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Gardner syndrome (GS) is a specific form of familial adenomatous polyposis (FAP), which manifests as colorectal polyps, multiple osteomas and soft tissue tumors, and in the oral cavity as osteomas of the jaws, odontomas, and abnormal tooth counts. The underlying cause of GS is attributed to mutations in the APC gene. Mutations in this gene disrupt the normal functioning of the protein and lead to the development of GS. To further investigate GS, a family affected by the syndrome was selected from Dongguan, Guangdong Province. The family members underwent a comprehensive survey, which involved collecting clinical data and peripheral venous blood samples. The samples were then used for genetic analysis. Whole exome sequencing (WES) and Sanger sequencing techniques were utilized to screen and identify specific mutation sites in the APC gene. The clinical findings for the GS family included the presence of gastrointestinal polyps and odontomas. After analyzing the genetic sequencing results, a novel mutation site c.4266dupA on the APC gene was found in the patients, which leading to the APC protein truncation. As a result of this study, it is suggested that odontoma may be an early indicator of GS. Additionally, the identification of this novel mutation site in the APC gene expands the known spectrum of genetic mutations associated with the disease. This discovery has significant implications for the early diagnosis of GS, thus enabling timely intervention to reduce the risk of developing colon cancer and other related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small subset of cases is associated with Gardner syndrome, a phenotypic variant of familial adenomatous polyposis caused by mutations in the APC gene resulting in aberrant activation of WNT/β-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding β-catenin) in 22 of 36 cases (61.1%), harbouring allelic frequencies ranging from 0.04 to 0.53, with the known S45P variant representing the most frequent alteration. Based on NanoString multiplex expression profiling performed in a subset of cases, CTNNB1-mutated osteomas segregated in a defined "WNT-cluster", substantiating functionality of CTNNB1 mutations which are associated with β-catenin stabilization. Our findings for the first time convincingly show that osteomas represent genetically-driven neoplasms and provide evidence that aberrant WNT/β-catenin signaling plays a fundamental role in their pathogenesis, in line with the well-known function of WNT/β-catenin in osteogenesis. Our study contributes to a better understanding of the molecular pathogenesis underlying osteoma development and establishes a helpful diagnostic molecular marker for morphologically challenging cases., (© 2021. The Author(s).)

Bone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular mechanisms behind these tumours, including the group of bone forming tumours (osteoma, osteoid osteoma, osteoblastoma and osteosarcoma). Increased knowledge on the molecular mechanism could help to identify novel diagnostic markers and/or treatment options. Osteoid osteoma and osteoblastoma are bone forming tumours without malignant potential that have overlapping morphology. They were recently shown to carry FOS and-to a lesser extent-FOSB rearrangements suggesting that these tumours are closely related. The presence of these rearrangements could help discriminate these entities from other lesions with woven bone deposition. Osteosarcoma is a malignant bone forming tumour for which different histological subtypes are recognised. High-grade osteosarcoma is the prototype of a complex karyotype tumour, and extensive research exploring its molecular background has identified phenomena like chromothripsis and kataegis and some recurrent alterations. Due to lack of specificity, this has not led to a valuable novel diagnostic marker so far. Nevertheless, these studies have also pointed towards potential targetable drivers of which the therapeutic merit remains to be further explored.

Familial adenomatous polyposis patients often present with non-malignant extra-intestinal manifestations which include dental anomalies that may be evident prior to the appearance of the colonic adenomas. The aims of this study were to describe the prevalence and type of dental anomalies and the relationships between gene mutations and dental anomalies in these patients. Twenty-two pediatric familial adenomatous polyposis patients and 46 controls, who were age and gender matched participated. Familial adenomatous polyposis patient's had a dental examination with panoramic radiograph and medical record review for age at diagnosis, the presence of the adenomatous polyposis coli gene mutation, and determination of other extra-intestinal manifestations on the body. The control group was identified from a retrospective chart review and selected if there was a current panoramic radiograph. The only significant difference between familial adenomatous polyposis patients and controls were the presence of jaw osteomas and sclerosis (p = .0001). Patients with a mutation in, or upstream of codon 1309 had a higher frequency of osteomas (77.8%) and jaw-bone sclerosis (44.4%), and 77% of these had at least one dental anomaly. This preliminary study showed an association between a genetic variant at, or upstream of codon 1309, and radiographic dental anomalies.

