolol is not an option? The topical beta blocker, Timolol (which has been use for years in glaucoma patients with great safety), has encouraging results and appears to be well tolerated. This has been effective in facial lesions particularly around the eye.  For lesions near the eye in neonates 1 drop BID is the generally accepted dose.

Other therapy for IH includes corticosteroids, systemic therapy, pulsed dye laser, cryotherapy and Imiquimod.  An important concept with the overall management of hemangiomas is that management is not a “one size fits all” approach and therapy needs to be individualized.

Hand-Foot-Mouth and Beyond…

Over the last few years, atypical cases of HFMD have been reported to the CDC. Many of these cases looked like eczema herpeticum, but oral erosions and palmar lesions looked like HFMD. Coxsackie A-6 infection seems to be a virus that is now appearing in clinical practice. Fortunately, multiple PCR panels are commercially available and can aid dermatologists in the detection of these worrisome viruses.

What about onychomycosis?

Dermatologists need to remember that fungal nail infections DO affect children and the incidence may be increasing due to occlusive foot lifestyle and genetics. **Utilizing a curette is a good way to obtain a nail specimen in a child without provoking fear or fuss. Terbinafine 5mg/kg/d is an effective systemic therapy used to treat onychomycosis as well as fluconazole. Data has also shown that that children, with Onychomycosis not involving the matrix, can be effectively treated with topical ciclopirox lacquer.

Atopic Dermatitis

Dr Eichenfield addressed atopic dermatitis in the pediatric population. Key takeaway messages included:

What is the association between filaggrin and AD? Not all patients have filaggrin mutations and fillagrin mutations vary in AD patients from country to country. However, filaggrin expression decreases with inflammation even in AD patients without filaggrin mutations. When treating these patients, address the barrier, i.e., hydration.   How do we best treat pediatric AD patients? Anti-inflammatory treatment is effective and proper education can help to improve therapeutic outcomes.  It is also important to remember that microbes are not just bacteria, inflammation decreases diversity and increases staph infection; bleach baths and other products can be used as reasonable adjuvant therapy.  Mental health conditions, such as ADHD, are associated comorbidities among AD patients. Family attention and appropriate screening may be necessary.  In conclusion, don’t forget about allergy in AD patients; selective testing for foods may be beneficial.

Inflammatory Disorders

Dr Cordoro discussed inflammatory disorders in pediatric patients and what to do when creams aren’t enough to effectively manage these conditions. Because of the lack of data and treatment guidelines currently available for the pediatric population, managing these disorders with systemic and biologic therapies can be challenging for dermatologists. Different factors can affect and determine the appropriate therapeutic choice.

Practical Pearls for the Use of Systemic Therapy in the Pediatric Population
  • Let explosive –onset psoriasis evolve a bit before committing to systemic therapy
  • When you need speed, choose cyclosporine
  • Oral retinoids are often the best initial choice for sever guttate and pustular psoriasis in children
  • Is there a place for biologic therapy in children with psoriasis? The answer is yes.
  • Remember to assess which is worse: the disease or the treatment. Do not withhold treatment because “nothing is approved for use in children”

Pediatric Pearls Perfectly Repolished: Part 4 The Vitamin D Dilemma

Sheila Fallon Friedlander, MD

Dr Friedlander reviews the many questions that face clinicians regarding vitamin
D in their pediatric patients.  Patients still come in and ask and about what do regarding Vitamin D and sun protection;  as dermatologists it is important to provide them with accurate and useful information.

Historical Perspective

Why do we or should we care about Vitamin D? In the 1700s, it was noted that some children had “bowed” legs. Some of them also developed  tetany and laryngeospasm. This was more frequent during the industrial revolution  likely due to less exposure to direct sunlight. In 1921, sunlight was found to be a treatment for Vitamin D deficiency , in1922 cod liver oil was found to be helpful and in 1925 scientists identified Vitamin D1 and Vitamin D2. The concept that has evolved over the last few years is that of Vitamin D as the “super hormone.”  It is well established that Vitamin D is important for bone mineral density and bone strength and appropriate levels  decrease risk for fracture.  Over the last decade, several studies have demonstrated that Vitamin D may also protect us from certain types of cancer, multiple sclerosis and cardiovascular mortality; however, there is still much controversy around these studies.

How can Vitamin D do so much?

Vitamin D binds to cell surface receptors and nuclear receptors (VDR). The presence of polymorphisms in the receptor may be a reason why not all studies show the same results with the same Vitamin D levels. Vitamin D has an impact on gene expression and regulates growth and differentiation.

