Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.

PURPOSE: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function (LoF) LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs). METHODS: 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions. RESULTS: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate MAPK signaling. CONCLUSION: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs.

Novel causative variants in Legius syndrome: SPRED1 Genotype spectrum expansion.

Legius syndrome, commonly referred to as SPRED1-related neurofibromatosis type 1-like syndrome, is a rare autosomal dominant disorder characterized by café-au-lait macules, freckling, lipomas, macrocephaly, and heterogeneous neurodevelopmental manifestations, including a different degree of learning difficulties. Although a partial clinical overlap exists with neurofibromatosis type 1 (NF1), Legius syndrome is distinguished by its genetic etiology and the absence of neurofibromas, indicating an inherent lack of tumor risk. The SPRED1 gene encodes the Sprouty-related protein with an EVH1 domain 1 (SPRED1), a negative regulator of the RAS-MAPK signaling pathway with a crucial role in cellular growth and development. Despite various genetic variants and genomic deletions associated with Legius syndrome, the full genetic spectrum of this condition remains elusive. In this study, we investigated the underlying genetic etiology in a cohort of patients presenting with typical manifestations of Legius syndrome using a custom Next Generation Sequencing (NGS) panel and Multiplex Ligation-Dependent Probe Amplification (MLPA) for NF1 and SPRED1. We identified 12 novel SPRED1 damaging variants segregating with the phenotype in all families. These rare variants affect conserved residues of the protein and are predicted damaging according to in silico tools. No clear genotype-phenotype correlations could be observed in the current cohort and previously reported patients, underscoring the heterogeneous genotype spectrum of this condition. Our findings expand the understanding of SPRED1 variants causing Legius syndrome and underscore the importance of comprehensively characterizing the genetic landscape of this disorder. Despite the absence of clear genotype-phenotype correlations, elucidating the genetic etiology of Legius syndrome is pertinent for facilitating accurate diagnosis, genetic counseling, and therapeutic interventions.

Dermoscopy aids in differentiating café-au-lait macules from congenital melanocytic nevi in patients with darker skin phototypes.

Dermoscopy aids in the diagnosis and management of pigmented growths and disorders of pigmentation in children. However, there is limited literature on the dermoscopic appearance of café-au-lait macules (CALMs) and congenital melanocytic nevi in patients with dark skin. We report two cases of young children with dark skin and many hyperpigmented patches in whom dermoscopy was utilized to accurately diagnose CALMs and facilitate testing for neurofibromatosis.

Jaffe-Campanacci syndrome; a case series and review of the literature.

BACKGROUND: Jaffe-Campanacci syndrome is a rare syndrome, characterized by multiple non-ossifying fibromas (NOF) and cafe-au-lait patches. The name was coined in 1982 by Mirra after Jaffe who first described the case in 1958. Although it's suggested there is a relation with Neurofibromatosis type 1, there is still no consensus on whether Jaffe-Campanacci syndrome is a subtype or variant of neurofibromatosis-1(NF-1). CASE PRESENTATION: In this article, we present a case series of 2 patients. The first case is a 13-year-old male with Jaffe-Campanacci syndrome who presented with a distal femur fracture. His father had positive features of both Jaffe-Campanacci syndrome and NF-1, while his sister only had features of NF-1, so we presented both. CONCLUSION: Jaffe-Campanacci has a clear relationship with type 1 neurofibromatosis, which still has to be genetically established. Due to the presence of several large non-ossifying fibromas of the long bones, it is linked to a significant risk of pathological fractures. We concur with previous authors, that an osseous screening program should be performed for all patients with newly diagnosed type 1 neurofibromatosis, to identify non-ossifying fibromas and assess the potential for pathological fracture. Moreover, siblings of patients with NF-1 should be screened for multiple NOFs that may carry a high risk of pathological fractures.

