Study on phelan mcdermid syndrome

Study on phelan mcdermid syndrome Seventy-five percent of individuals with Phelan-McDermid Syndrome have pure 22q deletions, which are either terminal or interstitial. A terminal deletion involves a single break in the long arm of chromosome 22 that removes the distal portion. An interstitial deletion occurs when two breaks occur within the long arm of chromosome 22 and only the segment between the two breaking points is lost. In Phelan-McDermid Syndrome, terminal deletions occur more commonly than interstitial. As is the case for many other terminal deletion syndromes, the pure deletions most often occur on the chromosome that is inherited paternally. The remaining 25 percent of individuals with Phelan-McDermid Syndrome have deletions that result from other structural translocations or rearrangements (Phelan, 2007; Bonaglia et al., 2006). The mode of inheritance for 80 percent of affected individuals is a de novo chromosome deletion (Phelan, 2007). A de novo chromosome deletion is an anomaly that occurs in the individual and is not inherited from the parents, who have normal karyotypes (National Human Genome Research Institute, 2010). Thus, the recurrence risk of Phelan-McDermid Syndrome for the future pregnancies of parents with normal karyotypes is highly unlikely. However, about 20 percent of affected individuals experience a familial mode of inheritance in which one parent passes on an unbalanced chromosome. When a familial mode of inheritance is involved, there is an increased risk of having other affected pregnancies. Therefore, it is highly recommended for these parents to receive genetic counseling in order to address future recurrence risks (Cusmano-Ozog, Manning, Hoyme, 2007; Robin, 2008). Individuals with Phelan-McDermid Syndrome share a common phenotype that includes hypotonia, global developmental delay, normal to accelerated growth, severely delayed to absent expressive language, autistic-like behaviors, and dysmorphic features (ONeill, Kniffin, Hamosh, Dolan, McKusick, 2009). The first presenting symptoms of the syndrome, which begin to become evident during infancy, are usually hypotonia, feeding problems, and developmental delay (Phelan, 2008). Typical craniofacial characteristics of individuals with this syndrome include a high forehead, a disproportionately long and narrow head, puffy and drooping eyelids, large ears, a smooth philtrum without Cupids bow, a wide nasal tip, and a pointed chin. (Manning et al., 2004; Cusmano-Ozog, Manning, Hoyme, 2007). Other common physical traits are large, fleshy hands, swollen feet, syndactyly of the toes, and a chronic lack of perspiration that often leads to overheating (Havens, Visootsak, Phelan, Graham, 2004). Althoug h chronic otitis media is common, most individuals with this syndrome have normal hearing (Phelan, 2007). As noted, autistic-like behaviors are present. These include poor eye contact, self-stimulatory actions, tactile sensitivity, and a decreased interest in socializing. It has been suggested that Phelan-McDermid Syndrome is a type of syndromic autism (Phelan, 2008). Additional behavioral aspects present include an increased tolerance to pain, frequent mouthing and chewing of non-food objects, hyperactivity, short attention span, and, at times, aggression (Havens, Visootsak, Phelan, Graham, 2004; Philippe et al., 2008). Most individuals with Phelan-McDermid Syndrome experience a severe to profound intellectual disability (Phelan, 2007). The degree of phenotype expression and severity of Phelan-McDermid Syndrome are dependent upon the size of the deletion (Manning et al., 2004). The size of deletion varies from a very small 100 kilobases to a substantial 9 megabases. One hundred kilobases are equivalent to 100,000 deleted base pairs of DNA, and 9 megabases are equivalent to 9 million deleted base pairs of DNA (Phelan, 2008). Prasad and colleagues (2000) presented case studies of individuals affected by Phelan-McDermid Syndrome. Of their case studies, the patient with the largest deletion presented the most severe developmental delay in addition to other comorbid features, such as seizures. Recent findings have suggested that deletion of the SHANK3 gene, which is also called PROSAP2, is responsible for the neurological features of global developmental delay and severely delayed to absent expressive language that are demonstrated in individuals affected by Phelan-McDermid Syndrome (Durrand et al., 2007). The SHANK3 gene belongs to a family of proteins and it is involved in the formation and maintenance of synapses. This gene is located in the critical region for this syndrome, 22q13.3, and a deletion of the SHANK3 gene has been present in all reported cases of the syndrome. In fact, a SHANK3 gene deletion hot spot has been identified in numerous unrelated cases where the breakpoint has occurred in an essentially identical location. However, it is important to note that individuals who have the same type of SHANK3 gene deletion will still present different degrees of severity in their phenotype due to other confounding factors (Bonaglia et al., 2006). The first diagnosed case of Phelan-McDermid Syndrome was documented in 1985 (Prasad et al., 2000), and, since then, there have been more than 500 cases identified worldwide (Unique, 2008). Among the documented