Skin manifestations among GATA2-deficient patients.

GATA2 mutations have been identified in various diseases, such as MonoMAC syndrome, Emberger syndrome, familial myelodysplastic syndrome, acute myeloid leukaemia and dendritic cell, monocyte, B-cell and natural killer-cell deficiency. These syndromes present a wide range of clinical features, dominated by severe infections and haematological disorders such as myelodysplastic syndrome. Up to 70% of patients with GATA2 mutations have dermatological features, mainly genital or extragenital warts, panniculitis or erythema nodosum and lymphoedema. We report three patients presenting with common dermatological and haematological features leading to the diagnosis of GATA2 deficiency, but also with skin manifestations that have not been previously described: gingival hypertrophy, macroglossitis and glossitis and granulomatous lupoid facial lesions. Dermatologists can encounter patients with GATA2 mutations and should recognize this disorder.

Tetraploid/diploid mosaicism with generalized aggressive periodontitis.

BACKGROUND: Changes of chromosome number diploid to triploid or tetraploid states are rare in human pregnancies, where the main clinical features of tetraploidy are delayed growth and/or craniofacial abnormalities. The present report describes the oral features of tetraploid/diploid mosaicism. Although the medical literature described the physical manifestations of this genetic abnormality, the oral features of this disorder were not previously described. METHODS: A 13-year-old patient presented because of his severe periodontal conditions. Clinical, radiological, microbiologic, immunologic, and genetic examinations were conducted. RESULTS: Long eyelashes and mandibular micrognathia were noticeable in his extraoral examination. Intraoral examination revealed significant generalized edema of the gingiva and severe sulcular bleeding on probing. Generalized maxillary and mandibular alveolar destruction was determined with radiographic examination. Actinobacillus actinomycetemcomitans was also detected in his subgingival samples. He was diagnosed as generalized aggressive periodontitis. His medical cytogenetic examination revealed 92,XXYY (25%)/46,XY (75%) karyotype indicating tetraploid/diploid mosaicism. He was given initial and advanced periodontal therapy and he is currently under a routine follow-up period. CONCLUSIONS: This report provides information on the oral characteristics of tetraploid/diploid mosaicism and describes periodontal treatment. Severe periodontal conditions such as aggressive periodontitis may accompany tetraploid/diploid mosaicism subjects and these patients should be frequently seen by their dental practitioners. It is suggested that initial and/or advanced periodontal procedures may be a way of treating tetraploid/diploid mosaicism subjects with aggressive periodontitis. The importance of physical examination and medical consultation is also discussed.

[Risk factors conditioning the incidence and severity of cyclosporine A-induced gingival overgrowth and methods of prevention]. / Fattori condizionanti l'incidenza e la severità dell'ipertrofia gengivale indotta da ciclosporina A e possibilità di prevenzione.

Cyclosporin A (CsA) induced gingival overgrowth is one of the major side-effects conditioning the quality of life of the patient under immunosuppressive therapy. This adverse effect has been first reported in 1983 and affects almost 30% of treated patients. Several papers have been published concerning the cellular/molecular mechanisms by which CsA may induce, at the same time, an immunosuppressive and proliferative action. In this review various factors concerning the patient and his milieu that account for the different prevalence of the severity of gingival overgrowth in clinical studies are analyzed and briefly discussed. In particular, age, sex, pharmacokinetic properties, pharmaceutical preparation, genetic predisposition, association with other drugs and the parodontal conditions before transplantation are considered. In addition, a unique approach to the patients with gingival overgrowth as well as effective methods of prevention and therapy are suggested.

CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects.

Previous studies suggested that the onset of phenytoin-induced gingival overgrowth depended on serum phenytoin concentration. Cytochrome P450 2C (CYP2C) plays an important role in phenytoin metabolism. Recently, single nucleotide polymorphisms in the coding region of CYP 2C influencing phenytoin metabolism were identified. The purpose of the present study was to see if CYP 2C polymorphisms might relate to the onset and severity of phenytoin-induced gingival overgrowth. Twenty-eight epileptic patients taking phenytoin aged 15 to 75 (mean age: 42.2 years old, 20 males and 8 females) and 56 unrelated healthy subjects aged 30 to 48 (mean age: 36.8 years old, 48 males and 8 females) were examined for CYP 2C polymorphisms. All epileptic subjects were examined for the degree of gingival overgrowth, daily phenytoin dose and serum phenytoin concentration. The results indicated about 7% of the subjects including epileptic and healthy subjects examined were positive for CYP 2C9*3. However, the degree of gingival overgrowth did not directly correlate with CYP 2C polymorphisms. Nevertheless, the subjects with severer gingival overgrowth exhibited significantly higher serum phenytoin concentration, indicating that phenytoin metabolism is an important determinant for the severity of the disease. Additionally, CYP 2C9*3 carriers exhibited significantly higher serum drug concentration to drug dose. Therefore, we concluded although the gene analysis is not directly related to diagnose the disease itself, it can be utilized in estimating serum phenytoin concentration from drug dose, which in turn serves to predict the future development and clinical course of the disease.

Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

[Pathogenesis of cyclosporine induced gingival overgrowth]. / Patogenesi degli aumenti di volume gengivale causati da ciclosporina.

