A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor ß (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-ß promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-ß as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-ß in aggressive life-threatening familial forms of the disease.

Cutaneous mastocytosis with atypical mast cells and giant cytoplasmic granules.

A 12-year-old male presented with an 8-year history of five firm cream colored papules on the right vertex of the scalp. A biopsy showed a dense infiltrate of monomorphous mast cells involving the dermis and extending into the subcutis. A relatively well-circumscribed cluster of larger cells showed pleomorphic nuclei with bilobed and multilobed morphology. Both mast cell populations had an eosinophilic cytoplasm filled with granules ranging in size from small to giant forms. By immunohistochemistry, the cells expressed CD117, tryptase and CD68, and were negative for AE1/AE3, CD1a, CD2 and CD25. S-100 staining revealed only faint cytoplasmic positivity and myeloperoxidase had an inhomogeneous patchy pattern, with an overall staining of less than 5% of the cells. A diagnosis of cutaneous mastocytosis was made and after 6 months follow-up, no progression observed. Clinical correlation and awareness of these unusual morphologic features as being part of the spectrum of cutaneous mastocytosis are important to avoid an erroneous diagnosis of malignancy. Although pleomorphic, multilobed nuclear morphology and giant cytoplasmic granules have not been associated with an aggressive behavior or systemic mastocytosis, close clinical observation is warranted in this context.

Incontinentia pigmenti in an XY boy: case report and review of the literature.

BACKGROUND: Incontinentia pigmenti (IP) is a rare genetic skin disorder with X-linked dominant inheritance and a characteristic sequence of cutaneous manifestations, which is regarded as lethal in XY males. OBJECTIVE: To report a case of a surviving XY male with the common IKBKG (NEMO) gene deletion confirming IP. METHODS AND RESULTS: A newborn XY male with suspected IP underwent a skin biopsy on affected tissue for histopathology. Molecular genetic testing was also performed on the specimen and revealed the common IKBKG gene deletion with a pattern suggestive of somatic mosaicism. Our findings are aligned with a PubMed literature review for XY males with IP and documented IKBKG mutation. We determined that only 10 such genetically proven cases have been reported, including our case. CONCLUSION: Although relatively rare, cases of IP in XY males with the common NEMO mutation have likely been underreported due to the unavailability of appropriate testing in the past. Karyotype and molecular testing should be considered when clinical suspicion of IP arises for a male patient.