doi: 10.1111/j.1346-8138.2006.00148.x
Journal of Dermatology 2006; 33: 635–638
CASE REPORT Blackwell Publishing Asia
Segmental neurofibromatosis: Report of two cases Engin SEZER,1 Atilla SENAYLI,2 Taner SEZER,3 Unal BICAKCI2 Departments of 1Dermatology, 2Pediatric Surgery and 3Pediatrics, Gaziosmanpasa University School of Medicine,Tokat,Turkey
ABSTRACT Neurofibromatosis (NF), or von Recklinghausen’s disease is comprised of a heterogeneous group of disorders, primarily affecting the skin, soft tissue, bone and central nervous system. Segmental neurofibromatosis (SN) is a rare form of NF, characterized by “café-au-lait” macules, freckles, and/or neurofibromas limited to a body segment. There are approximately 150 cases reported in the English published work. Bilateral segmental neurofibromatosis is a rare subtype of SN, manifesting with bilateral involvement of the body segments. Herein, we report two patients with SN; one associated with pectus excavatum, and the other case diagnosed as bilateral segmental neurofibromatosis. Asymmetry of the skull and thorax, kyphoscoliosis and segmental bone hypertrophy of the leg are skeletal abnormalities previously reported with SN. To the best of our knowledge, this is the first case of SN in association with pectus excavatum. Key words: bilateral segmental neurofibromatosis, pectus excavatum, segmental neurofibromatosis.
INTRODUCTION Neurofibromatosis (NF) is comprised of a diverse group of genetic conditions characterized by increased pigmentation of the skin (“café-au-lait” spots) and skin tumors, partly of ectodermal and neural origin. Segmental neurofibromatosis (SN) is a rare variant, presenting with a restricted distribution of café-au-lait (CAL) macules, freckling or neurofibromata, often in a unilateral, segmental distribution. In this article, we describe two patients with SN; one associated with pectus excavatum, and the other case diagnosed as bilateral segmental neurofibromatosis.
CASE REPORT Case 1 was an 11-year-old male who presented with a 3-year history of pigmented lesions over the left cervical and axillary region. The family history was negative for CAL macules and freckles. Physical examination revealed numerous freckles confined
to the C3-4 dermatomes on the left side of the neck, ipsilateral axillary CAL macules and freckles, and pectus excavatum (Fig. 1). Ophthalmological examination for Lisch nodules was negative, and the following investigations were all normal: complete blood count, routine biochemical analysis, urinalysis, electroencephalogram and ultrasonography of the abdomen. Case 2 was a 12-year-old female who was referred to dermatology for evaluation of a 1-year history of hyperpigmented macular lesions over the trunk and axillary area. The family history was unremarkable for neurofibromatosis. Physical examination showed bilateral multiple CAL macules and freckles with a clear demarcation line over the abdominothoracic region, upper back and axillae following lines of Blaschko (Fig. 2). Eye examination for Lisch nodules was negative. Liver and renal function tests, complete blood count, cranial magnetic resonance imaging, electroencephalogram and abdominal ultrasonography were all normal.
Correspondence: Engin Sezer, MD, Gaziosmanpasa Universitesi Hastanesi, Dermatoloji Anabilim Dalı, Tokat, 60100, Turkey. Email:
[email protected] Received 14 July 2005; accepted 3 March 2006.
© 2006 Japanese Dermatological Association
635
E. Sezer et al.
Figure 1. (A) Ipsilateral axillary freckling and “café-au-lait” (CAL) macules (Crowe’s sign) in association with pectus excavatum. (B) Cervical freckles distributed through the C3–4 segments, on the left side.
DISCUSSION Neurofibromatosis was first described by von Recklinghausen in 1882.1 The major features are CAL macules, often with axillary freckling, multiple neurofibromas, pigmented iris hamartomas (Lisch nodules) and osseous lesions. Associated features can include learning disability, seizures, central
nervous system tumors, malignant peripheral nerve sheath tumor and precocious puberty.1,2 Because of the heterogeneity and complexity of the clinical presentation, Riccardi classified NF into eight subtypes based upon clinical manifestations, genetic transmission, and prognosis.3 (Table 1). Type-5 or SN is characterized by CAL spots, freckles, and/or cutaneous neurofibromas limited to
Table 1. Riccardi’s classification of neurofibromatosis NF-1 NF-2 NF-3 NF-4 NF-5 NF-6 NF-7 NF-8
636
Classical form (von Recklinghausen’s disease), constitutes 90% of all cases Acoustic form, bilateral acoustic neuromas Mixed form, combines features of NF-1 and NF-2 Variant form, diffuse “café-au-lait” (CAL) macules and neurofibromas Segmental form, limited distribution of CAL macules and/or neurofibromas Multiple CAL spots without neurofibromas Late onset form, onset of neurofibromatosis after the age of 20 years Not otherwise specified, definitive neurofibromatosis, but not characteristic of any other category
© 2006 Japanese Dermatological Association
Segmental neurofibromatosis
Figure 2. (A) Multiple freckles and CAL macules with an arciform pattern on the abdominothoracic region. (B) Distribution of bilateral lesions on the back.
