Phelan-McDermid Syndrome

Phelan-McDermid syndrome (PMS), also known as 22q13.3 deletion syndrome, is a rare genetic condition characterized by a spectrum of symptoms that typically include neonatal hypotonia (i.e., decreased muscle tone in the newborn), intellectual disabilities, delayed or absent speech, and developmental delays. Individuals with PMS often also exhibit behavioral challenges, including difficulties with social interactions and repetitive behaviors. Other common features may involve seizures, renal malformations, dysmorphic facial features, and lymphedema. 

PMS is caused primarily by a deletion or mutation in the terminal end of the long arm of chromosome 22 that commonly results in a spontaneous (i.e., de novo) break in the 22q13.3 region of the chromosome and a loss or alteration of genetic material. These deletions, referred to as "simple deletions" aren't usually inherited from the parents; instead, they originate as a new genetic change in the developing embryo. 

The absence or mutation of specific genes within this region, particularly the SHANK3 gene, is associated with the characteristic features of PMS. SHANK3 is part of the larger family of Shank proteins and is specifically involved in the organization and regulation of the development of the nervous system. It helps to anchor specific receptors and signal molecules at the synapses, which are the connections between neurons in the brain and is essential for proper communication between neurons. While most cases of PMS are due to deletions in chromosome 22, there can be variations in the size and extent of the deletion or, in rarer cases, other genetic mutations that lead to this syndrome.

Phelan-McDermid syndrome presents a spectrum of symptoms that vary considerably among affected individuals. Facial characteristics of individuals with PMS include a long face with a rounded nose, a pointed chin, and large or low-set ears. Notably, neonatal hypotonia, characterized by low muscle tone, is among the first signs identified in individuals with PMS, which may also manifest as difficulty in feeding, weak crying, and poor head control. The associated hypotonia can contribute to motor delays and challenges with coordination and motor skills (e.g. rolling over, sitting, crawling, and walking). 

Intellectual difficulties, ranging from mild to severe, that impact cognitive functioning, are a common hallmark of PMS. Speech development is often significantly delayed, and some individuals may be unable to speak. Behavioral challenges are also prevalent in those with PMS, which include difficulties in social interactions, repetitive movements or behaviors such as mouthing or chewing non-food items and heightened sensory sensitivities evident from early childhood. 

Seizures may also be identified, varying in type and intensity. Sleep disturbances, including difficulties falling or staying asleep, have also been reported in individuals affected by PMS.

Diagnosing Phelan-McDermid syndrome involves a comprehensive approach that encompasses clinical evaluations and genetic testing. Initially, a thorough review of the individual's medical history and a physical examination are conducted to identify any distinct physical traits as well as behavioral or developmental patterns linked to PMS. Chromosomal microarray analysis (CMA), the primary diagnostic tool, can assess for deletions or mutations specifically where the SHANK3 gene is located on the 22q13.3 piece of chromosome 22 as well as for SHANK3 sequence variants. Next generation sequencing (NGS)-based methods, which refer to advanced genetic sequencing techniques that rapidly analyze DNA sequences allowing the simultaneous study of multiple genes, can also be used to identify such genetic alterations. The absence or alteration of genetic material in this region confirms the diagnosis of PMS. Depending on the case, additional assessments, such as neurological evaluations and electroencephalograms (EEGs), may be recommended to address specific symptoms or concerns. 

As there is no cure for PMS, treatment emphasizes addressing specific challenges associated with the syndrome in order to improve the individual’s quality of life. Early intervention services, such as occupational therapy, speech therapy, and physical therapy to aid in developmental delays and improve motor skills, communication, and daily living activities are vital. Behavioral interventions guided by healthcare professionals through social skills training or behavioral analysis play a significant role in managing behavioral symptoms. Management with anti-epileptic medication, like lamotrigine, carbamazepine, or lorazepam, may be needed for those who experience associated seizures.  

Continuous monitoring and care through regular follow-ups with healthcare professionals can ensure that individuals with Phelan-McDermid syndrome benefit from the best treatment plan. Each treatment plan is personalized and involves a multidisciplinary approach encompassing healthcare professionals, educators, therapists, and support groups to provide comprehensive care and support for individuals affected by PMS. Supportive services like counseling and support groups offer crucial emotional support, guidance, and resources to families and individuals affected by PMS. 

Phelan-McDermid Syndrome (PMS), or 22q13.3 deletion syndrome, is a rare genetic condition marked by intellectual disabilities, difficulties with or absent speech, and developmental delays. Behavioral challenges, facial characteristics, low muscle tone, seizures, and renal malformations are other common characteristics of this syndrome. PMS results from a spontaneous deletion in chromosome 22's long arm, causing changes in the SHANK3 gene, crucial for nervous system development. Diagnosis involves clinical evaluations and genetic testing, while treatment aims at managing symptoms. Early interventions, behavioral therapies, and medical management for seizures are key components. Regular follow-ups with a multidisciplinary team ensure personalized care and support.