P.C.J. de Laat

Scoring the proliferative activity of haemangioma of infancy: the Haemangioma Activity Score (HAS)

Background.  Haemangioma of infancy (HOI) is the most frequently occurring benign tumour of infancy. A good, reliable and objective scoring system for haemangioma activity is not yet available.

Multiple cutaneous infantile haemangiomas and the risk of internal haemangioma

Infantile hemangioma (IH) is a frequently occurring tumor in infancy of which the pathogenesis is not completely understood. Although IHs are self-limiting, they can cause problems during their active growth and therapy may then be indicated. Generally, screening for internal hemangiomas is recommended when five or more cutaneous IHs are present. This recommendation, however, is lacking solid scientific evidence. In this chapter, we discuss some controversies regarding the prevalence of IH, the nomenclature of “hemangiomas,” the nomenclature of multiple hemangiomas/hemangiomatosis, the therapy of IH, and the abovementioned screening recommendation. Since 1993, children with IHs have been evaluated in outpatient consultations by the working group on vascular anomalies Rotterdam (WEVAR), using an approach protocol. This protocol aimed at determining the relation between number of IHs and the occurrence of internal hemangiomas. We included all patients presenting with five or more cutaneous IHs in the period of 1993–2011. These patients had all been referred for an ultrasound study for internal hemangiomas. We distinguished between children with ten or more IHs (hemangiomatosis group, group 1) and children with five to nine IHs (multiple IH group, group 2). Forty-three patients were included, 27 in group 1 and 16 in group 2. Nine infants in the hemangiomatosis group 1 showed internal hemangiomas versus none in group 2. Further examination for internal hemangiomas in children with fewer than ten cutaneous IHs is controversial and does not seem to be necessary. However, we do recommend ultrasound examination for children with ten or more cutaneous IHs.

Do we have to check glucose in patients with haemangioma of infancy treated with beta-blockers?

Editor From the day that Léauté-Labrèze et al. published their well known report until now, there is a growing number of publications describing the efficacy and effectiveness of oral propranolol in the treatment of haemangioma of infancy (HOI). Recently, propranolol ointment (1% and 5%) and other beta-blockers such as timolol (ophthalmic solution 0.5% or gel 0.1%) are also found to be effective. Further investigation has to focus on the mechanism of action and the optimal dosage and duration of therapy. Also, side effects that are however rare, have to be considered. The most common serious side effects of propranolol include bradycardia and hypotension. Bronchospasm can be seen in patients with reactive airway diseases. Hypoglycaemia is another side effect. However, it is well known that this occurs mostly in the neonatal period. Older infants and children are considered to be at low risk, and HOI therapy is generally started after the neonatal period. So, why do most doctors (and reviewers) stress out to check glucose? Probably because of the available case reports published after the discovery of Léauté-Labrèze et al., describing side effects (hypoglycaemia) in children with HOI, treated with propranolol. However, when reading all the cases thoroughly, it can be seen that most patients who were hypoglycaemic, had an underlying condition, often they are ill or have fever (rectal temperature <36 or >38.5 degrees Celsius) and were in state of fasting (bad oral intake due to the fever). This has been summarized by Holland et al. The mechanism by which hypoglycaemia develops, aside from less oral intake, is not completely understood. Also, normal glucose homeostasis is thought to be impaired through inhibition of adrenergic mediated glycogenolysis, gluconeogenesis and lipolysis. Children (and infants) seem to be at a higher risk for this adverse effect because their glucose use is higher while fasting (attributed partly to their greater brain mass relative to their body weight). In addition, glycogen stores are lower in infants and children compared with adults, leading to a reduced fasting ability. Thus, when treating healthy infants with beta-blockers, hypoglycaemia normally does not occur. Therefore, it is not necessary to check the glucose level frequently. Especially when treating with topical beta-blockers: there is a minimal use and the penetration through the skin is also minimal. This is in line with our experiences; in healthy patients we have never seen hypoglycaemia. We recommend the following: • Beta-blockers are safe in terms of hypoglycaemia. • We check the glucose level only one time at the start of therapy (fasting glucose level after three doses of propranolol). When it is normal, there is no need to check it again at a later time if the child remains healthy. • We inform the parents that in case of an illness or fever, their child is not allowed to fast. Parents have to see to it that their child has a sufficient intake or else they have to come to the hospital. Of course, glucose control is then indicated. • There is no need to check glucose in patients treated with topical beta-blockers. In very large, non-alarming HOI, treated with topical beta-blockers, we check glucose once. • Pay special attention on concomitant medication also causing hypoglycaemia!

