Hemi 3 Syndrome: A Comprehensive Review
Introduction
Hemi 3 syndrome is an extremely rare congenital neurodevelopmental disorder characterized by a distinctive constellation of four cardinal features: hemihypertrophy (overgrowth of one side of the body), hemihypaesthesia (decreased sensation on the affected side), hemiareflexia (absent reflexes on the affected side), and scoliosis. First described by Nudleman, Andermann, and colleagues in 1984 in the journal Brain, this syndrome represents a unique developmental anomaly believed to originate from defects in neural tube formation during early embryogenesis.[1][2][3][4]
The syndrome’s designation “Hemi 3” derives from its three unilateral neurological features (hemihypertrophy, hemihypaesthesia, and hemiareflexia) combined with progressive scoliosis, creating a distinctive clinical phenotype that distinguishes it from other hemihypertrophy syndromes and cerebral hemiatrophy conditions. Recognition of this syndrome is clinically important because it is associated with an increased prevalence of neural tube closure defects in affected families, necessitating genetic counseling and prenatal screening.[3][4][1]
Historical Background and Discovery
Hemi 3 syndrome was first identified and characterized in 1984 by Kenneth Nudleman, Eva Andermann, Frederick Andermann, Gilles Bertrand, and Eugene Rogala at the Montreal Neurological Institute and Hospital. The investigators described three unrelated girls who presented with an unusual developmental syndrome featuring unilateral body hypertrophy without facial involvement, combined with sensory and reflex abnormalities on the enlarged side, and progressive spinal deformity.[4][1][3]
This original description established the syndrome as a distinct clinical entity within the spectrum of neural tube closure defects, distinguishing it from:
- Hemiatrophy of cerebral origin (where the smaller side is abnormal)
- Isolated hemihyperplasia without neurological features
- Syndromic hemihypertrophy conditions such as Beckwith-Wiedemann syndrome[5][6][1][4]
Epidemiology
Hemi 3 syndrome is classified as an extremely rare disorder. Due to its rarity, precise prevalence and incidence data are not available. The condition has been reported primarily in female patients in the original case series, though this may reflect limited sample size rather than true gender predilection. The syndrome appears to occur sporadically, though familial neural tube defects are a consistent finding in affected families, suggesting a shared genetic susceptibility.[2][7][1][3][4]
Etiology and Pathophysiology
Neural Tube Closure Defect Hypothesis
The pathogenesis of Hemi 3 syndrome is theorized to involve a defect in the dorsal lip of the neural tube or neural crest during early embryonic development. This hypothesis is supported by several key observations from the original case series:[1][2][4]
- Association with myelomeningocele: One of the original three patients had a lumbar myelomeningocele, a classic neural tube closure defect[4][1]
- Family history of neural tube defects: All three original patients had positive family histories of neural tube closure defects including spina bifida and anencephaly, suggesting shared genetic susceptibility[1][4]
- Multifactorial inheritance pattern: The syndrome is believed to form part of a spectrum of genetically and embryologically related central nervous system malformations with multifactorial inheritance, similar to other neural tube defects[8][9][10][4][1]
Embryological Basis
Neural tube closure is a complex developmental process occurring during the third to fourth weeks of gestation. Defects in this process can manifest along a spectrum from severe (anencephaly, myelomeningocele) to more subtle abnormalities. The postulated mechanism in Hemi 3 syndrome involves:[9][10][11][8]
- Asymmetric neural tube/neural crest defect: The unilateral nature of the clinical findings suggests a defect affecting only one side of the developing neural tube or neural crest structures[4][1]
- Dorsal lip abnormality: Specifically, the dorsal lip of the neural tube is implicated, which gives rise to structures contributing to sensory and reflex pathways[2][1]
- Early embryonic timing: The association with other neural tube defects in the family suggests the developmental defect occurs during the critical period of neural tube formation[1][4]
Genetic Factors
While no specific gene mutations have been identified for Hemi 3 syndrome, the familial clustering of neural tube defects suggests genetic predisposition. Factors implicated in neural tube defects generally include:[10][8][9][4][1]