Several studies, during the last 20 years, tried to explain the pathogenetic mechanisms of the cyclosporine (CS) induced gingival overgrowth (and in general, of the drugs induced gingival overgrowth), but they are still poorly understood. The relationship between the drug and the different pharmacokinetic variables (dosage, duration of therapy, plasmatic and salivary Cs concentration) is still on discussion. It is accepted that a threshold concentration is necessary, in the gingival tissues, to begin or to enhance the morphostructural changes of the gums, but the total Cs weight, from the beginning of the therapy to the time of clinical examinations, has to be evaluated. The pharmacokinetic variables are associated with many other factors (first of all the oral hygiene score) that are probably connected with the developing of the gingival lesions. Gingival inflammation could be very important in the pathogenesis of gingival overgrowth. It has been shown by several cross-sectional studies a strong association between plaque and gingival lesions, but it is not yet clear if plaque accumulation is a causal factor or a consequence of the morphological gums changes. It would seem that the morphological alterations, in drug-induced gingival overgrowth, could be started by the plaque induced inflammation, and this would lead to an hyperemic and edematous gingival tissue. Oral hygiene (professional and at home) is more difficult and represents an irritation factor that makes the pathological cycle to go on. Other factors, probably connected with the cyclosporine induced gingival overgrowth, are represented by age, gender, genetic predisposition, alterations of gingival connective homeostasis and metabolism, inflammatory alterations, interactions with the growth factors and protective or synergic effects of other drugs.

[The causes of gingival overgrowth]. / Cauzele hipercresterii gingivale.

Gingival overgrowth includes a series of diseases with many clinical appearances. The pathological mechanisms being obscure there were used many terms for defining it. Thus, "gingival hyperplasia" and "gingival hypertrophy" were the definitions used to define this pathology. Therefore, the term of "gingival overgrowth" replaced in last decades the above two terms. This article have the goal of trying a classification of the entities forming the large family of gingival overgrowth.

Retinal changes and tumorigenesis in Ramon syndrome: follow-up of a Brazilian family.

We report on the clinical evolution of the Brazilian family with Ramon syndrome described by de Pina-Neto et al. [1986, Am J Med Genet 25:441-443]. Three members (patients IV-2, IV-18, and IV-19) have developed pigmentary changes in the retina and paleness of the optic disk. Patient IV-18 also has developed giant hypertrophy of the labia minora that, when examined histopathologically, was found to be due to neoplastic fibroblast and epithelial proliferation caused by a fibromatous process similar to that reported in the gingivae of the patients with this syndrome. Audiologic function of patient IV-2 was normal, and no skin lesions were detected. The articular signs and symptoms show that the affected relatives developed rheumatoid arthritis, which is currently inactive in patient IV-18, whereas patient IV-2 did not develop these alterations.

New multisystemic disorder involving heart valves, skin, bones, and joints in two brothers.

We report on 2 brothers with a severe progressive disorder characterized by thick skin, acne conglobata, "coarse" face, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. The youngest brother died at age 24 years because of heart failure. Biochemical and pathological studies excluded known metabolic diseases. We think that this is a new genetic disorder inherited in autosomal recessive or X-linked recessive manner.

A terminal deletion (14)(q31.1) in a child with microcephaly, narrow palate, gingival hypertrophy, protuberant ears, and mild mental retardation.

A female child with a terminal deletion on the long arm of chromosome 14, 46,XX,del(14)(q31.1), presented with microcephaly, narrow palate, gingival hypertrophy, protuberant ears, and a small haemangioma on the back. She was mildly mentally retarded. Only a few patients with a partial deletion of 14q (14q-) have been reported without consistent clinical findings. Although a clinical syndrome associated with ring chromosome 14, r(14), has been established, no distinct pattern has been so far reported in 14q-.

Cherubism, gingival fibromatosis, epilepsy, and mental deficiency (Ramon syndrome) with juvenile rheumatoid arthritis.

This is a report on four persons in one family with a condition similar to that described by Ramon et al [Oral Surg 24:436-48, 1967] in two sibs born to a consanguineous couple. Our patients also had mental deficiency, epilepsy, cherubism due to fibrous dysplasia of the maxillae, gingival fibromatosis, hypertrichosis, and stunted growth. This appears to be an autosomal recessive trait in both families. Our patients are the second set reported with this syndrome; they also have juvenile rheumatoid arthritis, which was not described in the family reported by Ramon et al [Oral Surg 24:436-48, 1967]. We conclude that the Ramon syndrome should also include juvenile rheumatoid arthritis.

Heterogeneity in gingival fibromatosis.

A review of cases indicated that gingival fibromatosis occurs in a variety of genetic entities. High risk for epilepsy and oligophrenia is associated if hypertrichosis is present. Other entities are symmetrical gingival fibromatosis; Zimmermann-Laband syndrome with bone, ear, nose and nail defects and hepatosplenomegaly; Murray syndrome with multiple hyaline dermal tumors; Rutherfurd syndrome with corneal dystrophy; Cowden syndrome with hypertrichosis, oligophrenia and giant fibroadenomatosis of breasts and Cross syndrome of hypopigmentation, oligophrenia and athetosis.