Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is a multisystem autosomal dominant genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes, and characterized by benign, highly vascular, hamartoma growths. Lesions occur in the eyes, brain, kidneys, heart, liver, lungs and skin, leading to seizures and epilepsy, intellectual disability, autism, and renal and pulmonary complications (Gomez et al, 1999; Astrinidis and Henske, 2005; Inoki et al, 2005; Kwiatkowski and Manning, 2005). The brain is almost invariably affected and brain lesions are the primary cause of morbidity in this disease in childhood.

Symptoms
The most common symptoms of TSC are seizures and developmental delay as well as benign tumors and lesions which can affect virtually every organ system of the body including the brain, kidneys, heart, lungs, eyes, skin, and other organs. In many instances, symptoms of TSC will be apparent in the first six months of life.

Diagnosis
Clinical diagnosis of TSC is based on a careful physician exam in combination with imaging of the brain, heart and kidneys. The physician will carefully examine the skin for the wide variety of skin lesions, often using an ultraviolet light called a Wood’s lamp which may be useful for finding skin features that can be hard to see on infants or individuals with pale skin.

There is no single clinical feature absolutely specific to the condition. In addition, many features of TSC, such as seizures and developmental delay, are seen in individuals without TSC. Therefore, a constellation of features is necessary for the diagnosis, and an increasing number of features make the clinical suspicious of TSC more likely. Please refer to for a summary of the clinical and genetic diagnostic criteria: http://www.tsalliance.org/pages.aspx?content=10.

Recently, genetic testing for TSC has become more readily available, and a positive genetic test can be considered diagnostic.

Treatment and Prognosis
There is no cure for TSC, though symptoms can be managed through a number of treatments. Anti-epileptic medications are available to control seizures. Afinitor can be used to treat SEGAs and kidney AMLs. Other treatments include medications for skin findings and medications or interventional treatments for behavioral problems associated with TSC. Surgery may be required for complications related to brain lesions such as cortical tubers, SENs, or SEGAs.

Phelan-McDermid Syndrome
Phelan-McDermid Syndrome or 22q13.3 deletion syndrome is caused by deletions of 22q13 or disruption/mutation of the SHANK3 gene. Phelan-McDermid Syndrome is characterized by hypotonia, global developmental delay/intellectual disability, motor skills deficits, delayed or absent speech and ASD. The SHANK3 gene codes for the SHANK3 protein which is involved in brain development and synaptic functioning. A loss of the SHANK3 gene interrupts neuronal communication and results in a decrease of synaptic signaling.

Symptoms
The table below reflects the features and incidence of Phelan-McDermid Syndrome.

http://www.ncbi.nlm.nih.gov/books/NBK1198/

Diagnosis
PMS is diagnosed by the results of genetic testing demonstrating a deletion or mutation of the SHANK3 gene.

Treatment and Prognosis
Symptoms of Phelan-McDermid Syndrome can be managed through a number of treatments. Anti-epileptic medications are available to control seizures. Behavioral interventions, physical and occupational therapies, speech and communication therapies are available treatment options for managing symptoms of PMS.

PTEN Hamartoma Tumor Syndrome (PHTS)
PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome. PTEN hamartoma tumor syndrome (PHTS) is characterized by hamartomatous tumors and germline PTEN pathogenic variants.

Symptoms
The most common symptoms of PHTS are benign tumors and lesions which can affect virtually every organ system of the body, global delay, and macrocephaly and autism spectrum disorder.

For more in depth clinical descriptions please refer to Eng C. PTEN Hamartoma Tumor Syndrome (PHTS) Jan 23, 2014 at http://www.ncbi.nlm.nih.gov/books/NBK1488/.

Diagnosis
PHTS may be suspected based on a number of clinical features. A definitive diagnosis of PHTS is made only when a PTEN pathogenic variant is identified.

Treatment and Prognosis
As the clinical manifestations of PHTS are variable, so are the treatment and prognosis. Management of symptoms vary from case to case, however, all individuals with PHTs should be monitored and imaged regularly for changes in their current symptoms or emergence of any new symptoms such as tumor growth.