An understanding of the role of inherited cancer predisposition syndromes in pediatric tumor diagnoses continues to develop as more information is learned through the application of genomic ...technology. Identifying patients and their relatives at an increased risk for developing cancer is an important step in the care of this patient population. The purpose of this review is to highlight various tumor types that arise in the pediatric population and the cancer predisposition syndromes associated with those tumors. The review serves as a guide for recognizing genes and conditions to consider when a pediatric cancer referral presents to the genetics clinic.
We present a series of seven patients who were previously diagnosed with Proteus syndrome, but who do not meet published diagnostic criteria for this disorder and whose natural history is distinct ...from that of Proteus syndrome. This newly recognized phenotype comprises progressive, complex, and mixed truncal vascular malformations, dysregulated adipose tissue, varying degrees of scoliosis, and enlarged bony structures without progressive bony overgrowth. We have named this condition congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) on a heuristic basis. In contrast to the bony distortion so characteristic of Proteus syndrome, distortion in CLOVE syndrome occurs only following major or radical surgery. Here, we contrast differences and similarities of CLOVE syndrome to Proteus syndrome.
The medical care of patients affected by rare disorders depends heavily on experiences garnered from prior cases, including those patients evaluated by the treating physician and those published in ...the medical literature. The utility of published cases is wholly dependent upon accurate diagnosis of those patients. In our experience, the rate of misdiagnosis in Proteus syndrome (PS) is high. Diagnostic criteria have been published, but these criteria have not been applied consistently and were published after many case reports appeared in the literature. We reviewed 205 cases of individuals reported to have PS in the literature and three of us independently applied the diagnostic criteria to these case reports. Our initial diagnostic congruence was 97.1% (199/205); the discrepancies in six cases were easily resolved. Only 97 (47.3%) of reported cases met the diagnostic criteria for PS; 80 cases (39%) clearly did not meet the criteria; and although 28 cases (13.7%) had features suggestive of PS, there were insufficient clinical data to make a diagnosis. Reported cases that met the PS criteria had a higher incidence of premature death, and other complications (scoliosis, megaspondyly, central nervous system abnormalities, tumors, otolaryngologic complications, pulmonary cystic malformations, dental and ophthalmogic complications) compared to those in the non-Proteus group. The cases that met the criteria were more often male, which has implications for hypotheses regarding the etiology and pathophysiology of PS. We also studied the attributes that led authors to conclude the reported patients had PS when we concluded they did not. We found that two of the diagnostic criteria (disproportionate overgrowth and connective tissue nevi) were often misinterpreted. In PS, the abnormal growth is asymmetric, distorting, relentless, and occurred at a faster rate compared to the rest of the body. Furthermore, PS was associated with irregular and disorganized bone, including hyperostoses, hyperproliferation of osteoid with variable calcification, calcified connective tissue, and elongation of long bones with abnormal thinning. In contrast, non-Proteus cases displayed overgrowth that was asymmetric but grew at a rate similar to the growth found in unaffected areas of the body. Also, the overgrowth in non-Proteus cases was associated with normal or enlarged bones together with ballooning of the overlying soft tissues. Taken together, these data show that (1) PS diagnostic criteria sort individuals with asymmetric overgrowth into distinct groups; (2) individuals with PS were more likely to have serious complications; (3) PS affects more males than females; and 4) the published diagnostic criteria are useful for clinical care and research. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.
Video game playing has become a very popular activity among adolescents. Its impact on the mental health and well-being of players is just beginning to be explored. This paper reports on the ...prevalence of problematic gaming in a representative sample of 2,832 Ontario students in grades 7 to 12. The survey included questions about the school grade, family and school related problems, frequency of video game playing and video game related problems as measured by the Problem Video Game Playing scale (PVP). Most of the students (85 %) reported playing video games in the past year and 18.3 % reported playing video games daily. Slightly less then 1 in 10 of the students (9.4 %) endorsed 5 or more of the PVP items (males 15.1 %; females 3.1 %). Further research is required to delineate the concept of excessive video game playing, its relation to other addictions, and the impact on adolescents’ psychosocial functioning.
Purpose: Hypothalamic hamartomas (HHs) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with ...other findings associated with Pallister‐Hall syndrome (PHS), have a more benign course.
Methods: Thirty‐seven of 40 PHS patients and 16 of 16 patients with isolated HH had a lesion confirmed on magnetic resonance imaging (MRI). Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, number of antiepileptic medications (AEDs) at the time of evaluation, past AEDs, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems.
Results: All isolated HH patients had a history of seizures, compared with 13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than those in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than were PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH.
Conclusions: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurologic dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well‐controlled seizures and other endocrine disturbances than precocious puberty. Patients with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered.
Evolution of skin lesions in Proteus syndrome Twede, James V.; Turner, Joyce T.; Biesecker, Leslie G. ...
Journal of the American Academy of Dermatology,
05/2005, Volume:
52, Issue:
5
Journal Article
Peer reviewed
Proteus syndrome is a rare overgrowth disorder that is generally progressive, but the natural history of the skin lesions is not known.
Our purpose was to document the evolution of 4 common skin ...lesions in 16 patients with Proteus syndrome.
Most epidermal nevi and vascular malformations were reported to appear in the first month of life and had little tendency for expansion or development of additional lesions. Subcutaneous lipomas and cerebriform connective tissue nevi were commonly noted in the first year of life, but not in the first month. Most patients reported that subcutaneous lipomas and cerebriform connective tissue nevi progressively increased in size, and in most patients additional lesions developed at new locations. Of the 4 types of skin lesions, plantar cerebriform connective tissue nevi were most frequently cited as a source of symptoms.
Skin lesions of Proteus syndrome may not appear until later infancy or early childhood, making it difficult to diagnose in young children.
Proteus syndrome: misdiagnosis with PTEN mutations Cohen, Jr, M Michael; Turner, Joyce T; Biesecker, Leslie G
American journal of medical genetics. Part A,
2003-Nov-01, Volume:
122A, Issue:
4
Journal Article
Contiguous gene syndromes cause disorders via haploinsufficiency for adjacent genes. Some contiguous gene syndromes (CGS) have stereotypical breakpoints, but others have variable breakpoints. In CGS ...that have variable breakpoints, the extent of the deletions may be correlated with severity. The Greig cephalopolysyndactyly contiguous gene syndrome (GCPS-CGS) is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes. In addition, non-CGS GCPS can be caused by deletions or duplications in GLI3. Although fluorescence in situ hybridisation (FISH) can identify large deletion mutations in patients with GCPS or GCPS-CGS, it is not practical for identification of small intragenic deletions or insertions, and it is difficult to accurately characterise the extent of the large deletions using this technique. We have designed a custom comparative genomic hybridisation (CGH) array that allows identification of deletions and duplications at kilobase resolution in the vicinity of GLI3. The array averages one probe every 730 bp for a total of about 14 000 probes over 10 Mb. We have analysed 16 individuals with known or suspected deletions or duplications. In 15 of 16 individuals (14 deletions and 1 duplication), the array confirmed the prior results. In the remaining patient, the normal CGH array result was correct, and the prior assessment was a false positive quantitative polymerase chain reaction result. We conclude that high-density CGH array analysis is more sensitive than FISH analysis for detecting deletions and provides clinically useful results on the extent of the deletion. We suggest that high-density CGH array analysis should replace FISH analysis for assessment of deletions and duplications in patients with contiguous gene syndromes caused by variable deletions.
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