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Molecular screening strategies for NF1-like syndromes with cafe-au-lait macules (Review).

ABSTRACT: Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of genetic disorders presenting with CALM have mutations that are involved in human skin pigmentation regulation signaling pathways, including KIT ligand/KIT proto?oncogene receptor tyrosine kinase and Ras/mitogen?activated protein kinase. These disorders, which include Legius syndrome, Noonan syndrome with multiple lentigines or LEOPARD syndrome, and familial progressive hyperpigmentation) are difficult to distinguish from NF1 at early stages, using skin appearance alone. Furthermore, certain syndromes are clinically overlapping and molecular testing is a vital diagnostic method. The present review aims to provide an overview of these 'NF1?like' inherited diseases and recommend a cost?effective strategy for making a clear diagnosis among these diseases with an ambiguous borderline.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5112360 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Molecular screening strategies for NF1-like syndromes with café-au-lait macules (Review).

Zhang Jia J Li Ming M Yao Zhirong Z

Molecular medicine reports 20160922 5

Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of genetic disorders presenting with CALM have mutations that are involved in human skin pigmentation regulation signaling pathways, including KIT ligand/KIT proto‑oncogene receptor tyrosine kinase and Ras/mitogen‑activated protein kinase. These disorders, which include Legius syndrome, Noonan syndrome with multiple lentigines or LEOPARD s ...[more]

PMID: 27666661

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Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene.

Project description:Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and café-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no café-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A-->G) enlarging exon 32 by 4 bp at the 5' end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency.

| S-EPMC1235551 | biostudies-literature

Diagnostic and pathogenetic role of cafe-au-lait macules in nevoid basal cell carcinoma syndrome.

Project description:Café au lait spots (CALS) are common dermatologic findings that can at the same time arise in a variety of pathologic conditions such as Neurofibromatosis type 1 (NF1), together with numerous hereditary syndromes for which they represent either diagnostic criteria or associated elements (McCune Albright, Silver-Russell, LEOPARD, Ataxia-Telangiectasia). A review of the literature also revealed two cases of association with NBCCS. We report here the case of a female proband with CALS associated to Nevoid Basal Cell Carcinoma Syndrome (NBCCS) with known PTCH1 germline mutation (C.1348-2A>G) who had been misdiagnosed with NF1 in her childhood because of 5 CALS and cutaneous nodules. The patient presented a giant cell tumor of the skin, palmar and calcaneal epidermoidal cystic nodules, odontogenic keratocystic tumors and deformity of the jaw profile. Her family history brought both her brother and father to our attention because of the presence of KCOTs diagnosed at early age: after genetic testing, the same PTCH1 germline mutation was identified in the three family members. Clinical criteria are used for discerning NF1 diagnosis (size, number and onset age), while there are no definite guidelines concerning CALS except for their presence. In our experience, we have noted an association of CALS with NBCCS; this seems interesting because we already know clinical criteria are a dynamic entity and can be modified by epidemiologic evidences.

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A novel missense KIT mutation causing piebaldism in one Chinese family associated with cafe-au-lait macules and intertriginous freckling.

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Genome-wide association study of cafe-au-lait macule number in neurofibromatosis type 1.

Project description:BACKGROUND:Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressor NF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date. METHODS:In this study, we performed a genome-wide association analysis of the number of café-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1. RESULTS:A borderline genome-wide significant association was identified in the discovery cohort (CALM1, N = 112) between CALM number and rs12190451 (and rs3799603, r2 = 1.0; p = 7.4 × 10-8 ) in the intronic region of RPS6KA2. Although, this association was not replicated in the second cohort (CALM2, N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for the RPS6KA2 signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error. CONCLUSION:rs12190451 is located in a melanocyte-specific enhancer and may influence RPS6KA2 expression in melanocytes-warranting further functional studies.

| S-EPMC7549607 | biostudies-literature

McCune Albright syndrome - association of fibrous dysplasia, cafe-au-lait skin spots and hyperthyroidism - case report.

Project description:McCune-Albright syndrome is a rare sporadic disease characterized by bone fibrous dysplasia, café-au-lait skin spots and a variable association of hyperfunctional endocrine disorders. Fibrous dysplasia (FD), which can involve the craniofacial, axial, and appendicular skeleton, may range from an isolated, asymptomatic monostotic lesion to a severe disabling polyostotic disease involving the entire skeleton. A twenty-five-year old male patient presented to our clinic with recently developed heart palpitations. He had also been feeling pain in the right femur since he was younger, without any trauma history, leading to difficulties of ambulation and limping occasionally. His physical examination revealed café-au-lait spots with irregular borders and right testicular agenesis. Laboratory findings identified hyperthyroidism with hyperparathyroidism. Radiographs of the pelvis revealed multiple lytic lesions of the right femur and magnetic resonance imaging (MRI) characterized these lesions as specific to fibrous dysplasia of the bone, without any insufficiency fracture at this level. The association of café-au-lait skin spots with bone fibrous dysplasia, and hyperthyroidism in this patient suggested the diagnosis of McCune - Albright syndrome.