Introduction: Craniopharyngioma accounts for around 3% of all primary tumours of the central nervous system. It is usually located in the suprasellar region, although it may also have an ectopic location., Case Report: The case is presented on 29 year-old male who underwent surgery for a jaw osteoma when he was 19 years old and was subsequently diagnosed with Gardner's syndrome. He was admitted in our Hospital with right facial paresis and diplopia of one day onset. The examination showed mild right VII and VI cranial nerves paresis. Magnetic resonance imaging of the brain demonstrated a rounded solid and cystic lesion with well-defined contours of about 2cm in diameter filling the fourth ventricle. The patient underwent a posterior fossa craniotomy using a telovelar approach with complete removal of the tumour implanted at roof level of the fourth ventricle. The final histology of the tumour was reported as adamantinomatous craniopharyngioma., Conclusion: Craniopharyngioma may appear in another location other than the suprasellar region. Its atypical location may be related to Gardner syndrome by still unknown pathogenic mechanisms., (Copyright © 2016 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.)

Mutant mouse models are indispensable tools for clarifying the functions of genes and elucidating the underlying pathogenic mechanisms of human diseases. We carried out large-scale mutagenesis using the chemical mutagen N-ethyl-N-nitrosourea. One specific aim of our mutagenesis project was to generate novel cancer models. We screened 7012 animals for dominant traits using a necropsy test and thereby established 17 mutant lines predisposed to cancer. Here, we report on a novel cancer model line that developed osteoma, trichogenic tumor, and breast cancer. Using fine mapping and genomic sequencing, we identified a point mutation in the adenomatous polyposis coli (Apc) gene. The Apc1576 mutants bear a nonsense mutation at codon 1576 in the Apc gene. Although most Apc mutant mice established thus far have multifocal intestinal tumors, mice that are heterozygous for the Apc1576 mutation do not develop intestinal tumors; instead, they develop multifocal breast cancers and trichogenic tumors. Notably, the osteomas that develop in the Apc1576 mutant mice recapitulate the lesion observed in Gardner syndrome, a clinical variant of familial adenomatous polyposis. Our Apc1576 mutant mice will be valuable not only for understanding the function of the Apc gene in detail but also as models of human Gardner syndrome., (© 2013 Japanese Cancer Association.)

Objective: Gardner syndrome (GS) is an autosomal dominant genetic disorder with almost complete penetrance (80%) and variable expression. GS is a variant of familial adenomatous polyposis and characterized by extracolonic manifestations including osteomas and soft tissue tumors (desmoid tumors, epidermoid cysts). We describe clinical and surgical approaches in a family in which the genetic disorder was diagnosed in 3 generations., Study Design: The studied family underwent clinical history and instrumental and genomic studies. Two members of this family, affected with GS, underwent surgery for skeletal osteomas., Results: The patients that we treated with clinical-instrumental monitoring for a period of 5 years had no major disturbances of the stomatognathic system and no clinical signs of pathology of the gastrointestinal tract, eyes, or endocrine systems., Conclusions: The orofacial complex disorders are exclusively functional and esthetic, concerning primarily the stomatognathic system. We had no cases of malignant transformation of osteomatosis lesions. Clinical sequelae are manly facial eumorphy and occlusion problems of the temporomandibular joint., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We report a case of osteoma cutis associated with a GNAS mutation in a 7-month-old boy. The patient displayed no other laboratory or physical abnormalities to suggest other GNAS-associated disorders of cutaneous ossification, including Albright's hereditary osteodystrophy or pseudohypoparathyroidism 1A, although a history of intrauterine growth restriction was troubling for progressive osseous heteroplasia. A review of the clinical and laboratory manifestations of these disorders is discussed, as well as differentiating features., (© 2012 Wiley Periodicals, Inc.)

Plate-like osteoma cutis is a rare disorder that has been historically classified as a congenital syndrome. It has a possible relationship to a mutation in the gene (GNAS1) that encodes the α-subunit of the stimulatory G protein, which regulates adenyl cyclase activity. We report a case of extensive plaque-like masses on the scalp and face with no abnormalities in calcium or phosphate metabolism and no preceding inflammatory cutaneous conditions. With less than ten reported cases, to our knowledge, this is one the few cases of acquired plate-like osteoma cutis described in the literature.

