Journal of Dermatology 2015; 42: 703–705
doi: 10.1111/1346-8138.12862
CONCISE COMMUNICATION
Family with Legius syndrome (neurofibromatosis type 1-like syndrome) Noriyasu SAKAI, Tatsuro MAEDA, Hiroshi KAWAKAMI, Masaki UCHIYAMA, Kazutoshi HARADA, Ryoji TSUBOI, Yoshihiko MITSUHASHI Department of Dermatology, Tokyo Medical University, Tokyo, Japan
ABSTRACT Legius syndrome (Online Mendelian Inheritance in Man no. 611431) or neurofibromatosis type 1 (NF1)-like syndrome was first reported by Legius et al. in 2007. We herein report the first instance of Legius syndrome occurring in two female siblings in Japan. Both individuals presented cafe-au-lait macules and freckling. Mutation analysis revealed a mutation of c.349C>T resulting in p.Arg117* in the SPRED1 gene as the cause of the Legius syndrome. The National Institutes of Health criteria for NF1 are insufficient to rule out the condition. For this reason, and because the clinical course of each condition is quite different, we stress the need to differentiate Legius syndrome from NF1 clearly.
Key words:
cafe-au-lait macules, Legius syndrome, neurofibroma, neurofibromatosis type 1, SPRED1.
INTRODUCTION Legius syndrome (Online Mendelian Inheritance in Man no. 611431), or neurofibromatosis type 1 (NF1)-like syndrome, was reported by Legius et al. in 2007.1 Due to the clinical similarities with NF1, such as multiple cafe-au-lait macules (CALM) and freckling arising from autosomal dominant inheritance, it is conceivable that Legius syndrome patients have been misdiagnosed in the past. However, while no mutations of the NF1 gene were found in the present patients, mutations of the SPRED1 gene located on chromosome 15q13.2 and the presence of an inhibitor of the Ras/extracellular signal-regulated kinase pathway2 were subsequently detected. This study constitutes the first report from Japan of Legius syndrome occurring in siblings. A gene test on the subjects’ family revealed a nonsense mutation in SPRED1.
CASE REPORT Case 1, a 36-year-old woman, visited our outpatient clinic in August, 2013. She presented no medical complaints other than CALM and a history of three spontaneous abortions. Her family history revealed that her father, grandfather, younger sister, niece and nephew reported the same CALM. The patient noticed several brown macules when she was of elementary school age. Incidentally, her younger sister was recently diagnosed with von Recklinghausen’s disease because of the presence of a dozen brownish spots. The patient was prompted by concerns that she may be suffering from the same condition as her sister, and therefore came to us for a consultation.
A physical examination revealed four CALM on the abdomen and back, and dense freckling on the abdomen (Fig. 1a). We found no skin tumors or Lisch nodules, which are visible by macroscopic examination. Dysmorphism and any other non-cutaneous features were not recognized. Case 2, a 30-year-old woman and younger sibling of case 1, noticed brown macules when she was of elementary school age. Clinical examination revealed a dozen CALM on the trunk and extremities (Fig. 1b), and dense freckling on both sides of the axillae. Any skin tumor non-cutaneous features was not recognized. Case 3, a 3-year-old girl and the daughter of case 2, presented only one CALM, which had been present from birth, on the right side of the abdomen (Figs. 1c,2).
Mutation analysis Genomic DNA was extracted from peripheral blood leukocytes according to the standard procedure.1 Mutation analysis was performed using a sequencing analysis on the SPRED1 gene. After obtaining the informed consent of the patients, all eight exons were sequenced. The results disclosed a mutation in cases 1 and 2 of c.349C>T resulting in p.Arg117* in exon 4. However, case 3 presented no mutations in the SPRED1 gene (Fig. 3).
DISCUSSION Legius syndrome, an autosomal dominant disorder, was described for the first time in 2007.1 It shares clinical similarities with NF1, but is caused by a heterozygous mutation in SPRED1, unlike NF1. The SPRED1 protein is constructed by 444 amino acids and comprises three domains. SPRED1 is an
Correspondence: Yoshihiko Mitsuhashi, M.D., Ph.D., Department of Dermatology, Tokyo Medical University 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Email: [email protected] Received 13 November 2014; accepted 16 February 2015.