[Neurofibromatosis type 2 in the otorhinolaryngological practice]. / Neirofibromatoz 2-go tipa v praktike vracha-otorinolaringologa.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disease (frequency 1 in 25-90 000) characterized by the formation of tumors of the central nervous system due to a mutation in the NF2 gene on chromosome 22q12. Bilateral vestibular schwannomas are recognized as absolute diagnostic criteria of NF2 and occur in 95% of patients, are accompanied by hearing impairment, manifest at the age of 18-24 years. Skin manifestations can precede vestibular schwannomas for several years and predict the course of the disease: neurofibromas, cafe-au-lait macules, hypopigmented spots, recently described mesh capillary malformations. Despite the benign nature of schwannomas, they can lead to hearing loss, vestibular dysfunction, facial nerve paralysis, gait disorders, pain and convulsions, there is a risk of early death from compression of the brain stem. The probability of progressive hearing loss is partly determined by the type of mutation. We described a clinical case of NF2 in a 21-year-old patient with bilateral vestibular schwannomas without hearing loss, whose skin examination by ENT specialist revealed this disease. The importance of the presented observation is that the doctor should assume neurofibromatosis type 2 in a young patient with bilateral vestibular schwannomas. It is necessary to undertake a further examination of this patient, including: skin examination for the identification of characteristic neurofibromas and cafe-au-lait macules, consultation with an ophthalmologist, neurologist, MRI of the brain and spinal cord with contrast, genetic analysis - for timely initiation of therapy that prevents hearing loss and vestibular disorders.

Disorders of hyperpigmentation. Part I. Pathogenesis and clinical features of common pigmentary disorders.

Disorders of hyperpigmentation are common and, depending on the extent and location of involvement, can affect the quality of life and pose a significant psychologic burden for patients. Given the similarities in presentation of the various causes of hyperpigmentation, it is often difficult to elucidate the etiology of these conditions, which is important to guide management. Furthermore, certain disorders, such as lichen planus pigmentosus and ashy dermatosis, have similar clinical and/or histologic presentations, and their classification as distinct entities has been debated upon, leading to additional confusion. In this review, the authors selected commonly encountered disorders of hyperpigmentation of the skin, subdivided into epidermal, dermal, or mixed epidermal-dermal disorders based on the location of pigment deposition, along with disorders of hyperpigmentation of the mucosa and nails. Melanocytic nevi, genetic disorders, and systemic causes of hyperpigmentation were largely excluded and considered to be outside the scope of this review. We discussed the pathogenesis of hyperpigmentation as well as the clinical and histologic features of these conditions, along with challenges encountered in their diagnosis and classification. The second article in this 2-part continuing medical education series focuses on the medical and procedural treatments of hyperpigmentation.

Piebaldism with café-au-lait macules resulting from a novel mutation of KIT gene in a three-generation Chinese family.

BACKGROUND: Piebaldism is a rare, autosomal dominant, and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SLUG genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. METHODS: In this paper, we report a case of piebaldism with café-au-lait macules resulting from a novel mutation of KIT gene c.1982C > T (p.Thr661Ile) in a three-generation Chinese family. The whole-exome sequencing, mitochondrial gene 3000X, and bioinformatics tools were used to identify the mutation in this new-found pedigree. In addition, we searched the databases of "Punmed, Chinese National Knowledge Infrastructure, CMJD, WANFANG MED ONLINE", reviewed 88 cases of piebaldism caused by KIT gene mutation, and summarized the relationship between clinical phenotype and genotype of piebaldism through logistic regression and other statistical methods. RESULTS: The proband and her affected mother carried a heterozygous c.1982C > T missense mutation (p.Thr661Ile) on KIT gene. Bioinformatics analysis hinted that it had potential pathogenicity. The data showed that piebaldism patients with cafè-au-lait macules had KIT mutations almost located in the intracellular tyrosine kinase domain and were mostly related to the severe clinical phenotype of piebaldism. CONCLUSION: The new heterozygous c.1982C > T missense mutation on KIT caused piebaldism with café-au-lait macules in this Chinese family. This study provides a new reference index for clinicians to judge the severity of clinical phenotypes of piebaldism, broadens the understanding of the correlation between clinical phenotypes and genotypes of piebaldism, and provides reference of genetic counseling and prenatal diagnosis for affected families.

McCune-Albright Syndrome: A Case Report and Review of Literature.

