[Research progress on the pathogenic mechanisms, diagnosis and treatment of McCune-Albright syndrome].

McCune-Albright syndrome is a rare chimeric disorder due to mutations in the postzygotic GNAS gene. It belongs to the group of guanine nucleotide-binding protein diseases, affecting a wide range of individuals. It is characterized by fibrous dysplasia, café-au-lait skin macules, and precocious puberty with other variable clinical manifestations. At present, there are difficulties in the molecular diagnosis of McCune-Albright syndrome, and there is a lack of effective clinical treatments to halt or reverse the course and regression of the disease. This article summarizes the clinical manifestations, diagnosis, pathogenic molecular mechanisms, treatment and relevant fertility guidelines of McCune-Albright syndrome, with a view to further research and therapy of McCune-Albright syndrome.

Neurofibroma: Case Series with Clinical Features and Recommendations.

Neurofibroma is an autosomal benign disorder. It can be localized, diffuse or invasive like plexiform neurofibroma that involves the nerves, muscle, tissues, skeleton. It represents itself as a destructive variant of neurofibroma, mostly present as orbital or periorbital neurofibroma or may be associated with autosomal dominant disease. Clinical diagnosis of neurofibromatosis (NF) according to National Institutes of Health (NIH) criteria should have more than two of the seven features including lisch nodules, cafe'- au-lait spots, plexiform neurofibroma, optic glioma, freckling, first degree relative with NF or dysplasia of cortical bones. However, proper early diagnosis is still crucial due to its various presentation such as cheek mass, painless swelling on skin, chalazion, intratracheal tumor, genital swelling or ptosis. It is reported that neurofibroma often represents as ocular or facial swelling. Here we are presenting features of neurofibroma of eight cases of patients from Civil Hospital, Karachi. These cases had main complain of overhanging skin mass mainly on orbital or periorbital region that damage the area and with poor daily activities. Multiple nodules on face and body along with them Cafe'-au-lait spots and lisch nodules were main signs. While, other signs i.e. ptosis, pterygium, telecanthus and muddy discoloration of conjunctiva need further evaluation for correlation with neurofibromatosis. Debulking surgery was planned for most of the cases but the huge disfigurement caused by overhanging skin mass and nodules made it a challenge for plastic surgeons to provide good outcomes with minimum damage. Keywords: neurofibroma; lisch nodules; ptosis; Cafe'-au-lait spot; periorbital; overhanging skin.

[Analysis of clinical features and variants of NF1 gene in 12 patients with Neurofibromatosis type 1].

OBJECTIVE: To explore the types of NF1 gene variants and clinical characteristics among patients with Neurofibromatosis type I (NF1). METHODS: Clinical data of 12 patients diagnosed at Ningbo Women and Children's Hospital between December 2019 and May 2022 were retrospectively analyzed. The probands and their family members were subjected to high-throughput sequencing, and candidate variants were verified by Sanger sequencing and chromosome microarray analysis. RESULTS: The 12 patients had ranged from 4 months to 27 years old, with a male-to-female ratio of 2 : 1. Cafè-au-lait spots were found in all patients. 83.3% of them also had axillary and/or inguinal freckling, 58.3% had neurofibromas, and 16.7% had congenital pseudarthrosis of the tibia. Five types of NF1 gene variants were identified in the patients, including 5 nonsense variants, 4 frameshift variants, 1 missense variant, 1 splice variant, 1 large deletion involving the whole gene. Six patients were found to harbor de novo variants, 2 had inherited the variants from their parents, and 4 were not verified for their parental origin. The c.3379del (p.Thr1127Glnfs*15) and c.6628_6629del (p.Glu2210Thrfs*10) variants were unreported in literature and databases. CONCLUSION: Most NF1 patients may present with Cafè-au-lait spots initially and are due to pathogenic variant of the NF1 gene. High-throughput sequencing can efficiently identify such variants among the patients and enable the definite diagnosis.

