Phelan-McDermid Syndrome

What is Phelan-McDermid syndrome?

Phelan-McDermid Syndrome is a genetic syndrome caused by the disruption of SHANK3/ProSAP2 gene on the terminal end of the chromosome 22. The most common form of Phelan-McDermid is caused by a de novo chromosomal deletion. As such the original name for PMS was 22q13 deletion syndrome.⁽⁸⁾

Signs and Symptoms

Phelan-McDermid syndrome can be characterized by moderate to a profound mental retardation. Speech is typically absent or severely delayed in this syndrome. Receptive communication is more advanced than expressive language. Individuals are delayed in acquisition of skills required to the coordination of mental and the muscular activity.

Most infants with this syndrome exhibit intrauterine growth with normal to above average growth after birth which is called postnatal. Children also experience significant delay in reaching early developmental milestones such as rolling over, crawling and walking. ^(10),(8)

The symptoms also include:

Facial features:

• long head shape –dolicocephaly
• large/prominent ears
• full brow
• long eyelashes
• flat midface
• wide nasal bridge
• bulbous nose
• deepset eyes
• full or puffy eyelids
• droopy eyelids—ptosis
• full or puffy cheeks
• pointed chin
• Minor dimorphic

Behaviour features:

• tactile defensiveness
• anxiety in social situations
• avoidance of eye contact
• self-stimulatory behavior
• increased tolerance to pain
• obsessive chewing of non-food items.

Other features:

• large hands
• underdeveloped toe nails—dysplastic^{(2)(4),(5),(8)}

Causes

Blood test to check both parents’ chromosomes is essential to find out why 22q13 deletion occurred. In around 80% of published cases, the 22q13 deletions occur when both the parents have normal chromosomes. The term that geneticists use for this is de novo. De novo 22q13 deletions are caused by a change that occurs when the parents sperm or egg cells were formed. Some of 22q13 deletions are accompanied by gain of material from another chromosome. It may also cause as a result of a rearrangement in one parent’s chromosomes. This rearrangement is known as a balanced translocation in which the material has swapped places between chromosomes.

Chromosome change due to environmental dietary or lifestyle factors are not known. De novo 22q13 deletions are caused by a sporadic mistake that occur when the parents sperm or egg cells are formed. The other way that a deletion and a duplication could theoretically arise during the formation of egg or sperm cells. Two matching chromosomes(left) split into the centromere each, ready to pair and exchange segments. The shaded bars show the similar sequences of DNA in the chromosome that enable correct pairing. When the chromosomes separate (right), the impairing has given rise to two normal and two abnormal chromosomes, one with a deletion and the other with duplication. ^(3),(7),(1)

Can it happen again?

Possibility of having another pregnancy with a 22q13 deletion depends on parents’ chromosomes. If both the parents have normal chromosomes, the deletion is very unlikely to happen again. If either of the parents has a chromosome rearrangement involving 22q13, the possibility is greatly increased of having other affected pregnancies.

In such cases parents have the opportunity to consult a genetic counsellor to discuss the specific recurrence risks for prenatal and preimplantation genetic diagnosis. it requires the use of in vitro fertilization and embryo biopsy and only healthy embryos are transferred to the mother’s uterus. If such parents choose to conceive naturally, prenatal diagnosis options include chorionic villus sampling (CVS) and amniocentesis to test the baby’s chromosomes. Testing is generally very accurate. But all of these tests may not be available in all parts of the world. ^(9),(10)(7)

Diagnosis

Phelan-McDermid syndrome can be diagnosis based on the demonstration of a deletion or disruption of the chromosome region 22q13. A simple deletion of 22q13 is often difficult to detect. Unbalanced translocations may be cryptic or hidden because 22q13 has been replaced by a chromosomal segment that is similar in size and staining pattern.

In these cases, fluorescence in situ hybridization, also known as FISH is required to detect the deletion. FISH is a molecular cytogenetic technique because it uses methods that are common to cytogenetic studies as well as methods common to molecular studies. FISH is recommended in addition to the chromosome studies to diagnosis Phelan-McDermid syndrome.

If the diagnosis of Phelan-McDermid syndrome is suspected and the chromosome studies appear normal based on clinical evaluation. Fluorescence in situ hybridization should be performed to confirm the diagnosis. FISH studies for deletion 22q13 are indicated in any infant with hypotonia of unknown cause and in older individuals with a history of hypotonia and absent speech.

