1. Clinical Genetics and Genetic Testing

Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method. Chromosomal microarray should be ordered in children with suspected developmental delays or ASD. Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence "in situ" hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3).

Clinical genetic evaluations and dysmorphology exams should be done to evaluate growth, pubertal development, dysmorphic features (table 1) and screen for organ defects (table 2)

2. Cognitive and Behavioral Assessment

All patients should undergo comprehensive developmental, cognitive and behavioral assessments by clinicians with experience in developmental disorders. Cognitive evaluation should be tailored for individuals with significant language and developmental delays. All patients should be referred for specialized speech/language, occupational and physical therapy evaluations.

3. Neurological Management

Individuals with PMS should be followed by a pediatric neurologist regularly to monitor motor development, coordination and gait, as well as conditions that might be associated with hypotonia. Head circumference should be performed routinely up until 36 months. Given the high rate of seizure disorders (up to 41% of patients) reported in the literature in patients with PMS and its overall negative impact on development, an overnight video EEG should be considered early to rule out seizure activity. In addition, a baseline structural brain MRI should be considered to rule out the presence of structural abnormalities.

4. Nephrology

All patients should have a baseline renal and bladder ultrasonography and a voiding cystourethrogram should be considered to rule out structural and functional abnormalities. Renal abnormalities are reported in up to 38% of patients with PMS. Vesicouretral reflux, hydronephrosis, renal agenesis, dysplasic kidney, polycystic kidney and recurrent urinary tract infections have all been reported in patients with PMS.

5. Cardiology

Congenital heart defects (CHD) are reported in samples of children with PMS with varying frequency (up to 25%)(29,36). The most common CHD include tricuspid valve regurgitation, atrial septal defects and patent ductus arteriousus. Cardiac evaluation, including echocardiography and electrocardiogram, should be considered.

6. Gastroenterology

Gastrointestinal symptoms are common in individuals with PMS. Gastroesophageal reflux, constipation, diarrhea and cyclic vomiting are frequently described.

Table 3: Clinical Assessment Recommendations in Phelan McDermid Syndrome.

Diagnosis is based on clinical findings and can be confirmed by cytogenetic testing, when the deletion is in an average of 5 Mb (millions of base pairs). Nowadays is a common practice to run an aCHG (array chromosome hybridization genome) study on peripheral blood of the patient, in order to limit the extent of the loss of the genomic area, and the deleted genes.

Ring chromosome 14 syndrome is extremely rare, the true rate of occurrence is unknown (as it is "less than" 1 per 1,000,000), but there are at least 50 documented cases in the literature.

Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of ring 18 is usually made via a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible via amniocentesis or chorionic villus sampling.

Most individuals with this condition do not survive beyond childhood. Individuals with MDS usually die in infancy and therefore do not live to the age where they can reproduce and transmit MDS to their offspring.

Most affected people have a stable clinical course but are often transfusion dependent.

Diagnosis is achieved by examining the structure of the chromosomes through karyotyping; while once born, one can do the following to ascertain a diagnosis of the condition:

- MRI

- EEG

While no cure for MDS is available yet, many complications associated with this condition can be treated, and a great deal can be done to support or compensate for functional disabilities. Because of the diversity of the symptoms, it can be necessary to see a number of different specialists and undergo various examinations, including:

- Developmental evaluation

- Cardiologists evaluation

- Otolaryngology

- Treatment of seizures

- Urologic evaluation

- Genetic counseling-balanced chromosomal translocation should be excluded in a parents with an affected child are planning another pregnancy, so parents with affected children should visit a genetic counselor.

While no genetic syndrome is capable of being cured, treatments are available for some symptoms. External fixators have been used for limbic and facial reconstructions.

The ring 20 abnormality may be limited to as few as 5% of cells, so a screen for chromosomal mosaicism is critical. Newer array technology will not detect the ring chromosome and the standard metaphase chromosome analysis has been recommended. A karyotype analysis examining at least 50 cells should be requested to properly detect mosaicism.

At present, treatment for ring 18 is symptomatic, meaning that the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, it is suggested that people with ring 18 undergo routine screenings for thyroid, hearing, and vision problems.

Diagnosis is based on the distinctive cry and accompanying physical problems. These common symptoms are quite easily observed in infants. Affected children are typically diagnosed by a doctor or nurse at birth. Genetic counseling and genetic testing may be offered to families with individuals who have cri du chat syndrome. Prenatally the deletion of the cri du chat related region in the p arm of chromosome 5 can be detected from amniotic fluid or chorionic villi samples with BACs-on-Beads technology. G-banded karyotype of a carrier is also useful. Children may be treated by speech, physical and occupational therapists. Heart abnormalities often require surgical correction.

13q deletion syndrome can only be definitively diagnosed by genetic analysis, which can be done prenatally or after birth. Increased nuchal translucency in a first-trimester ultrasound may indicate the presence of 13q deletion.

Diagnosing Jacobsen Syndrome can be difficult in some cases because it is a rare chromosomal disorder. There are a variety of tests that can be carried out like karyotype, cardiac echocardiogram, a renal sonogram, a platelet count, blood count, a brain imaging study. Genetic testing can be carried out for diagnosis. In which chromosomes are stained to give a barcode like appearance and studied under the microscope which reveals the broken and deleted genes. It can also be diagnosed early in the prenatal stage if there are any abnormalities seen in the ultrasound. A simple assessment of the symptoms can be done to diagnose the Syndrome. A thorough physical examination could be carried out to assess the symptoms.

