What are the key differences between Tuberous Sclerosis Complex (TSC), Fragile X Syndrome (FXS), Rett Syndrome (RTT), Angelman Syndrome (AS), Prader-Willi Syndrome (PWS), and Smith-Lemli-Opitz Syndrome (SLOS)?

Key Differences Between Genetic Neurodevelopmental Syndromes

The key distinguishing features of these genetic neurodevelopmental disorders are their specific genetic causes, characteristic clinical presentations, and associated comorbidities, which guide diagnosis and management approaches.

Tuberous Sclerosis Complex (TSC)

• Autosomal dominant disorder caused by mutations in either TSC1 (hamartin) or TSC2 (tuberin) genes, resulting in hyperactivation of the mTOR pathway 1, 2
• Complete penetrance but variable expressivity, even within the same family 3
• Key clinical features include:
  • Multiple organ involvement with tumors in brain, skin, heart, lungs, and kidneys 2
  • Cortical tubers (considered a subtype of focal cortical dysplasia IIb) 3
  • Subependymal nodules and giant cell astrocytomas 3
  • Epilepsy (nearly universal and often refractory) 1
  • Neurodevelopmental disorders including autism spectrum disorder 2
• Diagnostic criteria include genetic testing for pathogenic variants in TSC1 or TSC2 and clinical features 3
• Treatment includes mTOR inhibitors for renal angiomyolipomas, brain subependymal giant cell astrocytomas, and pulmonary lymphangioleiomyomatosis 2

Prader-Willi Syndrome (PWS)

• Genetic disorder affecting chromosome 15q11-q13 on the paternally derived chromosome 3, 4
• Three main genetic mechanisms:
  • Paternal deletion of 15q11-q13 (>70% of cases) 3, 4
  • Maternal uniparental disomy (approximately 28% of cases) 3, 4
  • Imprinting defects (<2% of cases) 3
• Key clinical features include:
  • Neonatal hypotonia with poor suck and feeding difficulties 4
  • Developmental delay and intellectual disability 5
  • Hyperphagia and obesity in childhood 6
  • Hypogonadism and hypothalamic insufficiency 5
  • Characteristic behavioral phenotype with obsessive-compulsive symptoms 5
• Diagnosis through methylation analysis using Southern hybridization with methylation-sensitive SNRPN or PW71B probes 3, 4
• Management focuses on early intervention, growth hormone therapy, and behavioral management 4

Angelman Syndrome (AS)

• Genetic disorder affecting chromosome 15q11-q13 on the maternally derived chromosome 3
• Four genetic mechanisms:
  • Maternal deletion of 15q11-q13 (approximately 70% of cases) 3
  • Paternal uniparental disomy (3-5% of cases) 3
  • Imprinting defects (in about one-third of the remaining 25% of cases) 3
  • UBE3A gene mutations (remaining cases) 5
• Key clinical features include:
  • Severe cognitive and neurologic impairment 5
  • Seizures and ataxia 5
  • Minimal or absent speech 6
  • Happy demeanor with frequent laughter 6
  • Sleep disturbances 6
• Diagnosis through methylation analysis and UBE3A gene testing 3
• Management focuses on seizure control, physical and communication therapy 3

Fragile X Syndrome (FXS)

• X-linked genetic disorder caused by expansion of CGG trinucleotide repeats in the FMR1 gene 3
• Most common inherited cause of intellectual disability 3
• Key clinical features include:
  • Moderate to severe intellectual disability, more severe in males 3
  • Characteristic physical features: long face, large ears, prominent jaw 3
  • Behavioral issues including attention deficit, hyperactivity, and autism spectrum features 3
  • Macro-orchidism in post-pubertal males 3
• Diagnosis through FMR1 gene testing 3
• Management includes educational interventions, behavioral therapy, and treatment of associated conditions 3

Rett Syndrome (RTT)

• X-linked dominant disorder primarily affecting females, caused by mutations in the MECP2 gene 3
• Key clinical features include:
  • Normal early development followed by regression of acquired skills 3
  • Loss of purposeful hand movements with development of stereotypic hand movements 3
  • Impaired language and communication 3
  • Breathing abnormalities and seizures 3
  • Scoliosis and growth failure 3
• Diagnosis through clinical criteria and MECP2 gene testing 3
• Management includes multidisciplinary care addressing communication, bone health, gastrointestinal dysmotility, nutrition, growth, and scoliosis 3

Smith-Lemli-Opitz Syndrome (SLOS)

• Autosomal recessive disorder caused by mutations in the DHCR7 gene, resulting in cholesterol deficiency 7
• Key clinical features include:
  • Multiple congenital malformations 7
  • Intellectual disability 7
  • Distinctive facial features 7
  • Syndactyly of toes 7
  • Genital and cardiac anomalies 7
• Diagnosis through clinical features and measurement of elevated 7-dehydrocholesterol levels 7
• No proven treatment, though cholesterol supplementation is being investigated 7

Diagnostic Approach

• Comprehensive genetic testing is recommended for all these disorders 3
• For PWS and AS, methylation analysis should be the first-line diagnostic test 4
• For TSC, search for pathogenic variants in TSC1 and TSC2 is recommended for all patients with suspected disease 3
• High-sensitivity genetic analysis is recommended for TSC when standard testing is negative but clinical suspicion remains high 3
• Chromosome analysis should be performed routinely to rule out other abnormalities or rare translocations 3

Management Considerations

• Early diagnosis is critical for all these conditions to implement appropriate interventions 3
• Multidisciplinary care is essential, with specialists tailored to the specific manifestations of each syndrome 3
• Genetic counseling is important for all families, with recurrence risks varying by disorder and genetic mechanism 3, 4
• Regular monitoring for known complications of each syndrome is necessary throughout the lifespan 3
• Treatment approaches should target specific symptoms and may include medications, therapies, and educational interventions 3, 2