McCune-Albright syndrome (MAS) is a rare sporadic condition defined by the classic triad of fibrous dysplasia of bone, café au lait skin macules, and hyperfunctioning endocrinopathies. The molecular basis of MAS has been ascribed to the post-zygotic somatic gain-of-function mutations in the GNAS gene, which encodes the alpha subunit of G proteins, leading to constitutive activation of several G Protein-Coupled Receptors (GPCRs). The co-occurrence of two of the above-mentioned cardinal clinical manifestations sets the diagnosis at the clinical level. In this case report, we describe a 27-month-old girl who presented with gonadotropin-independent precocious puberty secondary to an estrogen-secreting ovarian cyst, a café au lait skin macule and growth hormone, and prolactin excess, and we provide an updated review of the scientific literature on the clinical features, diagnostic work-up, and therapeutic management of MAS.

Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency.

Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch-repair deficiency (CMMRD), caused by germline bi-allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD-like patients, have not previously been reported as germline PVs despite all being well-known somatic mutations in hyper-mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger "mutator" effect than known PPAP-associated POLE PVs and may cause a CMMRD-like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD.

Predictors of Patient Return to a Tertiary Neurofibromatosis Subspecialty Clinic.

OBJECTIVE: To evaluate sociodemographic and medical predictors of patient return to a neurofibromatosis subspecialty clinic. STUDY DESIGN: Data were collected from the Washington University Neurofibromatosis Clinical Program electronic medical records. A total of 713 subjects with initial visits to the Washington University Neurofibromatosis Clinical Program between July 1, 2005 and December 18, 2020 were included. Variables collected included sex, race, ethnicity, age, date of first visit, place of residence, diagnosis, insurance payer, physician recommendation for return, and subject return. Return rates for each demographic group were calculated. Bivariate analyses were performed to inform variable inclusion in the model, and a binary logistic regression model was calculated to predict subject return. RESULTS: The overall return rate was 76%. The binary logistic regression model was statistically significant (χ29 = 131.094; P < .001) and showed that subjects who self-identified as Black and/or African American, presented with or received a diagnosis of café-au-lait macules at their initial visit, were from a rural area, were older, or who lived farther from the Washington University Neurofibromatosis Clinical Program were less likely to return to clinic. CONCLUSIONS: These findings support the implementation of tailored communication and monitoring interventions to improve the care for children with neurofibromatosis type 1.

Evaluation of the impact of the 2021 revised Neurofibromatosis type 1 diagnostic criteria on time to diagnosis.

Neurofibromatosis type 1 (NF1) has historically been diagnosed clinically based on the NIH Consensus Conference diagnostic criteria. The molecular and clinical knowledge of NF1 has subsequently improved, and an international group of experts published revised diagnostic criteria in 2021, incorporating new diagnostic criteria such as pathogenic variants in NF1. This study aimed to investigate the impact of these new diagnostic criteria on time to diagnosis (TTD) of NF1. A retrospective chart review of individuals evaluated for a diagnosis of NF1 at the Medical Genetics Clinic at Stanford Children's Health was performed. The TTD was determined by calculating the days between their first visit with a medical geneticist for NF1 and the date they would have received a diagnosis based on the previous NF1 diagnostic criteria and the 2021 updated diagnostic criteria. The revised diagnostic criteria for NF1 decreased TTD. The mean difference in TTD was 113 days shorter for the new criteria (p-value = 1.306x-05 ). This study highlights that the revised 2021 NF1 diagnostic criteria can decrease the TTD. The addition of a heterozygous pathogenic variant in NF1 as a criterion was the change that decreased TTD.

Comparison of the safety and efficacy of low fluence Q-switched 1064-nm and conventional Q-Switched 755-nm lasers in the treatment of café-au-lait macules: A prospective self-controlled trial.

