RESUMO
The molecular aetiology of Proteus syndrome (PS) remains elusive. Germline mutations in PTEN cause Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are hereditary hamartoma syndromes. Some features-eg, macrocephaly, lipomatosis, and vascular malformations-can be seen in all three syndromes. We examined PTEN in patients with PS and undefined Proteus-like syndromes (PS-like) and identified de-novo germline mutations in two of nine patients with PS and three of five patients with PS-like. Germline PTEN mutation analysis should be done in individuals with PS and PS-like because of its association with increased risk of cancer development and potential of germline-mutation transmission.
Assuntos
Genes Supressores de Tumor/genética , Mutação em Linhagem Germinativa , Monoéster Fosfórico Hidrolases/genética , Síndrome de Proteu/genética , Proteínas Supressoras de Tumor , Síndrome do Hamartoma Múltiplo/genética , Heterozigoto , Humanos , PTEN Fosfo-HidrolaseRESUMO
Short stature and developmental delay may be observed in many genetic conditions and well-defined syndromes. A 7-year-old girl presented with the non-specific findings of subtle dysmorphism, short stature and developmental delay. Although a genetic syndrome was suspected, a definitive diagnosis was not made until the dental findings of KBG syndrome were recognised, namely grossly enlarged maxillary permanent central incisors and hypodontia.
Assuntos
Anormalidades Múltiplas , Anormalidades Dentárias , Criança , Cavidade Pulpar/anormalidades , Deficiências do Desenvolvimento , Nanismo , Fácies , Feminino , Humanos , Incisivo/anormalidades , Síndrome , Anormalidades Dentárias/patologiaRESUMO
Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an approximately 5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Cromossomos Humanos Par 5/genética , Genes Dominantes/genética , Ligação Genética/genética , Proteínas de Membrana/genética , Mutação/genética , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Criança , Pré-Escolar , Citosol/química , Análise Mutacional de DNA , Éxons/genética , Feminino , Humanos , Escore Lod , Masculino , Proteínas de Membrana/química , Dados de Sequência Molecular , Osteoblastos/metabolismo , Linhagem , Proteínas de Transporte de Fosfato , Estrutura Terciária de Proteína , RNA Mensageiro/análise , RNA Mensageiro/genéticaRESUMO
The autosomal recessive multicentric osteolytic disorders of childhood-Torg, Winchester, and François syndromes-predominantly affect the carpal, tarsal, and interphalangeal joints, and their progressive bone loss and crippling arthritic deformities mimic severe juvenile rheumatoid arthritis. In a consanguineous Saudi Arabian family two affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life that eventually progressed to the proximal joints and resulted in crippling ankylosis and severe generalized osteopenia. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Routine hematologic, chemistry, and rheumatoid studies were within normal limits. Histologic examination of bone marrow and an interphalangeal joint biopsy were not informative. The autosomal recessive inheritance, clinical, and radiologic characteristics of the affected sibs suggested that they had a form of multicentric osteolysis most closely resembling the Torg syndrome, but with a unique facial appearance, fibrocollagenous pads, and body hirsutism not noted in the original description of the syndrome.
Assuntos
Artrite/genética , Osteólise Essencial/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adulto , Artrite/diagnóstico por imagem , Artrite/patologia , Consanguinidade , Feminino , Humanos , Masculino , Osteólise Essencial/diagnóstico por imagem , Osteólise Essencial/patologia , Linhagem , Radiografia , Arábia Saudita , SíndromeRESUMO
The acronym WHIM refers to Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The latter refers to the retention of white cells in the marrow, which becomes hypercellular. We have found approximately 20 examples of WHIM syndrome in the literature under various designations; the first examples are Zuelzer [1964] and Krill et al. [1964]. Chronic noncyclic neutropenia and hypercellular bone marrow represent defective release of marrow cells into the peripheral stream (myelokathexis). The hypermature neutrophils are bizarre in form. Condensed nuclei connected by long, stringy filaments and vacuolated cytoplasm suggest apoptosis. Fever or other stress increases the release of neutrophils. Hypogammaglobulinemia is marked and associated with recurrent upper respiratory infections (sinusitis, tonsillitis, otitis media, pneumonia). Patients have numerous warts, some venereal, with resultant cervical and vulval premalignant dysplasia. We report on a kindred of 6 affected individuals in 3 generations with autosomal dominant WHIM syndrome. The sex ratio among reported patients and in our kindred is 17 female to 8 male. Because there had been no male-to-male transmssion, search of the entire X-chromosome including the pseudoautosomal area was carried out and no linkage was found. Recently, the propositus has had an unaffected daughter, confirming our finding that the gene is not X-linked. A genome-wide search is being carried out.
