Association of segmental neurofibromatosis 1 and oculo-auriculo-vertebral spectrum in a 24-year-old female

ARTICLE

Auteur(s) : Marco Castori¹, Silvia Majore¹, Francesco Romanelli², Biagio Didona³, Paola Grammatico¹, Giovanna Zambruno⁴

¹Medical Genetics, Experimental Medicine Department, University La Sapienza, S. Camillo-Forlanini Hospital, Circonvallazione Gianicolense 87, 00152 Rome, Italy
²Medical Pathophysiology Department, University La Sapienza, Viale del Policlinico 155, 00161 Rome, Italy
³I Division of Dermatology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy
⁴Laboratory of Molecular and Cell Biology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy

accepté le 29 Août 2007

Neurofibromatosis 1 (NF1) is an autosomal dominant multisystemic disorder with a birth incidence of 1:2,500 and a minimum prevalence of 1:4,000-5,000. It is caused by germline mutations in the NF1 gene, mapping to 17q11.2 [1]. In contrast, segmental NF1 (SNF1) is a rarer condition, which occurs in 1:36,000-40,000 individuals and is usually characterized by the regionally limited distribution of NF1 skin lesions [2]. The original hypothesis by Crowe et al. (1956) [3] that SNF1 may result from NF1 somatic mutations arising after conception in the developing embryo has recently been substantiated at the molecular level [4]. While there is a consensus statement concerning the minimum diagnostic criteria for generalized NF1 [5], the diagnosis of SNF1 is essentially based on multiple specific pigmentary changes (i.e. multiple café-au-lait spots, freckling) and/or neurofibromas intermingled with areas of otherwise healthy skin, often configuring specific mosaic patterns.

Oculo-auriculo-vertebral spectrum (OAVS), including Goldenhar syndrome, is the most common first and second branchial arch malformation syndrome, affecting approximately one in 5,600 individuals [6]. OAVS primarily involves aural, oral and mandibular development. Its clinical spectrum is extremely wide and the main clinical features comprise external ear anomalies, ranging from anotia to preauricular tags, conductive/neurosensorial hearing loss, epibulbar dermoids, mandibular hypoplasia, a variable degree of facial asymmetry, and axial skeleton anomalies, including cervical and upper thoracic metamere malformations [7]. OAVS is both etiologically and pathogenetically heterogeneous. In fact, chromosomal imbalances, mendelian mutations as well as environmental factors have been equally evoked to explain the wide spectrum of anomalies observed in this condition [8]. However, only a fragmented picture has emerged to date about the biological basis of OAVS and no causative gene has been identified so far.

Here, we report a 24-year-old female presenting a constellation of features fitting with both SNF1 and OAVS. To the best of our knowledge, this association has never been reported in the literature.

Case report

Physical examination revealed marked facial asymmetry with left mandibular hypoplasia. The ears were not significantly malformed, although two small preauricular tags were noted on the right one (figure 1A). On the left cheek, the surgical scar was still visible (figure 1B) and a deep cartilagineous remnant of the preauricular tag could be appreciated by palpation. Exploration of the oral cavity demonstrated the presence of a non-traumatic substance defect affecting the left margin of the tongue, most likely secondary to localized muscle hypoplasia (figure 1C). A large light brown lesion extending over the left scapular region, homolateral shoulder, breast and hemi-abdomen with indented margins and sharp midline demarcation was evident (figure 2A and B). Intense freckling on the left axilla extended beyond the anterior axillary fold to the thoracic skin, where it was intermingled with the huge hyperpigmented patch (figure 2C and D). Six round/oval café-au-lait spots with a diameter over 15 mm were present along the left arm (figure 2D and E). The rest of the body surface was unaffected and there was no evidence of neurofibromas. The proband also presented scoliosis associated with a considerable lower limb asymmetry (i.e. left leg 2.5 cm shorter than the right one).

A skull X-ray demonstrated marked hypoplasia of the left hemimandibula particularly affecting the ramus, without involvement of the homolateral maxillary bone (figure 3A). This finding was confirmed by radiographic orthopanoramic (figure 3B). Spine roentgenographic exam disclosed multiple costo-vertebral anomalies mainly involving the cervical and thoracic metameres and including C2-C3 vertebral block, the presence of an additional cervical vertebra fused with T1, thirteen pair of ribs, posterior arch schisis of C6 and T2, and a malformed lumbar vertebra resulting from the fusion of L3 with a right hemivertebra below (i.e. semisegmented hemivertebra; figure 4). Neurosensorial hearing loss exclusively affecting the left ear was demonstrated by audiological investigation. Ophthalmologic surveys, including fundoscopy and slit-lamp examination, heart, abdominal and kidney ultrasounds were all negative. Peripheral lymphocyte karyotype at 400-band level on 100 metaphases resulted normal female.