Vitamin D Synthesis

Vitamin D synthesis is a complicated process. The overall concept is that  precursors are present on the skin surface, and when the precursors are exposed to sunlight, we get one form of Vitamin D3, cholecalciferol That is then metabolized in the liver to another  form that can be measured. Finally, in the kidney, the final , active form is synthesized. This  active form, 1,25-Vitamin D3, does not have a long half-life, and therefore levels of this form are not used in clinical practice.

Vitamin D Deficiency—How much?

A recent study found that 70% of children in the United States have low levels of Vitamin D.  What is really a low level? This can be confusing and puzzling. as “normal” values vary depending on the expert discussing the isse and  healthcare providers have no perfectly clear standards . There were also some studies that rickets may also be increasing. In a study conducted in Glasgow, the researchers looked at all children with suspected Vitamin D deficiency from 2002-2008. There were a total of 160 cases, the median age was 24 months, the majority of the patients were dark skinned and 40% of the patients presented with bowed legs. (There was one seizure). There were twice as many cases of Rickets in 2008 as in the previous six years. The question is, are people looking harder now because they are more aware?

Why are dermatologists concerned about this?

As dermatologists, we tell our patients to protect themselves from the sun; therefore,  we are interfering with “the natural order” of getting sunlight. Are we putting our patients at risk with this advice? Is there really a problem?

The problem is that the ultraviolet action spectrum for Vitamin D photosynthesis is identical to that for DNA damage and skin cancer, so we cannot  separate out this action spectrum.

Known Facts

Ultraviolet radiation from the sun is a carcinogen. It is responsible for the  majority of 1.3 million cases of skin cancer in the United States every year. In animal models, ultraviolet radiation is directly related to squamous cell carcinoma, basal cell carcinoma and metastatic melanoma. The use of sunscreen decreases one’s risk of malignant melanoma. Ultraviolet radiation compromises the skin’s function and can negatively affect one’s appearance.

Sunscreen, Vitamin D & Skin Cancer

In a 2011 review by Burnett and Wang, they found that sunscreen use has little or no impact on clinically relevant Vitamin D levels. Eide et al, in 2011, showed us that an increased baseline serum 24-OH Vitamin D level was significantly associated with an increased non-melanoma skin cancer risk. Basically, the more Vitamin D people had, the more skin cancer they had.

Natural Sources of Vitamin D Other Than the Sun

It can be hard to get enough Vitamin D from food.

  • Milk (but  4 glasses needed to get 400 IUs)
    Not such a good idea for the lactose-intolerant
  • Salmon, mackerel – but you need wild for the highest amount (600-1000 IU  &   $$$$)
  • Shittake mushrooms
  • Cod liver oil (grandma was right!)
  • Eggs
  • Could make it if you eat mushrooms & salmon a lot

Some feel that a little sun may be helpful to get the extra Vitamin D, but how much?

We know that white skin is more efficient than dark skin at “procuring” Vitamin D conversion from the sun. White skin is also more vulnerable to the bad, cancer-associated effects of the sun. How much one needs really depends from patient to patient.

So where do experts  stand on this issue? In New Zealand, they feel that sun exposure depends on the time of year and UV index along with one’s skin type. In the summer months, they believe that people receive sufficient Vitamin D through incidental sun exposure outside peak UV times (11am-4pm). For skin types 1 or 2, the recommendation is 5 minutes per day to the face, hands and forearms. For skin types 5-6, the recommendation is up to 20 minutes per day. ( However, according to the AAD and the AAP, this is a no-go. They feel it is inappropriate to recommend intentional exposure to natural or artificial UV light in order to obtain Vitamin D.  These two organizations believe the risks clearly outweigh the benefits and Vitamin D should come from diets and supplements.

So, to the rescue came  supplemental Vitamin D3; however, it is still not clear  how much to give, but  researchers began to demonstrate the positive effects of Vitamin D3 and its potential to reduce many health risks; therefore, people began to supplement and supplement and supplement….In 2001, $40 million was spent on Vitamin D supplements, in 2009, $425 million was spent and the federal government took notice.

The government got involved and asked the Institute of Medicine (IOM) to provide some answers regarding Vitamin D:

  1. What health outcomes are impacted by Vitamin D levels?
  2. How much Vitamin D is needed for a beneficial effect?
  3. How much is too much?