Assuntos
Agamaglobulinemia/genética , Genes Dominantes , Neutropenia/genética , Verrugas/genética , Adolescente , Adulto , Agamaglobulinemia/sangue , Criança , Eosinófilos/patologia , Feminino , Ligação Genética , Humanos , Infecções , Contagem de Leucócitos , Masculino , Neutropenia/sangue , Neutrófilos/patologia , Linhagem , Síndrome , Verrugas/sangue , Cromossomo XRESUMO
The purpose of this paper is to report the occurrence of odontogenic keratocysts in a young child. Odontogenic keratocysts are one of the principal features of nevoid basal cell carcinoma syndrome. Their occurrence in this syndrome is usually during the second or third decades of life. This report describes the occurrence of odontogenic keratocysts in a 5-year-old, which proved to be the initial presentation of nevoid basal cell carcinoma syndrome and highlights the need to consider this syndrome as a possible diagnosis in all cases of odontogenic keratocysts.
Assuntos
Síndrome do Nevo Basocelular/diagnóstico , Doenças Mandibulares/diagnóstico , Cistos Odontogênicos/diagnóstico , Pré-Escolar , Seguimentos , Humanos , Masculino , Dente Molar/patologia , Recidiva , Dente Decíduo/patologia , Dente Supranumerário/diagnóstico , Dente não Erupcionado/diagnósticoAssuntos
Síndrome do Nevo Basocelular/patologia , Neoplasias Cutâneas/patologia , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/metabolismo , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Fibroblastos/efeitos da radiação , Genes Supressores de Tumor/genética , Humanos , Proteínas de Membrana/genética , Receptores Patched , Receptores de Superfície Celular , Pele/efeitos da radiação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.
Assuntos
Anormalidades Múltiplas/genética , Síndrome do Hamartoma Múltiplo/genética , Monoéster Fosfórico Hidrolases/genética , Proteínas Supressoras de Tumor , Anormalidades Múltiplas/patologia , Células Cultivadas , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 10/genética , Estudos de Coortes , Anormalidades Craniofaciais/genética , Saúde da Família , Feminino , Triagem de Portadores Genéticos , Marcadores Genéticos , Genótipo , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/patologia , Heterozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Mutação , PTEN Fosfo-Hidrolase , Linhagem , Fenótipo , SíndromeRESUMO
The cases of two patients with Robinow fetal face syndrome, an 11-year-old Thai boy and a newborn Caucasian girl, are described. The Thai boy had the characteristics typical of the dominant type of the syndrome with a few newly recognized signs, including communicating hydrocephalus, underdeveloped sinuses, short roots of the teeth, narrow and thick-floored pulp chambers, hypoplastic nipples, absent middle phalanges of the second to fifth toes, cone-shaped epiphyses of the second and fourth fingers and fifth toes, single creases of the fourth and fifth fingers, clinodactyly of the third fingers, dysmorphic umbilicus, and shawl scrotum. The girl had anomalies typical of the recessive type of the syndrome. She also had capillary hemangioma at the tip of her nose and hypoplastic fourth metatarsal bones, which are the newly recognized features of the recessive type. Infrequently reported clinical manifestations of the syndrome are discussed.