a circumscribed area in a segmental distribution.4 SN is a rare entity with approximately 150 cases reported in the published work.4 Epidemiological data reveals that females are affected twice as often as males, and the disease primarily affects Caucasians. The age of onset indicates a bimodal distribution, with peaks at 10–30 years and 50–70 years.5 Goldberg emphasized that two or more features restricted to a unilateral segment are required for diagnosis of SN: (i) CAL macules; (ii) freckles; (iii) neurofibromas; (iv) Lisch nodules; (v) optic glioma; and (vi) NF-specific bone lesions.6 A recent study of 39 patients with SN revealed that 56% of the cases had only CAL macules and axillary freckles without neurofibromas, as were observed in our cases.2 The lesions are most commonly located on the cervix, thorax and abdomen (55% of the patients), and less often on the upper extremities, lower extremities or
© 2006 Japanese Dermatological Association
face.7 In our opinion, SN patients with only macular lesions are underdiagnosed, because of the limited signs and lack of symptoms. Our first case presented with cervical freckles distributed through the C3–4 segments on the left side and ipsilateral axillary CAL spots and freckles (Crowes’ sign), consistent with SN. Asymmetry of the skull and thorax, kyphoscoliosis, and segmental bone hypertrophy of the leg are the skeletal abnormalities previously reported with SN.1,7,8 To the best of our knowledge, this is the first case of SN in association with pectus excavatum. Whether this association of pectus excavatum is a manifestation of SN or an incidental finding is unclear based on our case. Further case reports are needed to establish the significance of this phenomenon. Colon adenocarcinoma, bronchoalveolar lung carcinoma, visceral neurofibromas and
637
E. Sezer et al.
ipsilateral renal agenesis are other extracutaneous features reported in association with SN.7,9 In contrast with NF1, neurological abnormalities have never been reported with SN. Segmental neurofibromatosis results from a postzygotic mutation in the NF1 gene leading to somatic mosaicism.2 In a recent study, Tinschert et al. demonstrated microdeletion of the NF1 gene in fibroblasts cultured from CAL macules of a SN patient.8 Because many reported cases have not met Riccardi’s stringent criteria, Roth et al. further subdivided SN into four subtypes: (i) true segmental neurofibromatosis adhering to Riccardi’s definition; (ii) localized cases with deep involvement; (iii) localized cases with genetic transmission; and (iv) bilateral segmental neurofibromatosis.1 Bilateral segmental neurofibromatosis (BSN) is a rare subtype of SN first reported by Gamel et al. in 1931.10 The disease is believed to result from double, coincidental mutation.11 Twenty cases of BSN have been reported to date.10 Including our case, six cases of BSN have clinically presented with only macular lesions.10 Tinschert et al. reported a SN patient with freckles and CAL macules following the lines of Blaschko and proposed that skin lesions in SN should not reveal a strictly dermatomal sense.8 Our patient also demonstrated bilateral abdominothoracic lesions distributed along Blaschko’s lines, supporting the author’s opinion on this point. Lisch nodules are rarely encountered in SN patients.11 Some authors have suggested that, in the absence of Lisch nodules, the risk of genetic transmission is minimal.7 In comparison with classical NF, Lisch nodules are observed unilaterally when present in SN.12 Eye examinations revealed that our patients and relatives were free of Lisch nodules. We
638
consider that a definitive family history and clinical examination of first-degree relatives, including eye examinations are mandatory for appropriate genetic counseling in SN patients.
REFERENCES 1 Roth RR, Martines R, James WD. Segmental neurofibromatosis. Arch Dermatol 1987; 123: 917–920. 2 Listernick R, Mancini AJ, Charrow J. Segmental neurofibromatosis in childhood. Am J Med Genet A 2003; 121: 132–135. 3 Riccardi VM. Neurofibromatosis: clinical heterogeneity. Curr Probl Cancer 1982; 7: 1–34. 4 Schultz ES, Kaufmann D, Tinschert S, Schell H, von den Driesch P, Schuler G. Segmental neurofibromatosis. Dermatol 2002; 204: 296–297. 5 Sanchez Conejo-Mir J, Herrera Saval A, Camacho Martinez F. Segmental neurofibromatosis. J Am Acad Dermatol 1989; 20: 681–682. 6 Goldberg NS. What is segmental neurofibromatosis? J Am Acad Dermatol 1992; 26: 638–640. 7 Demierre MF, Gerstein W. Segmental neurofibromatosis with ipsilateral renal agenesis. Int J Dermatol 1996; 35: 445–447. 8 Tinschert S, Naumann I, Stegmann E et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur j Hum Genet 2000; 8: 455–459. 9 Yalcin B, Toy GG, Tamer E et al. Increased expression of segmental neurofibromatosis with bronchoalveolar lung carcinoma. Dermatol 2004; 209: 342. 10 Nagaoka Y, Asahina A, Yano S, Tamaki K. Bilateral segmental neurofibromatosis. Acta Derm Venereol 2002; 82: 219–220. 11 Micali G, Lembo D, Giustini S, Calvieri S. Segmental neurofibromatosis with only macular lesions. Pediatr Dermatol 1993; 10: 43–45. 12 Finley EM, Kolbusz RV. Segmental neurofibromatosis clinically appearing as a nevus spilus. Int J Dermatol 1993; 32: 358–360.
© 2006 Japanese Dermatological Association