Background: Multiple miliary osteoma cutis (MMOC) is a rare nodular skin disease characterized by tiny bone nodules which usually form on the facial skin, typically in middle age. The aetiology of this phenomenon is poorly understood., Objectives: To search for possible bone formation progenitors and to look for a possible association with mutations in the GNAS gene (encoding the G-protein α-stimulatory subunit) and related hormonal parameters in patients with MMOC. We also reviewed the literature and discuss the aetiology and pathogenesis of adult-onset primary osteomas., Methods: We report four cases of MMOC. Histological samples were analysed for bone morphogenetic protein (BMP)-2, BMP-4 and oestrogen receptor-α known to be involved in bone formation. Endocrinological laboratory investigations and hand X-rays were performed to exclude a systemic disease. The GNAS gene was sequenced from DNA extracted from peripheral blood in all four patients and from a skin sample in one patient to exclude somatic mutations., Results: Histological analyses revealed intramembranous cutaneous bone formation resembling the findings seen in GNAS gene-based osteoma cutis disorders. However, we did not find any germline or somatic GNAS gene mutations in our patients and all laboratory investigations gave normal results. BMP-2 and -4 were expressed normally in MMOC samples, but oestrogen receptor-α was not expressed. Altogether 47 MMOC cases, 41 female and six male, have been published between 1928 and 2009. Of these cases, 55% had a history of pre-existing acne and only 15% had extrafacial osteomas., Conclusions: MMOC is a rare but distinct disease entity of unknown aetiology. Histologically, the tiny nodular osteomas show intramembranous superficial ossification but the aetiology appears to be different from GNAS-related disorders. The osteomas seem to increase slowly in number after appearing in middle age., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Gardner fibroma represents a rare and recently described soft tissue tumor entity in children and young adults. It consists of haphazardly arranged coarse and hyalinized collagen fibers combined with loosely arranged bland spindle and fibroblastic cells. The case of a 13-year-old male patient with Gardner fibroma and osteoma and multicentric desmoid type fibromatosis in his mother is presented with detection of a (heterozygotic) germline mutation of the APC gene leading to a de novo stop codon (deletion of base pairs 5033-5036). FISH analysis revealed a structural loss of heterozygosity (LOH) in the APC gene on chromosomal locus 5q21 in one out of five analysed desmoids of the mother, no LOH of APC gene in the Gardner fibroma. Gardner fibroma in children and young adults may serve as an indicator lesion for familial adenomatous polyposis (FAP), Gardner syndrome, a familial desmoid type fibromatosis without other manifestations of APC or a new APC gene mutation. For the clinician, this diagnosis should be commented upon accordingly by the surgical pathologist. As the result of a detected APC gene mutation, continuous follow-up for the development of colorectal tumors and desmoid type fibromatosis as well as a familial screening for FAP is recommended.

Gardner's syndrome (GS) is a hereditary autosomal dominant disease of the colon that presents with extra-colonic manifestations such as osteomas, skin lesions and dental abnormalities. Osteomas are commonly found in the skull, jaws and the paranasal sinuses. We present a family of four sisters affected with GS with a wide range of anomalies. The role of Cone beam computed tomography (CBCT) in the early detection and evaluation of osteomas and dental anomalies with precise assessment of their relationship to adjacent anatomic structures is described here in detail. The careful interpretation of CBCT may be of a great value in surgical and orthodontic treatment planning in the presence of jaw lesions. Management of dental problems in GS may be challenging due to the presence of odontomas and increased bone density. A multidisciplinary approach in the management of GS can achieve the best treatment results.

Gardner syndrome (GS) is an abnormality of familial adenomatous polyposis accompanied by characteristic jaw lesions. Gardner syndrome intestinal polyps have a 100% risk of undergoing malignant transformation; consequently, early identification and surgical intervention of the disease are important to prolong the life of the patient. We present a case of GS in a 55-year-old woman. Familial adenomatous polyposis, osteomatous jaw and ocular lesions, several dental abnormalities, and an abdominal desmoid tumor are the characteristic features of this case. This case demonstrates the presence of unusual, widespread, hereditary, osteomatous jaw lesions that caused diagnostic confusion with familial gigantiform cementoma.

Various inactivating mutations in guanine nucleotide-binding protein, alpha-stimulating activity polypeptide1 (GNAS1) gene have been described with poor phenotype correlation. Pseudohypoparathyroidism type 1a (PHP1a) results from an inactivating mutation in the GNAS1 gene. Hormone resistance occurs not only to parathyroid hormone (PTH), but typically also to other hormones which signal via G protein coupled receptors including thyroid stimulating hormone (TSH), gonadotropins, and growth hormone releasing hormone. In addition, the phenotype of Albright hereditary osteodystrophy (AHO) is observed, which may include short stature, round facies, brachydactyly, obesity, ectopic soft tissue or dermal ossification (osteoma cutis) and psychomotor retardation with variable expression. We present a 2-year-old boy with PHP 1A who initially presented at age 3 weeks with congenital hypothyroidism. By 17 months of age, he manifested osteoma cutis, psychomotor retardation, obesity, brachydactyly and resistance to PTH with normocalcemia and mild hyperphosphatemia. Genetic analysis revealed a novel mutation in exon 13 of GNAS1 in our patient. This mutation, c.1100_1101insA, resulted in a frameshift and premature truncation of bases downstream. This mutation was also found in the mother of this patient who was also noted to have short stature, obesity, brachydactyly and non progressive osteoma cutis, but no hormone resistance.We report a novel heterozygous mutation causing PHP1A with PTH and TSH resistance and AHO which has not been described previously. PHP1A is also a rare presentation of congenital hypothyroidism.