Characteristics of Café-au-lait Macules and their Association with the Neurofibromatosis type I Genotype in a Cohort of Greek Children.

Cafe-au-lait macules are the most distinctive clinical finding in neurofibromatosis type I. The aim of this prospective study of Greek children diagnosed with neurofibromatosis type I was to describe the dermatological phenotype and to analyse the characteristics of cafe-au-lait macules and their association with genotype. Pigment intensity and melatonin content of cafe-au-lait macules were measured with a narrowband spectrophotometer. A total of 63 children aged 6 months to 16 years old were studied. Mean melanin content varied, both among patients, and within each patient (p < 0.001). Females had a higher number of cafe-au-lait macules than did males (p = 0.025), and the melanin content of cafe-au-lait macules was lower in females than males (p < 0.001). Patients with protein-truncating variants in the neurofibromatosis type I gene had higher melanin content of cafe-au-lait macules than other types of genetic variants t (55) = 2.196, p = 0.032. Plexiform neurofibromas were also detected in the majority of patients with protein- truncating variants, while juvenile xanthogranulomas were detected equally in patients with protein-truncating and non-protein-truncating variants. In conclusion, cafe-au-lait macules with high melatonin content are associated with patients carrying non-protein-truncating variants. Therefore, measurement of cafe-au-lait macule pigment intensity might provide useful information for initial assessment of patients with neurofibromatosis type I and the severity of their future phenotype.

Genetic evaluation of 50 Turkish patients with neurofibromatosis type 1: 2 years experience of a single center.

BACKGROUND/AIM: Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder. Clinical diagnosis is difficult in early childhood, and it is possible to miss a critical interval for tumour screening. In this study, we aimed to characterize the mutational spectrum of Turkish patients and discuss the benefits of molecular testing. MATERIAL AND METHODS: Fifty individuals from 35 unrelated families were included. Main referral reasons for genetic testing were as follows: to confirm a clinical diagnosis, to use in differential diagnosis and to evaluate first-degree family member of a known patient. Two-step process consisting of initial next generation sequencing of the NF1 gene and consequent multiplex ligation-dependent probe amplification were performed. RESULTS: We identified a total of 30 variants in 28 individuals. Variant detection rate was 56% in the entire study group and 71.4% within the index patients. Four novel variants were found. Truncating variants constituted 60% of the entire mutation spectrum. A deletion or duplication was not detected. The most common feature was cafe au lait macules in 70% of the patients, followed by focal areas of signal intensity on brain imaging (26%), cutaneous neurofibromas (24%) and axillary freckling (24%). CONCLUSIONS: Early sequencing in all suspected patients followed by deletion/duplication analysis in patients meeting clinical criteria and a case-to-case based consideration for RNA studies seems to be the effective algorithm for NF-1 diagnosis.

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.

Turner Syndrome and Neurofibromatosis 1: Rare Co-Existence with Important Clinical Implications.

A 16.5-year-old Indian female presented with secondary amenorrhoea, cubitus valgus, scoliosis and multiple lentigines on the face. Karyotyping revealed mosaic Turner syndrome (TS) with 45, X/46, X iXq. She also had multiple café-au-lait macules and axillary freckles but no neurofibroma and did not fulfil the classic criteria for diagnosis of Neurofibromatosis-1 (NF1). Many of her macules were smaller than 15 mm in diameter, which might be due to her hypoestrogenic state. However, exome-sequencing found a pathologic variant consistent with NF1. She was started on daily oral estrogen, and oral progesterone for 10 days every month with close monitoring for neurofibroma and/or glioma expansion. Co-occurrence of NF1 and TS is extremely rare, TS and NF1 can both affect growth and puberty, cause different cutaneous and skeletal deformities, hypertension, vasculopathy and learning disabilities. Our case highlights the need for genetic testing in some cases with NF1 who do not strictly fulfil the NIH diagnostic criteria. We also emphasize the need for close monitoring during therapy with growth hormone, estrogen and progesterone due to the potential risk of tumour expansion in NF1.

