Cutaneous Mastocytosis in Children: Analysis of Somatic and Germline Mutations

Pediatric mastocytosis is an orphan disease, which encompasses several clinically distinct entities including solitary mastocytoma, urticaria pigmentosa, diffuse cutaneous mastocytosis and the newly recognized mast cell activation syndrome. The most common form of pediatric mastocytosis is cutaneous maculopapular mastocytosis (CMPM), also known as urticaria pigmentosa (UP). There are significant knowledge gaps regarding the genetic basis of pediatric mastocytosis and the functional activity of mast cells in this condition. The Pediatric Dermatology and Pediatric Oncology services at the University of Minnesota Masonic Children's Hospital are seeing significant growth in clinical volumes of pediatric mastocytosis, including rare, familial cases. The aims of this study are to prospectively explore germline risk for UP and to perform a mutational analysis to identify somatic mutations, beyond those currently identified, in pediatric patients with UP.

Study Overview

• Status: Completed
• Conditions: Urticaria Pigmentosa; Cutaneous Mastocytosis
• Intervention / Treatment: Other: skin biopsy; Other: blood draw

Detailed Description

Urticaria pigmentosa (UP) is a relatively common disorder in pediatric patients, and little is known regarding the somatic and germline genetic variants associated with the disease. The University of Minnesota Masonic Children's Hospital is a regional referral center for pediatric patients with mast cell disorders. Collaborators on this study include several University departments including: Pediatric Dermatology, Pediatric Oncology, the Biomedical Genomics program, Lab Medicine and Pathology department. We hypothesize that because of differences observed in the clinical behavior of pediatric- and adult-onset mast cell disease, specifically UP, we will identify novel somatic gene variants in addition to c-KIT . We further hypothesize that we will observe novel germline genetic variants in pediatric UP distinct from what has previously been described in adults.

Specific Aims include the following:

Specific Aim 1: RNA Sequencing for Gene Expression and Mutation Analysis. Utilizing RNA sequencing (RNA-Seq), we will perform paired lesional and peripheral blood sequencing in UP cases to identify variation in gene expression and define novel somatic mutations associated with pediatric UP.

Specific Aim 2: Exploration of Germline Risk. Utilizing single nucleotide polymorphism (SNP) array, we will perform linkage analysis in UP cases and their unaffected family members to identify germline genetic variants associated with UP.

1. Discordant sibling analysis: Children with UP and their unaffected siblings will be compared to identify germline variants.
2. Identical twin and parent analysis: Identical infant twins with a severe UP phenotype will be compared with their unaffected parents.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with urticaria pigmentosa and first degree relatives

Description

Inclusion Criteria:

Affected subject:

Subjects will be eligible to participate in the study if all of the following conditions exist:

1. Clinical diagnosis of urticaria pigmentosa/cutaneous mastocytosis with representative skin lesions
2. Age <23 years
3. Capable of giving consent if 18 or older

Inclusion Criteria for Parent:

1. Over 16 years of age
2. Biologic parent to affected subject
3. Capable of providing consent

Inclusion Criteria for Sibling:

1. Biologic sibling to affected subject 2. Capable of giving consent if 18 or older

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Exclusion Criteria:

1. Absence of skin findings representative of classic urticaria pigmentosa
2. Patients with primarily systemic mastocytosis
3. Unable or unwilling to participate in study procedures

Exclusion Criteria for Parent/Sibling:

1. Unable or unwilling to participate in study procedures

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with Urticaria Pigmentosa; This group will undergo skin biopsy, blood and buccal swab analyses	Other: skin biopsy; A skin biopsy will be obtained from a typical UP lesion in affected patients; Other: blood draw; Blood will be obtained from subjects, parents and unaffected siblings
Family members of affected patients; This group will undergo blood and buccal swab analyses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RNA sequencing	Fresh tissue from lesional skin will be obtained for gene expression and mutational analysis	1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SNP microarray analysis	SNP microarray analysis will be performed on DNA obtained from buccal swabs or whole blood samples. Samples from patients and unaffected family members will be compared.	1.5 years

Collaborators and Investigators

• Sponsor: University of Minnesota

Publications and helpful links

General Publications

• Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, Matito A, Broesby-Olsen S, Siebenhaar F, Lange M, Niedoszytko M, Castells M, Oude Elberink JNG, Bonadonna P, Zanotti R, Hornick JL, Torrelo A, Grabbe J, Rabenhorst A, Nedoszytko B, Butterfield JH, Gotlib J, Reiter A, Radia D, Hermine O, Sotlar K, George TI, Kristensen TK, Kluin-Nelemans HC, Yavuz S, Hagglund H, Sperr WR, Schwartz LB, Triggiani M, Maurer M, Nilsson G, Horny HP, Arock M, Orfao A, Metcalfe DD, Akin C, Valent P. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 Jan;137(1):35-45. doi: 10.1016/j.jaci.2015.08.034. Epub 2015 Oct 21.
• Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1609-14. doi: 10.1073/pnas.96.4.1609.
• Fried AJ, Akin C. Primary mast cell disorders in children. Curr Allergy Asthma Rep. 2013 Dec;13(6):693-701. doi: 10.1007/s11882-013-0392-6.
• Fett NM, Teng J, Longley BJ. Familial urticaria pigmentosa: report of a family and review of the role of KIT mutations. Am J Dermatopathol. 2013 Feb;35(1):113-6. doi: 10.1097/DAD.0b013e31826330bf.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): May 1, 2020

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: May 2, 2016
• First Posted (Estimate): May 4, 2016

Study Record Updates

• Last Update Posted (Actual): August 20, 2020
• Last Update Submitted That Met QC Criteria: August 19, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Hypersensitivity, Immediate; Skin Diseases, Vascular; Hypersensitivity; Neoplasms, Connective Tissue; Pigmentation Disorders; Immune Complex Diseases; Urticaria; Mastocytosis; Mastocytosis, Cutaneous; Mastocytoma; Urticaria Pigmentosa
• Other Study ID Numbers: 1608M92621

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No