Hereditary Trichilemmal Cysts are Caused by Two Hits to the Same Copy of the Phospholipase C Delta 1 Gene (PLCD1).

The autosomal dominant presentation of trichilemmal cysts is one of the most common single gene familial diseases in humans. However, the genetic basis for the inheritance and genesis of these lesions has remained unknown. We first studied patients with multiple trichilemmal cysts using exome and Sanger sequencing. Remarkably, 21 of 21 trichilemmal cysts from 16 subjects all harbored a somatic p.S745L (c.2234 G > A) mutation in phospholipase C delta 1 (PLCD1), a proposed tumor suppressor gene. In addition to this specific somatic mutation in their tumors, 16 of the 17 subjects with multiple trichilemmal cysts were also heterozygous for a p.S460L (c.1379 G > A) germline variant in PLCD1 which is normally present in only about 6% of this population. The one patient of 17 that did not show the p.S460L germline variant had a germline p.E455K (c.1363 C > T) mutation in the same exon of PLCD1. Among 15 additional subjects, with a history suggesting a single sporadic trichilemmal cyst, six were likely familial due to the presence of the p.S460L germline variant. Of the remaining truly sporadic trichilemmal cysts that could be sequenced, only half showed the p.S745L somatic mutation in contrast to 100% of the familial cysts. Surprisingly, in contrast to Knudsen's two hit hypothesis, the p.S745L somatic mutation was always on the same chromosome as the p.S460L germline variant. Our results indicate that familial trichilemmal cysts is an autosomal dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene. The c.1379 G > A base change and neighboring bases are consistent with a mutation caused by ultraviolet radiation. Our findings also indicate that approximately one-third of apparently sporadic trichilemmal cysts are actually familial with incomplete penetrance. Sequencing data suggests that the remaining, apparently sporadic, trichilemmal cysts are genetically distinct from familial cysts due to a lack of the germline mutations that underlie familial cysts and a decreased prevalence of the p.S745L somatic mutation relative to familial trichilemmal cysts.

Low-grade developmental and epilepsy associated brain tumors: a critical update 2020.

Brain tumors represent the second most frequent etiology in patients with focal seizure onset before 18 years of age and submitted to epilepsy surgery. Hence, this category of brain tumors, herein defined as low-grade, developmental, epilepsy-associated brain tumors (LEAT) is different from those frequently encountered in adults as (A): 77% of LEAT occur in the temporal lobe; (B): the vast majority of LEAT are of low malignancy and classified as WHO I°; (C): LEAT are often composed of mixed glial and neuronal cell components and present with variable growth patterns including small cysts or nodules; (D): LEAT do not share common gene driving mutations, such as IDH1 or 1p/19q co-deletions. Characteristic entities comprise the ganglioglioma (GG), the dysembryoplastic neuroepithelial tumor (DNT), the angiocentric glioma (AG), the isomorphic diffuse glioma (IDG) and the papillary glio-neuronal tumor (PGNT), representing 73.2% of 1680 tumors collected in a large German series of 6747 patients submitted to epilepsy surgery. In the realm of exciting discoveries of genetic drivers of brain tumors new genes have been also reported for LEAT. BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT. Rare availability of LEAT in a single center is a challenging obstacle, however, to systematically unravel the neurobiological nature and clinical behavior of LEAT. Other challenges in need of clarification include malignant tumor progression of LEAT entities, seizure relapse in patients following bulk tumor resection and the controversial issue of associated focal cortical dysplasia as additional pathomechanism. In order to advance our understanding and promote reliable diagnostic work-up of LEAT, we recommend, therefore, international collaboration to achieve our goals.

Nasal fistula, epidermal cyst and hypernatremia in a girl presenting holoprosencephaly due to a rare ZIC2 point mutation.

