Legius syndrome (LS) is a rare and underrecognized disorder that is often misdiagnosed as neurofibromatosis type 1 (NF1). It is characterized by café-au-lait macules without the tumoral manifestations of NF1. We report the case of an 11-year-old patient with multiple café-au-lait macules and intertriginous freckling who was admitted for bloody stools, joint pain, and weight loss. His clinical and endoscopic findings were consistent with inflammatory bowel disease (IBD). He also met the clinical diagnostic criteria for NF1 but not for LS. Genetic testing played a pivotal role in the differential diagnosis and revealed a loss-of-function mutation in the SPRED1 gene, confirming the diagnosis of LS. This is the first reported case of a patient with IBD and LS. The subtle manifestations of LS make it an underdiagnosed disease, which reduces the likelihood of it being diagnosed in association with other diseases, such as IBD. There are, however, 10 published case reports linking IBD and NF1, and some pathophysiological mechanisms have been proposed. Continued reporting will help clarify the relationship between IBD and RASopathies such as NF1 and LS.

UNASSIGNED: Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive disease carrying an increased risk of cancers (paediatric tumours of central nervous system, haematolymphoid malignancies along with gastrointestinal (GI) cancer(s), which are usually seen in the second and third decades), leading to syndromic presentation. Causal mutations are detected in DNA mismatch repair (MMR) genes, including MLH1, PMS2, MSH2 and MSH6 that are also known for their established role in Lynch syndrome. We describe a case of CMMRD with an earlier (first decade of life) presentation of mediastinal acute lymphoblastic lymphoma and colorectal malignancy.
UNASSIGNED: A 5-year-old boy presented with respiratory complaints, bilateral cervical lymphadenopathy, multiple café-au-lait macules (CALMs) on the lower back and history of parental consanguinity with the death of three sisters due to brain tumour within 6 months of diagnosis. Computerised tomographic scan chest revealed a huge mediastinal mass. The patient underwent a trucut biopsy of the mass. The results were significant for a pre-T-cell acute lymphoblastic lymphoma. Suspicion of CMMRD was raised based on a combination of factors described above. A panel of MMR proteins was applied on the biopsy tissue that revealed loss of nuclear expression of MLH1 and PMS2 immunostaining in tumour cells with positive external controls. While on maintenance therapy for lymphoma, about a year later, the patient developed subacute intestinal obstruction due to a stenosing polypoidal circumferential tumour in the mid-sigmoid colon found on flexible sigmoidoscopy that was followed by endoscopic biopsies and insertion of a fully covered self-expanding metallic adult biliary stent with a diameter of 10 mm and length of 6 cm leading to immediate relief of obstruction. Biopsies revealed adenocarcinoma with neuroendocrine differentiation. Metastatic tumour deposits were seen in the omentum, anterior abdominal wall and the left peritoneal wall.
UNASSIGNED: Earlier (first decade) presentation of GI malignancy warrants that an earlier screening through radiological scans for any possible tumours and MMR protein expression analysis (loss in tumour plus normal non-tumour cells) are essential in patients having CALMs and family history of paediatric tumours.

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.

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.
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.

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.
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.

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.
METHODS: 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.

UNASSIGNED: Plexiform neurofibroma with neurofibromatosis type 1 (NF1) or Von Recklinghausen\'s disease is a rare entity and occurs in approximately 5-15% patients. These are slow growing, painless and locally infiltrating tumors. The pattern of inheritance is autosomal dominant and its penetrance is almost complete by 5 years of age.
UNASSIGNED: We hereby report a case of 13 years old boy visited presenting with swelling of right eyelid and forehead. After surgical removal, the tissue was sent for histopathological evaluation. Microscopy revealed an unencapsulated tumor mass comprising of well organized mixture of multiple nerve bundles with interlacing neural tissue in background of spindle shaped cells along with myxoid areas and numerous blood vessels.
UNASSIGNED: The NF1 gene responsible for the disease is located on chromosome 17 at locus 17q11.2 that codes for the protein neurofibromin. The frequency of neomutations is particularly high and almost half of the cases are sporadic. NF1 is characterized by a wide variability of clinical expressions, even within a given family. Majority of patients can be diagnosed only after thorough physical examination.
UNASSIGNED: The wide variation of the clinical expression, the tumor risk and the totally unpredictable evolution of the disease impose regular monitoring of NF1 patients. This surveillance is mainly clinical and has to be adapted to the patient\'s age in order to assure early management of complications.

BACKGROUND: Jaffe-Campanacci syndrome is characterized by multiple non-ossifying fibromas, café-au-lait macules and giant cell granulomas of the jaw. Even if the association between all these peculiar features and neurofibromatosis type 1 have been described, it has not yet been clarified whether Jaffe-Campanacci syndrome represents a distinct entity or it can be regarded as a neurofibromatosis type 1 subtype.
METHODS: The patient here described is a young boy, who fulfilled the clinical diagnostic criteria for both syndromes. He had a complex clinical history with café-au-lait macules, axillary and inguinal freckling, multiple non-ossifying fibromas, giant-cell granuloma of the jaw, neurofibromas, plexiform fibroma, ocular Lisch nodules, optic chiasmatic- hypothalamic glioma, pseudarthrosis, scoliosis, short stature, vascular anomalies, seizures. Molecular analysis of the NF1 gene both on blood cells and non-ossifying fibroma\'s biopsy tissue allowed the detection of a novel variant within the coding region, NM_000267.3:c.2789_2791delATC(p.Tyr930_Pro931delinsSer), with loss of heterozygosity (second hit mutation) in the non-ossifying fibroma.
CONCLUSIONS: This result indicates that every patient with clinical features of Jaffe-Campanacci syndrome should be further evaluated to detect features related to neurofibromatosis type 1 and genetically investigated for mutations in the NF1 gene, since this could lead to a definite diagnosis, but also could clarify and quantify the real genotype-phenotype overlap between neurofibromatosis type 1 and Jaffe-Campanacci syndrome.

Legius syndrome is a rare genetic disorder caused by heterozygous germ line loss-of-function SPRED1 mutation. In Japan, a family with Legius syndrome was first described in 2015 by Sakai et al. We described a first solitary case of Legius syndrome identified by next-generation sequencing in Japan. A 37-year-old woman presented with multiple café-au-lait macules and freckles but has no other features of neurofibromatosis type 1 (NF-1). Sequencing results showed the presence of a mutation in exon 2 of SPRED1 c.70C>T, resulting in the protein at position 24 (p.Arg24X). When a dermatological clinician sees an adult patient showing only pigmented lesions and no other specifically diagnostic features of NF-1, it is important to suspect the possibility of Legius syndrome.