Giant congenital fibroblastic connective tissue nevus associated with vascular anomalies.

We described an unusual combination of fibroblastic connective nevus (FCTN) already present at birth with underlying vascular anomalies. Overall, the lesion appeared as a large purplish-brown mass in the groin region up to the third of the right thigh, with partial spontaneous regression during the first three months of life. The FCTN observed exhibited several unusual characteristics: it was congenital, large in size, and located in the lower limbs. Finally, it represented the first case described in which an FCTN arose in association with vascular anomalies.

Asymptomatic CD34+ plaque on the scalp of a child.

Fibroblastic connective tissue nevus (FCTN) is a rare, benign dermal mesenchymal lesion of fibroblastic and myofibroblastic lineage. We report a case of a 2-year-old male who presented with an 18-month history of an erythematous, asymptomatic, unchanging dermal plaque on the right medial frontal scalp. A punch biopsy showed a disorderly, bland, dermal fibroblastic spindle cell proliferation extending to the superficial subcutis. It stained positive for CD34, and concern for dermatofibrosarcoma protuberans was raised. However, FISH was negative for PDGFB rearrangement, and the constellation of findings was most consistent with FCTN. This case underscores the importance of distinguishing CD34+ mesenchymal tumors for both dermatologists and dermatopathologists. As these represent a rather diverse group of lesions with different biological behaviors, a knowledge of the differential diagnosis of these entities is critical for proper patient management.

Pharmacodynamic Study of Miransertib in Individuals with Proteus Syndrome.

Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.

Late-onset Proteus syndrome with cerebriform connective tissue nevus and subsequent development of intraductal papilloma.

Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55-year-old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. We report the identification of the AKT1 c.49G > A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating AKT1 variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the AKT1 variant. The tumor also contained two likely pathogenic variants in PIK3R1, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder.

[Mucinous nevus]. / L'image du mois. Naevus mucineux.

Mucinous nevus is an exceptional entity and presents as flesh-colored to brownish papules or plaques, coalescing to form a pigmentary or verrucous lesion with either a blaschkoid, linear, grouped or zosteriform disposition. It usually appears at birth or during early childhood, but late onset has also been described. Mucinous nevus does not require additional work-up as no internal pathologies have been described. Abstention of any therapeutic intervention is usually preferred.

: Le naevus mucineux est une entité exceptionnelle, se présentant par des papules ou des plaques de couleur chair à brunâtre qui confluent sous la forme d'une lésion pigmentaire ou verruqueuse de distribution blaschkoïde, linéaire, groupée ou zostériforme. Il est le plus souvent congénital ou d'apparition précoce, mais des formes tardives ont également été rapportées. Le naevus mucineux n'est jamais associé à une pathologie interne et ne nécessite pas d'exploration complémentaire. Au vu du caractère bénin, l'abstention thérapeutique est généralement la règle.

Buschke-Ollendorff syndrome with LEMD3 germline stopgain mutation p.R678* presenting as multiple subcutaneous nodules with mucin deposition.

Buschke-Ollendorff syndrome (BOS; OMIM 166700) is a rare autosomal dominant disorder characterized by the existence of connective tissue nevus and/or osteopoikilosis. The skin lesions usually present as firm, yellow, or flesh-colored papules and nodules, which may coalesce into plaques and increase in size and number over time. We present a case of a 26-year-old male with multiple subcutaneous nodules on the waist and thigh for more than 20 years. Being deeply seated, his skin lesions were not visible and could only be appreciated by palpation. Accordingly, pathology showed an increase in thick, crossed, or paralleled, elastic fibers arranged between the collagen bundles in the lower part of the reticular dermis and the subcutaneous fat with mucin deposition. Heterozygous point mutation in exon 8 of the LEMD3 gene was detected, which confirmed the diagnosis of BOS. The deeply situated nature of skin lesions noted in our case has not been reported in the literature of BOS. Our case thus expands the clinical and pathological features of the disease.

Agminated fibroblastic connective tissue nevus in a 1-year-old boy.

Fibroblastic connective tissue nevus (FCTN) is a benign cutaneous mesenchymal lesion characterized by proliferation of CD34-positive fibroblastic/myofibroblastic spindle-shaped cells. We report a case of agminated FCTN on the right lower abdomen of a 1-year-old boy.

Medallion-like dermal dendrocyte hamartoma: A rare congenital CD34-positive dermal lesion clinically and pathologically overlapping with fibroblastic connective tissue nevus.

Both medallion-like dermal dendrocyte hamartoma and fibroblastic connective tissue nevus are rare benign dermal lesions composed of CD34-positive spindle cells. Although regarded as different diseases, it is sometimes difficult to distinguish between them due to their clinical and pathological similarities. We present a case of medallion-like dermal dendrocyte hamartoma that could also be diagnosed as fibroblastic connective tissue nevus and propose the possibility of overlap in these diseases.

Progress of an isolated collagenoma during pregnancy.

