Co-occurrence of neurofibromatosis type 1 and pseudoachondroplasia - a first case report.

BACKGROUND: Neurofibromatosis type 1 and pseudoachondroplasia are both rare autosomal dominant disorders, caused by pathogenic mutations in NF1 and COMP genes, respectively. Both neurofibromin 1 and cartilage oligomeric matrix protein (COMP) play a role in the development of the skeleton. Carrying both germline mutations has not been previously reported; however, it can affect the developing phenotype. CASE PRESENTATION: The index patient, an 8-year-old female presented with several skeletal and dermatologic anomalies resembling the coexistence of multiple syndromes. Her mother had dermatologic symptoms characteristic for neurofibromatosis type 1, and her father presented with distinct skeletal anomalies. NGS-based analysis revealed a heterozygous pathogenic mutation in genes NF1 and COMP in the index patient. A previously unreported heterozygous variant was detected for the NF1 gene. The sequencing of the COMP gene revealed a previously reported, pathogenic heterozygous variant that is responsible for the development of the pseudoachondroplasia phenotype. CONCLUSIONS: Here, we present the case of a young female carrying pathogenic NF1 and COMP mutations, diagnosed with two distinct heritable disorders, neurofibromatosis type 1 and pseudoachondroplasia. The coincidence of two monogenic autosomal dominant disorders is rare and can pose a differential diagnostic challenge. To the best of our knowledge, this is the first reported co-occurrence of these syndromes.

Superimposed Mosaicism in the Form of Extremely Extended Segmental Plexiform Neurofibroma Caused by a Novel Pathogenic Variant in the NF1 Gene.

Plexiform neurofibromas occurring in approximately 20-50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to compression of vital structures or transformation to malignant sarcomas or malignant peripheral nerve sheath tumors. All sizeable plexiform neurofibromas are thought to result from an early second mutation giving rise to a loss of heterozygosity of the NF1 gene. In this unusual case, a 12-year-old girl presented with a rapidly growing, extremely extensive plexiform neurofibroma with segmental distribution over the entire right arm, extending to the right chest wall and mediastinum, superimposed on classic cutaneous lesions of NF1. After several surgical interventions, the patient was efficiently treated with an oral selective MEK inhibitor, selumetinib, which resulted in a rapid reduction of the tumor volume. Molecular analysis of the NF1 gene revealed a c.2326-2 A>G splice-site mutation in the clinically unaffected skin, peripheral blood sample, and plexiform neurofibroma, which explains the general clinical symptoms. Furthermore, a novel likely pathogenic variant, c.4933dupC (p.Leu1645Profs*7), has been identified exclusively in the girl's plexiform neurofibromas. This second-hit mutation can explain the extremely extensive segmental involvement.

Primary Localized Cutaneous Amyloidosis in Central Europe: A Retrospective Monocentric Study on Epidemiology and Therapy.

Amyloid deposits can be the cause of many chronic diseases. Primary localized cutaneous amyloidosis (PLCA) is a chronic dermatologic condition with amyloid deposits in the papillary dermis. The most common types of the keratinocyte-derived form of PLCA include macular (MA), lichen (LA), and biphasic (BA) amyloidosis. The estimated prevalence of PLCA in the Asian population is 0.98/10,000, which is higher than in the European population; thus, epidemiologic data on PLCA in the Caucasian population are limited. We performed a retrospective single-center study analyzing epidemiologic characteristics of a Central European PLCA population. Epidemiologic data regarding age, sex, skin phototype (Fitzpatrick scale I-VI), disease duration, comorbidities, history of atopy, and family history of PLCA were collected. Clinical characteristics, localization of PLCA lesions, applied therapies and treatment outcomes were also analyzed. Dermoscopic characteristics were also evaluated. A total of 41 patients diagnosed with PLCA were included, with 22 presenting with macular, 18 with lichen, and 1 with biphasic amyloidosis. The male/female ratio was 16/25, and mean age at diagnosis was 54.6 ± 15.2 years (range 27-87 years). The mean age at the onset of PLCA was 53 ± 16.1 years (range 19-79 years) in MA, 46.7 ± 18.2 years (range 14-73 years) in LA, and 26 years in BA. The interscapular region in MA and the extensor surface of the lower extremities in LA proved to be localization-related areas. In our center, a wide range of therapeutic options was applied, with the most prescribed being topical corticosteroids in all types of PLCA. We presented a retrospective, monocentric study on the epidemiology of PLCA in the Central European region. By examining the medical data of a significant number of PLCA patients, we compared our epidemiologic data with that of the Asian PLCA population. Due to the rarity of the condition, further randomized controlled trials and guidelines are needed to improve therapeutic outcomes.

