What are the 10 rarest syndromes or diseases?

The 10 Rarest Syndromes and Diseases

While the provided evidence does not comprehensively list the 10 rarest syndromes, the literature identifies several ultra-rare and hyper-rare conditions that represent the extreme end of disease rarity.

Understanding Disease Rarity Categories

The concept of "hyper-rare" diseases has been introduced to describe conditions affecting fewer than 1 in 100 million individuals, which potentially outnumber all currently known rare diseases. 1 This category extends beyond traditional rare disease definitions (affecting <1 in 2,000 people in the EU or <200,000 people in the US) to capture the most exceptionally rare conditions. 2

Extremely Rare Syndromes Identified in Current Literature

Based on the most recent guideline evidence, the following represent some of the rarest documented syndromes:

1. Schinzel-Giedion Syndrome (SGS)

• Discussed as one of the rarest cancer predisposition syndromes requiring specialized surveillance protocols 3
• Prevalence data not specified in guidelines, indicating extreme rarity

2. Maffucci Syndrome

• Enchondromatosis with vascular overgrowths 3
• Significantly rarer than Ollier disease, with only scattered case reports in literature

3. Ollier Disease

• Prevalence estimated at approximately 1:100,000 3
• While more common than Maffucci syndrome, still qualifies as ultra-rare

4. Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) Syndrome

• Discussed as a rare cancer predisposition syndrome requiring specialized surveillance 3
• Exact prevalence not established in guidelines

5. Rubinstein-Taybi Syndrome (RSTS)

• Identified as a rare cancer predisposition syndrome 3
• Requires specialized cancer surveillance protocols

6. LRBA Deficiency with Concurrent STAT3 Mutation

• Represents an exceptionally rare combined immunodeficiency 4
• The combination of both genetic defects is extraordinarily uncommon

7. CEBPE-Mutated Autoinflammatory Disease

• Represents a noncanonical inflammasomopathy 5
• Extremely limited case reports in medical literature

8. Costello Syndrome

• RASopathy with 15% cancer risk by age 20 years 3
• Caused by specific HRAS mutations, prevalence not well-established

9. CBL Syndrome

• RASopathy with high but imprecisely defined cancer risk 3
• Represents one of the rarer RASopathies

10. Metachondromatosis

• Alternative diagnosis to enchondromatoses, mentioned as differential 3
• OMIM #156250, extremely limited case reports

Important Contextual Considerations

The total number of rare diseases is estimated at approximately 7,000, with over 6,000 different rare diseases documented, affecting more than 300 million people worldwide collectively. 2, 6 However, the majority of these conditions are extremely rare, with many qualifying as "hyper-rare." 1

Diagnostic Challenges

• The average diagnostic delay for rare diseases is 6-8 years, reflecting the difficulty in recognizing these conditions. 2, 6
• Most rare diseases (approximately 80%) have a genetic component, requiring advanced genomic screening methods for diagnosis 7, 8
• Autosomal recessive disorders are concentrated in consanguineous populations, and rare toxicities in rural areas, making their identification particularly challenging 1

Clinical Implications

• There are no effective treatments for 90% of rare diseases, emphasizing the importance of early diagnosis and supportive care. 2
• Many rare syndromes present with intellectual disability, neuropsychiatric disorders, epilepsy, and motor dysfunction 8
• The heterogeneity of clinical presentations, even within the same syndrome, significantly hampers detection and treatment selection 6

Emerging Categories

• X-linked and gain-of-function mutations create additional layers of rarity due to their random occurrence 1
• Concurrent diseases may create distinct illnesses through phenotype conversion or maintain separate phenotypes, potentially creating entirely new ultra-rare entities 1