Albright hereditary osteodystrophy is a rare syndrome, in which cutaneous and superficial soft tissue lesions traditionally include osteomas and calcifications. We report 4 patients from 2 families affected with Albright hereditary osteodystrophy and demonstrate that the spectrum of these cutaneous and soft tissue lesions is broader than is usually defined in the literature. In addition to osteomas in the dermis and subcutis, including so-called plaque-like osteoma, we identified the following lesions: calcifying aponeurotic fibroma-like lesion, calcinosis circumscripta-like lesion, and unusual nevi with osteoid and/or peculiar intranuclear pseudoinclusions. One osteoma and the calcifying aponeurotic fibroma-like lesion were analyzed by HUMARA and proved to be clonal. In a family, a novel mutation in the GNAS gene was also identified.

Progressive osseous heteroplasia (POH) is a rare, disabling disease of heterotopic ossification (HO) that progresses from skin and subcutaneous tissues into deep skeletal muscle. POH occurs in the absence of multiple developmental features of Albright hereditary osteodystrophy (AHO) or hormone resistance, clinical manifestations that are also associated with GNAS inactivation. However, occasional patients with AHO and pseudohypoparathyroidism 1a/c (PHP1a/c; AHO features plus hormone resistance) have also been described who have progressive HO. This study was undertaken to define the diagnostic and mutational spectrum of POH and progressive disorders of HO, and to distinguish them from related disorders in which HO remains confined to the skin and subcutaneous tissues. We reviewed the charts of 111 individuals who had cutaneous and subcutaneous ossification. All patients were assessed for eight characteristics: age of onset of HO, presence and location of HO, depth of HO, type of HO, progression of HO, features of AHO, PTH resistance, and GNAS mutation analysis. We found, based on clinical criteria, that POH and progressive HO syndromes are at the severe end of a phenotypic spectrum of GNAS-inactivating conditions associated with extra-skeletal ossification. While most individuals with superficial or progressive ossification had mutations in GNAS, there were no specific genotype-phenotype correlations that distinguished the more progressive forms of HO (e.g., POH) from the non-progressive forms (osteoma cutis, AHO, and PHP1a/c)., (2008 Wiley-Liss, Inc.)

L-2-Hydroxyglutaric aciduria (L-2-OHGA) is a rare autosomal recessive neurometabolic disease linked to chromosome 14q21.1 and is caused by mutations in the gene that most likely encodes L: -2-hydroxyglutarate dehydrogenase, which normally catalyses L: -2-hydroxyglutarate to alpha-ketoglutarate. It is characterized by progressive mental deterioration, pyramidal and cerebellar syndromes, macrocephaly and marked polycystic white-matter degeneration mainly involving frontal lobes. Brain tumours of variable nature have frequently been observed in L-2-OHGA. We report a patient affected by this disease who at the age of 20 years developed a bone tumour involving the right frontal region of the calvaria. He had first presented at the age of 10 years with psychomotor delay, clumsy gait and moderate mental impairment. Examination showed macrocephaly, cerebellar ataxia and quadripyramidal syndrome. Brain MRI showed low signal intensities on T1-weighted images and high signal intensities on T2-weighted images in cerebral subcortical white matter. Serum and urinary amino acid assay was normal. Urinary 2-hydroxyglutaric acid was 1418 mmol/mol creatinine (controls <25). Analysis of the L-2-hydroxyglutarate dehydrogenase gene revealed a homozygous mutation in exon 2 (A320G). At the age of 20 years, an osteoma of the right frontal bone was diagnosed. This finding reinforces the opinion concerning the association of L-2-OHGA and tumorigenesis and prompted us to verify the possible responsibility of some overproduced substances in this disease for the development of tumours and to look for any correlation between the type of mutation in the L-2-OHGA gene and the tumorigenic potential observed in some patients affected by this disease.

Gardner's syndrome is a rare variant of the Familial Adenomatous Polyposis (FAP) in which affected individuals develop thousands of polyps within the gastrointestinal tract, with a 100 % risk of eventual malignant change. They also have a variety of extraintestinal abnormalities - various soft and hard tissues tumors like fibroma, osteoma, epidermoid cysts, sebaceous cysts on the scalp. Gardner's syndrome is an autosomal dominant disease, caused by mutations in APC ( adenomatous polyposis coli ) gene, which is located in chromosomal locus 5q21- q22. Firstly it has been described in 1953 by Gardner and Richards. They have investigated a family of 51 members with polyposis, some of them with multiple epidermoid cysts, fibromas and jaw osteomas. Eight of them have died by colorectal carcinoma. If undetected or untreated virtually all patients develop colonic carcinoma at a young age. Due to this high risk of malignancy the patients with Gardner's syndrome usually undergo surgical treatment by total or subtotal proctocolectomy. We report a case with Gardner's syndrome - a 36 year-old male who has been operated on in Department of Surgery in Vth city clinical hospital in October 2003. He had multiple adenomatous polyposis of colon, rectal cancer, osteomas of skull bones, subcutaneous fibromas and lipomas. We discovered also by ultrasound examination a polyp of gall bladder. His father has had also multiple polyposis with malignancy and metastatic lesions and he has died at age of 49 years. We performed total proctocolectomy with definitive iliac anus and cholecystectomy.