The IOM determined that, with no sun exposure, 600 units of supplement is a good idea for just about everyone. Babies need a little less and older patients (70+) will do well with 800 units.  There many experts who felt that these levels were inappropriately low. Why would the IOM be so rigid about how much Vitamin D people need?…because the  risk-benefit data are not clear. The colorectal data is the most supportive; that is Vitamin D is protective. Prostate, pancreatic, and cardiovascular data is conflicting, i.e., there is data that shows an increased risk with higher doses. There is an increased risk of renal stones with modest (400mg) supplements. Some of these problems, as Dr Friedlander mentioned before, could be due to Vitamin D receptor polymorphisms.  There may be a U-shaped curve of response where a little is bad, a moderate amount is good, and too much is also bad.

The IOM and Their Conservative Recommendations

We should not base recommendations on imprecise, suboptimal data. Risks are also possible with increased dose.

It is important to remember that there is data that shows an increased risk of prostate and other cancers, increased cardiovascular mortality and stones with increased doses of Vitamin D. A little Vitamin D is bad, moderate amounts is good, and too much can be bad. For now, patients should stick with 600 IU/day, unless they are considered to be in a high-risk population. This includes breast fed infants, older adults, individuals who have limited sun exposure, people with dark skin, and those with fat malabsorption. Healthcare providers should consider blood levels and higher supplemental intake for  elderly adults and those with dorders putting them at risk for Vitamin D malabsorption..

Summary FAQs
  • Does everyone need to be supplemented?Not a bad idea
    Age IU
    <1 400
    1-70 600
    70+ 800
  • Should everyone get Vitamin D levels?No, it can be expensive.
    Yes, for high risk populations.
  • What kind of supplement is best?
    • Food
    • Vitamin D3


  • Is more Vitamin D better?Perhaps not
  • Does Vitamin D support bone Health?Absolutely
  • Does Vitamin D protect us from MS, cardiovascular disease and cancer?Evidence is imprecise, inconclusive, inconsistent and insufficient at this time
  • Should I get Vitamin D from the sun?Not needed
Vitamin D “Pseudo-controversy”

Sunlight (UVR) is a known carcinogen. You can’t make Vitamin D in your skin without inducing DNA damage. Vitamin D is certainly good for you and you can get a sufficient amount with incidental sun exposure and a reasonable diet +/- supplements.

What’s a clinician to do?
  • Adhere to IOM guidelines – for now
    • <1yr = 400 IU
    • 1-70 = 600 IU
    • 70+  = 800 IU,
    • Identify high risk groups, test prn,
      • Breast fed, dark skin, elderly, malabsorbers
      • Counsel your patients that supplements are more dependable & safer than sun exposure





Pediatric Pearls Perfectly Repolished: Part 3 Worry or Not Worry: Which Vascular Birthmarks Need Further Evaluation?

Ilona J. Frieden, MD


Sturge-Weber Update

Sturge-Weber syndrome (SWS) is the triad of a port wine stain involving a V1 distribution as well as brain vascular malformations and often times glaucoma along with other ocular sequalae.  A recent report, published in December of 2011, from the Brain Vascular Malformation Consortium and the Sturge-Weber Syndrome National Workgroup. The experts discussed the disease in a broader sense to really examine what is going on now with the disease, what can physicians do currently and what does future look like as far as new developments in science.

Neurologic  Status

Usually with PWS, the patient has roughly a 30% chance of having unilateral, ipsilateral brain involvement to the PWS; however, in some cases with bilateral PWS there can be bilateral brain involvement that can correlate to a poorer prognosis. Epilepsy was found in 75-80% of patients with SWS and the vast majority will have an onset by age one (75%). It important to know that if a child over the age of two presents with a PWS and have been asymptomatic neurologically they are unlikely to have SWS.  When looking at outcomes, cognition was variable but it was worse in patients with seizures. In older patients, migraines or migraine-like headaches were a major issue. Endocrine disorders, especially growth hormone  deficiency and central hypothyroidism, have also been seen in some  patients.

Imaging Studies: Which to Do and What They Tell Us

There really isn’t a right answer as to whether or not one should be doing routine imaging in all infants with PWS in a V1 distribution to assess for the possibility of Strurge-Weber. The standard imaging modality used MRI with contrast; however, that is not always diagnostic in young infants because it is not adequately sensitive. The newly developed Susceptibility Weighted Imaging (SWI) MRI may make earlier detection possible and is more sensitive for venous disease which also may be present as a part of SWS.   Currently, Dr Frieden typically does not routinely do imaging as this will not necessarily change management in otherwise asymptomatic children.  However she  does routinely send these at-risk children to an ophthalmologist.

Another important part of imaging studies, however, is in helping to  better understand the disease. Imaging has shown us that brain disease is progressive, not static in SWS and that though initially increased blood vessels and hyperperfusion are present, over time,  hypoperfusion of parenchyma develops and this  correlates with functional impact. Functional PET imaging is also playing an increasing role in prognosis and pre-surgery planning for patients with intractable seizures.