Lenalidomide has activity in 5q- syndrome and is FDA approved for red blood cell (RBC) transfusion-dependent anemia due to low or intermediate-1 (int-1) risk myelodysplastic syndrome (MDS) associated with chromosome 5q deletion with or without additional cytogenetic abnormalities. There are several possible mechanisms that link the haploinsufficiency molecular lesions with lenalidomide sensitivity.

The true prevalence of PMS has not been determined. More than 1200 people have been identified worldwide according the Phelan-McDermid Syndrome Foundation. However, it is believed to be underdiagnosed due to inadequate genetic testing and lack of specific clinical features. It is known to occur with equal frequency in males and females. Studies using chromosomal microarray for diagnosis indicate that at least 0.5% of cases of ASD can be explained by mutations or deletions in the "SHANK3" gene. In addition when ASD is associated with ID, "SHANK3" mutations or deletions have been found in up to 2% of individuals.

About 92% of pregnancies in Europe with a diagnosis of Down syndrome are terminated. In the United States, termination rates are around 67%, but this rate varied from 61% to 93% among different populations evaluated. When nonpregnant people are asked if they would have a termination if their fetus tested positive, 23–33% said yes, when high-risk pregnant women were asked, 46–86% said yes, and when women who screened positive are asked, 89–97% say yes.

Research on the risk for developing schizophrenia in Ashkenazi Jews and other populations showed that 3q29 microdeletion syndrome leads to a significant higher rate of schizophrenia.

When screening tests predict a high risk of Down syndrome, a more invasive diagnostic test (amniocentesis or chorionic villus sampling) is needed to confirm the diagnosis. If Down syndrome occurs in one in 500 pregnancies and the test used has a 5% false-positive rate, this means, of 26 women who test positive on screening, only one will have Down syndrome confirmed. If the screening test has a 2% false-positive rate, this means one of eleven who test positive on screening have a fetus with DS. Amniocentesis and chorionic villus sampling are more reliable tests, but they increase the risk of miscarriage between 0.5 and 1%. The risk of limb problems is increased in the offspring due to the procedure. The risk from the procedure is greater the earlier it is performed, thus amniocentesis is not recommended before 15 weeks gestational age and chorionic villus sampling before 10 weeks gestational age.

Two international research studies are currently underway. The International Genetic Study done with the Spinner Laboratory at The Children's Hospital of Philadelphia studies the ring 20 chromosome at the molecular level. The Clinical Research Study collects clinical information from parents to create a database of about the full spectrum of patients with ring chromosome 20 syndrome.

A clinical diagnosis of SCS can be verified by testing the TWIST1 gene (only gene in which mutations are known to cause SCS) for mutations using DNA analysis, such as sequence analysis, deletion/duplication analysis, and cytogenetics/ FISH analysis. Sequence analysis of exon 1 (TWIST1 coding region) provides a good method for detecting the frequency of mutations in the TWIST1 gene. These mutations include nonsense, missense, splice site mutation, and intragenic deletions/insertions. Deletion/duplication analysis identifies mutations in the TWIST1 gene that are not readily detected by sequence analysis. Common methods include PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA). Cytogenetic/FISH analysis attaches fluorescently labels DNA markers to a denatured chromosome and is then examined under fluorescent lighting, which reveals mutations caused by translocations or inversions involving 7p21. Occasionally, individuals with SCS have a chromosome translocation, inversion, or ring chromosome 7 involving 7p21 resulting in atypical findings, such as, increased developmental delay. Individuals with SCS, typically have normal brain functioning and rarely have mental impairments. For this reason, if an individual has both SCS and mental retardation, then they should have their TWIST1 gene screened more carefully because this is not a normal trait of SCS. Cytogenetic testing and direct gene testing can also be used to study gene/chromosome defects. Cytogenetic testing is the study of chromosomes to detect gains or losses of chromosomes or chromosome segments using fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization (CGH). Direct gene testing uses blood, hair, skin, amniotic fluid, or other tissues in order to find genetic disorders. Direct gene testing can determine whether an individual has SCS by testing the individual's blood for mutations in the TWIST1 gene.

Chromosomal deletion syndromes result from deletion of parts of chromosomes. Depending on the location, size, and whom the deletion is inherited from, there are a few known different variations of chromosome deletions. Chromosomal deletion syndromes typically involve larger deletions that are visible using karyotyping techniques. Smaller deletions result in Microdeletion syndrome, which are detected using fluorescence in situ hybridization (FISH)

Examples of chromosomal deletion syndromes include 5p-Deletion (cri du chat syndrome), 4p-Deletion (Wolf-Hirschhorn syndrome), Prader–Willi syndrome, and Angelman syndrome.

Although there is no cure for 13q deletion syndrome, symptoms can be managed, usually with the involvement of a neurologist, rehabilitation physician, occupational therapist, physiotherapist, psychotherapist, nutritionist, special education professional, and/or speech therapist. If the affected child's growth is particularly slow, growth hormone treatment can be used to augment growth. Plastic surgeries can repair cleft palates, and surgical repair or monitoring by a pediatric cardiologist can manage cardiac defects. Some skeletal, neurological, genitourinary, gastrointestinal, and ophthalmic abnormalities can be definitively treated with surgery. Endocrine abnormalities can often be managed medically. Special educators, speech and occupational therapists, and physiotherapists can help a child develop skills in and out of school.

3q29 microdeletion syndrome is a rare genetic disorder resulting from the deletion of a segment of chromosome 3. This syndrome was first described in 2005.

Surgery is an option to correct some of the morphological changes made by Liebenberg Syndrome. Cases exist where surgery is performed to correct radial deviations and flexion deformities in the wrist. A surgery called a carpectomy has been performed on a patient whereby a surgeon removes the proximal row of the carpal bones. This procedure removes some of the carpal bones to create a more regular wrist function than is observed in people with this condition.