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.



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.