AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.

Mast Cell Activation Syndrome.

A 51-year-old woman with a history of asthma and Hashimoto's thyroiditis presented to the dermatology service with a chief complaint of "itchy bumpy rashes" that persisted beyond 24 hours. She noted that, 3 days prior to the onset of urticaria, a pyrroloquinoline quinone supplement had been started. The urticaria was accompanied by variable episodes of transient facial swelling and difficulty breathing. The patient noted that exposure to fish, nuts, and nonsteroidal anti-inflammatory drugs triggered facial swelling. Other reported findings included a 5-year history of diarrhea, sense of memory deterioration, concentration difficulties, and clinical manifestations of anomic aphasia. Although her allergy testing was "negative," she had been given the diagnoses of lactose intolerance and gastroesophageal reflux disease. Laboratory studies on initial presentation were significant for a positive history of antithyroperoxidase antibodies and elevated total complement activity. Medications included budesonide/formoterol, fluticasone/salmeterol, levothyroxine, albuterol, and fexofenadine 180 mg twice daily. Although her "rash" had initially responded to fexofenadine, it soon became refractory to treatment. Her family history was significant only for thyroid disease.

Maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss.

OBJECTIVE: To determine whether an association exists between maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss (REPL). DESIGN: Observational cohort study. SETTING: Two academic medical centers. PATIENT(S): Women seen between 2004-2015 with a history of REPL, who were euthyroid or had subclinical hypothyroidism, had maternal antithyroid antibody testing and had at least one subsequent early pregnancy loss (<10 weeks' gestation). INTERVENTION(S): Thyroid function and antibodies were measured at consultation. Subsequent miscarriages were assessed by conventional cytogenetic analysis, and when indicated, microsatellite analysis and/or comparative genomic hybridization/single nucleotide polymorphisms were performed. MAIN OUTCOME MEASURE(S): Determine whether maternal antithyroid antibodies are associated with euploid miscarriage. RESULT(S): Cohort consisted of 74 subjects with REPL who had 130 subsequent early pregnancy losses. The prevalence of maternal antithyroid antibodies in the cohort was 17.6%. Mean TSH was significantly higher among subjects with maternal antithyroid antibodies. Otherwise, no significant differences in demographics were noted. When comparing types of early pregnancy losses between the two groups, a trend toward having more miscarriages than nonvisualized pregnancy losses was noted among subjects with maternal antithyroid antibodies (70% and 30%) compared with subjects without maternal antithyroid antibodies (55% and 43%). No significant difference was noted in the frequency of euploid miscarriage between subjects with and without maternal antithyroid antibodies (42% vs. 56%). CONCLUSION(S): Our study did not demonstrate an association between euploid miscarriage and maternal antithyroid antibodies in subjects with a history of REPL. Therefore, testing or treatment in this cohort may not be warranted.

The coexistence of a novel inactivating mutant thyrotropin receptor allele with two thyroid peroxidase mutations: a genotype-phenotype correlation.

CONTEXT: TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals. OBJECTIVES: The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual. PATIENTS AND METHODS: Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs. RESULTS: A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264S TSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation. CONCLUSIONS: TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.

Autoimmunity in patients with resistance to thyroid hormone.

CONTEXT: Resistance to thyroid hormone (RTH) is an inherited syndrome most often caused by thyroid hormone receptor beta (TRbeta) gene mutations. Given that autoimmune thyroid disease (AITD) is prevalent in the general population, its coexistence with RTH has been presumed coincidental. It was recently proposed that chronic TSH stimulation in RTH may induce an autoimmune response, thereby increasing the chance of their coexistence. OBJECTIVE: The aim was to examine the prevalence of AITD in a large cohort with RTH compared with their unaffected first-degree relatives. SUBJECTS AND METHODS: Among 130 families, 330 individuals with RTH confirmed by the presence of TRbeta gene mutations and 92 unaffected first-degree relatives were tested for thyroglobulin and thyroperoxidase antibodies. The presence of AITD was based on at least one of the two antibodies being positive. Data were analyzed according to genotype, gender, age, and familial association. A large homogeneous family was analyzed separately. RESULTS: Individuals with RTH had an increased likelihood of thyroid autoantibodies (odds ratio = 2.36; P = 0.002). In males, the odds of having AITD were higher in individuals with RTH compared to unaffected first-degree relatives (odds ratio = 2.91; P = 0.042). Although female subjects with RTH had an odds ratio of 1.95 for having thyroid autoantibodies, the difference was not statistically significant (P = 0.097). Antibody prevalence at different ages was not affected by genotype. CONCLUSIONS: Individuals with RTH due to TRbeta gene mutations have an increased likelihood of AITD compared to unaffected relatives, but the prevalence of thyroid autoantibodies with advancing age is not affected by genotype. These novel findings demonstrate that the association between RTH and AITD is not coincidental.

Loss-of-function mutations in the thyrotropin receptor gene as a major determinant of hyperthyrotropinemia in a consanguineous community.

CONTEXT: Resistance to TSH (RTSH) is a condition of impaired responsiveness of the thyroid gland to TSH, characterized by elevated serum TSH, low or normal thyroid hormone levels, and hypoplastic or normal-sized thyroid gland. OBJECTIVES: The aim of the study was to evaluate the clinical course and the genotype-phenotype relationship of RTSH caused by two different TSH receptor (TSHR) gene mutations in a consanguineous population. PATIENTS AND METHODS: We conducted a clinical and genetic investigation of 46 members of an extended family and 163 individuals living in the same town. In vitro functional studies of the mutant TSHRs were also performed. RESULTS: Two TSHR gene mutations (P68S and L653V) were identified in 33 subjects occurring as homozygous L653V (five subjects), heterozygous L653V (20 subjects), heterozygous P68S (four subjects), and compound heterozygous L653V/P68S (four subjects). With the exception of one individual with concomitant autoimmune thyroid disease, all homozygotes and compound heterozygotes presented with compensated RTSH (high TSH with free T(4) and T(3) in the normal range). Only nine of 24 heterozygotes had mild hyperthyrotropinemia. The L653V mutation resulted in a higher serum TSH concentration and showed a more severe in vitro abnormality than P68S. Haplotype analysis predicted a founder of the L653V six to seven generations earlier, whereas the P68S is older. Cross-sectional and prospective longitudinal studies indicate that TSH and T(4) concentrations remain stable over time. CONCLUSIONS: High frequency hyperthyrotropinemia in an Israeli Arab-Muslim consanguineous community is attributed to two inactivating TSHR gene mutations. Concordant genotype-phenotype was demonstrated clinically and by in vitro functional analysis. Retrospective and prospective studies indicate that in the absence of concomitant autoimmune thyroid disease, elevated TSH levels reflect stable compensated RTSH.