- Genes regulating folate one-carbon metabolism[9][10]
- Planar cell polarity pathway genes[10][9]
- Multifactorial inheritance involving both genetic and environmental factors[11][9][1]
Clinical Features
The syndrome is characterized by four cardinal features, all of which were present in the original case series:[3][2][4][1]
1. Hemihypertrophy
Characteristics:
- Overgrowth involving half the body or a quadrant (segmental hemihypertrophy)[3][4][1]
- Face is characteristically spared—this distinguishes Hemi 3 syndrome from other hemihypertrophy conditions[4][1]
- The clinical appearance is one of “inappropriately large size” of the affected side rather than contralateral atrophy[3][1][4]
Specific Findings:
- Muscle hypertrophy with increased power on the affected side[1][3][4]
- Increased bone diameter (but not length) of long bones—this is a distinctive feature, as isolated hemihyperplasia typically involves both bone diameter and length[6][4][1]
- The larger limbs appear thicker rather than longer[4][1]
2. Hemihypaesthesia
Sensory Abnormalities:
- Decreased pain sensation (hypoalgesia) on the enlarged side[3][1][4]
- Decreased temperature sensation on the enlarged side[1][3][4]
- These sensory deficits suggest involvement of spinothalamic tract pathways, which carry pain and temperature information[4][1]
3. Hemiareflexia
Reflex Abnormalities:
- Absent deep tendon reflexes (areflexia) on the hypertrophied side[3][1][4]
- This finding suggests involvement of the reflex arc components—either sensory afferents, motor efferents, or spinal cord integration centers[1][4]
4. Scoliosis
Spinal Deformity:
- Progressive scoliosis is a consistent feature[2][3][4][1]
- The scoliosis tends to worsen over time, distinguishing it from the static neurological abnormalities[4][1]
- Requires monitoring and often surgical correction[12][1][4]
Additional Features
Foot Deformities:
Myelomeningocele:
Symptom Frequency Classification
According to the Genetic and Rare Diseases Information Center (GARD) at the National Institutes of Health:[2]
Very Frequent (80-99% of cases):
- Hemihypertrophy
- Scoliosis
- Sensory abnormalities (hemihypaesthesia)
- Reflex abnormalities (hemiareflexia)
Frequent (30-79% of cases):
- Skeletal muscle hypertrophy
- Foot deformities
Occasional (5-29% of cases):
Diagnostic Evaluation
Clinical Diagnosis
Diagnosis of Hemi 3 syndrome is primarily clinical, based on recognition of the characteristic constellation of features:[2][1][4]
- Physical Examination:
- Documentation of asymmetric body size with measurement of limb circumference and length
- Assessment demonstrating facial sparing
- Neurological examination revealing unilateral sensory deficits (pain and temperature)
- Reflex testing demonstrating areflexia on the hypertrophied side
- Spinal examination for scoliosis
- Comparison to Contralateral Side:
- The key diagnostic approach is comparing the affected side to the unaffected side
Diagnostic Investigations
The original case series included comprehensive investigations to exclude alternative diagnoses:[4][1]
Neurophysiological Studies:
- Electromyography (EMG): Normal findings[1][4]
- Nerve conduction studies: Normal findings[4][1]
- Electroencephalography (EEG): Normal findings[1][4]
Neuroimaging:
- Skull X-rays: Normal[4][1]
- Pneumoencephalography (PEG): Normal (historical test, no longer used)[1][4]
- Cerebral CT scans: Normal[4][1]
- Myelography: Did not demonstrate enlarged cord; specifically, no evidence for syringomyelia[1][4]
Genetic Studies:
- Chromosome studies: Normal karyotypes in all original patients[4][1]
- Sex chromatin studies: Female on both sides in tested patients[1][4]
Additional Testing:
- Metabolic screening may be considered to exclude metabolic causes of asymmetry
- Genetic counseling evaluation for family members
Differential Diagnosis
Hemi 3 syndrome must be distinguished from several conditions:[5][6][2][4][1]
| Condition | Key Distinguishing Features |
| Hemiatrophy of cerebral origin | Smaller side is abnormal (atrophied); often associated with hemiparesis, hemisensory loss, and hemianopia; may have contralateral brain lesion[1][4][14] |
| Isolated hemihyperplasia (hemihypertrophy) | No neurological abnormalities (normal sensation and reflexes); increased risk of embryonal tumors (Wilms tumor, hepatoblastoma)[15][16][7][5][6][17] |
| Beckwith-Wiedemann syndrome | Hemihyperplasia plus macroglossia, omphalocele, organomegaly, ear abnormalities; 11p15 imprinting defects[15][18][5][6] |