Prenatal ultrasound finds no characteristic structural abnormalities that lead to the diagnosis of deletion 22q13. But some renal abnormalities have been detected in the fetuses that were found postnatally to have this syndrome. In some cases, the diagnosis of Phelan-McDermid syndrome can be determined before birth by specialized tests such as amniocentesis and chorionic villus sampling. ^{(1), (4),(6)}

The diagnosis may be carried out as follows:

Genetic Testing and Clinical Genetics

Genetic testing is necessary to confirm the diagnosis of Phelan-McDermid syndrome. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis. Terminal and interstitial deletions are too small to detect with this method. Chromosomal microarray should be ordered in children with suspected developmental delays. Most cases will be identified by microarray, however, small variations in genes might be missed.

For candidate gene evaluation the falling cost for whole exome sequencing may be replaced by DNA microarray technology. To rule out balanced translocations or inversions Biological parents should be tested with fluorescence in situ hybridization. Balanced translocation in a parent increases the risk for recurrence and heritability within families. Clinical dysmorphology exams and genetic evaluations should be done to evaluate pubertal development, growth, dysmorphic features and screen for organ defects.

Cognitive and Behavioral Assessment

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

Neurological Management

Individuals with Phelan-McDermid syndrome should be followed by a pediatric neurologist regularly to monitor coordination and gait, motor development, as well as conditions that might be associated with hypotonia. Until 36 months, head circumference should be performed routinely. To rule out seizure activity PMS and its overall negative impact on development, an overnight video EEG should be considered as early as possible. In addition to this, a baseline structural brain MRI should be considered to rule out the presence of structural abnormalities.

Nephrology

A voiding cystourethrogram and a baseline renal and bladder ultrasonography should be considered to rule out structural and functional abnormalities. Renal abnormalities are reported in up to 38% of patients with PMS.

The following are also observed in patients with PMS:

• Vesicouretral reflux
• hydronephrosis, renal agenesis
• dysplasic kidney
• polycystic kidney
• recurrent urinary tract infections

Cardiology

Congenital heart defects (CHD) are reported in samples of children with varying frequency with PMS up to 25%. The most common CHD include

• tricuspid valve regurgitation
• atrial septal defects
• patent ductusarteriousus
• Cardiac evaluation
• echocardiography
• electrocardiogram

Gastroenterology

In individuals with PMS Gastrointestinal symptoms are common. The following are observed frequently:

• Gastroesophageal reflux
• Constipation
• Diarrhea
• Cyclic vomiting ^(7),(9)

Treatment

Individuals diagnosed with Phelan-McDermid Syndrome benefit from various types of therapies at various stages in their lives. Many parents find that an early intervention is a big help in developing skills in their children. Some of the therapies that can benefit individuals with PMS are Physical Therapy, Speech Therapy, Occupational Therapy, Hydrotherapy and Music Therapy.

Medical Terminology

• Clinical scientist— Oversees specialist tests for managing and diagnosing disease. They advise on interpreting data, tests, and carry out research to understand.
• Biomedical scientist—Analyze specimen to provide data to help the doctors diagnose and treat disease.
• Geneticist—- Assesses the impact of changes in structure and the possibility of passing a genetic problem from one generation to the next.
• Dieticians—-Uses the science of nutrition to devise eating plans for patients to treat medical conditions. They promote good health by helping to facilitate a positive change in food choices.
• Neurology—- Assess and treat the function of the brain, nerves and brain or nervous control of the body.
• Health Visitors—- Helps to promote health, offering health promotion and health education usually for children.
• Nurses— Registered in one or more than one of four areas, Adult health, Children’s Health, Learning Disability and Mental Health. Nurses can become specialists, educators and case managers.
• Pediatrics—- Take care of children usually under the age of 18 or 14.
• Paramedics—– Specialist care and give treatment to patients who are injured. They can administer a range of drugs and carry out certain surgical techniques.
• Physician—- An authorized practitioner of medicine who graduates from a college of medicine or osteopathy and licensed by the appropriate board; one who practices medicine as distinct from surgery. Their site gives good information about expectations for the conduct and skills of medical professionals.
• Pharmacists—– Working in a community, hospitals and group health environments, educate and support people to understand and make good use of medications and treatments prescribed by themselves and other practitioners.
• Rehabilitation—- Focused on helping people with chronic problem that disrupts the function to cope with and overcome the impact of their difficulties or limitations.
• Practitioner psychologists—- Attempt to understand the role of mental functions in an individual and their social behaviour, to improve wellbeing of the individual.
• Rehabilitation—- Focused on helping people with chronic problem that disrupts the function to cope with and overcome the impact of their difficulties or limitations.

