Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype-phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects.     

SOS1: a new player in the Noonan-like/multiple giant cell lesion syndrome

Noonan-like/multiple giant cell lesion syndrome is a rare condition with phenotypic overlap with Noonan syndrome (NS) and cherubism. PTPN11 gene mutations were described in several individuals with this phenotype, and it is recently considered as a variant phenotype of NS. Gain-of-function mutations in the SOS1 gene were recently described as the second major cause of NS. Here, we report for the first time the involvement of SOS1 gene in a family with the Noonan-like/multiple giant cell lesion phenotype.     

SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

We report five cases of multiple giant cell lesions in patients with typical Noonan syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) syndrome before the molecular definition of Noonan syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and p.Arg552Thr). The latter are the first SOS1 mutations reported outside PTPN11 in NL/MGCL syndrome. MGCL lesions were observed in jaws (‘cherubism'') and joints (‘pigmented villonodular synovitis''). We show through those patients that both types of MGCL are not PTPN11-specific, but rather represent a low penetrant (or perhaps overlooked) complication of the dysregulated RAS/MAPK signaling pathway. We recommend discarding NL/MGCL syndrome from the nosology, as this presentation is neither gene-nor allele-specific of Noonan syndrome; these patients should be described as Noonan syndrome with MGCL (of the mandible, the long bone…). The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan syndrome, with or without mutations of the SH3BP2 gene.     

Hybrid central giant cell granuloma and central odontogenic fibroma-like lesions of the jaws

Ten lesions from eight cases are presented of a rare intra-osseous jaw lesion with the combined histological features of giant cell granuloma and central odontogenic fibroma. Lesions arose over a wide age range and presented as monolocular or multilocular radiolucencies with cortical expansion and, in one case, perforation. Two lesions recurred after curettage, one being eradicated by a second curettage and one by conservative excision. Histologically, zones of typical giant cell granuloma lay in a fibrous stroma containing islands, strands and clusters of epithelial cells. Islands often contained duct-like spaces or hyaline basement membrane globules. Trabeculae of osteoid were present in five lesions. Recurrent lesions showed features identical to the initial lesion, including recurrence of the prominent epithelial component. These features cannot be conclusively ascribed to a variant of either giant cell granuloma, central odontogenic fibroma or aneurysmal bone cyst, but the clinical features are slightly more suggestive of giant cell granuloma. Attention is drawn to the characteristic and potentially confusing histological appearances. The presence of giant cell granuloma-like areas in central odontogenic fibroma-like lesions is associated with an increased risk of recurrence following curettage.     

Myofibroblasts in central giant cell granuloma of the jaws: an ultrastructural study

The ultrastructure of stromal mononuclear cells and giant cells were studied in two cases of central giant cell granuloma of the jaws. The majority of stromal cells superficially resembled fibroblasts, but also contained intracytoplasmic myofilaments with electron dense bodies similar to smooth muscle cells. These cells were referred to as myofibroblasts. The other type of mononuclear cells resembled macrophages. Many of the myofibroblast type cells appeared close to giant cells and signs of early fusion between them could be demonstrated. It is suggested from these results that the giant cells in central giant cell granuloma form and increase in size through fusion of these cells.     

Are Noonan syndrome and Noonan‐like/multiple giant cell lesion syndrome distinct entities?

We report on a family with typical clinical findings of Noonan syndrome associated with giant cell lesions in maxilla and mandible.We discuss the obvious clinical overlap between Noonan syndrome and Noonan‐like/multiple giant cell lesion syndrome, and we give further clinical and molecular support that these two entities could be allelic conditions. © 2001 Wiley‐Liss, Inc.     

Malignancy in Noonan syndrome and related disorders

Noonan syndrome (NS) and related disorders, such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, and Costello syndrome, constitute an important group of developmental malformation syndromes with variable clinical and molecular features. Their underlying pathophysiologic mechanism involves dysregulation of the Ras/mitogen‐activated protein kinase signaling pathway, an essential mediator of developmental and growth processes in the prenatal and postnatal setting. Malignant tumor development is an important complication encountered in other RASopathies, such as neurofibromatosis type 1, but the neoplastic risks and incidence of malignant tumors are less clearly defined in NS and related disorders of the Noonan spectrum. Malignant tumor development remains an important complication variably seen in the RASopathies and, thus, a clear understanding of the underlying risks is essential for appropriate clinical care in this patient population. This review discusses previously published reports of malignancies in individuals with RASopathies of the Noonan spectrum.     

Cytologic features of central giant-cell granuloma of the jaw

In this present series, we studied in detail the cytologic features of five histopathologically verified cases of central giant-cell granuloma (CGCG). All the patients in this series were female, with an age range of 11-60 years. There were three cases with involvement of the lower jaw and two cases had upper jaw involvement. Cytology smears showed dispersed single cells in the background. Nuclei of the individual cells were round to ovoid with fine chromatin and inconspicuous nucleoli. The cytoplasm of these cells was moderate in amount with indistinct cell borders. Many randomly scattered multinucleated giant cells with 10-20 nuclei were present in the background. Combination of clinical features, radiologic pictures, and cytologic features may be helpful for diagnosis of CGCG on fine-needle aspiration cytology.     