Future Diagnostic Directions

Quantitative EEG (qEEG) in a non-invasive test that uses math signal processing for interpretation, rather than looking at just the morphology of the spikes and waves. qEEG was able to distinguish young infants with and without SWS correctly with high reliability (but small numbers). Transcranial Doppler is a non-invasive flow measure used in Sickle-Cell disease and there are ongoing studies looking at this modality for studying SWS.

Infantile Hemangiomas

Infantile hemangiomas cause multiple potential risks. This infant has a risk of eye disease as well as PHACE syndrome.

How do we begin to approach infants like this early on?

PHACE Syndrome
  • P: Posterior fossa and other brain anomalies
  • H: Large facial hemangiomas
  • A: Arterial anomalies especially CNS anterior circulation
  • C: Cardiac anomalies and aortic coarctation
  • E: Eye defects especially retinal vascular anomalies

PHACE Syndrome is the most common neurocutaneous vascular syndrome and is more common than SWS.  This is present in 30% of infants with large facial hemangiomas (> 5 cm in diameter).

Segments 1 and 3 have a much higher risk (50% or higher) compared to segment 2.

Elements of a PHACE Work-up
  • At risk if facial infantile hemangioma ≥ 5 cm
  • MRI and MRA with contrast
  • Eye exam (even if no perioccular vascular lesions)
  • Cardiac echo (looking for coarctation of the aorta in particular)
  • Consider other tests
    • ENT evaluation if “beard area”
    • Hearing tests (sensory-neural hearing loss independent of ear canal occlusion from a hemangioma)
    • Thyroid functions (occasionally central hypothyroidism is an issue)

The MRI and the MRA need to be individualized by patients due to the need to perform general anesthesia to due these procedures.

 Beard Area Segmental IH

Dermatologists should realize that hemangiomas distributed in the so-called “beard-area  pose a high risk of both airway disease and of PHACE.

Multifocal Hemangiomas

A prospective study by Horii et al, published in 2011, looked at the risk of liver hemangiomas in patients with multiple infantile skin hemangiomas. Abdominal ultrasound was performed on infants 6 months of age or less with 5 or more skin IH. They were compared with 50 infants who had 1-4 IH (control group). 24 (16%) of the 151 infants with 5 or more skin hemangiomas had hepatic hemangiomas (HH) versus 0/50 with less than 5 cutaneous (p = 0.003).

HH are similar to skin IH, in that, not all HH need treatment. More cutaneous IH are associated with a greater overall risk of HH but they are not necessarily more severe. In the prospective study mentioned above, only two of the 24 patients who had HH needed treatment specifically for the HH because they caused symptoms.

Risk of Life-Threatening “Diffuse” Disease

This is the feared complication of liver hemangiomas; whereby the liver is replaced by hemangiomas. In a recent study, the researchers found that the time to presentation for these patients is between a few weeks and 4 months. Symptoms include abdominal distention and poor feeding. If children have this, it is imperative to consider severe hypothyroidism, as it is commonly associated. The hemangioma itself causes a consumptive hypothyroidism by de-iodinating T3.

Do I need to worry about GI bleeding?

Dr Frieden states that most of us were taught that we needed to worry about GI bleeding when we saw patients with multiple hemangiomas. That actually turned out to be false. Large facial such as those seen in PHACE Syndrome, not multifocal IH, is a major risk factor for GI hemangiomas; usually in the small intestine.  In contrast, when you see multiple vascular lesions together with visceral involvement in sites such as the  brain, gastrointestinal tract, kidney, spleen, or adrenal glands this is more likely to be due to other multifocal vascular tumors such as multifocal lymphangioendotheliomatosis, rather than infantile hemangiomas.

Lumbosacral Hemangiomas

Regarding lumbosacral hemangiomas, dermatologists should worry about tethered cord and other anomalies.  In a 2010 prospective study by Drolet et al, the researchers studied 41 infants with IH greater than 2.5 cm midline overlying lumbar or sacral spine. The patients were imaged with ultrasound, MRI or both. The spinal abnormalities that were noted included lipoma or hemangioma and structural malformations of cord/tethered cord. Nearly 50% (21/41) had tethered cord, intraspinal hemangiomas, or both. High-resolution ultrasound was not optimal for evaluation (sensitivity 50%; specificity 78%).