Though rare, Gardner's syndrome is a systemic disease with frequent jawbones involvement. Dento-maxillo-facial lesions both in early and in advanced stages should be known by dentists and other specialists. In fact, these lesions should be sought in patients with intestinal polyposis, while they could be the first sign of Gardner's syndrome not yet diagnosed.

Purpose: To describe a rare presentation of familial choroidal osteoma in two siblings., Methods: The clinical findings in two siblings over 4 years' follow-up., Results: Two brothers (15 and 12 years old) had bilateral choroidal osteomas. Both had bilateral peripapillary yellowish-white lesions and midperipheral mottling pigment appearance, which are not seen in sporadic cases. Extensive midperipheral area with mottling pigment appearance was noted by fluorescein angiography (FA) as scattered multiple hyperfluorescent dots. The yellowish-white lesions showed diffuse hyperfluorescence with FA and hypofluorescence with indocyanine green angiography (ICG). ICG also revealed irregular hyperfluorescent areas within the tumor, indicating abnormal choroidal vessels on the tumor. In the left eye of the younger brother, the subretinal fibrosis due to choroidal neovascularization superior to the macula extended down toward the foveal region over 2 years, resulting in visual deterioration., Conclusion: The midperipheral mottling pigment appearance of familial choroidal osteoma cases is unique and different from most sporadic cases, suggesting that familial choroidal osteoma might have separate etiologic or modified factors.

Machado-Joseph shoe (MJS), defined as a shoe/slipper with a deep hallux imprint at its base, and hyperostosis/osteoma toe were two early ataxic signs in 17 of 31 patients (55%) and 24 of 31 patients (77%) with Machado-Joseph disease (MJD), respectively. The MJS plus hyperostosis/osteoma toes may be helpful in the diagnosis of MJD in a patient during early truncal ataxia., ((c) 2004 Movement Disorder Society.)

Gardner syndrome, a variant of familial adenomatous polyposis, is an autosomal dominant disease characterized by gastrointestinal polyps that develop in the colon as well as in the stomach and upper intestine (duodenum), multiple osteomas, and skin and soft tissue tumors. Cutaneous findings include epidermoid cysts, desmoid tumors, and other benign tumors. Polyps have a 100% risk of undergoing malignant transformation; consequently, early identification and therapy of the disease are critical. Osteoma is a benign neoplasm of bone tissue that is characterized by slow continuous growth and is the most common accompanying bone lesion seen in Gardner syndrome. The authors report a case of Gardner syndrome that was operated on because of the mandibular osteoma.

A 25-year-old man with suspected Gardner syndrome was introduced to our hospital by a dentist who, during examination of the patient, had found dental dysplasias and multiple osteomas of the jaw. Radiographs, endoscopy and biopsies revealed adenomatous polyposis of the colon. Genetic analysis of peripheral lymphocytes revealed a one-base deletion at codon 1556 in exon 15 of APC, which caused a frame shift and a premature stop at codon 1564. The pedigree analysis demonstrated five patients in his family who presented with dental abnormality and osteomas in addition to adenomatous polyposis of the colon. Although the relationship between the location of APC mutations and dental abnormalities remains controversial, this case supports the hypothesis that a mutation at around codon 1556 of APC is closely associated with dental abnormality and osteomas.

Gardner syndrome, a phenotypic variant of familial adenomatous polyposis, is characterized by the classical clinical triad of skin and soft tissue tumours, osteomas and intestinal polyposis, but disease patterns with pairs of these findings have also been reported. Different mutations in the adenomatous polyposis coli (APC) gene have been shown to be associated with Gardner syndrome disease phenotypes. A 36-year-old patient presented with multiple epidermal cysts on the face, left ear lobe and neck, and the possible diagnosis of Gardner syndrome was based on the additional findings of two classical osteomas in the left radius and ulna and a cold non-malignant nodule of the thyroid gland. Intestinal polyposis was lacking at the time of examination. Major deletions but not microdeletions were excluded by a cytogenetic analysis with 650 chromosomal bands per haploid set. Systematic sequencing of the entire coding region of the APC gene (> 8500 bp) of the patient and five healthy controls was also performed. As a results, new APC gene polymorphisms were identified in exons 13 [A545A (A/G)] and 15 [G1678G (A/G), S1756S (G/T), P1960P (A/G)]. We also detected D1822V (A/T) which has recently been reported to be potentially related to colorectal carcinoma, and genotyped 194 randomly chosen healthy individuals from the Glasgow area for this as well as for the above variants in exons 13 and 15. Interestingly, of the 194 controls, 112 carried the DD (57.7%), 71 the DV (36.6%), and the remaining 11 (5.7%), including our patient, the VV genotype. It is therefore unlikely that APC D1822V serves as an important marker for colorectal carcinoma. In conclusion, we failed to identify obvious germline candidate mutations in > 8500 bp of the coding region of the APC gene in a patient with multiple epidermal cysts, osteomas and a thyroid gland nodule; major chromosomal deletions were excluded. Therefore, we assume that only the presence of intestinal polyposis is a marker for Gardner syndrome.