Phenotypic characterization of mononuclear and multinucleated cells of giant cell reparative granuloma of small bones

Four cases of giant cell reparative granuloma (GCRG) of small bones were analysed in order to determine the pathogenesis of the lesion and the nature of the component mononuclear and multinucleated cells. In cell cultures, giant cells formed a non-proliferating homogeneous population which expressed features characteristic of the osteoclast phenotype, including leucocyte common antigen, CD68, vitronectin receptor, and tartrate-resistant acid phosphatase. The giant cells were capable of lacunar resorption and their activity was inhibited by calcitonin. In addition to numerous macrophage-like cells, some of which expressed osteoclast phenotypic characteristics, there were also mononuclear stromal cells which proliferated in culture and were alkaline phosphatase-positive; these cells expressed receptor activator of NF-kappaB ligand (RANKL) and were capable of supporting human osteoclast formation from circulating precursors in vitro. These findings suggest that the osteoclast-like giant cells in GCRG of small bones are formed from monocyte/macrophage-like osteoclast precursors which differentiate into osteoclasts under the influence of mononuclear osteoblast-like stromal cells.     

Classical Noonan syndrome is not associated with deletions of 22q11

Deletions of 22qll cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22qll deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22qll deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22qll deletion. A 2-month-old infant with several findings suggestive of NS did have a 22qll deletion, suggesting that a small number of 22qll deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. © 1995 Wiley-Liss, Inc.     

Patient with del(12)(q12q13.12) manifesting abnormalities compatible with Noonan syndrome

We report on a Japanese boy with interstitial deletion of chromosome 12q12–q13.12, who had multiple congenital anomalies with severe psychomotor retardation. Most of the clinical manifestations were compatible with Noonan syndrome phenotype except for the absence of cardiac defects. Severe mental retardation and intrauterine onset of growth retardation may have been due to the chromosomal deletion. The interstitial deletion does not overlap a putative Noonan syndrome locus, which was recently assigned to 12q22–qter by linkage analysis. Although correlation between the phenotype and del(12)(q12q13.12) was not confirmed, because this is the first report of deletion of proximal 12q, the deleted segment may contain another Noonan syndrome locus. Am. J. Med. Genet. 75:416-418, 1998. © 1998 Wiley-Liss, Inc.     

Locally aggressive orbital giant cell reparative granuloma in an infant: case report and literature review

Giant cell reparative granuloma (GCRG) is a non-neoplastic hyperplasia of bones that mostly happens in the mandible and maxilla in any age group but has a predilection for children and young adults. GCRGs that cause bone destruction are of very low frequency. Orbital-involved cases have been rarely reported since 1981, especially in children. We now report a 1-year-old girl with a rapidly enlarging post-traumatic orbital mass. CT scan and surgical resection showed a well-defined mass occupying the upper right orbit, causing bone destruction. Microscopically there was a proliferation of histocytes and some osteoclast-like multinucleated giant cells with hemosiderin, finally confirmed to be GCRG. 22 months’ follow up showed no evidence of recurrence. This case suggests infant orbital GCRG can be locally aggressive.     

伴破骨细胞样巨细胞或反应性肉芽肿的乳腺癌

目的 探讨伴破骨细胞样巨细胞或反应性肉芽肿的乳腺癌的临床病理特点。方法 复习11例伴破骨细胞样巨细胞的乳腺癌（carcinoma with osteoclastic giant cells,COGC）和8例伴反应性肉芽肿的乳腺癌（carcinoma with responsive granuloma,CRG）的临床病理资料,部分病例行免疫组化染色和特殊染色。结果 COGC患者平均年龄40.6岁,CRG患者平均年龄53.6岁,均因发现乳腺包块就诊。COGC多呈界限清楚的结节状,切面多为灰红、灰褐色。COGC肿瘤类型包括浸润性导管癌5例、浸润性乳头状癌、浸润性微乳头状癌和浸润性筛状癌各2例。肿瘤内破骨细胞样巨细胞大小形态各有差异,分布弥散或不均匀,与肿瘤细胞关系密切。肿瘤间质内尚见不同程度的新旧出血、血管和纤维组织增生。腋窝淋巴结癌转移灶保留原发灶的形态学特点。CRG形态多不规则,切面多为灰白色。肿瘤类型均为浸润性导管癌,伴随出现的肉芽肿多密切围绕在癌巢周围,由上皮样细胞和朗汉斯型巨细胞构成。抗酸染色和六胺银染色无阳性发现。进行免疫组化染色病例的破骨细胞样巨细胞和肉芽肿均呈CD68（KP1和PGM1）阳性,S-100蛋白和Ⅷ因子呈阴性。CD34染色显示COGC的微血管密度为（21.9±4.2）/HPF,与对照组浸润性导管癌无明显差异（P〉0.05）。获得随访资料的6例COGC和2例CRG在随访期内无复发、转移或死亡。结论 乳腺COGC和CRG均属少见肿瘤,前者的大体和组织学具有一定的特异性。破骨细胞样巨细胞和肉芽肿出现的预后意义尚需积累更多的病例进行分析。     

RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis

We report the case of a 14 years and 8 months girl, who is the first child of nonconsanguineous parents, with short stature, obstructive hypertrophic cardiomyopathy, multiple facial lentigines, high and wide forehead, downslanting palpebral fissures, low‐set ears, short neck, and pectus excavatum; all features suggestive of Noonan syndrome with multiple lentigines (NSML). In addition, the patient exhibited craniosynostosis. Molecular analysis of rats sarcoma (RAS)/mitogen‐activated protein kinase (MAPK) pathway genes with high‐resolution melting curve analysis followed by sequencing showed a RAF1 amino acid substitution of valine to glycine at position 263 (p.V263G). The present report provides clinical data regarding the first association of a RAF1 variant and craniosynostosis in a patient with clinical diagnosis of NSML.     

Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association

A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 pheno-types was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family. © 1996 Wiley-Liss, Inc.     

Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.     

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next-generation sequencing

Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a ‘landscaping effect’, with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.