Collagenomas are connective tissue naevi composed predominantly of collagen. Isolated collagenomas are usually localized to a single body region, acquired, and of rare occurrence. We describe a patient with an isolated collagenoma that showed an increase in size during pregnancy and regressed afterwards.

Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome.

BACKGROUND: The plantar cerebriform connective tissue nevus (CCTN) is the most common and problematic cutaneous manifestation of Proteus syndrome. OBJECTIVE: To gain insights into CCTN pathogenesis and natural history. METHODS: The size and location of plantar CCTN was measured on 152 images from 22 individuals with Proteus syndrome by 2 independent, blinded reviewers. Average measures of plantar CCTN were transformed into a linear mixed model to estimate proportionate change in size with age. RESULTS: Median patient age was 6.9 years at study onset. The intraclass correlation coefficient between 2 blinded reviewers was 0.946 for CCTN single measures. The CCTN relative area increased with age in children (n = 18, P < .0001) by 5.6% per year. Confluent papules and nodules extending beyond the boundaries of CCTNs were gradually replaced by typical CCTN over time. The location of CCTN in different individuals overlapped near the ball of the foot. A positive relationship between CCTN growth rate and AKT1 mutant allele frequency was observed (0.62, P = .10, n = 8). LIMITATIONS: This was a retrospective review using photographs. CONCLUSION: CCTN growth is affected by age and extent of the CCTN precursor lesion. Monitoring of CCTN size might prove useful for evaluating drug response in the treatment of Proteus syndrome.

Fibrous cephalic plaques in tuberous sclerosis complex.

BACKGROUND: Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of patients with tuberous sclerosis complex (TSC). They constitute a major feature for TSC diagnosis and may present before other TSC-related cutaneous hamartomas. OBJECTIVE: To describe the clinical characteristics of FCPs in TSC. METHODS: A total of 113 patients with TSC were enrolled in an observational cohort study. Retrospective analysis of medical records and skin photography was performed. FCPs were categorized by anatomic location and size. RESULTS: FCPs were observed in 36% of patients (41 of 113). Of 62 total lesions, 58% were 1 to less than 5 cm, 13% were 5 cm or larger, and 29% were of unknown size mostly because of prior excision. The distribution of lesions was 39% on the forehead, 27% on the face (nonforehead), 3% on the neck, and 31% on the scalp. Fourteen patients had similar lesions less than 1 cm in diameter. Histopathologically, FCPs displayed dermal collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas. LIMITATIONS: Men were under-represented because the cohort was enriched for patients with TSC with lymphangioleiomyomatosis, which occurs in adult women. CONCLUSION: Two-fifths of FCPs presented on the forehead, with most of the remainder in other locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis of TSC.

Fibroblastic connective tissue nevus: Clinicopathological and immunohistochemical study of 14 cases.

BACKGROUND: We present herein a series of 14 lesions showing overlapping features with the newly defined benign cutaneous mesenchymal neoplasm labeled as fibroblastic connective tissue nevus (FCTN). METHODS AND RESULTS: Total of 8 patients were male and 5 were female, ranging in age from 1 to 56 years. Lesions appeared as isolated nodules or plaques on the trunk (7 cases), the limbs (4 cases) and the neck (2 cases). Histologically, all cases were composed of bundles of bland spindle cells of fibroblastic/myofibroblastic lineage irregularly branching within the reticular dermis and along fibrous septa in the subcutis. Adnexal structures and dermal adipocytes were entrapped by the fascicles, the epidermis was often papillomatous and elastic fibers were decreased and fragmented. Expression of CD34 and ASMA was found in 8 and 7 cases, respectively. Follow-up was available for 7 patients (mean follow-up, 5 years; range, 1-10 years). None of the cases metastasized or recurred, even when incompletely excised. CONCLUSION: The differential diagnosis of FCTN is broad and includes hypertrophic scar, dermatofibroma, dermatomyofibroma, pilar leiomyoma, plaque-stage DFSP, CD34-positive plaque-like dermal fibroma, fibroblastic-predominant plexiform fibrohistiocytic tumor, lipofibromatosis, superficial desmoid fibromatosis and fibrous hamartoma of infancy, of which it represents probably the monophasic variant.

[Extensive connective tissue nevus in children]. / Hamartome conjonctif étendu de l'enfant.

BACKGROUND: Connective tissue nevus (CTN) is a rare condition of the extracellular matrix components that generally presents as papulae of normal skin colour. This condition may be syndromic or sporadic. PATIENTS AND METHODS: We report herein two isolated cases of extensive and infiltrative CTN in children at risk for subsequent joint stiffening. The pathology samples displayed respectively mixed hamartoma and a collagenoma. DISCUSSION: The onset of these lesions is often difficult to establish, since they are usually unnoticeable at first. When confronted with extensive CTN, the main differential diagnoses are eosinophilic fasciitis and morphea, and these must be ruled out by skin biopsy. CTN is associated with osteopoikilosis in Buschke-Ollendorf syndrome. Skeletal lesions are asymptomatic and are detected by means of iterative X-ray. Their management comprises symptomatic care.

