Three types of MCAD are currently known: systemic mastocytosis (SM); mast cell activation syndrome (MCAS); and mast cell leukemia (MCL). SM and MCL are thought to be rare, while MCAS is now believed to be much more common, and possibly even the underlying cause of various clinical presentations (such as IBS and fibromyalgia.) Very little is known about the heritability of these conditions , but many patients report that they have family members with similar symptoms.
A study examining the familiality of MCAD found that 74% of patients interviewed had at least one first degree relative (parents, siblings, children) with systemic MCAD, regardless of MCAD subtype or gender. The prevalence of systemic MCAD among first-degree relatives was 46%, while the prevalence in the control group is about 17%. The prevalence of MCAD among first-degree relatives of patients with MCAS was 60%; with SM was 44%.
MCAD subtype and severity of symptoms varied between family members. Variable genetic alterations in CKIT were detected. Activating CKIT mutations were found in 65% of patients, compared to 15% of the control group. The genetic mutations detected in the three families included mutations at position 816 of CKIT (D816G, D816V, S1A). This finding is remarkable in that it disproves the longstanding belief that the somatic nature of KIT and related exon 17 mutations means that it cannot be inherited. It also supports the belief that other mutations in genes that regulate mast cells could be contributing to these diseases. Multiple mutations were sometimes found in the same patient, including those found in other genes (JAK2, TET2, DNMT3A, ASLX1, CBL, U2AF1, SRSF2, MS4A2).
There was also no obvious relation between the CKIT mutations and clinical severity of MCAD. Although familial occurrence due to shared environmental factors cannot be ruled out, it is likely that there is a significant genetic contribution to this phenomenon. More females than males were affected. The prevalence of MCAS was expected to be at least within the single-figure percentage range in the population (1-9%.)
Systemic MCAD family histories include more systemic MCAD cases than would be expected when compared to the prevalence in the general population. This study advocates that the different subtypes of MCAD (MCAS and SM) should be more accurately regarded as varying types of the same disease rather than distinct diseases of mast cell dysfunction.
Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, No¨ then MM (2013) Familial Occurrence of Systemic Mast Cell Activation Disease. PLoS ONE 8(9):e76241. doi:10.1371/journal.pone.0076241