Dermatology Online Journal

Neurofibromatosis-Noonan syndrome: Case report and clinicopathogenic review of the Neurofibromatosis-Noonan syndrome and RAS-MAPK pathway
Irela Reig, Pablo Boixeda, Beatriz Fleta, Carmen Morenoc, Lucía Gámez, Mayte Truchuelo
Dermatology Online Journal 17 (4): 4

Departments of Dermatology and Pathology, Hospital Clinico, Universitario Valencia, Hospital Universitario Ramon y Cajal, Madrid, Spain

---

Abstract

Neurofibromatosis-Noonan syndrome is an entity that combines both features of Noonan syndrome and Neurofibromatosis type 1. This phenotypic overlap can be explained by the involvement of the RAS-MAPK pathway (mitogen-activated protein kinase) in both disorders. We report the case of a 17-year-old boy with Neurofibromatosis 1 with Noonan-like features, who complained of the progressive appearance of blue-gray lesions on his back.

---

History

A 17-year-old boy presented with a 3 months history of pseudoatrophic blue-gray lesions on his back. At the age of 5, he had been clinically diagnosed with Neurofibromatosis 1 with Noonan-like features. The diagnosis was made based on the presence of more than six café-au-lait macules, multiple Lisch nodules and neurofibromas. Genetic studies showed the patient had the mutation c.7192-7193delCT on chromosome 17 (17q11.2). His parents and brother did not harbor the mutation, so it was considered a sporadic mutation. The presence of Noonan syndrome major criteria, such as macrocephalia, triangular face, low-set posteriorly rotated ears, strabismus, and short neck, along with slightly delayed psychomotor development and language, short stature, hypertrophic cardiomyopathy, and pectus carinatum, supported the diagnosis of Neurofibromatosis 1 with Noonan-like features. He also suffered from growth hormone deficiency for which he was receiving replacement treatment.

Physical examination

Figure 1	Figure 2

At close examination, over 20 slightly depressed, dome-shaped, blue-grayish macules with an atrophic surface were observed all over his back. These ranged from 0.5 to 2 cm in size and were soft on palpation. The tumors had been appearing progressively, without any symptoms.

Histopathology

Figure 3

Biopsy specimens showed a nonencapsulated spindle cell proliferation in the reticular dermis, which extended to subcutaneous tissue, within a myxoid stroma. The epidermis and papillary dermis were normal. These findings were consistent with the diagnosis of neurofibroma.

Comment

Neurofibromas are one of the diagnostic criteria of Neurofibromatosis type 1. They usually appear as soft, skin-colored, pedunculated or sessile, papules or nodules, with solitary, multiple or segmentary distribution. Pseudoatrophic-appearing macules are considered as one clinicopathological variant of neurofibroma [1, 2]. In fact Zeller et al, in their review of 583 patients with neurofibromatosis type 1, found only 44 patients (7.54%) who presented with these kind of lesions [3]. These neurofibromas can be present at birth or arise during puberty as soft, dome-shaped, blue-grayish macules or patches with an atrophic surface, predominantly over the trunk [1, 2, 3]. Histopathology studies reveal reduction of collagen bundles and elastic fibers in the reticular dermis with diffuse replacement by neuroid tissue [2, 3, 4]. In the papillary dermis, thick-walled blood vessels with wide lumina can be observed. The reduction in collagen bundles, could explain the pseudoatrophic clinical appearance of the lesions [1].

Neurofibromatosis-Noonan syndrome (NFNS) describes the association of features of Noonan syndrome and neurofibromatosis type 1 [5, 6]. The genetic origin of these entities is controversial. Most recent reports suggest that NFNS is a variety of NF1 based on the fact that mutations of the PTPN11 were not found, whereas NF1 gene mutations were the most frequent in these patients [7].