© 2015 Japanese Dermatological Association
703
N. Sakai et al.
(a)
(b) Figure 2. Pedigree of the family.
(c)
Figure 3. Results of mutation analysis on SPRED1. C>T substitution at c.349 resulted in a premature stop codon at p.117 (p.Arg117*).
Figure 1. Clinical features of the patients with cafe-au-lait macules. (a) Case 1, (b) case 2 and (c) case 3.
inhibitor of renin–angiotensin system (RAS)–mitogen-activated protein kinase (MAPK) and operates along the RAS pathway to control the MAPK signal.3 Individuals with Legius syndrome typically present multiple CALM and freckling, but no complications such as Lisch
704
nodules, neurofibromas or other neural tumors such as are found in NF1. Variable dysmorphic features such as hypertelorism or macrocephaly, lipomas and mild learning disabilities or attention problems are sporadically reported. It is important to distinguish the Legius syndrome from NF1, because their clinical course is quite different.2 Not only benign neurofibromas, but also malignant neurological tumors, can develop in NF1. These tumors and the other features commonly associated with NF1 reduce the quality of life of NF1 patients. In Legius syndrome, on the other hand, freckling is virtually the only overt symptom. For this reason, Legius syndrome can be classified as a less severe type of NF1.3,4 Legius syndrome is thought to account for approximately 5% of cases diagnosed as NF1, as with case 2 in the present study.5 The National Institutes of Health (NIH) criteria for NF1
© 2015 Japanese Dermatological Association
Family with Legius syndrome
are insufficient to rule out the condition. The subjects in our report showed autosomal dominant inheritance. Cases 1 and 2 presented dense freckling and CALM, although there were fewer than six of the latter in case 1. Both cases could be diagnosed as NF1 according to the NIH criteria.6 However, in the absence of neurofibromas or Lisch nodules, a careful clinical examination of the CALM may alert the possibility of Legius syndrome. Importantly, the CALM in cases 1 and 2 were not visible at birth but developed after the elementary school age. In NF1, on the other hand, CALM exist at birth. We believe this constitutes an important difference between Legius syndrome and NF1.7 Precise dermatological description of the skin lesions of Legius syndrome is still insufficient. Observation of further cases may be necessary to verify this supposition. We identified a SPRED1 mutation in cases 1 and 2 as in the case reported in Belgium by Denayer et al.8 Although numerous mutations have been reported in all of the exons, no hotspots have been identified. The occurrence of the same mutation in our cases and in the Belgian case suggests that there are no founder effects but rather only random mutations. To date, 166 cases of Legius syndrome have been in Europe and North America. We add here the first instance of a familial case of Legius syndrome in Japan. Further research is necessary to determine whether there are any variations in the clinical and genetic features between European and Asian cases. Legius syndrome is still not well understood although it is clear that its course differs from that of NF1. It is important to
© 2015 Japanese Dermatological Association
differentiate the two conditions clearly in order to provide appropriate genetic counseling to the patients.
CONFLICT OF INTEREST:
None.
REFERENCES 1 Brems H, Chmara M, Sahbatou M et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 2007; 39: 1120–1126. -au-lait macules and 2 Stevens CA, Chiang PW, Messiaen LM. Cafe intertriginous freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and Legius syndrome. Am J Med Genet 2012; 158A: 1195–1199. 3 Brems H, Pasmant E, Van Minkelen R et al. Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat 2012; 33: 1538–1546. 4 Tanito K, Ota A, Kamide R et al. Clinical features of 58 Japanese patients with mosaic neurofibromatosis 1. J Dermatol 2014; 41: 724– 728. 5 Stowe IB, Mercado EL, Stowe TR et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev 2012; 26: 1421–1426. 6 Muram-Zborovski TM, Vaughn CP, Viskochil DH et al. NF1 exon 22 analysis of individuals with the clinical diagnosis of neurofibromatosis type 1. Am J Med Genet part A 2010; 152: 1973–1978. 7 Stevenson D, Viskochil D, Mao R. Legius syndrome. GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK47312/ 8 Denayer E, Chmara M, Brems H et al. Legius syndrome in fourteen families. Hum Mutat 2011; 32: 1985–1998.