We describe a rare case of progressive osseous heteroplasia of the face in a child. Biopsy showed osteoma cutis superficially with ectopic bone formation in the deeper tissues including skeletal muscle. Analysis of DNA from peripheral blood leukocytes showed mutations in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1), confirming the diagnosis of progressive osseous heteroplasia.

Desmoids represent the most important cause of death, after colorectal cancer, in patients affected with familial adenomatous polyposis (FAP), an inherited disease due to mutations in the APC gene. The aims of our study were to estimate the risk of developing desmoids in FAP patients and to evaluate the association between desmoids and different risk factors. The occurrence of desmoids, colorectal cancer and other extra-colonic manifestations were assessed in 897 FAP patients, 653 of whom were also investigated for APC mutations. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using an unconditional multiple logistic regression model. Desmoids developed in 107 patients (11.9%), with a cumulative risk of 20.6%. Females had a significantly higher risk than males (OR = 2.1; 95% CI 1.4-3.1). Family history of desmoids (OR = 8.75; 95% CI 5.66-13.51), osteomas (OR = 2.9; 95% CI 1.8-4.8) and epidermoid cysts (OR = 1.8; 95% CI 1.1-3.2) was also significantly associated with the occurrence of disease. Subjects with APC mutations beyond codon 1444 had a 12-fold increased risk, compared with patients with mutations located upstream. Mutations beyond codon 1309 conferred a 17-fold higher risk, compared with mutations upstream codon 452. Multivariate analysis identified as independent predictors mutation beyond codon 1444 (OR = 6.2; 95% CI 2.5-15.8), family history of desmoids (OR = 5.8; 95% CI 3.1-10.6), female gender (OR = 2.1; 95% CI 1.1-3.8) and the presence of osteomas (OR = 1.9; 95% CI 1.1-3.4). Our results indicate that integrating genetic and clinical data is helpful in defining subgroups of patients at higher risk for desmoids, who may benefit from specific prevention programs., (Copyright 2001 Wiley-Liss, Inc.)

Pseudoxanthoma elasticum (PXE) is a heritable disorder of elastic fibers characterized by yellowish, coalescing papules on the loose and wrinkled flexural area. There have been no reports of osteoma cutis associated with PXE. A 17-year-old Korean girl presented cutis laxa-like marked wrinkling on the flexural area, and a skin biopsy specimen revealed multiple foci of ossification with irregularly clumped, basophilic-stained elastic fibers in the reticular dermis and calcium deposits along the elastic fibers. Ultrasonographic evaluation showed multiple tiny osteomas diffusely scattered along the entire abdominal wall, axillae, and medial aspect of the upper arms. We report the first case of osteoma cutis coexisting with cutis laxa-like PXE.

Based on the 3 cases, the authors describe the Gardner-syndrome which is not so well-known in Hungary. The most important features of the Gardner syndrome are the malignized large intestine polyposis, the multiplex osteomies and the different skin tumours. The earliest symptoms suspecting the clinical picture, are usually dental and/or mandibular lesions. Being aware of the above mentioned facts the dentist noticing the symptoms first is highly responsible.

We report a case of bilateral limbal dermoids and bilateral choroidal osteomas in a 14-year-old girl with no extraocular anomalies. Histopathological examination of a limbal lesion confirmed the clinical diagnosis of dermoid. Computerized tomography and ultrasonography were compatible with a diagnosis of choroidal osteoma. Limbal dermoids were present in the patient's mother, in a brother with Down syndrome, and in an aunt with no choroidal osteoma. The present pedigree is compatible with autosomal dominant inheritance of bilateral limbal dermoids. The same gene may be involved in the pathogenesis of ocular choristomas in same patients.

We describe a 21-year-old patient hospitalised because of a dislocated mandibular fracture and accidentally found to have multiple osteomas of the skull. A subsequent gastroenterological examination revealed the presence of multiple polyps in the large intestine, typical of familial adenomatous polyposis. A disease causing germline mutation in the adenomatous polyposis coli gene was identified by molecular genetic analysis. Although extracolonic features such as multiple osteomas, multiple epidermal cysts and desmoids are frequently found, most cases without a family history of familial adenomatous polyposis or colorectal cancer are only diagnosed because of colonic disease manifestations with colorectal cancer already present. This case report strikingly illustrates that in the absence of a family history the presence of extracolonic features allows presymptomatic diagnosis in familial adenomatous polyposis patients before colorectal cancer has developed.

