Neurofibromatosis Type 1 With Cherubism-like Phenotype, Multiple Osteolytic Bone Lesions of Lower Extremities, and Alagille-syndrome: Case Report With Literature Survey

Abstract

Background/aim: Neurofibromatosis type 1 (NF) is an autosomal dominant hereditary disease. The cardinal clinical findings include characteristic skeletal alterations. Difficulties in diagnosis and therapy can arise if an individual has further illnesses.

Case report: This is a case report of a 16-year-old patient affected by NF1. She also suffered from Alagille syndrome and the consequences of fetal alcohol exposure. The patient's facial phenotype showed findings that could be assigned to one or more of the known diseases. The patient was referred for treating a cherubism-like recurrent central giant cell granuloma (CGCG) of the jaw. The patient developed bilateral, multilocular non-ossifying fibromas (NOF) of the long bones of the lower extremity. Treatment of the skeletal lesions consisted of local curettage. While NOF regressed after surgery, the CGCG of the jaw remained largely unchanged. Extensive genetic tests confirmed a previously unknown germline mutation in the JAG1 gene, the germline mutation of the NF1 gene, and the somatic mutation in the NF1 gene in the diffuse plexiform neurofibroma, but not in the CGCG.

Conclusion: Assigning facial findings to a defined syndrome is ambiguous in many cases and especially difficult in patients who have multiple diseases that can affect the facial phenotype. Surgical therapy should be adapted to the individual findings.

Keywords: Alagille syndrome; Jaffe-Campanacci syndrome; Neurofibromatosis type 1; central giant cell granuloma; central giant cell lesion; cherubism; non-ossifying fibroma; root resorption.

Figure 1. Clinical findings in a patient with NF1 and cherubism-like phenotype. (A) View en face from below. The bilateral cheek swelling is noticeable. The photograph reveals tumorous protrusions on the right margin of the lower jaw next to the chin, broad glabella, hyperpigmentation of the eye lids and multiple small lentigines with perioral accumulation. (B) View from the side shows prominent glabella, flat nose and lips, flattened philtrum, and mandibular tumorous protrusion. (C) Dorsal view of the patient shows further pigmentation disorders and the crooked position of the hips. (D) A diffuse plexiform neurofibroma of the right forearm is depicted prior (D) and after (E) surgical intervention. (F) The oral mucosa has scarred after several surgical interventions and is otherwise normal. The dark discolored upper right central incisor is non-vital after dental trauma. (G) Oral aspect after detachment of the vestibular mucosa and excavation of the soft tissue tumor. Note the significantly thinned cortical bones. Figure (H) shows a representative specimen of the bone tumors.

Figure 2. Magnetic resonance images of patient with NF1 and cherubism-like phenotype. (A) Coronal view shows bilateral nodular neurofibroma of the neck arranged in string-like pattern. (B) Axial view shows bilateral inhomogeneous enhancement of mandibular cancellous bone. Expansion of the lesion is noticeable on the right side. Signal hyperintensities are obvious in adjacent buccal soft tissues. (C) Coronal view shows basal nodular lesions. (D) Coronal view shows expansion of lesions in both mandibular angles and rami. (E) Adjacent skull base is not affected by lesions.

Figure 3. Cone beam computed tomography of midfacial region in a patient with NF1 and cherubism-like phenotype. (A) The coronal projection shows the deformation of the orbital floor on the right side, intact orbital floor and soft tissue tumor present directly adjacent to the bone at this site. (B) The superior, medial, and lateral borders of the orbits have developed symmetrically. The lesion infiltrates the lateral maxillary sinus wall on the right side. A small, circumscribed soft tissue-equivalent radio-translucent lesion complementary to the bone lesion bulges in the right maxillary sinus. However, the entire sinus system is ventilated. (C) In the surface reconstruction of the midface bones, the extensive osteolysis on both sides becomes evident. The figure illustrates the asymmetry of the orbit at the entrance, which is characterized by a narrower vertical dimension and an approximately horizontally oriented oval compared to the unaffected left side.

Figure 4. A series of panoramic views illustrates bone remodeling in a patient with NF1 and cherubism-like phenotype during a period of six and a half years. (A) Extensive, inhomogeneous osteolysis of the jaws with intact radiological morphology of the teeth. When comparing Figure (A) to (C), the bubble-like osteolysis of the mandibular angle and apical region of the inferior right wisdom tooth 48 was conspicuous at the initial examination (A). However, the bone re-ossifies in the further course following surgical reduction of CGCG (B, C). On the other hand, the osteolysis around the lower left second molar increased in size within three years (D-G), without any effect on tooth position and integrity. However, within a further two years, the bone ossified, especially in the interradicular area of teeth 36 and 37 and further caudal to these molars. The tilting of the retained tooth 38 and the wisdom tooth’ approximation to the second molar took place at the end of the osteolytic phase and continued during the consolidation phase of the bone in the left jaw angle (G, H). The sequence of the X-ray images (A-H) shows that repeated curettage of the tumor from the right-sided basal expansion of the lower jaw had no long-lasting effect on bone shape.

Figure 5. Cone beam computed tomograms of maxilla in a patient with NF1 and cherubism-like phenotype. Figure (A) shows the traumatized tooth 11, which developed resorptions of the root after repositioning and integration in the dental arch. Bone-isointense radiopacity is almost completely absent in the anterior dentoalveolar area and only shown in continuity in narrow traces on the floor of the nose. (B) Extensive osteolysis of the maxilla extends to the floor of the nose on both sides, and a thin line of alveolar bone is evident around the molars, without the internal framework of the skeleton being destroyed (C). (D) The histological image shows the invasive growth of the lesion with prominent osteoclasts at the interface between the lesion and bone (Goldner staining).

Figure 6. Radiological findings of bilateral non-ossifying fibroma of lower extremities. (A) and (B) Plain radiographs of the distal femur, upper tibia and fibula region depict an oval subcortical radio-translucent lesion in both the femora and right tibia adjacent to epiphyses. Lesions present with a sclerotic margin. In the region of maximum horizontal diameter of both femoral lesions, the contour of the bone appears somewhat bulging outwards. On magnetic resonance imaging (C and D), hyperintense lesions of the femora are prominent on T2-weighted images (C). T1 weighted images show intact cortical layer of the bones.

Figure 7. Histology of CGCG. Giant cell granuloma in neurofibromatosis 1: (A) hematoxylin and eosin (H&E) stain reveals a proliferation of spindle cells intermingled with small histiocytic elements and giant cells; (B) immunohistochemically demonstration of smooth muscle actin (SMA, brown stain) in spindle cells (not shown: expression of vimentin, no expression of S100 protein, EMA, CD34 and desmin); (C) demonstration of CD68 in small histiocytic elements and giant cells; (D) demonstration of a proliferation index of 5.8% in fibrohistiocytes using Ki67-antibodies, no labelling of giant cells; scale in (A)=100 μm also applies for pictures (B-D).

Figure 8. Dermal neurofibroma with predominantly diffuse growth and scattered intraneural plexiform tumor parts: (A) over-view depicting a diffusely growing tumor composed of cells expressing S100 protein (brown stain) with occasional circumscribed tumor areas indicating intraneural growth (upper right); (B) S100 protein immunohistochemistry as in A, demonstrating the plexiform tumor portion at a higher magnification; (C) demonstration of an intact perineurium surrounding the intraneural tumor parts with antibodies against epithelial membrane antigen (ring shaped brown stain); (D) detection of scattered residual axons within the plexiform tumor areas with antibodies against neurofilament (brown dots); scale bars in A and B=100 μm, scale in B also applies for C and D.