Het Kasabach-Merritt-syndroom

SummaryKasabach-Merritt syndrome or phenomenon is characterized by thrombocytopenia, consumptive coagulopathy and a microangiopathic hemolytic anemia, seen in patients with an enlarging vascular lesion (especially Kaposiform haemangioendothelioma; khe). Due to the coagulopathy the mortality rate is high. Many treatments have been tried showing different results. This article describes succesful treatment with vincristine.samenvattingHet Kasabach-Merritt-syndroom of -fenomeen (kmf) wordt gekenmerkt door trombocytopenie, verbruikscoagulopathie en een microangiopathische hemolytische anemie bij patiënten met een groeiende vasculaire laesie (vooral het Kaposiform haemangioendothelioma; khe). Tengevolge van de stollingsafwijkingen is er een hoge mortaliteit. Verschillende therapieën zijn tot dusver met wisselend succes geprobeerd. In dit artikel wordt een casus beschreven waarbij uiteindelijk vincristine succesvol was.

Intractable vascular autonomic dysregulation (Harlequin phenomenon) in two brothers: another indication for propranolol?

Vascular autonomic dysregulation, in the most extreme presentation known as Harlequin phenomenon, is a rare condition. It manifests as a sudden and brief paroxystic change in skin color, resulting in two different colors on the body. It is supposed that this condition occurs due to a vasomotor instability. This again is caused by sympathetic disautonomy, which is a consequence of hypothalamic peripheral vascular tone control immaturity in the newborn. Typically, there is spontaneous regression. We describe two brothers who both had this condition in their first life years. Clinical symptoms included frequent attacks of discoloration of extremities (up to four times per day) accompanied with terrifying crying fits, interpreted by the parents as pain. These patients were treated with propranolol, a nonselective beta‐blocker, resulting in improvement of symptoms: only occasional attacks were seen. Beta‐blockers act on β1‐adrenoceptors in the heart, thereby preventing the positive chronotropic and inotropic effects mediated by these receptors. We hypothesize that propranolol, which is very lipophilic and therefore also acts on β‐receptors of the central nervous system, acts on the sympathetic system.

Scoring the proliferative activity of haemangioma of infancy: To HAS or not to HAS? Reply from author

Semkova and Kazandjieva recently commented on the Haemangioma Activity Score (HAS) we developed and reported in a recent issue of Clinical and Experimental Dermatology. Although every system will have its shortcomings, we believe that the HAS remains a valuable option for scoring the activity of infantile haemangioma (IH). We would like to address two clinically relevant issues raised by Semkova and Kazandjieva. First, they point out that the HAS does not assess the residual lesions (telangiectatic vessels) and IH size. We understand these concerns, but we believe that scoring for both IH size and telangiectatic vessels, which are in fact secondary efflorescences, is not a necessity for a small, simple and rapid system such as the HAS, and thus we did not include these items. The HAS, unlike other systems such as the recently published system by Haggstom et al., is not very timeconsuming and does not take much time during busy consultations. IHs grow very rapidly, and most of the changes occur in the first year of life. After proliferation, regression starts, and this can last for up to 10 years. During this long period, individual IHs do not change greatly per year, compared to the changes that occur in the first year. Therefore, there is no need for scoring the IHs during the later years. However, during the first year of life, a scoring system is necessary to (objectively) measure (re)growth or regression and, perhaps more importantly, to evaluate the effect of treatment. During this first year, the colour and swelling (if present) do change a great deal. Consequently, the score will be different in IHs at different time points, meaning that size does not have to be taken into account. We saw the effectiveness of the HAS in the early stages of treatment. It does not seem relevant that, for example, a patient at the age of 5 years had IH in regression with a HAS of 0.5 and at the age of 6 years has a HAS of 0 but with telangiectatic lesions. Our score is not a severity score that tells you whether or not to treat, but rather an activity score that reflects whether the therapy is working. Therefore, this system can also be used in research. The choice of treatment is in our opinion dependent on a number of factors, such as location (for instance, rapidly growing IHs around the eye are more problematic) or appearance (e.g. the presence of ulceration or telangiectatic lesions in regressed IHs that provoke cosmetic distress), and thus we consider that there is no demand for severity scores. Second, Semkova and Kazandjieva proposed that consistency of the lesion should be taken into account. We deliberately left this out, and in fact, considered swelling of the IH as an alternative. In that context, there is some overlap, but we use a different terminology. In addition, consistency cannot be evaluated on photographs, and the fact that HAS can be performed on photographs is an extremely important aspect of this method. We are currently planning a large validation study to validate the HAS. We also encourage others to validate the HAS and, if desirable, to compare the HAS with other assessments, such as change in lesion consistency.