Therapy

• Applied behavior analysis –– Behavior analysts focus on the observable relationship of behavior to the environment to the exclusion of what they call hypothetical constructs.
• Arts therapists —- Encourage the patients to express their feelings and emotions through art such as painting and drawing, drama or music.
• Hydrotherapy —Provides a warm, relaxed atmosphere for treating chronic and acute conditions. The optimum temperature of 34°C provides muscle relaxation which helps to decrease pain and increase range of movement and muscle activity. The main aim is to strengthen muscles and enhance core stability to restore or improve function.
• Occupational therapists— Specific activities are used to promote independence in all aspects of daily life. Provides and advises on adaptations, aids, and equipment to make things easier.
• Physiotherapists— Deals with human function and help to achieve full physical potential. They use physical approaches to maintain and restore wellbeing.
• Play specialists— Helps children understand and master their feelings using therapeutic activities like theatre procedures, to understand a child’s feelings and needs expressed through play. They support therapeutic activity.
• Speech and language therapists— Assesses, treats and helps with language, speech and swallowing difficulties.

Alternative Therapies

Complementary therapies are those instead of conventional therapies.

• Acupuncture— Use heat, electricity and direct needle penetration of energy points to treat pain
• Aromatherapy– Use fragranced oils and resins to provoke the body’s own defences and systems
• Chiropractor– To restore equilibrium and improve function
• Homeopathy– Using minute quantities of substances to provoke body’s own response
• Hypnotherapy– Treat conditions such as pain sleep problems, nightmares, etc.
• Massage therapy– Support and improve health relaxation and function.
• Osteopathy–Looks to improve the structure and function of bone, ligaments, muscles and tendons.
• Prevention

Appropriate evaluations provide important information on targets for early intervention and prevention for the best clinical practices. Establishing natural history of PMS is also an important step toward designing effective clinical trials.

Prognosis

Almost all the people with Phelan-McDermid syndrome need assistance for daily living and require medical support throughout their life. Individuals with Phelan-McDermid syndrome may survive into adult life.

References:

1. Aldinger KA; et al. (2013). “Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion.”. Am J Med Genet A. 161 (1): 131–6
2. Anderlid, Britt-Marie; Schoumans, Jacqueline; Annerén, Göran; Tapia-Paez, Isabel; Dumanski, Jan; Blennow, Elisabeth; Nordenskjöld, Magnus (2002-05-01).
3. Boccuto, Luigi; Lauri, Maria; Sarasua, Sara M.; Skinner, Cindy D.; Buccella, Daniela; Dwivedi, Alka; Orteschi, Daniela; Collins, Julianne S.; Zollino, Marcella (2013-03-01).
4. Cusmano-Ozog, Kristina; Manning, Melanie A.; Hoyme, H. Eugene (2007-11-15)
5. Durand, Christelle M.; Betancur, Catalina; Boeckers, Tobias M.; Bockmann, Juergen; Chaste, Pauline; Fauchereau, Fabien; Nygren, Gudrun; Rastam, Maria; Gillberg, I. Carina (2007-01-01)
6. Napoli E; et al. (2012). “Mitochondrial Dysfunction in Pten Haplo-Insufficient Mice with Social Deficits and Repetitive Behavior: Interplay between Pten and p53.”. PLoS One. 7(8): 1–13.
7. Phelan K, Boccuto L, Rogers RC, Sarasua SM, McDermid HE (2015). “Letter to the editor regarding Disciglio et al.: interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome.”. Am J Med Genet A. 167 (7): 1679–80.
8. Phelan MC, Rogers RC, Saul RA, et al. (2001). “22q13 deletion syndrome”. Am. J. Med. Genet. 101 (2): 91–9.
9. Shcheglovitov A; et al. (2013). “SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.”. Nature. 503 (7475): 267–71.
10. Simenson K; et al. (2013). “A patient with the classic features of Phelan-McDermid syndrome and a high immunoglobulin E level caused by a cryptic interstitial 0.72-Mb deletion in the 22q13.2 region.”. Am J Med Genet A. 164A (3): 806–9.