Holoprosencephaly is the most common brain malformation in humans and it is a complex genetic disorder. We report on a patient with holoprosencephaly caused by a rare ZIC2 mutation presenting a bifid nose associated with a nasal fistula and an epidermal cyst, besides hypernatremia. The patient was a 1 year and 4 months old girl that developed an important neuropsychomotor delay. Currently, she uses a wheelchair to move around and only emits sounds. Computed tomography (CT) scan revealed a semilobar holoprosencephaly and a Dandy-Walker variant. Head magnetic resonance imaging also disclosed corpus callosum agenesis and prefrontal subarachnoid space enlargement. On physical examination at 1 year and 4 months of age, we verified growth retardation, microcephaly, bilateral epicantic fold, upslanting palpebral fissures, bifid nose, and limbs spasticity secondary to hypertonia. Later, she began to present hypernatremia; however, its precise cause was not identified. At 6 years and 10 months of age, a nasal fistula was suspected. Facial CT scan showed an epidermal cyst at cartilaginous portion of the nasal septum. High resolution GTG-Banding karyotype was normal. However, molecular analysis through direct sequencing technique showed a mutation at regulatory region of the ZIC2 gene: c.1599*954T > A, a genetic variation previously described only in a Brazilian patient. Our patient presented findings still not reported in literature among patients with holoprosencephaly, including those with ZIC2 mutations. Thus, the spectrum of abnormalities associated to ZIC2 mutations may be broader and include other defects as those observed in our patient.

Genomic profile of a primary squamous cell carcinoma arising from malignant transformation of a pineal epidermoid cyst.

Malignant transformation of intracranial epidermoid cysts is a rare occurrence. We present the second case of such an event occurring in the pineal region and the first case sent for detailed genomic profiling. MRI demonstrated two lesions: a cyst in a quadrigeminal cistern with restricted diffusion on DWI-weighted images and an adjacent, peripherally enhancing tumor with cerebellar infiltration. Both the lesions were completely resected with a small residual of the epidermoid cyst. The final pathology of both lesions was consistent with epidermoid cyst and squamous cell carcinoma (SCC), respectively. The tumor specimen was sent for comprehensive genomic profiling which revealed stable microsatellite status and loss of CDKN2A/B, MTAP (exons 2-8), and PTEN (exons 6-9). Although reports of primary SCC originating from the epidermoid cyst have been previously described, this is the first description of the genomic profile of such a tumor.

A Monoallelic Two-Hit Mechanism in PLCD1 Explains the Genetic Pathogenesis of Hereditary Trichilemmal Cyst Formation.

Trichilemmal cysts are common hair follicle-derived intradermal cysts. The trait shows an autosomal dominant mode of transmission with incomplete penetrance. Here, we describe the pathogenetic mechanism for the development of hereditary trichilemmal cysts. By whole-exome sequencing of DNA from the blood samples of 5 affected individuals and subsequent Sanger sequencing of a family cohort including 35 affected individuals, this study identified a combination of the Phospholipase C Delta 1 germline variants c.903A>G, p.(Pro301Pro) and c.1379C>T, p.(Ser460Leu) as a high-risk factor for trichilemmal cyst development. Allele-specific PCRs and cloning experiments showed that these two variants are present on the same allele. The analysis of tissue from several cysts revealed that an additional somatic Phospholipase C Delta 1 mutation on the same allele is required for cyst formation. In two different functional in vitro assays, this study showed that the protein function of the cyst-specific 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase delta-1 protein variant is modified. This pathologic mechanism defines a monoallelic model of the two-hit mechanism proposed for tumor development and other hereditary cyst diseases.

"Cyst" on the forearm of a 28-year-old female: Case report of a CIC-rearranged sarcoma.

