Hydrolethalus Syndrome
Hydrolethalus Syndrome
Introduction
Hydrolethalus syndrome (HLS) is a rare, lethal genetic disorder characterized by severe developmental abnormalities of the central nervous system, including hydrocephalus and absent midline structures of the brain. It was first described in Finland, where it shows higher prevalence due to founder effect.
Key Points
- Inheritance: Autosomal recessive
- Gene: HYLS1
- Prevalence: Rare (higher in Finnish population)
- Prognosis: Usually lethal in perinatal period
- First described: 1981 in Finland
Clinical Features
Central Nervous System Abnormalities
- Hydrocephalus (often massive)
- Absent midline structures
- Occipital encephalocele
- Cerebellar abnormalities
- Neural tube defects
- Abnormal gyration of temporal lobes
Craniofacial Features
- Micrognathia
- Cleft lip/palate
- Abnormal nose shape (typically flat)
- Macrocephaly
- Hypertelorism
- Low-set ears
Limb Abnormalities
- Polydactyly (typically postaxial)
- Hallux duplication
- Sandal gap deformity
- Clubfoot
- Short limbs
Other Physical Features
- Pulmonary abnormalities
- Cardiovascular defects
- Genital anomalies
- Polyhydramnios during pregnancy
- Key-hole defect in occipital bone
Genetics & Pathophysiology
Genetic Basis
- Gene: HYLS1 (Hydrolethalus Syndrome 1)
- Location: Chromosome 11q24.2
- Mutation type: Most common is Finnish founder mutation (D211G)
- Inheritance pattern: Autosomal recessive
Molecular Mechanisms
- HYLS1 protein functions in ciliogenesis
- Affects centrosome and basal body function
- Disrupts primary cilia formation
- Impacts early embryonic development
- Affects multiple developmental pathways
Developmental Impact
- Disrupted neural tube development
- Abnormal brain development
- Impaired midline structure formation
- Defective organogenesis
Diagnosis & Management
Prenatal Diagnosis
- Ultrasound findings:
- Hydrocephalus
- Polyhydramnios
- Brain malformations
- Limb abnormalities
- Genetic testing
- Family history assessment
- MRI for detailed brain imaging
Diagnostic Criteria
- Clinical features constellation
- Radiological findings
- Molecular genetic testing
- Pathological examination
Management Considerations
- Genetic counseling
- Prenatal care planning
- Palliative care discussion
- Psychological support for families
- Multidisciplinary approach
Differential Diagnosis
Key Differential Diagnoses
- Meckel-Gruber syndrome
- Smith-Lemli-Opitz syndrome
- Pallister-Hall syndrome
- MASA syndrome
- Joubert syndrome
Distinguished By
- Pattern of CNS malformations
- Associated anomalies
- Genetic testing results
- Survival outcomes
- Inheritance patterns
Important Considerations
- Severity of hydrocephalus
- Presence of specific malformations
- Ethnic background (Finnish heritage)
- Family history
