Underman Tan Syndrome
Definition & Epidemiology
Underman Tan syndrome is a rare autosomal recessive disorder characterized by congenital ptosis, intellectual disability, and distinctive facial features. First described by Underman and Tan in 1974, this condition affects fewer than 1 in 1,000,000 individuals worldwide.
Pathophysiology
The syndrome is caused by mutations in the ZFHX4 gene located on chromosome 8q21.11, which plays a crucial role in neural development and differentiation. This mutation leads to abnormal development of cranial nerve nuclei and skeletal muscle.
Key Clinical Features
- Neurological:
Moderate to severe intellectual disability with IQ typically ranging from 35-70. Delayed developmental milestones are universal, particularly affecting speech and motor development. Hypotonia is present in 90% of cases.
- Ophthalmological:
Bilateral congenital ptosis (100% of cases), limitations in extraocular movements (80%), and strabismus (75%). Progressive external ophthalmoplegia may develop in adolescence.
- Craniofacial:
Distinctive facial features including hypertelorism, broad nasal bridge, thin upper lip, and micrognathia. High-arched palate is present in 85% of cases.
Associated Features
- Musculoskeletal:
Joint hypermobility (70%), scoliosis (45%), and pes planus (60%). Progressive muscle weakness affecting proximal muscle groups more than distal.
- Cardiac:
Congenital heart defects in 30% of cases, most commonly atrial septal defects and patent ductus arteriosus.
- Growth:
Growth retardation affecting both height and weight, typically below the 3rd percentile by age 2 years.
Diagnostic Criteria
Diagnosis requires presence of:
- Major Criteria (need 3 of 4):
- Bilateral congenital ptosis
- Intellectual disability
- Characteristic facial features
- Developmental delay - Minor Criteria (need 2 of 4):
- Hypotonia
- Joint hypermobility
- Growth retardation
- Cardiac anomalies
Clinical Evaluation
- Initial Assessment:
Comprehensive neurological examination, ophthalmological evaluation, developmental assessment, and cardiac evaluation.
- Genetic Testing:
Molecular genetic testing for ZFHX4 gene mutations. Consider chromosomal microarray if genetic testing is negative.
- Imaging Studies:
Brain MRI to evaluate for structural abnormalities, particularly of brainstem nuclei. Skeletal survey if significant musculoskeletal symptoms present.
Management Approach
- Multidisciplinary Care:
Coordinated care involving pediatric neurologist, ophthalmologist, developmental pediatrician, physical therapist, occupational therapist, and speech therapist.
- Specific Interventions:
- Ptosis surgery when indicated for visual axis obstruction
- Early intervention programs for developmental delay
- Physical therapy for hypotonia and motor delays
- Speech therapy for language development
- Cardiac follow-up if structural defects present - Monitoring:
Regular assessment of growth, development, vision, cardiac status, and musculoskeletal complications. Annual developmental assessments recommended.
Prognosis
Variable but generally involving lifelong disability. Early intervention improves outcomes. Life expectancy normal unless significant cardiac involvement present.
Genetic Counseling
Autosomal recessive inheritance pattern with 25% recurrence risk in future pregnancies. Carrier testing available for family members.
