Researchers presented a case study of an African American female who was born at 38 weeks and later diagnosed with aggressive systemic mastocytosis (SM). The mother’s pregnancy was complicated by intrauterine growth restriction and a breech presentation that led to a Cesarean delivery.

The presence of aggressive (SM) in utero is a rare finding, manifesting with end-organ involvement that is secondary to mast cell proliferation. The case study was recently published in The Journal of Allergy and Clinical Immunology: In Practice.

At birth, the baby girl was small for gestational age, with a body weight of 2260 grams, approximately 4.98 lbs. She exhibited prominent dermatologic findings with diffuse, red-brown indurated nodules and plaques that contained overlying blisters, erosions, and dyschromia. Further, she had a protuberant abdomen with marked hepatosplenomegaly and diffuse adenopathy.

Her initial laboratory assessment revealed thrombocytopenia (119,000 platelets/mL), direct hyperbilirubinemia
(1.4 mg/dL), elevated alkaline phosphatase (67 units/L), and elevated gamma-glutamyl transpeptidase (GGT;
231 units/L). Her tryptase level on the first day of life (DOL) was 306 ng/dL. A skin biopsy showed diffuse infiltration of mast cells throughout the dermis, with strong positive staining for c-kit (CD117 antibody) and tryptase.

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On DOL 1, treatment with H1 and H2 blockade was initiated, but the patient’s clinical course worsened. On
DOL 13, a lymph node biopsy was obtained. It demonstrated more than 15 mast cells in aggregate clusters, atypical mast cells with round- to spindle-shaped nuclei with irregular nuclear contours, and co-expression of CD2.

The performance of peripheral and tissue flow cytometry ruled out the presence of mast cell leukemia or other types of neoplasm. The criteria for SM were fulfilled and the infant girl was diagnosed with aggressive SM, exhibiting the end-organ damage associated with thrombocytopenia, abnormal hepatic function, and malabsorption. No family history of SM was reported at diagnosis or at follow-up.

On DOL 13, oral and topical cromolyn were initiated, which was associated with improvement in cutaneous lesions; however, the patient’s hepatosplenomegaly continued to progress. Pregestimil was initiated to treat her malabsorption and prophylactic amoxicillin was given for functional asplenia.

Because of her worsening clinical status and multi-organ involvement, cytoreductive therapy with hydroxyurea 40 mg per day was initiated on DOL 19. At 1 month following delivery, she was discharged from the hospital with a stable body weight of 2660 g, no anaphylaxis, and no bacterial infections.

Solid tumor mutational analysis of the patient’s original skin biopsy revealed a KIT p.D816Y substitution, along with a SETD2 missense p.K13E variant of unknown significance. Because both of these variants were replicated in samples from peripheral blood and lymph nodes, but not in skin fibroblast cultures, a hematopoietic somatic mutation was confirmed.

Because of the presence of a KIT variant, progressive hepatomegaly, and splenomegaly, along with increasing GGT and tryptase levels despite continued hydroxyurea administration, a more targeted treatment was initiated—the multikinase inhibitor midostaurin 12.5 mg (4.4 mg/kg/dose) twice daily at approximately 7.5 weeks of age. Because of a worsening diffuse cutaneous rash and a rise in tryptase levels at 4 months of age, the patient’s midostaurin dose was weight-adjusted to 18.75 mg twice daily (4.3 mg/kg/dose).

At 6 months of age, she attained the 3rd percentile for weight, and her cutaneous symptoms and laboratory markers were improving with the resolution of her thrombocytopenia. At 20 months old, her midostaurin dose was increased to 25 mg twice daily (2.4 mg/kg/dose).

Currently, at 4 years of age, she exhibits no signs of toxicity from midostaurin. As of March 2022, her SM was clinically stable, with tryptase levels of 54.5 ng/mL and a GGT of 93 u/L.

The authors indicated, “We intend to allow [the patient] to outgrow her midostaurin dose.” They pointed out that “the duration of cytoreductive therapy and long-term effects in pediatric patients with mastocytosis have not been determined.”


Voelker D, Bednarski JJ, Nieman E, Carter MC, Polk B. Hematopoietic KIT D816Y mutation presenting as in utero aggressive systemic mastocytosis with response to midostaurin. J Allergy Clin Immunol Pract. Published online December 26, 2022. doi:10.1016/j.jaip.2022.12.016