A case of solitary osteoma of the parietal skull is described in a mother and her 12-year-old son. There were no other craniofacial or dysmorphic features and there was no history of previous cranial trauma or inflammatory process and no radiographic evidence of other skeletal lesions in both patients. Family history was otherwise unremarkable. Gardner syndrome was ruled out by excluding other associated clinical abnormalities and by family history. The clinical and radiological features of the patients' osteomas were different from those of Albright hereditary osteodystrophy, fibrodysplasia ossificans progressiva, progressive osseous heteroplasia and familial ectopic ossification. To the author's knowledge this is the first case of the familial presentation of osteomas.

Background: Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q., Aims: This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP., Methods: Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed., Results: FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621., Conclusions: Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) and predisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).

Germline mutations of the adenomatous polyposis coli gene are associated with the dominantly inherited syndrome of familial adenomatous polyposis. Somatic mutations in this gene are an early event in sporadic colorectal tumorigenesis. Here we report a family with genetic characteristics that do not conform exactly to either of these situations. The index case and three siblings presented with colorectal cancer, and another sibling had lung cancer. There was no evidence of colorectal cancer susceptibility in previous generations, although one case of gastric cancer was observed. Using restriction fragment length polymorphism, single-strand conformational polymorphism, and sequencing analysis, we screened each living family member for alterations in the mutation cluster region of exon 15 of the APC gene. A constitutional single base pair substitution at codon 1317 was observed in two of the siblings with colorectal cancer, but neither exhibited any colonic features typical of FAP nor an early onset of cancer. This constitutional change is a missense mutation and therefore does not result in the truncation of the APC protein, the most commonly observed result of mutation in this gene. We present evidence that this change is not a polymorphism and may be capable of conferring a growth advantage. This particular germline APC mutation does not completely cosegregate with cancer in this family; therefore, we conclude that another gene locus may be responsible for the increased cancer risk observed.

Pantomography of the mandible was performed in 98 patients with sporadic colorectal adenocarcinoma. Twenty-eight patients (29%) had osteomas versus 5% in a control group (P < 0.001). Mandibular osteomas are found in most patients with the premalignant dominant syndrome familial adenomatous polyposis. Sporadic colorectal cancer examinations of married couples have shown that diet has only a moderate influence on the development of colorectal cancer, whereas pedigree studies indicate a genetic component. On this basis we conclude that mandibular osteomas are probably genetic markers of the development of sporadic colorectal carcinoma.

The syndrome of Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) is clinically and genetically heterogeneous. Classically, patients with PHP have the skeletal features of AHO, resistance to multiple hormones that work via cAMP such as parathyroid hormone and thyroid stimulating hormone, and deficient activity of Gs protein, the guanine nucleotide-binding protein that stimulates adenylate cyclase. However, patients without hormone resistance but with AHO and Gs deficiency were described (PPHP), as well as patients with multiple hormone resistance but without AHO or Gs deficiency. In a few patients with deficient Gs activity, hypothyroidism rather than hypocalcemia was the initial presentation of the disorder. We describe here a new variant of the syndrome, affecting 5 individuals in a 3 generation family with AHO, normal Gs activity and hypothyroidism. In the first 2 generations, mild features of AHO were present. The 2 sibs in the third generation had severe manifestations of AHO, including mild mental retardation as well as hypothyroidism. Diagnosis of congenital osteoma cutis at birth of the proband led to the diagnosis of the family. Elucidation of the molecular defect will shed light on the relationship between hormone resistance and AHO, as well as on the physiological mechanism of hormonal signal transduction.

Cytogenetic analysis of a cemento-ossifying fibroma from a patient with nonfamilial bilateral multicentric retinoblastoma revealed three reciprocal translocations with the karyotype 46,XY,t(1;18)(q21;q21.3),t(3;10)(p13;q22),t(6;11)(p22;p15). Routine and high-resolution cytogenetic analysis of peripheral blood leukocytes showed an apparently normal, 46,XY chromosome pattern with no deletion of chromosome 13. Molecular analysis demonstrated no gross differences in the retinoblastoma gene or the TP53 gene between constitutional and tumor DNA. This is the first cytogenetic analysis of a cemento-ossifying fibroma and the first report of this tumor in a retinoblastoma patient. The data may be added to the small, but growing literature on cytogenetic aberrations in benign tumors and may lend insight into genes involved in cell proliferation and neoplastic transformation.

We studied two cases of bilateral choroidal osteoma in an otherwise healthy 5-year-old boy and his only sibling, a 7-year-old sister. Both children were known to have normal fundus appearances at younger ages. The tumor showed slow growth in all four eyes, but severe visual acuity loss developed in three eyes because of neovascular complications that could not be effectively treated by photocoagulation. Secondary retinal cysts developed in three eyes.

