PracticeUpdate Dermatology February 2019

EXPERT OPINION 22

Changing Perceptions of Pediatric Mastocytosis By Warren R. Heymann MD

Dr. Heymann is Professor of Medicine and Pediatrics and Head of the Division of Dermatology at Cooper Medical School of Rowan University, and Clinical Professor of Dermatology at Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania.

I have always been disquieted by mastocytosis. Its constellation of clinical presentations from childhood to adulthood, spectrum of systemic involvement, variable prognoses, and therapeutic challenges never allow for complacency or certainty. Even when the diagnosis is straightforward with an excellent prognosis, trouble can ensue. I will never forget eliciting the Darier sign on a toddler’s masto- cytoma, witnessing his entire cutaneous surface turn crimson red from the massive histamine release. I’m not sure who was about to pass out first – the child, his parents, or me. (A word to the wise – skip the Darier sign on large mastocytomas.) This commentary will focus on pediatric mastocytosis. According to Macri and Cook 1 : “Mastocytosis is a disorder characterized by mast cell accumulation, commonly in the skin, bone marrow, gastrointesti- nal (GI) tract, liver, spleen, and lymphatic tissues. The World Health Organization (WHO) divides cutaneous mastocytosis into three main presentations. The first has solitary or few (less than or equal to 3) lesions called 'mastocytomas.' The second involves multiple lesions ranging from less than 10 to greater than 100 which is referred to as 'urticaria pigmentosa' (UP). The last presentation involves diffuse cutaneous involvement. Urticaria pigmentosa is the most com- mon cutaneous mastocytosis in children, and it can form in adults as well. It is thought to be a benign, self-resolving condition that remits in adolescence. Unlike adult forms of mastocytosis, there is rarely any internal organ involvement in UP.” Based on a systematic review of 1747 cases of pedi- atric mastocytosis, although the majority of cases hold true to aforementioned tenets, the outcome may not be favorable. 2 Méni et al report that lesions occurred before the age of 2 years in 90% of cases and presented as urticaria pigmentosa (75%), mas- tocytoma (20%), or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1:4. A KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2.9% of patients. The authors

assert that the development of aggressive forms several years after the onset of “benign” forms of pediatric mastocytosis (both mastocytoma and urticaria pigmentosa) confirms the importance of long-term follow-up for these patients. The c-kit gene encodes for Kit (CD117), a transmem- brane receptor with intrinsic tyrosine kinase activity and pleotropic effects on multiple cell types. 3 Upon binding to stem cell factor (SCF), dimerization of Kit results in intracellular tyrosine kinase activation. In adults, >90% of patients with systemic mastocytosis have a somatic mutation of the c-kit gene in exon 17, resulting in D816V Kit. In pediatric mastocytosis, mul- tiple mutations of c-kit are found in several exons; approximately 40% of mutations are reported to be outside exon 17. Despite the overall lower preva- lence of the D816V mutation in pediatric patients, it is still the most frequently detected variation, reported in approximately 30% of pediatric mastocytosis patients. Evidence from small studies indicates that pediatric patients who harbor the D816V mutation may be more likely to have systemic rather than cutaneous mastocytosis at the time of diagnosis compared with patients with non-D816V mutations. Evaluation of children with mastocytosis depends on the results of a thorough history and physical exam- ination. 1 With gastrointestinal symptoms, a barium study or endoscopy may be needed. Bone pain or fractures may warrant a skeletal survey or bone scan. " Imight changemy approach. Since 2005 when Lee et al reported the case of an 86-year-old man with telangiectasia macularis eruptive perstans that responded to topical pimecrolimus, there have been just a smattering of reports utilizing calcineurin inhibitors… "

PRACTICEUPDATE DERMATOLOGY