Noonan syndrome (NS) is an autosomal dominant disease with an incidence of 1 in 1000-2500 individuals [6]. Its diagnosis includes typical facies (triangular face, hypertelorism, low-set posteriorly rotated ears and thick helix, epicantus, strabismus), short stature, heart defects, thorax abnormalities, pulmonary stenosis, cryptorchidism, and bleeding anomalies, among other features. The mutation PTPN11 is the most frequently reported in 50 percent of cases. Other mutations reported are SOS1, RAF1, KRAS [6, 8].

Neurofibromatosis type 1 (NF1) has an incidence of 1 in 3000 and an autosomal dominant inheritance. Major criteria include more than six café-au-lait macules, Lisch nodules, axillary and inguinal freckling, and benign neurofibromas. Other clinical findings are optic glioma and skeletal abnormalities. It is caused by the mutation of gene NF1 [6, 8] (Table 1).

Overlapping features of NS and NF1 can be explained by a common pathogenic mechanism, dysregulation of the RAS-MAPK pathway, an important signaling pathway for cell proliferation, differentiation, survival and apoptosis (Table 2). RAS proteins (HRAS, NRAS and KRAS) are small guanosine-binding proteins, which act as signal switch molecules that integrate extracellular inputs and activate downstream effectors. In its GTP-bound form, RAS can activate several intracellular pathways, including the MAPK pathway. The number of different affected genes and the diversity of mutations within each gene are reflected in the variety of phenotypic features, leading to different syndromes [8]. These “RASopathies” share characteristic overlapping features including craniofacial dysmorphology, cardiac malformations and cutaneous, musculoskeletal and ocular abnormalities, varying degrees of neurocognitive impairment and, in some syndromes, an increased risk of developing cancer [9]. Clinical and molecular overlap also includes LEOPARD, Costello and cardio-facio-cutaneous syndrome [6, 8]. In contrast with the higher malignancy potential of somatic mutations in RAS/MAPK components, as in bladder cancer or melanoma, germline mutations have presented more variable effects that depend on which specific genes are affected. Patients with Costello syndrome are predisposed to rhabdomyosarcoma, ganglioneuroblastoma and bladder cancer because of germline HRAS mutations, whereas patients with NF1 mutations frequently present with neurofibromas and show an increased risk of neurofibrosarcoma, astrocytoma, pheochromocytoma, and juvenile myelomonocytic leukemia. NS patients principally exhibit an increase in the prevalence of juvenile myelomonocytic leukemia and multiple giant cell lesions (MGCL), although both conditions affect only a small percentage of patients [8].

References

1. Westerhof W, Konrad K. Blue-red macules and pseudoatrophic macules: additional cutaneous signs in neurofibromatosis. Arch Dermatol 1982;118(8):577-81. [PubMed]

2. Chiu CS, Wang JD, Yen CY, et al. Pseudoatrophic macules associated with neurofibromatosis-1. Pediatr Dermatol 2009;26(2):231-2. [PubMed]

3. Piqué E, Olivares M, Fariña MC, et al. Pseudoatrophic macules: a variant of neurofibroma. Cutis. 1996 Feb;57(2):100-2. [PubMed]

4. Zeller J, Wechsler J, Revuz J, et al. Blue-red macules and pseudoatrophic macules in neurofibromatosis 1. Ann Dermatol Venereol 2002;129(2):180-1. [PubMed]

5. Thiel C, Wilken M, Zenker M, et al. Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome. Am J Med Genet A 2009;149A(6):1263-7. [PubMed]

6. Nystrom AM, Ekvall S, Allanson J, et al. Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1. Clin Genet 2009;76(6):524-34. [PubMed]

7. De Luca A., Bottillo I., Sarkozy A. et al. NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis-Noonan Syndrome. Am J Hum Genet 2005; 77:1092-1101.

8. Jorge AA, Malaquias AC, Arnhold IJ, et al. Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res 2009;71(4):185-93. [PubMed]

9. Tydiman W. E., Rauen K. A. The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009 June ; 19(3): 230-236.

10. Hüffmeier U, Zenker M, Hoyer J, et al. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet Part A 140A:2749-2756.

© 2011 Dermatology Online Journal