705
doi: 10.1111/1346-8138.12862
CONCISE COMMUNICATION
Family with Legius syndrome (neurofibromatosis type 1-like syndrome) Noriyasu SAKAI, Tatsuro MAEDA, Hiroshi KAWAKAMI, Masaki UCHIYAMA, Kazutoshi HARADA, Ryoji TSUBOI, Yoshihiko MITSUHASHI Department of Dermatology, Tokyo Medical University, Tokyo, Japan
ABSTRACT Legius syndrome (Online Mendelian Inheritance in Man no. 611431) or neurofibromatosis type 1 (NF1)-like syndrome was first reported by Legius et al. in 2007. We herein report the first instance of Legius syndrome occurring in two female siblings in Japan. Both individuals presented cafe-au-lait macules and freckling. Mutation analysis revealed a mutation of c.349C>T resulting in p.Arg117* in the SPRED1 gene as the cause of the Legius syndrome. The National Institutes of Health criteria for NF1 are insufficient to rule out the condition. For this reason, and because the clinical course of each condition is quite different, we stress the need to differentiate Legius syndrome from NF1 clearly.
Key words:
cafe-au-lait macules, Legius syndrome, neurofibroma, neurofibromatosis type 1, SPRED1.
INTRODUCTION Legius syndrome (Online Mendelian Inheritance in Man no. 611431), or neurofibromatosis type 1 (NF1)-like syndrome, was reported by Legius et al. in 2007.1 Due to the clinical similarities with NF1, such as multiple cafe-au-lait macules (CALM) and freckling arising from autosomal dominant inheritance, it is conceivable that Legius syndrome patients have been misdiagnosed in the past. However, while no mutations of the NF1 gene were found in the present patients, mutations of the SPRED1 gene located on chromosome 15q13.2 and the presence of an inhibitor of the Ras/extracellular signal-regulated kinase pathway2 were subsequently detected. This study constitutes the first report from Japan of Legius syndrome occurring in siblings. A gene test on the subjects’ family revealed a nonsense mutation in SPRED1.
CASE REPORT Case 1, a 36-year-old woman, visited our outpatient clinic in August, 2013. She presented no medical complaints other than CALM and a history of three spontaneous abortions. Her family history revealed that her father, grandfather, younger sister, niece and nephew reported the same CALM. The patient noticed several brown macules when she was of elementary school age. Incidentally, her younger sister was recently diagnosed with von Recklinghausen’s disease because of the presence of a dozen brownish spots. The patient was prompted by concerns that she may be suffering from the same condition as her sister, and therefore came to us for a consultation.
A physical examination revealed four CALM on the abdomen and back, and dense freckling on the abdomen (Fig. 1a). We found no skin tumors or Lisch nodules, which are visible by macroscopic examination. Dysmorphism and any other non-cutaneous features were not recognized. Case 2, a 30-year-old woman and younger sibling of case 1, noticed brown macules when she was of elementary school age. Clinical examination revealed a dozen CALM on the trunk and extremities (Fig. 1b), and dense freckling on both sides of the axillae. Any skin tumor non-cutaneous features was not recognized. Case 3, a 3-year-old girl and the daughter of case 2, presented only one CALM, which had been present from birth, on the right side of the abdomen (Figs. 1c,2).
Mutation analysis Genomic DNA was extracted from peripheral blood leukocytes according to the standard procedure.1 Mutation analysis was performed using a sequencing analysis on the SPRED1 gene. After obtaining the informed consent of the patients, all eight exons were sequenced. The results disclosed a mutation in cases 1 and 2 of c.349C>T resulting in p.Arg117* in exon 4. However, case 3 presented no mutations in the SPRED1 gene (Fig. 3).
DISCUSSION Legius syndrome, an autosomal dominant disorder, was described for the first time in 2007.1 It shares clinical similarities with NF1, but is caused by a heterozygous mutation in SPRED1, unlike NF1. The SPRED1 protein is constructed by 444 amino acids and comprises three domains. SPRED1 is an
Correspondence: Yoshihiko Mitsuhashi, M.D., Ph.D., Department of Dermatology, Tokyo Medical University 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Email: [email protected] Received 13 November 2014; accepted 16 February 2015.