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma.

Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic variants in PRKAR1A are identified in most cases, while large exonic or chromosomal deletions have only been reported in a few cases. Our aim was to identify the causal genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and whole genome sequencing (WGS) were performed in the proband, one clinically affected and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7 + 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A in heterozygous form in the affected family members. The exact breakpoints and the increased enzyme activity in deletion carriers compared to wild type carrier were proved. Segregation analysis and functional evaluation of PKA activity confirmed the pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene was proved to be the cause of CNC. Our study underlines the need for WGS in molecular genetic testing of patients with monogenic disorders where conventional genetic analysis fails.

Dermoscopic Patterns of Genodermatoses: A Comprehensive Analysis.

(1) Background: Genodermatoses are a clinically and genetically heterogenous group of inherited skin disorders. Diagnosing inherited skin diseases is a challenging task due to their rarity and diversity. Dermoscopy is a non-invasive, easily accessible, and rapid tool used in dermatology not only for diagnostic processes but also for monitoring therapeutic responses. Standardized terminologies have been published for its proper use, reproducibility, and comparability of dermoscopic terms. (2) Methods: Here, we aimed to investigate dermoscopic features in various genodermatoses by conducting a systematic review and comparing its results to our own findings, data of patients diagnosed with genodermatoses at the Department of Dermatology, Venereology and Dermatooncology, Semmelweis University. (3) Results: Our systematic search provided a total of 471 articles, of which 83 reported both descriptive and metaphoric dermoscopic terminologies of 14 genodermatoses. The literature data were then compared to the data of 119 patients with 14 genodermatoses diagnosed in our department. (4) Conclusion: Dermoscopy is a valuable tool in the diagnosis of genodermatoses, especially when symptoms are mild. To enable the use of dermoscopy as an auxiliary diagnostic method, existing standardized terminologies should be extended to more genodermatoses.

Correlation of systemic involvement and presence of pathological skin calcification assessed by ex vivo nonlinear microscopy in Pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE (OMIM 264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE results in ectopic calcification primarily in the skin, eye and blood vessels that can lead to blindness, peripheral arterial disease and stroke. Previous studies found correlation between macroscopic skin involvement and severe ophthalmological and cardiovascular complications. This study aimed to investigate correlation between skin calcification and systemic involvement in PXE. Ex vivo nonlinear microscopy (NLM) imaging was performed on formalin fixed, deparaffinized, unstained skin sections to assess the extent of skin calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. From CA and CD, calcification score (CS) was determined. The number of affected typical and nontypical skin sites were counted. Phenodex + scores were determined. The relationship between the ophthalmological, cerebro- and cardiovascular and other systemic complications and CA, CD and CS, respectively, and skin involvement were analyzed. Regression models were built for adjustment to age and sex. We found significant correlation of CA with the number of affected typical skin sites (r = 0.48), the Phenodex + score (r = 0.435), extent of vessel involvement (V-score) (r = 0.434) and disease duration (r = 0.48). CD correlated significantly with V-score (r = 0.539). CA was significantly higher in patients with more severe eye (p = 0.04) and vascular (p = 0.005) complications. We found significantly higher CD in patients with higher V-score (p = 0.018), and with internal carotid artery hypoplasia (p = 0.045). Significant correlation was found between higher CA and the presence of macula atrophy (ß = - 0.44, p = 0.032) and acneiform skin changes (ß = 0.40, p = 0.047). Based on our results, the assessment of skin calcification pattern with nonlinear microscopy in PXE may be useful for clinicians to identify PXE patients who develop severe systemic complications.