The Gardner syndrome (GS) is a dysplasia in which neoformations in the intestines, soft tissue and osseous tissue are associated. Since extra-intestinal manifestations, in particularly osteomas, appear promptly even in infants, and above all in the light of the possibility of malignant degeneration, the presence of mandibular osteomas indicates the necessity of carrying out investigations in order to ascertain the eventual existence of an intestinal polyposis typical of GS. This study describes a typical case of GS diagnosed merely upon suspicion of the existence of the syndrome in a patient who came to our Department with a mandibular osteoma. The study underlines the importance not only of carrying out investigations in order to ascertain the presence of GS (rectocolonoscopy), but also that of studying the relatives of the patient in light of the fact that this particular dysplasia is transmitted genetically.

Relatives of 88 long-term survivors of childhood sarcoma were examined for the familial cancer syndrome of sarcoma, breast cancer, and other neoplasms (Li-Fraumeni syndrome). Twenty-six of 402 close relatives developed cancer (expected, 23.8), including breast cancer in four mothers (expected, 3.1). Two sarcoma probands who developed second malignant tumors have multiple relatives with cancer and might have an inherited predisposition. An increased cancer risk and exceptional requirement for disease screening appear to be confined to first-degree relatives of a small fraction of children with sarcoma, notably probands with second cancers.

Three siblings (a sister and two identical-twin brothers) had bilateral choroidal osteomas. The sister was seen at 11 years of age, and the tumor showed significant growth two years later. The twin brothers' tumors were diagnosed at 9 years of age, and their conditions remained stable over two years except for a new, isolated lesion that occurred in one eye of one brother. The siblings' mother had a yellow mottling situated nasal to the disk in each eye that was similar in appearance to that in one eye of one of the twins. She showed no evidence of calcium on ultrasonography. The appearance of osteomas in three siblings suggests a choristoma as the cause of this tumor.

The aim of the present report is to describe the overall mandibular and extramandibular lesions correlated to Gardner's syndrome which were found in the same family (mother and two daughters). In two cases (mother and one daughter) mandibular lesions consisted of osteoma. In the latter, these were associated with composite odontoma. In the other daughter the lesions consisted of desmoid fibroma. The two daughters revealed single colonic polyposis whereas the mother was affected by multiple colonic polyposis and subcutaneous lipoma. Such a constellation of lesions may be attributed to Gardner's syndrome, a Mendelian hereditary syndrome which is often incomplete. In fact, intestinal polyposis can only be associated with one of the various extraintestinal manifestations of the syndrome. The recognition of the syndrome is important given the high percentage of intestinal polyp-adenocarcinoma associations.

A case of Gardner syndrome associated with alterations of the skin and bones and precancerous gastrointestinal polyposis is presented. Particular interest attached to the extension of polyposis to the entire digestive tract, the early appearance of abdominal signs attributable to the polyposis, and - as new symptoms - polycystic lung and widespread superficial naevus lipomatosus.

Through a family form study and a literature review, the authors define the symptoms of the Gardner's disease and the checkup to be carried out. Sometimes, the surgical treatment, proposed in an aesthetical purpose, is difficult to carry out due to the tumor location and consistency. Incomplete forms are likely to be more frequent but the risk of colic degeneration remains the same as for the usual form. Examination and multi-departmental care are required.

Osteomatous jaw lesions have been reported to occur in connection with familial adenomatous polyposis (FAP) of the intestines. The disease is fatal if not treated. The aim of this investigation was to study the occurrence of bone jaw lesions in Swedish families, where some family members have developed FAP, in order to evaluate if these bone changes may be regarded as clinical markers of the disease. 132 individuals from ten families with FAP and a matched control group of 250 individuals were examined. Osteomatous lesions were diagnosed in 24 per cent in the FAP families and in 2 per cent in the controls. Individuals with verified FAP showed an increased occurrens of jaw lesions. Also in family members without verified FAP, first-degree relatives and other relatives, showed a significant higher incidence of osteomatous jaw lesions compared to the controls. Our results suggest that osteomatous jaw lesions in families with FAP are of predictive significance.

Extracolonic manifestations are often associated with familial polyposis coli, but the cysts and osteomas may be few and inconspicuous. Abnormal fibrous reactions may also occur and may be a cause of death. These manifestations act as "external markers" for the later appearances of adenomas. In any family, some individuals may manifest some extracolonic manifestations and other individuals may not. Other abnormalities, usually neoplastic, described in familial polyposis coli families, are probably fortuitous occurrences, but medulloblastoma has been found relatively frequently. Turcot's syndrome, described in a unique family, should be used more restrictively. Diagnosis depends on histology showing adenomas, but no particular number is required in an afflicted family member. Total reliance on sigmoidoscopy alone is potentially hazardous as the descending colon may be affected initially. Inherent problems regarding "isolated cases" are outlined.