Capicua transcriptional repressor (CIC)-rearranged sarcomas are part of the group of Ewing-like sarcomas or atypical Ewing sarcomas which, thanks to the progress in molecular diagnosis, are being defined by particular genetic abnormalities separating this group into distinct entities with their own particular histological and immunohistochemical features, as well as different survival outcomes. We report the case of a healthy 28-year-old female presenting with a tender lesion on her forearm which after ultrasound examination was clinically favored to represent an infected sebaceous cyst. Hematoxylin-eosin staining showed a lobulated neoplasm within the subcutis composed of poorly differentiated epithelioid to round cells with a small amount of amphophilic cytoplasm. Frequent mitotic figures and tumor necrosis were present. Immunohistochemical studies showed patchy focal CD99 membranous positivity, negative WT1 and TLE1 staining and diffuse nuclear positivity for ETV4 (performed at outside laboratory). FISH analysis showed significant CIC rearrangement enabling a final diagnosis of an undifferentiated small round cell sarcoma harboring the t(4;19)(q35;q13.1) and CIC-DUX4 fusion. This case shows the importance of awareness of this entity as, unlike Ewing sarcoma, these lesions present in the soft tissues rather than bone and may, as in this case, arise in the superficial soft tissues and be submitted to a dermatopathology practice.

Novel heterozygous BPIFC variant in a Chinese pedigree with hereditary trichilemmal cysts.

BACKGROUND: Trichilemmal cysts (TCs) are common intradermal or subcutaneous cysts, which are commonly sporadic and rarely autosomal dominantly inherited. However, little is known about the disease-determining genes in families with TCs exhibiting Mendelian inheritance. OBJECTIVE: The aim of this study was to identify the causative gene in a family with TCs. METHODS: Whole-exome sequencing was performed on a TCs family to identify the candidate gene. Sanger sequencing was conducted to validate the candidate variants and familial segregation. RESULTS: We identified the heterozygous variant c.3G>C (p.Met1?) within the BPIFC gene. Sanger sequencing confirmed the cosegregation of this variant with the TCs phenotype in the family by demonstrating the presence of the heterozygous variant in all the 12 affected and absence in all the seven unaffected individuals. This variant was found to be absent in dbSNP141, 1,000 Genomes database and 500 ethnicity matched controls. CONCLUSION: Our results imply that BPIFC is a causative gene in this Chinese family with hereditary TCs. Further studies should be performed to validate the role of BPIFC in the pathogenesis of this disease.

Distinct Biological Types of Ocular Adnexal Sebaceous Carcinoma: HPV-Driven and Virus-Negative Tumors Arise through Nonoverlapping Molecular-Genetic Alterations.

PURPOSE: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies. EXPERIMENTAL DESIGN: We present next-generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from eight OA sebaceous carcinomas from 29 patients. RESULTS: We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting TP53 and/or RB1 [20/29 (70%) patients, including 10 patients whose primary tumors contained coexisting TP53 and RB1 mutations] with frequent concomitant mutations affecting NOTCH genes. These tumors arise in older patients and show frequent local recurrence. The second subtype [9/29 (31%) patients] lacks mutations affecting TP53, RB1, or NOTCH family members, but in 44% (4/9) of these tumors, RNA sequencing and in situ hybridization studies confirm transcriptionally active high-risk human papillomavirus. These tumors arise in younger patients and have not shown local recurrence. CONCLUSIONS: Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions.

Genome-wide linkage and exome analyses identify variants of HMCN1 for splenic epidermoid cyst.

BACKGROUND: Splenic epidermoid cyst is a benign tumor-like lesion affecting the spleen and sometimes occurs in familial form. The causality of such rare diseases remain challenging, however recently, with the emergence of exome re-sequencing, the genetics of many diseases have been unveiled. In the present study, we performed a combinatorial approach of genome-wide parametric linkage and exome analyses for a moderate-sized Japanese family with frequent occurrence of splenic epidermoid cyst to identify the genetic causality of the disease. METHODS: Twelve individuals from the family were subject to SNP typing and exome re-sequencing was done for 8 family members and 4 unrelated patients from Kosovo. Linkage was estimated using multi-point parametric linkage analysis assuming a dominant mode of inheritance. All of the candidate variants from exome analysis were confirmed by direct sequencing. RESULTS: The parametric linkage analysis suggested two loci on 1q and 14q with a maximal LOD score of 2.5 . Exome generated variants were prioritized based on; impact on the protein coding sequence, novelty or rareness in public databases, and position within the linkage loci. This approach identified three variants; variants of HMCN1 and CNTN2 on 1q and a variant of DDHD1 on 14q. The variant of HMCN1 (p.R5205H) showed the best co-segregation in the family after validation with Sanger sequencing. Additionally, rare missense variants (p.A4704V, p.T5004I, and p.H5244Q) were detected in three unrelated Kosovo patients. The identified variants of HMCN1 are on conserved domains, particularly the two variants on calcium-binding epidermal growth factor domain. CONCLUSIONS: The present study, by combining linkage and exome analyses, identified HMCN1 as a genetic causality of splenic epidermoid cyst. Understanding the biology of the disease is a key step toward developing innovative approaches of intervention.