BACKGROUND: Conventional high fluence Q-switched (HFQS) Alexandrite 755-nm are widely used in clinical café-au-lait macules (CALMs) treatment. There have been recent concerns regarding the efficacy and safety of low fluence Q-switched (LFQS) Nd: YAG 1064-nm lasers. OBJECTIVE: To evaluate the efficacy and safety of the conventional HFQS and LFQS laser in the treatment of CALMs. METHODS: Within 3 months, 20 patients underwent prospective self-controlled split-lesion treatments with HFQS once or twice depending on the recovery rate, and with LFQS six times biweekly. Then the more effective laser was selected for continued treatments. Efficacy outcomes were evaluated by a visual analog scale (VAS) biweekly during the comparative trail. Recovery process, side effects and recurrence were recorded during the trial and follow-up visit. Patient and physician preferences for laser selection were also recorded. RESULTS: The average VAS scores of areas treated with HFQS and LFQS were 2.92 ± 0.86 and 2.93 ± 1.13, respectively (p > 0.05). The most significant efficacy change of LFQS was after the fourth laser treatment (VAS score: 1.82-2.37, p < 0.001). 11 lesions treated with LFQS and 7 with HFQS achieved an optimal treatment response (3.67 ≤ VAS ≤ 4). Three patients relapsed on one side (one on LFQS, two on HFQS) and five on both sides. Adverse effects included temporary hypopigmentation, hyperpigmentation, uneven pigmentation, and mottled hypopigmentation. Doctors thought 80% of patients were suitable for LFQS. 70% of patients preferred LFQS posttreatment. CONCLUSIONS: The efficacy difference between the LFQS 1064-nm laser and HFQS 755-nm laser in treating CALMs in a 3-month comparative trial was statistically insignificant. LFQS is preferred by doctors and patients and is likely to help more patients achieve treatment efficacy than the HFQS within a short time, with fewer temporary adverse reactions, and a more even pigmentation. But it can cause mottled hypopigmentation. The LFQS had obvious lesion clearance after the fourth treatment.

Value of a café-au-lait macules screening clinic: Experience from The Hospital for Sick Children in Toronto.

BACKGROUND/OBJECTIVES: Café-au-lait macules (CALMs) are a characteristic feature of neurofibromatosis type 1 (NF1), but also occur in other genetic disorders. Differential diagnosis of CALMs remains challenging and can be stressful for families. We sought to examine the role of an established CALMs screening clinic in diagnosing CALMs-related disorders. METHOD: We retrospectively reviewed patients seen between July 2012 and January 2019 in a CALMs screening clinic at The Hospital for Sick Children, a tertiary pediatric hospital in Toronto, Canada. Pediatric patients were referred because of multiple CALMs or suspected NF1. Selection was based on a chronological referral sample with no exclusions. A pediatric dermatologist examined all patients for CALMs and NF1 manifestations. Genetic testing was offered to confirm a clinical diagnosis or when clinical findings were inconclusive. RESULTS: Three hundred patients, of which 152 (50.7%) were female and had a mean age of 5.6 ± 4.8 years were seen during the study period. NF1 was diagnosed in 76 (25.3%) patients, mosaic NF1 in 38 (12.7%) patients, and 8 (2.7%) patients received other genetic diagnoses. One hundred and twelve (37.3%) patients were diagnosed with isolated CALMs not associated with an underlying genetic disease. Furthermore, 36 (12%) of our patients did not have CALMs. CONCLUSIONS: The CALMs screening clinic aided in the early diagnosis of genetic disorders such as NF1 and distinguished CALMs from other hyperpigmented lesions. We encourage the adoption of this clinic model in referral centers to streamline and optimize care of patients with presumptive diagnosis of CALMs.

Comparison of the efficacy and safety between a low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum garnet laser and a conventional Q-switched 532-nm laser for the treatment of cafe-au-lait macules in 40 Chinese children: a prospective, randomized, parallel-controlled, evaluator-blinded trial.