© 2015 Japanese Dermatological Association
703
N. Sakai et al.
(a)
(b) Figure 2. Pedigree of the family.
(c)
Figure 3. Results of mutation analysis on SPRED1. C>T substitution at c.349 resulted in a premature stop codon at p.117 (p.Arg117*).
Figure 1. Clinical features of the patients with cafe-au-lait macules. (a) Case 1, (b) case 2 and (c) case 3.
inhibitor of renin–angiotensin system (RAS)–mitogen-activated protein kinase (MAPK) and operates along the RAS pathway to control the MAPK signal.3 Individuals with Legius syndrome typically present multiple CALM and freckling, but no complications such as Lisch
704
nodules, neurofibromas or other neural tumors such as are found in NF1. Variable dysmorphic features such as hypertelorism or macrocephaly, lipomas and mild learning disabilities or attention problems are sporadically reported. It is important to distinguish the Legius syndrome from NF1, because their clinical course is quite different.2 Not only benign neurofibromas, but also malignant neurological tumors, can develop in NF1. These tumors and the other features commonly associated with NF1 reduce the quality of life of NF1 patients. In Legius syndrome, on the other hand, freckling is virtually the only overt symptom. For this reason, Legius syndrome can be classified as a less severe type of NF1.3,4 Legius syndrome is thought to account for approximately 5% of cases diagnosed as NF1, as with case 2 in the present study.5 The National Institutes of Health (NIH) criteria for NF1
© 2015 Japanese Dermatological Association
Family with Legius syndrome
are insufficient to rule out the condition. The subjects in our report showed autosomal dominant inheritance. Cases 1 and 2 presented dense freckling and CALM, although there were fewer than six of the latter in case 1. Both cases could be diagnosed as NF1 according to the NIH criteria.6 However, in the absence of neurofibromas or Lisch nodules, a careful clinical examination of the CALM may alert the possibility of Legius syndrome. Importantly, the CALM in cases 1 and 2 were not visible at birth but developed after the elementary school age. In NF1, on the other hand, CALM exist at birth. We believe this constitutes an important difference between Legius syndrome and NF1.7 Precise dermatological description of the skin lesions of Legius syndrome is still insufficient. Observation of further cases may be necessary to verify this supposition. We identified a SPRED1 mutation in cases 1 and 2 as in the case reported in Belgium by Denayer et al.8 Although numerous mutations have been reported in all of the exons, no hotspots have been identified. The occurrence of the same mutation in our cases and in the Belgian case suggests that there are no founder effects but rather only random mutations. To date, 166 cases of Legius syndrome have been in Europe and North America. We add here the first instance of a familial case of Legius syndrome in Japan. Further research is necessary to determine whether there are any variations in the clinical and genetic features between European and Asian cases. Legius syndrome is still not well understood although it is clear that its course differs from that of NF1. It is important to
© 2015 Japanese Dermatological Association
differentiate the two conditions clearly in order to provide appropriate genetic counseling to the patients.
CONFLICT OF INTEREST:
None.
REFERENCES 1 Brems H, Chmara M, Sahbatou M et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 2007; 39: 1120–1126. -au-lait macules and 2 Stevens CA, Chiang PW, Messiaen LM. Cafe intertriginous freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and Legius syndrome. Am J Med Genet 2012; 158A: 1195–1199. 3 Brems H, Pasmant E, Van Minkelen R et al. Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat 2012; 33: 1538–1546. 4 Tanito K, Ota A, Kamide R et al. Clinical features of 58 Japanese patients with mosaic neurofibromatosis 1. J Dermatol 2014; 41: 724– 728. 5 Stowe IB, Mercado EL, Stowe TR et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev 2012; 26: 1421–1426. 6 Muram-Zborovski TM, Vaughn CP, Viskochil DH et al. NF1 exon 22 analysis of individuals with the clinical diagnosis of neurofibromatosis type 1. Am J Med Genet part A 2010; 152: 1973–1978. 7 Stevenson D, Viskochil D, Mao R. Legius syndrome. GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK47312/ 8 Denayer E, Chmara M, Brems H et al. Legius syndrome in fourteen families. Hum Mutat 2011; 32: 1985–1998.
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