cases, the age at which individuals have been diagnosed with this syndrome has widely ranged from prenatally (with the use of amniocentesis) to 46 years of age (Cusmano-Ozog, Manning, Hoyme, 2007). Reportedly, the deletion does not have a gender preference as it is equally frequent in males and females. Because no life-threatening characteristics are associated with this syndrome, overall life expectancy is considered to be normal (Unique, 2008). This syndrome is highly under-diagnosed due to clinical and laboratory difficulties. Therefore, its true incidence is unknown. At the clinical level, healthcare professionals may be unfamiliar with or fail to notice the phenotypical characteristics associated with this syndrome that would warrant a referral for further cytogenetic testing (Phelan et al., 2001). Also, at the laboratory level, the deletion is often subtle and it can be undetected by a routine chromosome analysis. In fact, over 30% of individuals with Phelan-McDermid Syndrome have required two or more chromosome analyses to discover the deletion (Phelan, 2008). Thus, enhanced molecular cytogenetic testing, such as fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (array CGH), are utilized to verify the presence of the 22q13.3 deletion (Feenstra, Brunner, Van Ravenswaaij, 2006; Sathyamoorthi et al., 2009). FISH and array CGH are used to detect the deletion of a specific genetic segment in the chromosome that goes undetected due to its small size. These tests differ in that FISH focuses on a specific genomic region, while array CGH is able to focus on a specific region and test hundreds of additional genomic regions simultaneously during one experiment (Robin, 2008). By aiding in the detection of the 22q13.3 deletion, FISH and array CGH also assist in the differential diagnosis of Phelan-McDermid Syndrome. Several of its phenotypical features, such as hypotonia and global developmental delay, are also common features that are found in other disorders. Individuals with Phelan-McDermid Syndrome are often initially misdiagnosed with another condition until further testing is conducted. This syndrome is most commonly misdiagnosed as Angelman Syndrome or Velocardiofacial Syndrome (Phelan, 2008). Management Phelan-McDermid Syndrome is a life-long condition, and its management involves the assistance of several healthcare professionals. Among these professionals are the primary care physician, clinical geneticist, neurologist, physical therapist, and speech-language pathologist. The following are some of the responsibilities of these professionals with regard to this syndrome. In addition to providing routine medical treatment, the primary care physician is involved in noting the clinical presentation of the syndromes phenotype and referring a patient for genetic testing. The clinical geneticist is responsible for performing the cytogenetic testing that is necessary to confirm the diagnosis of Phelan-McDermid Syndrome. The neurologist and physical therapist will often work together to treat the hypotonia (Cusmano-Ozog, Manning, Hoyme, 2007; Phelan, 2008). Role of the Speech-Language Pathologist The hypotonia that begins to become evident during infancy usually results in feeding and swallowing difficulties. Thus, a speech-language pathologist is often necessary for the purpose of feeding and swallowing evaluations and intervention. Several behavioral aspects, such as hyperactivity, self-stimulatory actions, and attention difficulties, are often treated with medication. However, in addition to the physicians pharmacological approach, a speech-language pathologist can also help with the implementation of functional alternatives to these challenging behaviors. A speech-language pathologist will also focus on addressing the negative pragmatic aspects of this syndrome that include aversion to socializing and aggressiveness (Phelan, 2008). Many studies have found that individuals with Phelan-McDermid Syndrome have receptive language skills that are significantly greater than their expressive language abilities. Thus, these individuals often benefit from the use of augmentative and alternative communication (AAC) systems. A speech-language pathologist can implement the use of AAC systems, such as a simple picture card system, so that individuals with Phelan-McDermid Syndrome who have significant language delays are able to better communicate with those around them (Havens, Visootsak, Phelan, Graham, 2004). Picture exchange communication systems (PECs), computer touch screens, and voice based systems are most commonly recommended for these individuals because these systems are compatible with their needs and the presence of hypotonia, which makes it difficult to communicate through other methods, such as sign language (Unique, 2008). In conclusion, individuals with Phelan-McDermid Syndrome exhibit a common phenotype that includes several cognitive, behavioral, and physical aspects. This syndrome is a life-long condition, and its management requires the help of a multidisciplinary team of professionals. The role of the speech-language pathologist in this syndrome is especially important due to the feeding and swallowing difficulties, challenging behaviors, and the significant communicative impairment experienced by individuals affected by Phelan-McDermid Syndrome.