Novel, heterozygous, de novo pathogenic variant (c.4963delA: p.Thr1656Glnfs*42) of the NF1 gene in a Chinese family with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) presents an autosomal dominant, haploinsufficient, and multisystemic disorder with patches of skin café-au-lait spots, lisch nodules in the iris, even tumors in the peripheral nervous system or fibromatous skin. In this study, a Chinese young woman who suffered from NF1 disease with first-trimester spontaneous abortion was recruited. Analysis for whole exome sequencing (WES), Sanger sequencing, short tandem repeat (STR), and co-segregation was carried out. As results, a novel, heterozygous, de novo pathogenic variant (c.4963delA:p.Thr1656Glnfs*42) of the NF1 gene in the proband was identified. This pathogenic variant of the NF1 gene produced a truncated protein that lost more than one-third of the NF1 protein at the C-terminus including half of the CRAL-TRIO lipid-binding domain and nuclear localization signal (NLS), thus leading to pathogenicity (ACMG criteria: PVS1 + PM2 + PM2). Analysis for NF1 conservation in species revealed high conservation in different species. Analysis of NF1 mRNA levels in different human tissues showed low tissue specificity, which may affect multiple organs presenting other symptoms or phenotypes. Moreover, prenatal NF1 gene diagnosis showed both alleles as wild types. Thus, this NF1 novel variant probably underlays the NF1 pathogenesis in this pedigree, which would help for the diagnosis, genetic counseling, and clinical management of this disorder.

Constitutional Mismatch Repair Deficiency Syndromes, a Neurofibromatosis 1 Mimicker That Hinders Timely Management.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare, autosomal recessive disease caused by a biallelic germline mutation in one of the DNA mismatch repair genes ( MLH1 , MSH2 , MSH6 and PMS2 ). In addition to colorectal, brain, and hematological malignancies, many additional premalignant and non-malignant features that can point toward the diagnosis of CMMRD have been reported. The report from the CMMRD consortium revealed that all children with CMMRD have café-au-lait macules (CALMs) but the number of CALMs does not reach > 5 in all CMMRD patients, which is one of the diagnostic criterions of NF1. About half of the patients with CMMRD develop brain tumors and up to 40% develop metachronous second malignancies. METHODS: This is an observational retrospective case series describing five pediatric patients with CMMRD. RESULTS: All the five patients in our cohort developed brain tumors and showed a predilection to the frontal lobe. In our cohort, multiple Mongolian spots, coloboma, obesity, CHD, dysmorphism, and clubfoot were also encountered. In all our patients, NF1 and other tumorigenic predisposing syndromes were initially suspected. CONCLUSION: Increasing awareness of this condition and its shared reminiscent NF1 features, particularly CALMs among child neurologists, oncologists, geneticists, and dermatologists can help uncover the tip of the iceberg of CMMRD that carries an important consequence on management.

Low rates of neurological abnormalities in patients with pigmentary mosaicism: A retrospective cohort study from a tertiary dermatology center.

BACKGROUND: Pigmentary mosaicism (PM) is a descriptive term encompassing a range of hyper- and hypo-pigmented phenotypes in various patterns. Information from the neurology literature initially noted neurological abnormalities (NA) in up to 90% of children with PM. The dermatology literature suggests lower associated rates (15%-30%) of NA. Variations in terminology, inclusion criteria, and small population sizes makes interpreting existing PM literature complicated. We aimed to assess rates of NA in children presenting to dermatology with PM. METHODS: We included patients <19 years, diagnosed with PM, nevus depigmentosus and/or segmental café au lait macules (CALM) seen in our dermatology department between 1 January 2006 and 31 December 2020. Patients with neurofibromatosis, McCune-Albright syndrome, and non-segmental CALM were excluded. Data collected included pigmentation, pattern, site(s) affected, presence of seizures, developmental delay, and microcephaly. RESULTS: One hundred fifty patients were included (49.3% female), with a mean age at diagnosis of 4.27 years. Patterns of mosaicism were ascertained for 149 patients and included blaschkolinear (60/149, 40.3%), blocklike (79/149, 53.0%), or a combination of both patterns (10/149, 6.7%). Patients with a combination of patterns were more likely to have NA (p < .01). Overall, 22/149 (14.8%) had NA. Nine out of twenty-two patients with NA had hypopigmented blaschkolinear lesions (40.9%). Patients with ≥4 body sites affected were more likely to have NA (p < .01). DISCUSSION: Overall, our population had low rates of NA in PM patients. A combination of blaschkolinear and blocklike patterns, or ≥4 body sites involved were associated with higher rates of NA.