Angiofibromas with multiple epidermoid cysts in tuberous sclerosis: new mutation or post-traumatic?

Tuberous sclerosis is a genetic multisystem disorder characterized by widespread hamartomas in several organs. Clinically, more than 90% of affected patients have skin lesions including facial angiofibromas, periungual fibromas, hypomelanotic macule, etc. Periungual fibroma is one of the major diagnostic criteria of tuberous sclerosis and has the same pathology (angiofibroma) as the facial papules. We herein describe an interesting histologic variant of angiofibromas coupled with multiple epidermoid cysts in a 33-year-old patient with tuberous sclerosis.

Eruptive vellus hair cysts: a systematic review.

We report the results of the first systematic review of the worldwide literature on eruptive vellus hair cysts (EVHC). It is likely that EVHC are less rare than it may appear from the scarcity of related publications in the literature. EVHC may be present at birth and may appear at any age, although they show a clear trend towards occurring during the first 3 decades of life. A strong clue to the heavy influence of genes on the occurrence of EVHC is provided by the numerous reports of families in whom two or more members were affected. EVHC lesions present clinically in a rather monomorphous fashion, i.e. round, dome-shaped, skin-colored, asymptomatic, soft-tender papules with a smooth surface and grouped or disseminated in a symmetric pattern. EVHC may affect any cutaneous area, even if the upper part of the body and some distribution patterns are particularly frequent and recognizable, i.e. cephalic, upper trunk around the midline, upper limb including axillae, and proximal lower limb. Such a distribution is likely not random and seems to grossly overlap with that of pilosebaceous and apocrine units. Like clinical morphology, the histologic features of EVHC papules are rather monomorphous, indeed, the diagnostic hallmark being the presence of vellus hair shafts within the cystic space. Peculiar subgroups (familial, late-onset, unilesional, and associated with steatocystoma multiplex) are also identified and discussed. In conclusion, EVHC are basically a cosmetic concern to patients but represent a chronic and difficult-to-treat condition. On the basis of our review, future studies are warranted, mainly concerning (i) further nosographic framing involving genetic and tissue analysis, (ii) implementation of non-invasive diagnostic procedures, and (iii) therapeutic trials of interventions shown to achieve some effectiveness.

[Steatocystoma multiplex in 39 year-old female]. / Steatocystoma multiplex hos 39-årig kvinde.

A clinical case of the rare disorder steatocystoma multiplex is described in a 39-year-old female. The patient was diagnosed with generalized intradermal lesions that started presenting in early adulthood. There was no family history of similar lesions.Skin examination showed multiple, skin-coloured cystic lesions on the chest, abdomen, axillae and back. The patient's clinical presentations and history were compatible with steatocystoma multiplex. Various treatment options for steatocystoma multiplex and steatocystoma multiplex suppurativum have been published and include oral antibiotics, isotretinoin, excision and incision techniques.

Leukonychia totalis associated with multiple pilar cysts: report of a five-generation family: FLOTCH syndrome?

The association of familial totalis leukonychia with multiple pilar cysts is a rare condition that could represent a separate syndromic entity. Since Bauer described a family with totalis leukonychia and sebaceous cysts in 1920, only four new affected families have been reported. We report a five-generation family with a total leukonychia and multiple pilar cysts on the scalp. The hypothesis of a deficiency of a gene regulating the structure of keratin has been postulated but the exact genetic mechanism has not been yet determined. In our family, no other keratinizing structures were involved.