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Disorder Definitions

Tuberous Sclerosis Complex (TSC)

Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant genetic disorder caused by mutations in the TSC1 or TSC2 genes. It is characterized by benign, highly vascular, hamartoma growths. Lesions occur in the eyes, brain, kidneys, heart, liver, lungs and skin, leading to seizures, epilepsy, intellectual disability, autism, 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.


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.

Brain and Neurological Function:

In 95% of individuals with TSC, the brain is somehow affected. This usually takes the form of cortical tubers, subependymal nodules (SEN) and subependymal giant cell astrocytomas (SEGA), which can be detected by brain imaging.

Epilepsy is by far the most common medical condition in TSC, occurring in 80-90% of individuals. In about one-third of individuals with TSC, epilepsy starts out as infantile spasms. Peak onset occurs at about 4-6 months of age.

Individuals with TSC have an increased risk of having neurodevelopmental and behavioral impairment. Although approximately 50% of individuals with TSC have normal intelligence, developmental delay and learning disabilities are commonly found in children with TSC. Additionally, up to 60% of individuals with TSC can develop autism.


Skin lesions, including those found on the face, body and nails, are found in almost all individuals with TSC. The earliest sign may be white skin patches (hypomelanotic macules), which are best seen under ultraviolet light. As a child grows older, a characteristic facial rash across the nose and cheeks may appear.


Cardiac (heart) involvement is common in TSC and is found in up to 66% of the individuals. Benign heart tumors (cardiac rhabdomyomas) are often an early sign of TSC. Fortunately, these tumors often regress spontaneously, shrinking or completely disappearing with time.


Kidney lesions occur in over half of all children at the time of initial evaluation. Benign renal lesions, called angiomyolipomas, account for 75% of abnormalities, are made up of vascular tissue, smooth muscle, and fat. They usually grow very slowly and may not be problematic until young adulthood. Renal cysts are also common in TSC. Larger or numerous angiomyolipoma or cysts can reduce renal function or increase the risk for hypertension. Larger angiomyolipoma increases the likelihood of renal aneurysms that may cause bleeding or pain that if undiagnosed or untreated can be life-threatening.


Clinical diagnosis of TSC is based on a careful physical 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 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.

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. Pharmacologic inhibitors of mTOR, such as everolimus and sirolimus, can be used to treat SEGAs, refractory epilepsy, kidney angiomyolipoma, and LAM disease of the lungs. 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 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.


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

>95%Neonatal hypotonia
Global developmental delay
Absent or severely delayed speech
>75%Normal to accelerated growth
Large, fleshy hands
Dysplastic toenails
Long eyelashes
Decreased sensitivity to pain
Mouthing/chewing/tooth grinding
Autism/autistic-like behavior
Prominent or large ears
Full brow
Full or puffy cheeks
Full or puffy eyelids
Deep-set eyes
Flat midface
Wide nasal bridge
Bulbous nose
Pointed chin
Sacral dimple
Decreased perspiration with the tendency to overheat
Feeding difficulties
Renal problems
Gastroesophageal reflux
Malocclusion/wide-spaced teeth
Epicanthal folds
Long philtrum
High-arched palate


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) 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.


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


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.


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