Investigating the familial occurrence of systemic and cutaneous mastocytosis in adults: A retrospective cohort study

Mastocytosis occurs when too many mast cells accumulate in the skin and/or hematopoietic organs due to a gain of function mutation of the KIT gene. The two main forms of mastocytosis are cutaneous, affecting the skin, and systemic, affecting more than one part of the body. Most cases are caused by somatic mutations and are not inherited. However, there is some evidence of familial occurrence in children (with an estimated frequency of 11–13%) but data in adults are limited.

In this retrospective study published in the British Journal of Haematology,¹ Tanasi and colleagues studied the prevalence of familial disease in a large cohort of adult patients. The study also described the clinical and molecular features of familial adult cases and their findings are summarized here.

Study details

• Multicenter, retrospective, observational cohort study
  • to determine the rate of familial mastocytosis; and
  • to describe the clinical and molecular characteristics of familial mastocytosis, both in index patients and relatives.
• The study is based on a cohort of adult patients (n = 1,541) from eight Italian institutions who were diagnosed with systemic mastocytosis (SM) or cutaneous mastocytosis (CM), based on World Health Organization (WHO) 2016 criteria.

Results

Prevalence

• Twenty-three clustered cases of mastocytosis were identified, resulting in an estimated prevalence of 1.5% familial cases.

Clinical and molecular characteristics

• The median age at diagnosis was 44 years for index patients, and 20 years for relatives with mastocytosis.
• Clinical and molecular characteristics of index patients and relatives are listed in Table 1.
• Out of 23 index cases, 16 (69.5%) had SM and four (17.4%) had CM, compared to seven SM (30.4%) and 13 CM (52.2%) cases in their relatives.
• Ten out of 16 (62.5%) SM index patients had indolent systemic mastocytosis (ISM), four (25.0%) had bone marrow mastocytosis (BMM), one (6.2%) had aggressive SM (ASM), and one (6.2%) had SM with associated hematologic neoplasm (SM-AHN).
• Almost all index patients with SM, except one, (93.7%) had a KIT D816V mutation in either the bone marrow (BM) or peripheral blood (PB). The KIT mutational status was only available in four of the seven relatives with SM, and three of these expressed mutated KIT D816V; five relatives with maculo-papular cutaneous mastocytosis (MPCM) and one with mastocytosis in the skin (MIS) were negative for KIT D816V mutation in the BM or PB.
• Of the 23 index/relative relationships, eight were parents and children (34.8%), eight were siblings (34.8%) and seven were other relationships (30.4%).
• 47.8% of clustered cases had disease onset during adulthood, compared to 26.1% cases in which symptoms appeared in childhood. In six families (26.1%), symptoms appeared either in childhood (index case) and in adulthood (relative), or vice versa.
• The clinical phenotype was highly heterogeneous and did not present any clear correlation between members of the same familial cluster.
• In one case, both the index patient and her sister presented SM-AHN associated with a triple-negative myeloproliferative neoplasm and chronic myeloid leukemia, respectively.

Table 1. Indices and relatives’ clinical and molecular characteristics*

ASM, aggressive systemic mastocytosis; BM, bone marrow; BMM, bone marrow mastocytosis; ISM, indolent systemic mastocytosis; MIS, mastocytosis in skin; MPCM, maculopapular cutaneous mastocytosis; ND, not determined; PB, peripheral blood; SM, systemic mastocytosis; SM-AHN, systemic mastocytosis with associated hematologic neoplasm. *Number of patients tested or with available molecular data.
Characteristics	Indices (n = 23)	Relatives (n = 23)
Sex M/F, n	12/11	14/9
Median age at diagnosis, years (range)	44 (16–70)	20 (0–70)
Diagnosis, % SM               ISM               BMM               SM-AHN               ASM MPCM MIS Cutaneous mastocytoma	69.5 62.5 25.0 6.2 6.2 13.0 13.0 4.3	30.4 42.9 14.3 28.5 0 30.4 13.0 26.0
KIT D816V mutated (BM), % SM MIS MPCM Cutaneous mastocytoma	93.3 ND 0 0	42.9 ND 0 ND
KIT D816V mutated (PB), % SM MIS MPCM Cutaneous mastocytoma	92 0 ND ND	100 0 0 ND

Conclusion

This retrospective cohort study represents the largest report on the prevalence of familial mastocytosis in adult patients with a description of the clinical and molecular characteristics of adult index patients with mastocytosis and their affected relatives. An interesting finding from the study was that most of the identified index cases expressed the KIT D816V mutation, which has never previously been described in familial mastocytosis. However, the study is limited by the retrospective and limited data on relatives’ mutational status. Future studies of familial cases of mastocytosis should including complete sequencing of the KIT gene, genetic analyses on skin biopsy samples, and exome sequencing to identify new molecular determinants of the disease.