Cafe-au-lait macules (CALMs) affect the appearance of patients and can result in serious psychological problems. Successful treatments without adverse effects remain challenging. We designed a prospective, randomized, controlled, evaluator-blinded trial on 40 pediatric patients to compare the efficacy between a low-fluence 1064-nm Q-switched Nd:YAG laser and a Q-switched Nd:YAG 532-nm laser for the treatment of solitary CALMs in children. We randomly assigned participants into 2 groups. We treated those in the first group with 3 sessions of 532-nm QS laser at 1-month intervals, and those in the second group with 6 sessions of 1064-nm LFQS laser at 2-week intervals. We found no significant differences in treatment efficacy (p = 0.14). The 1064-nm laser group referred significantly less pain than the 532-nm laser group (p = 0.0001). Side effects were detected in 5 patients in the 532-nm laser group. The difference of the side effects was statistically significant (p = 0.04). Two patients in 532-nm laser group were recurred and none in 1064-nm laser group. On a univariate logistic regression analysis, lesions with brown color, small size, and irregular edges were significantly associated with better outcomes (> 50% clearance). Multivariate logistic regression analysis found that brown lesions and lesions with irregular edges had higher odds of getting > 50% clearance (p < 0.05). In conclusion, the 1064-nm LFQS laser produced fewer side effects, less pain, and shorter recovery time than the 532-nm laser. Irregular-bordered, smaller, brown lesions improved better than smooth-bordered, larger, light brown lesions. Moreover, the 1064-nm laser may be a better choice for treating large size CALMs. However, no significant differences were found in terms of the treatment efficacy and recurrence.

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study. / Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles.

BACKGROUND: The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. PATIENTS AND METHODS: Case-control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. RESULTS: The prevalence of nevus anemicus (NA) (P<.001) and juvenile xanthogranulomas (JXG) (P<.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% (confidence interval): 95.4-99.96%] and a positive predictive value (PPV) of 98.80% [92.54-99.94%] were estimated for NA and a specificity of 99.27% [95.4-99.96%] and a PPV of 92.86% [64.17-99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (P=.025) and in relation to generalized itching with no other cause (P<.001). CONCLUSIONS: NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study.

BACKGROUND: The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. PATIENTS AND METHODS: Case-control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. RESULTS: The prevalence of nevus anemicus (NA) (p<0.001) and juvenile xanthogranulomas (JXG) (p<0.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% [confidence interval (CI): 95.4-99.96%] and a positive predictive value (PPV) of 98.80% [92.54-99.94%] were estimated for NA and a specificity of 99.27% [95.4-99.96%] and a PPV of 92.86% [64.17-99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (p 0.025) and in relation to generalized itching with no other cause (p<0.001). CONCLUSIONS: NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation-dependent probe amplification and genotype-phenotype correlation in 138 Turkish patients.

OBJECTIVE: To investigate the variant spectrum and genotype-phenotype correlations in a Turkish cohort with Neurofibromatosis Type-1 (NF1). MATERIALS AND METHODS: We retrospectively investigated the clinical and molecular data of 138 NF1 patients from 129 families who had been followed-up for a median of 3.9 (1.25-18.5) years. RESULTS: NF1 sequencing revealed 73 different intragenic variants, 19 of which were novel. Seven large deletions were detected by multiplex ligation-dependent probe amplification (MLPA) analyses. The total detection rate of pathogenic NF1 variants was found to be 87.1%. Comparing age groups, cutaneous neurofibromas, freckling, and Lisch nodules were more prevalent in patients older than 12 years (p > .05). Optic glioma detected in 17.3% of the patients and was significantly more common before the age of 6 (p > .001). Other solid tumors developed in 5% of the patients. There was no genotype-phenotype correlation between patients with truncating and nontruncating variants. However, six out of seven patients with large deletions had significant developmental delay, one patient with the c.2970_2972delAAT (p.Met992del) variant had only typical pigmentary features, and another patient with the c.4267A > G (p.Lys1423Glu) variant had CALMs, freckling, neurofibromas, and Noonan-like phenotype. CONCLUSIONS: We described 19 novel variants and seven large deletions in NF1. Applying MLPA assay in NF1 is useful in expanding the molecular diagnosis. Although very limited genotype-phenotype correlation has been reported in NF1, the fact that specific phenotypic findings were observed in our patients with large deletions and two intragenic variants supports the studies published recently.