Rhabdomyosarcoma as the first presentation in Neurofibromatosis Type 1: case series and review of the literature.

Neurofibromatosis Type 1 (NF1) is a neurocutaneous syndrome characterized by multiple café-au-lait macules, neurofibromas, and predisposition to malignancies, including rhabdomyosarcomas (RMS). Somatic NF1 mutations occur in RMS and other cancers, and ∼1% of patients with RMS have NF1. We describe three patients who presented prior to one year of age with RMS and were subsequently diagnosed with NF1. Compared to sporadic RMS, patients with this cancer predisposition syndrome are diagnosed younger, genitourinary sites are more common, and tumors are almost exclusively the embryonal subtype. Genomic sequencing of the tumor was initiated in one patient, and we identified a second sequence variant in NF1. The identification of molecular drivers in tumors is changing the nature of pediatric oncology by informing therapeutics targeted to specific molecular pathways and selecting patients who are likely to harbor germline variants in cancer predisposition genes who would benefit from a Medical Genetics assessment.

Neurofibromatosis Type 1: Diagnostic Timelines in Children. / Cronología del diagnóstico de la neurofibromatosis tipo 1 en la infancia.

BACKGROUND AND OBJECTIVES: The neurofibromatosis 1 (NF1) diagnosis is challenging in young children without a family history of NF1. The aims of this study were to estimate diagnostic delays in children without a family history of NF1 and to examine the effects of using café au lait macules and skin fold freckling as a single diagnostic criterion. PATIENTS AND METHODS: Retrospective, descriptive, observational study of all patients diagnosed with NF1 before the age of 18 years who were seen at our hospital. The medical records of those included were reviewed to identify the date on which the diagnostic criteria of NF1 were objectified. The patients were categorized into 2 groups: those with a known parental history of NF1 and those without. Café au lait macules and skin fold freckling were assessed as a single diagnostic criterion, and genetic evidence was considered to confirm highly suspicious cases. RESULTS: We studied 108 patients younger than the age of 18 years with a diagnosis of NF1. Mean (SD) age at diagnosis was 3.94 (±3.8) years for the overall group, 1 year for patients with a parental history of NF1, and 4 years and 8 months for those without. Diagnosis was therefore delayed by 3 years and 8 months in patients without a family history. CONCLUSION: Skin lesions were the first clinical manifestation of NF1 in most patients. We believe that the National Institutes of Health's diagnostic criteria for NF1 should be updated to aid diagnosis in young children.

A fortuitous discovery of a neurofibroma in a female patient with type 1 neurofibromatosis: a case report.

Neurofibromatosis type 1 (NF1) is a neurocutaneous condition with an autosomal dominant pattern of inheritance. This congenital disease is characterized by a wide spectrum of clinical manifestations and degree of severity. This case report describes a female patient in her early 20s who presented with a complaint of lumbosciatica-like pain evolving for several months. The condition initially escaped the attention of clinicians until a lumbar computed tomography scan and spinal magnetic resonance imaging were performed. The patient was then transferred to the general surgery department, where a clinical diagnosis of NF1 was established. The clinical manifestations were specific for this disease, including café-au-lait macules, plexiform neurofibroma, and a history of neurofibromatosis in her mother. The patient underwent surgical resection of the neurofibroma, which resulted in a favorable outcome. However, 2 years later, a new mass attached to the second lumbar spinal nerve was revealed by a follow-up computed tomography scan. Long-term and close follow-up of NF1 is required because of the high risk of malignancy and recurrence in NF1 patients.

