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1.
Fam Cancer ; 13(1): 57-63, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23934601

ABSTRACT

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.


Subject(s)
Hamartoma Syndrome, Multiple/genetics , Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Germ-Line Mutation , Heterozygote , Humans , Infant , Kaplan-Meier Estimate , Middle Aged , Mutation, Missense , Syndrome , Thyroid Neoplasms/genetics , Young Adult
2.
Am J Med Genet A ; 158A(9): 2292-6, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22821701

ABSTRACT

We report on a father and his 4-year-old son sharing a characteristic dysmorphic facial phenotype (including hyperteleroism, prominent forehead, and wide nasal bridge), macrocephaly, hearing loss, palatal clefting, developmental delay, hypotonia and bony abnormalities including marked cranial sclerosis and sclerosis of the ribs and long bones, which evolved in severity in the son between the ages of 2 and 4 years. The father's radiographs also showed prominent coarse striations, patchy metaphyseal sclerotic plaques, markedly increased bone density and cortical thickening of long bones, and significant degenerative changes in the thoracic spine. The son has an additional history of sleep apnea resulting from multi-level airway obstruction that includes adenoid hypertrophy, lingual tonsil hypertrophy, subglottic stenosis, and supra-arytenoid tissue consistent with laryngomalacia and tracheomalacia. The clinical, radiographic, and genetic findings in father and son are consistent with a sclerosing skeletal dysplasia syndrome with similarities to mixed sclerosing bone dysplasia (MSBD) including metaphyseal plaques, osteopathia striata, and cranial sclerosis (OS-CS). This family may represent one of the first descriptions of familial inheritance and evolving phenotype in MSBD. The evidence for male-male transmission would support the existence of an autosomal mechanism of inheritance for a novel form of MSBD with characteristic syndromic features.


Subject(s)
Osteosclerosis/pathology , Adult , Child, Preschool , Female , Humans , Male , Syndrome
4.
Am J Med Genet A ; 155A(4): 855-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21412975

ABSTRACT

We report on a male infant with otopalatodigital syndrome type 2 (OPD2) associated with a novel c.514C>G FLNA mutation and unusual clinical features including bifid tongue and congenital corneal clouding. Bifid tongue and congenital corneal clouding have each only been described once previously in a patient with OPD2, and this is the first description of Dandy-Walker malformation (DWM) in OPD2. The presence of these clinical findings in a mutation-confirmed case of OPD2 supports the notion that corneal clouding, bifid tongue, and DWM are part of the constellation of abnormalities caused by mutations in FLNA.


Subject(s)
Corneal Opacity/complications , Dandy-Walker Syndrome/complications , Tongue, Fissured/complications , Amino Acid Substitution/genetics , Brain/diagnostic imaging , Brain/pathology , Contractile Proteins/genetics , Craniofacial Abnormalities/complications , Craniofacial Abnormalities/diagnostic imaging , Craniofacial Abnormalities/genetics , Filamins , Hand Deformities, Congenital/complications , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/genetics , Humans , Infant, Newborn , Male , Microfilament Proteins/genetics , Mutation/genetics , Osteochondrodysplasias/complications , Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/genetics , Phenotype , Radiography
5.
Genet Med ; 12(6): 344-54, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20467323

ABSTRACT

PURPOSE: To create a practical desk reference for clinicians focused on the differential diagnosis of individuals presenting with features that suggest an inherited disorder of connective tissue. METHODS: We searched the medical literature for distinct clinical entities that shared clinical features with Marfan syndrome and other classical inherited disorders of connective tissue. RESULTS: Thirty-six distinct heritable disorders of connective tissue were identified that have overlapping features. These disorders were organized into two matrices according to clinical characteristics and according to causative genes. CONCLUSIONS: A broad differential diagnosis is emerging for individuals presenting with features suggestive of altered connective tissue. Recent advances in molecular genetics have aided in the delineation of these disorders.


Subject(s)
Connective Tissue/pathology , Marfan Syndrome/diagnosis , Diagnosis, Differential , Guidelines as Topic , Humans , Marfan Syndrome/genetics
6.
Pediatr Res ; 64(3): 240-5, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18535488

ABSTRACT

In mammals, the rate of somatic growth is rapid in early postnatal life but then slows with age, approaching zero as the animal approaches adult body size. To investigate the underlying changes in cell-cycle kinetics, [methyl-H]thymidine and 5'-bromo-2'deoxyuridine were used to double-label proliferating cells in 1-, 2-, and 3-wk-old mice for four weeks. Proliferation of renal tubular epithelial cells and hepatocytes decreased with age. The average cell-cycle time did not increase in liver and increased only 1.7 fold in kidney. The fraction of cells in S-phase that will divide again declined approximately 10 fold with age. Concurrently, average cell area increased approximately 2 fold. The findings suggest that somatic growth deceleration primarily results not from an increase in cell-cycle time but from a decrease in growth fraction (fraction of cells that continue to proliferate). During the deceleration phase, cells appear to reach a proliferative limit and undergo their final cell divisions, staggered over time. Concomitantly, cells enlarge to a greater volume, perhaps because they are relieved of the size constraint imposed by cell division. In conclusion, a decline in growth fraction with age causes somatic growth deceleration and thus sets a fundamental limit on adult body size.


Subject(s)
Cell Cycle/physiology , Cell Proliferation , Kidney/cytology , Kidney/growth & development , Liver/cytology , Liver/growth & development , Animals , Animals, Newborn , Body Size , Bromodeoxyuridine , Cell Enlargement , Hydrogen , Male , Mice , Mice, Inbred C57BL , Organ Size , Thymidine , Time Factors , Tritium
7.
Development ; 132(23): 5173-83, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16251209

ABSTRACT

During appendage regeneration in urodeles and teleosts, tissue replacement is precisely regulated such that only the appropriate structures are recovered, a phenomenon referred to as positional memory. It is believed that there exists, or is quickly established after amputation, a dynamic gradient of positional information along the proximodistal (PD) axis of the appendage that assigns region-specific instructions to injured tissue. These instructions specify the amount of tissue to regenerate, as well as the rate at which regenerative growth is to occur. A striking theme among many species is that the rate of regeneration is more rapid in proximally amputated appendages compared with distal amputations. However, the underlying molecular regulation is unclear. Here, we identify position-dependent differences in the rate of growth during zebrafish caudal fin regeneration. These growth rates correlate with position-dependent differences in blastemal length, mitotic index and expression of the Fgf target genes mkp3, sef and spry4. To address whether PD differences in amounts of Fgf signaling are responsible for position-dependent blastemal function, we have generated transgenic fish in which Fgf receptor activity can be experimentally manipulated. We find that the level of Fgf signaling exhibits strict control over target gene expression, blastemal proliferation and regenerative growth rate. Our results demonstrate that Fgf signaling defines position-dependent blastemal properties and growth rates for the regenerating zebrafish appendage.


Subject(s)
Fibroblast Growth Factors/physiology , Regeneration/physiology , Signal Transduction , Animals , Animals, Genetically Modified , Gene Expression Regulation, Developmental , Growth , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Protein Tyrosine Phosphatases/genetics , Time Factors , Zebrafish , Zebrafish Proteins/genetics
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