Nevus Simplex (Salmon Patch)

The incidence of the nevus simplex also known as the salmon patch, is quite high (greater than 15%; range 19-82%). How do we know that this isn’t a Port Wine Stain? Clues to this diagnosis include its medial location and very blotchy, less well-demarcated borders.   We know that the classic locations include the glabella, the eyelids as well as the nape. Dr Frieden and colleagues have reported on some cases of extensive nevus simplex that included additional sites such as the scalp (67%), the nose (67%), the lip (60%), lumbosacral skin (56%) and the upper and mid back (15%). In this case series, most of the children were referred to Dr Frieden’s group because of the vascular anomalies. There were no associated abnormalities and imaging was not needed.

“Nevus Simplex Complex”

Infants with widespread nevus simplex were termed “Nevus simplex complex”. The patients had no other conditions. In a literature search, however, prominent NS was found to be associated with some rare syndromes such as:

  • Beckwith-Wiedemann
  • Macrocephaly-Capillary Malformation
  • Ondotodysplasia
  • Roberts-SC phocomelia
  • Nova syndrome

We also know that there is also an increased incidence of NS in infants with IH. Of note, patients with NS respond very well to pulsed dye laser treatment.

In 2011, Sillard et al published on a condition they termed  “Medial Fronto-Facial Capillary Malformation.” This was a retrospective study of 84 children. The distribution was the same as that of nevus simplex complex with “extended forms” in 26%. Neurologic anomalies were found in 9.5% of the patients. The researchers argue that this “looks like salmon patch” but it is not the same; it is darker, wider, slower, and there is less complete resolution.




Pediatric Pearls Perfectly Repolished: Part 2 Rapamycin Sheila Fallon Friedlander, MD

In this presentation, Dr Friedlander  discusses the many clinical applications of rapamycin, a target of the P13K pathway which was previously discussed by Dr Frieden.

Is Rapamycin the new wonder drug for kids?

Rapamycin (sirolimus) is an immunosuppressant used to prevent rejection. It is a macrolide and derives from a  Streptomyces species. Rapamycin was first discovered on Easter Island (Rapa Nui) and was originally used an antifungal.. It  blocks the mammalian target of rapamycin (mTOR) pathway by affecting  cyclin-dependent pathways .  These pathways are essentially messengers which can mediate cell  proliferation, metabolism and angiogenesis.

If you think of mTOR as a conductor that is mediating the effect of various growth factors, then  if we have a substance  which can inhibit mTOR, we can impair cell proliferation, cell metabolism and angiogenesis.

Why do dermatologists care about Rapamycin?

There are several diseases with cutaneous manifestions in which  proliferation is a major component of the pathology, for which we have no safe effective treatment. There is evidence that Rapamycin may be effective in treating at least a few of these disorders; in particular  tuberous sclerosis, port wine stains have been investigated,  Rapamycin has also been utilized in an animal model of infantile hemangiomas.

It has been  established that Rapamycin significantly improves facial angiofibroma lesions in patients with TS.  What about port wine stains (PWS)? We know that PWS can recur after PDL treatment. It is hypothesized that the cell trauma of treatment stimulates new blood vessel growth.  Dr Stuart Nelson and others have conducted studies in animal models which show that rapamycin can inhibit regrowth of vessels following laser therapy.


Rapamycin is currently under investigation by Nelson and his colleagues to determine if PWS treatment outcomes can be improved with the use of rapamycin in addition to pulsed dye laser.

One of the challenges with Rapamycin, as found by De Klotz et al, is that of compounding the agent into the right formulation. Scientists are working on optimizing the formulation. Rapamycin is also rather expensive.

Side Effects

Because Rapamycin is an immunosuppressant we have to worry about oral ulcers, diarrhea, and infections, to name just a few concerns. Topical Rapamycin appears to have less side effects.

Rapamycin and Infantile Hemangiomas

In an animal infantile hemangioma model, rapamycin was able to suppress the growth of the tumor via the inhibition of stem cell renewal capability, vasculogenesis, and differentiation.  What’s the difference between angiogenesis and vasculogenesis?  Many healthcare providers are confused regarding angiogenesis and vasculogenesis.  Angiogenesis occurs when new  vessels sprout  and develop  from an existing vessel. Vasculogenesis is de novo new formation of a  vessel presumably from stem cells. The effect of Rapamycin is distinct from that of corticosteroids, i.e., the pathways are  very different.

The Promise of Rapamycin

Rapamycin is a topical  as well as systemic formulation that can inhibit angiogenesis, proliferation and perhaps vasculogenesis. Rapamycin also inhibits stem cell renewal. Given these characteristics, , it could well be an excellent therapy in topical formulation for both angiofibromas and PWS., and perhaps infantile hemangiomas.  However, we  do need to better investigate its possible  side effects before  utilizing on a wide scale basis.