Assuntos
Anormalidades Múltiplas/genética , Disostose Craniofacial/genética , Síndrome , Criança , Disostose Craniofacial/diagnóstico por imagem , Disostose Craniofacial/patologia , Feminino , Dedos/anormalidades , Genitália/anormalidades , Humanos , Recém-Nascido , Masculino , Radiografia , Dedos do Pé/anormalidades , Anormalidades Dentárias/genéticaRESUMO
Three unusual dental anomalies are presented which should be of interest to the pediatric radiologist: otodental syndrome - an autosomal dominant syndrome of bizarre, greatly enlarged teeth with bulbous crowns (globodontia) that spares the incisors, in combination with sensorineural hearing loss; oculo-facio-cardio-dental syndrome - an X-linked dominant syndrome that is lethal in males, characterized by congenital cataracts, unusual facies, atrial septal defect (ASD), ventricular septal defect (VSD), and canine teeth that cease to grow only when they cut off their own blood supply by growing through the orbit and lower border of mandible; and lobodontia - a dominant disorder characterized by teeth whose crowns resemble those of a wolf.
Assuntos
Anormalidades Múltiplas , Coroa do Dente/anormalidades , Anormalidades do Olho/genética , Face/anormalidades , Genes Letais , Perda Auditiva Neurossensorial/congênito , Cardiopatias Congênitas/genética , Humanos , Odontometria , Radiografia , Síndrome , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/genética , Cromossomo XRESUMO
We report on a family of seven affected with a new syndrome of multiple deep schwannomas, multiple nevi (both intradermal and compound types), and multiple leiomyomas of the vagina. Inheritance is dominant, whether autosomal or X-linked cannot be determined at this time. The nevi, which are congenital, appear to be a marker for the syndrome. Both the schwannomas and leiomyomas do not manifest until adulthood.
Assuntos
Leiomioma/genética , Neoplasias Primárias Múltiplas/genética , Síndromes Neoplásicas Hereditárias/genética , Neurilemoma/genética , Nevo/genética , Neoplasias Cutâneas/genética , Neoplasias Vaginais/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurilemoma/patologia , LinhagemRESUMO
The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.
Assuntos
Cromossomos Humanos Par 10 , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/genética , Monoéster Fosfórico Hidrolases , Proteínas Tirosina Fosfatases/genética , Proteínas Supressoras de Tumor , Mapeamento Cromossômico , Éxons , Feminino , Genótipo , Humanos , Masculino , PTEN Fosfo-Hidrolase , Fenótipo , Síndrome , Células Tumorais CultivadasRESUMO
We describe two boys with global developmental delay and a phenotype of microcephaly, midface hypoplasia, enlarged fleshy ears, depressed nasal bridge, anteverted nostrils, central palatal ridge, and high forehead. Bilateral congenital fat pads are present anteromedial to the heels. Fetal finger and toe pads are present and palmar and plantar grooves are deeper than normal with "pillowing" of the areas between the grooves. No patients with similar clinical findings have been located, but these two children have a remarkably similar clinical presentation which we consider a "new" syndrome.
Assuntos
Deficiências do Desenvolvimento/genética , Doenças do Pé/genética , Lipomatose/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Dedos/anormalidades , Doenças do Pé/congênito , Deformidades da Mão/genética , Humanos , Deficiência Intelectual/genética , Lipomatose/congênito , Masculino , Microcefalia/genética , Distúrbios da Fala/genéticaRESUMO
The Ekman-Westborg-Julin Syndrome is reveiwed and a new case reported.
Assuntos
Anormalidades Dentárias/patologia , Adolescente , Orelha Externa/anormalidades , Face/anormalidades , Humanos , Masculino , Dente Molar/anormalidades , Odontometria , Prognatismo/patologia , Síndrome , Coroa do Dente/anormalidades , Dente Decíduo/anormalidadesRESUMO
We describe a small, term, male infant with corticospinal tract aplasia secondary to motor cortex dysplasia from a neuronal proliferation and/or migrational defect. The infant also had microdolichocephaly, sloping forehead, hypertelorism, flat nose, apparently low-set ears, micrognathia, arthrogryposis without muscle wasting, cortical thumbs, rocker-bottom feet, scoliosis, single umbilical artery, and hypospadias with chordee. Oligohydramnios was present prenatally. Neurologic examination showed a comatose state, seizures, minimal spontaneous movement, minimal response to pain, and absent primitive reflexes. At autopsy, hypoplasia of kidneys and adrenal glands was found. There was no aqueductal stenosis or pulmonary hypoplasia. Chromosomes were apparently normal. These manifestations do not correspond to those of any recognized syndrome; therefore, this patient may represent a previously undefined syndrome.