Fibroblastic connective tissue nevus.

Fibroblastic connective tissue nevus (FCTN) is a newly recognized, benign cutaneous mesenchymal lesion of fibroblasts/myofibroblastic lineage, which expands the classification of connective tissue nevi. We present three cases of FCTN and discuss significant clinical, morphologic and immunophenotypic overlap with dermatomyofibroma. Our cases were from young women, aged 32, 24 and 10, and presented as 1.2 and 1 cm nodules on the posterior neck and right upper flank, respectively while presenting as a linear plaque of the right posterior thigh in the latter case. The lesions showed a poorly circumscribed proliferation of hypercellular spindle cells arranged in short to longer intersecting fascicles entrapping adnexal structures. Superficial adipose tissue was also entrapped in one case. The spindle cells had fibroblastic features with pale eosinophilic cytoplasmic extensions and inconspicuous nucleoli. The spindle cells were positive for CD34 in two cases. One case was negative for CD34, smooth muscle actin (SMA), desmin and S100. The overall features were consistent with a diagnosis of FCTN. In two cases, we further elucidated the fibroblastic differentiation of the spindle cells in FCTN with electron microscopy, which has not been previously described.

Proteus syndrome review: molecular, clinical, and pathologic features.

Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.

Nevus anelasticus: how should such lesions be classified?

Nevus anelasticus represents a rare entity that is most commonly classified as a connective tissue nevus. It typically presents before 20 years of age with asymmetrically distributed white-to-skin-toned or pink-to-red papules or plaques on the trunk and upper extremities. The lesion is defined histopathologically by the absence or degeneration of elastic fibers in the dermis. We report the case of a healthy 17-year-old female who presented with an asymptomatic slowly progressive plaque on the right inferior areola. Histopathologic examination showed the absence of elastic fibers in the papillary and upper reticular dermis and fragmented elastic tissue fibers in the deep reticular dermis. Although there is ongoing controversy regarding the nosology of this uncommon disorder, we propose that it is a distinct entity based on its histopathologic and clinical features.

Ossifying fibroma in Buschke-Ollendorff syndrome.

Buschke-Ollendorff syndrome represents an autosomal dominant disorder characterized by connective tissue nevi and osteopoikilosis. Cutaneous lesions may contain either predominantly elastic fibers or predominantly collagen fibers or may show both connective tissue components. The disease results from mutations in LEMD3 (MAN1), which lead to enhanced transforming growth factor-ß (TGF-ß) signaling and resultant changes in fibroblast function. TGF-ß alterations have been implicated in a number of fibrotic disorders, and it is therefore not surprising that a range of cutaneous and skeletal abnormalities have been associated with Buschke-Ollendorff syndrome. Herein, we report a novel association between ossifying fibroma and Buschke-Ollendorff syndrome and discuss how these conditions are likely to be mechanistically linked.

Connective tissue nevus misdiagnosed as juvenile localized scleroderma.

BACKGROUND: Connective tissue nevi (CTN) are congenital hamartomas caused by excessive proliferation of dermis components. In children, CTN can mimic juvenile localized scleroderma (JLS), an immune mediated skin disorder that requires aggressive immunosuppression. OBJECTIVES: Aim of our study was to describe a series of pediatric patients with CTN misdiagnosed as JLS and the discerning characteristics between the two conditions. METHODS: Retrospective analysis of children referred to our Center during the last two decades for JLS who received a final diagnosis of CTN. Clinical, laboratory, histopathological and instrumental data (MRI and thermography) were collected and compared with those with JLS. RESULTS: Seventeen patients with mean age at onset 4.6 years entered the study. All came to our Center with a certain diagnosis of JLS (n = 15) or suspected JLS (n = 2). The indurated skin lesions were flat and resembled either circumscribed morphea or pansclerotic morphea. In 14 patients (82.4%) they were mainly localized at the lower limbs and in three (17.6%) at the upper limbs. No patient had laboratory inflammatory changes or positive autoantibodies. Skin biopsies confirmed the diagnosis of CTN: non-familial collagenoma in eleven (64.7%), mixed CTN in four (23.5%) and familial CTN in two (11.8%). Mean age at final diagnosis was 9.5 years, with a mean diagnostic delay of 4.8 years (range 1-15 years). Sixteen patients underwent musculoskeletal MRI that was normal in all except two who showed muscle perifascial enhancement. Thermography was normal in all patients. At our first evaluation, eleven patients (64.7%) were on systemic treatment (methotrexate 11, corticosteroids 7, biologics 2), three (17.6%) on topical corticosteroids and three untreated. CONCLUSIONS: CTN can be misdiagnosed as JLS and therefore aggressively treated with prolonged and inappropriate immunosuppression. The absence of inflammatory appearance of the skin lesions, normal instrumental and laboratory findings and the accurate evaluation of skin biopsy are crucial to address the right diagnosis.