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Association of Piebaldism, multiple cafe-au-lait macules, and intertriginous freckling: clinical evidence of a common pathway between KIT and sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1).

Project description:Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5-year-old boy who had the white forelock and leukoderma of piebaldism, but the presence of many café-au-lait macules and axillary and inguinal freckling complicated the diagnosis. Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty-related, Ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) mutations that also has multiple café-au-lait macules and intertriginous freckling. Based on our current understanding of KIT and SPRED1 protein interactions, we propose that café-au-lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1.

| S-EPMC3967413 | biostudies-literature

Genetic modifiers of neurofibromatosis type 1-associated cafe-au-lait macule count identified using multi-platform analysis.

Project description:Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

| S-EPMC4199479 | biostudies-literature

Congenital grouped albinotic spots of the retinal pigment epithelium in a patient with hemihypertrophy and cafe au lait spots.

Project description:PurposeTo describe the finding of circularly grouped hypomelanotic spots in the central macula of a patient with syndromic characteristics.MethodsCase report of a patient with albinotic spots grouped within the macula, café au lait spots, and left-sided hemihypertrophy.ResultsA 15-year-old boy presented with hypomelanotic spots which were hyperautofluorescent on fundus autofluorescence imaging with no disruption of the retinal laminae or photoreceptor inner and outer segment (IS/OS) junction on spectral domain optical coherence tomography. His developmental history included hemihypertrophy, café au lait spots over his axilla and extremities, and surgically corrected left-sided cryptorchidism. Other ocular history included resolved convergence insufficiency and red-green color blindness.ConclusionsIt is essential to recognize that circularly grouped hypomelanotic spots are a benign condition. The location and arrangement of the hypomelanotic spots were atypical for congenital grouped albinotic spots of the retinal pigment epithelium (CGAS) as they were grouped within the macula in addition to a more characteristic linear "bear track" formation in the periphery. To the authors' knowledge, this is the first report of CGAS present in a patient with hemihypertrophy, café au lait spots, and cryptorchidism and may represent a novel syndromic association.

| S-EPMC9119418 | biostudies-literature

Coffin-Siris syndrome with cafe-au-lait spots, obesity and hyperinsulinism caused by a mutation in the ARID1B gene.

Project description:Coffin-Siris syndrome (CSS) (MIM 135900) is characterized by developmental delay, severe speech impairment, distinctive facial features, hypertrichosis, aplasia or hypoplasia of the distal phalanx or nail of the fifth digit and agenesis of the corpus callosum. Recently, it was shown that mutations in the ARID1B gene are the main cause of CSS, accounting for 76% of identified mutations. Here, we report a 15 year-old female patient who was admitted to our clinic with seizures, speech problems, dysmorphic features, bilaterally big, large thumb, café-au-lait (CAL) spots, obesity and hyperinsulinism. First, the patient was thought to have an association of neurofibromatosis and Rubinstein Taybi syndrome. Because of the large size of the NF1 gene for neurofibromatosis and CREBBP gene for Rubinstein Taybi syndrome, whole exome sequence analysis (WES) was conducted and a novel ARID1B mutation was identified. The proband WES test identified a novel heterozygous frameshift mutation c.3394_3395insTA in exon 13 of ARID1B (NM_017519.2) predicting a premature stop codon p.(Tyr1132Leufs*67). Sanger sequencing confirmed the heterozygous c.3394_3395insTA mutation in the proband and that it was not present in her parents indicating de novo mutation. Further investigation and new cases will help to understand this phenomenon better.

| S-EPMC4995424 | biostudies-literature

Treatment of Cafe-Au-Lait Spots Using Q-Switched Alexandrite Laser: Analysis of Clinical Characteristics of 471 Children in Mainland China.

Project description:Background and objectivesCafé-au-lait spots, also known as café-au-lait macules (CALMs), are a common pigmentary disorder. Although various laser modalities have been used to treat CALMs, the efficacy of laser treatment in children differs from that in adults. We investigated the efficacy, safety, and clinical factors of the treatment of CALMs using Q-switched alexandrite laser (755?nm) therapy in children.MethodsIn total, 471 children with CALMs underwent Q-switched alexandrite laser therapy at a treatment interval of 3-12 months. The safety and efficacy of the laser treatment were evaluated by reviewing clinical records and photographs before and after treatments.ResultsOf the 471 patients, 140 (29.72%) were cured completely, 124 (26.33%) showed substantial improvement, 110 (23.35%) showed improvement, and 97 (20.60%) showed no improvement after one to nine treatments. The overall treatment success rate was 79.41%, and the treatment efficacy was positively correlated with the number of laser treatments (rs?=?0.26, P?<?0.0001). Sex and the interval of laser treatments were also associated with significant differences in treatment outcomes (P?<?0.05). No obvious adverse effects were observed. Multivariate logistic regression analysis showed that the number of treatments influenced the treatment efficacy (odds ratio, 2.130; 95% confidence interval, 1.561-2.908).ConclusionsQ-switched alexandrite laser (755?nm) therapy is safe and highly effective for CALMs in children, and the number of treatments affects the treatment efficacy. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

| S-EPMC6771696 | biostudies-literature

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