Cerebral developmental venous anomalies in children with mismatch repair deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is one of the rare cancer predisposition syndromes. The aim of this study was to evaluate the cerebral developmental venous anomalies in children with central nervous system tumors associated with CMMRD, an area in which there is extremely little experience. METHODS: Data from children diagnosed with medulloblastoma and high grade central nervous sytem tumor were retrospectively collected. According to the European CMMRD criteria, nine patients were diagnosed as CMMRD syndrome and the others consisted of the group without CMMRD. All radiological examinations of these children were retrospectively reviewed. Whole exome sequencing was performed to index cases` germline DNA. RESULTS: Nine children from four families, six females and three males, were studied. The median age at the first tumor diagnosis was 4.5 years (range, 9 months to 14 years). All CMMRD patients had café au lait spots, but none fulfilled the diagnostic criteria for neurofibromatosis. The patients developed high-grade glial tumor (n: 7) and medulloblastoma (n: 2). The affected genes in the three families were MSH6 [c.478C > T (p.Gln160Ter)], MSH6 [c.2871dupC (p.Phe958LeufsTer5)] and MLH1 [c.236G > A(p.Arg79Lys)], respectively. Seven patients had multiple developmental venous anomalies; six patients had leptomeningeal enhancement; and five patients had cavernomas. None of these findings were present in the group without CMMRD. CONCLUSIONS: Constitutional mismatch repair deficiency should be considered when multiple developmental venous anomalies, cavernomas, and leptomeningeal enhancement are detected, especially in patients with café au lait spots.

[Genetic diagnosis of a child with Café-au-lait macules and juvenile xanthogranuloma].

OBJECTIVE: To explore the genetic basis for a child with café-au-lait macules and juvenile xanthogranuloma. METHODS: Clinical data and peripheral blood samples of the patient and her family members were collected and subjected to targeted capture and high-throughput sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: A deletional variant in exon 23 of the NF1 gene was detected in the proband. Sanger sequencing has verified it as a de novo variant, which was highly correlated with the clinical manifestations of the patient and her mother. The diagnosis of neurofibromatosis 1 (NF1) was established. The variant was unreported previously. CONCLUSION: Targeted capture and next-generation sequencing combined with Sanger sequencing can facilitate early diagnosis of NF1 and provide a basis for the clinical treatment, genetic counseling and prenatal diagnosis.

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.

Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents.

PURPOSE: Examining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). METHODS: A database search in the hospital information system of the University Children's Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. RESULTS: A total of 75 patients were identified (median age 11.0 years [range 1.1-22.6 years]; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. CONCLUSION: In our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.

Bone deformities in patients with neurofibromatosis type 1: Single-center experience.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is the most common neurocutaneous syndrome with an autosomal dominant inheritance. However, half of the cases are de novo mutations. Involvement of bone, skin (cafe au lait macules), as well as ocular and tumoral formations is also associated with NF-1. Here, we present our case series of patients with bone deformities. METHODS: The medical files of patients with NF-1 who were followed up by the same doctor in the pediatric neurology outpatient clinic over 2 years were retrospectively analyzed. RESULTS: Overall, 19 girls and 13 boys were diagnosed with NF-1. Of these 32 patients, 12 (nine girls, three boys) were found to have bone pathologies. The average age was of these patients with bone pathology was 7.5 and 9.5 years. Scoliosis, bowing, short stature, and long bone cysts were found in descending order of frequency. Severe adhesions in the hands and feet as well as phalangeal hypoplasia were noted in one patient. CONCLUSION: NF-1 requires a multidisciplinary approach. Routine follow-up is very important as it is known that deformities that affect different systems may appear or increase with age. Severe hand and foot anomalies seen in one of our patients did not seem to be associated with NF-1.

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.