Discussion

A late postzygotic NF1 mutation can easily explain the localized café-au-lait spots and axillary freckling observed in our patient. In addition, the flag-like distribution of the huge hyperpigmented patch may be interpreted either as a large atypical café-au-lait spot, or as the mosaic manifestation of the background skin pigmentation, usually observed in generalized NF1. The identification of the causative NF1 mutation in SNF1 patients is complicated by several factors. In fact, clinical manifestations of SNF1 are extremely variable and the predominance of either pigmentary lesions or neurofibromas most likely depends on the cell type (s) bearing the mutation. In particular, it has been postulated that in SNF1 with isolated pigmentary changes, the mutation could be limited to melanocytes and/or keratinocytes [2, 9]. Moreover, the proportion of mutated cells may be so low that DNA analysis from cultured fibroblasts/keratinocytes could not be adequate to seek evidence for mosaicism and cell cloning with allele-specific polymerase chain reaction might be required [10]. Unfortunately, in the present case, we have not been able to confirm the mosaicism molecularly because the patient refused a skin biopsy.

In two SNF1 patients, the affected segment appeared smaller than the unaffected body counterpart [2, 4]. It has been speculated that the regional hypoplasia may reflect the localized effect of the mutated NF1 gene on body growth, as demonstrated by the frequent final height reduction in generalized NF1. In our patient, the hemimandibular, tongue and lower limb hypoplasia is homolateral to the SNF1 manifestations. However, these structures did not display any pigmentary lesion and, therefore, a direct influence of NF1 mutation on their development is unlikely. Moreover, preauricular skin tags and vertebral segmentation defects do not belong to the phenotypic manifestations of this gene. In particular, spine malformations observed in our patient are clinically and radiographically distinct from those causing dystrophic scoliosis in generalized NF1 [11]. Thus, the pleiotropic action of NF1 could not explain the entire spectrum of abnormalities reported in this case.

The hypothesis that our patient is affected by two distinct genetic disorders (i.e. SNF1 and OAVS) is very probable. However, their spatial relationship (i.e. the co-occurrence of SNF1, hemimandibular and tongue hypoplasia, as well as more severe ear anomalies on the same body side) might underlie a common etiopathogenetic mechanism. Oculo-auriculo-vertebral spectrum is a developmental field defect which occurs early in blastogenesis (i.e. during the 2^nd-4^th gestational week) and recognizes a wide spectrum of genetic and environmental causes [12]. This condition has occasionally been associated with chromosome mosaicism, such as mosaic trisomy 7, 9, 18 and 22 [13-16], thus suggesting that, at least in a proportion of cases, it may be caused by a postzygotic mutation. On a pathogenetic perspective, some authors suggested that OAVS craniofacial anomalies may be considered as the consequence of an abnormality of neural crest cell migration into the developing first and second branchial arches [8, 17]. Therefore, in the present patient, most, if not all, of the observed anomalies could be related to the dysfunction of cells derived from the same embryonic structure, as, admittedly, melanocytes also derive from neural crests. According to this hypothesis, a single postzygotic mutational event, such as a two-breakpoint chromosome abnormality (e.g. reciprocal translocation, or deletion) or an epigenetic mutation, has simultaneously involved NF1 and a second, still unknown gene responsible for the OAVS phenotype. Interestingly, a patient presenting localized multiple neurofibromas in close proximity with a nevus sebaceous of Jadassohn has been described [18], suggesting that the coexistence of SNF1 and other entities caused by post-zygotic mutations could be underestimated.

A further causal relationship for the association of SNF1 and OAVS could be considered in our patient. Oculo-auriculo-vertebral spectrum is etiologically heterogeneous and, in selected cases, might result from an in utero disruptive vascular event [8, 19]. On the other hand, it is well known that the NF1 phenotype may also include vascular anomalies, such as congenital heart disease. Moreover, alterations of vascular field formation during early embryogenesis have been evoked to explain the relatively high frequency of structural abnormalities in this condition [20]. Therefore, it might be hypothesized that, in our patient, a NF1 postzygotic mutation has interacted with additional genetic and/or non-genetic factor (s) capable of directly influencing angiogenesis, and, thus, facilitating the occurrence of OAVS features on the same body side.

Finally, it is also possible that the concurrent observation of SNF1 and OAVS in the same patient is occasional. However, if we combine the overall frequency of OAVS and SNF1 in the general population, the probability of an occasional association is 1:201,600,000. Moreover, if we consider that OAVS is more pronounced on the left body side (as observed in our patient) in only 33% cases [6] and that, in case of an occasional association, SNF1 may involve either body halves with the same frequency (i.e. 50%), this probability lowers to 1:1,209,600,000. Given this extreme rarity, our patient might truly represent the first reported example of this occasional association. However, she received the proper diagnosis only in her thirties, thus suggesting that the co-occurrence of SNF1 and OAVS could be overlooked, especially in younger patients and a possible etiopathogenetic link between these two sporadic conditions cannot be excluded. Future studies are needed to confirm this hypothesis, which, at the moment, is entirely based on clinical evidence.
Table 1 Clinical features of the present patient

^bThe clinical manifestations of oculo-auriculo-vertebral spectrum also include a wide range of non-specific cephalic and extracephalic malformations (mainly affecting radius, heart, genitourinary and central nervous systems).

Acknowledgements

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