Constitutional mismatch repair deficiency in childhood colorectal cancer harboring a de novo variant in the MSH6 gene: a case report.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is caused by biallelic pathogenic variants in one of the mismatch repair genes, and results in early onset colorectal cancer, leukemia, brain tumors and other childhood malignancies. Here we report a case of CMMRD with compound heterozygous variants in the MSH6 gene, including a de novo variant in multiple colorectal cancers. CASE PRESENTATION: An 11-year-old girl, who presented with multiple spots resembling café-au-lait macules since birth, developed abdominal pain, diarrhea and bloody stool over two months. Colonoscopy revealed multiple colonic polyps, including a large epithelial tumor, and pathological examination revealed tubular adenocarcinoma. Brain magnetic resonance imaging (MRI) showed an unidentified bright object (UBO), commonly seen in neurofibromatosis type 1 (NF1). Genetic testing revealed compound heterozygous variants, c. [2969T > A (p.Leu990*)] and [3064G > T (p.Glu1022*)] in the MSH6 gene; c.2969T > A (p.Leu990*) was identified as a de novo variant. CONCLUSIONS: We present the first report of a CMMRD patient with a de novo variant in MSH6, who developed colorectal cancer in childhood. CMMRD symptoms often resemble NF1, as observed here. Physicians should become familiar with CMMRD clinical phenotypes for the screening and early detection of cancer.

Cutaneous findings in Fanconi anemia.

BACKGROUND: Fanconi anemia (FA) is a genetic disorder that results in bone marrow failure, physical abnormalities, and solid organ malignancies. The diagnosis of FA is often delayed because the early disease characteristics have not been well established. OBJECTIVE: To outline the spectrum of cutaneous findings seen in patients with FA. METHODS: A cross-sectional study in which patients with FA received a full-body skin examination. Patient characteristics are summarized with mean (SD) for continuous and count (%) for categorical variables. Poisson regression and logistic regression models were used to examine the relationships between pigmentary changes and patient characteristics. RESULTS: At least 1 cutaneous pigmentary alteration was present in 96.8% of patients, most arising before the teenage years. The most common finding was café-au-lait macules. Other findings included hypopigmented macules, skin-fold freckle-like macules, extensive sun-exposed freckling, and both hypopigmented and hyperpigmented pigment macules. LIMITATIONS: Patients received a single assessment, so the number of pigmentary changes could not be assessed over time. CONCLUSIONS: Characteristic morphology of FA includes faint and ill-defined café-au-lait macules, hypopigmented skin-fold freckle-like macules and the concurrence of hypopigmented and hyperpigmented macules. The recognition of these findings could aid clinicians in making earlier diagnoses.

Evaluation of clinical findings and neurofibromatosis type 1 bright objects on brain magnetic resonance images of 60 Turkish patients with NF1 gene variants.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. This retrospective study aims to evaluate the clinical manifestations and brain magnetic resonance images (MRI) analysis in 60 genetically confirmed NF1 patients. The results of next-generation sequencing (NGS), Sanger sequencing, and MLPA of NF1 gene were evaluated. A total of 54 different variants were identified. Fourteen out of them were novel variants (25.9%). Patients who complied with NIH criteria had most frequently frameshift variants (11/32 patients), and those with only CALMs had missense variants (9/28 patients). Neurofibromatosis type 1 bright objects (NBOs) on T2-weighted MRI were detected in 42 patients (42/56; 75%). These brain lesions were detected mostly in basal ganglia and in cerebellar vermis. NBOs were detected more in the patients who complied with NIH criteria (80.6%) compared to those who were only CALMs (68%). While frameshift variants (33.3%) were the most common type variants in the patients who had NBOs, the most common variants were splicing (35.7%) and missense (35.7%) variants in the patients whose MRIs were normal. Frameshift variants (11/28 patients; 39.3%) were the most common in the patients with more than one brain locus involvement. Therefore, we consider that frameshift variants may be associated with increased incidence of NBOs and involvement of more than one brain locus. In addition, NBOs may occur less frequently in the patients with splicing variants. To our knowledge, this is the first study evaluated the relationship between NF1 gene variants and NBOs. Future studies may help us understand the etiology of NBOs.