| Proteus syndrome | Progressive, disproportionate, asymmetric overgrowth; cerebriform connective tissue nevi; vascular malformations; PTEN pathway involvement[15][5][6] |
| Klippel-Trenaunay syndrome | Capillary malformations (port-wine stain), venous malformations, limb hypertrophy; vascular etiology[15][18][5][6] |
| Russell-Silver syndrome | Asymmetric growth but with intrauterine growth restriction, triangular face, limb asymmetry (typically one side smaller)[5][19] |
| Neurofibromatosis type 1 | Hemihypertrophy may occur but with café-au-lait spots, neurofibromas, Lisch nodules, skeletal abnormalities[15][18][5][6] |
| Syringomyelia | Dissociated sensory loss (pain/temperature affected, proprioception preserved), muscle atrophy, scoliosis; MRI shows syrinx in spinal cord[1][4] |
Key Differentiating Features of Hemi 3 Syndrome:
- Hypertrophy (larger side is abnormal) rather than atrophy
- Facial sparing
- Unilateral sensory deficits (pain and temperature)
- Unilateral areflexia
- Negative neuroimaging (no syrinx, no brain lesion)
- Normal nerve conduction studies and EMG
- Family history of neural tube defects[4][1]
Management and Treatment
Curative Treatment
Presently, there is no cure for Hemi 3 syndrome. Management is primarily supportive and symptomatic, focusing on preventing complications and optimizing function.[2]
Multidisciplinary Approach
Optimal care requires coordination among multiple specialists:
- Neurologist
- Orthopedic surgeon (spine specialist)
- Physical therapist
- Occupational therapist
- Geneticist/Genetic counselor
- Pediatrician or internist
Scoliosis Management
Progressive scoliosis is the most clinically significant complication requiring active management:[12][2][1][4]
Monitoring:
- Regular spinal examination and radiographic surveillance
- Assessment of curve progression over time
Conservative Treatment:
- Bracing may be attempted for moderate curves in growing children[20][12]
- Physical therapy for core strengthening and posture optimization
Surgical Treatment:
- Spinal fusion is often required for progressive scoliosis[12][1][4]
- Surgical intervention may include instrumentation (pedicle screws, rods) for deformity correction and stabilization[21][12]
- The neurological abnormalities are static and do not preclude surgical intervention[1][4]
Limb Length Discrepancy Management
When significant limb length discrepancy is present:[22][6]
Conservative Measures:
- Shoe lifts for mild discrepancies
- Physical therapy for gait optimization
Surgical Options:
- Epiphysiodesis: Removal of part of the growth plate of the longer limb to allow the shorter limb to “catch up” (in growing patients)[6][22]
- Bone resection: Removal of part of the bone in patients who have completed growth[6]
- Leg lengthening procedures: May be considered in select cases[6]
Neurological Management
The neurological abnormalities (hemihypaesthesia and hemiareflexia) are typically static and do not progress:[4][1]
- Patient education regarding sensory deficits and injury prevention
- Protective measures for the affected limb with decreased sensation
- Regular neurological reassessment to ensure stability
Foot Deformity Management
- Orthotic devices may help with foot deformities
- Surgical correction if functionally limiting
Genetic Counseling
Genetic counseling is a critical component of care for Hemi 3 syndrome patients and their families:[2][1][4]
Familial Risk
The association with neural tube defects in the family has important implications:[1][4]
- Probands (affected individuals), their parents, siblings, and parents’ siblings should be counseled that their offspring have increased risks of spina bifida and anencephaly[4][1]
- The recurrence risks are similar to those in relatives of probands with classical neural tube defects[1][4]
- General population risk for neural tube defects: approximately 1-2 per 1,000 pregnancies[11][9]
- Risk in first-degree relatives of affected individuals: increased 2-5 fold depending on specific family history[8][9]
Prenatal Diagnosis
Prenatal screening should be offered to at-risk family members:[4][1]
- Maternal serum alpha-fetoprotein (MSAFP) screening: Elevated levels suggest open neural tube defects
- Detailed fetal ultrasound: Can detect many neural tube defects including spina bifida, anencephaly, and limb asymmetry
- Fetal MRI: May provide additional detail if anomalies are suspected
- Amniocentesis: For alpha-fetoprotein and acetylcholinesterase levels if indicated
Folic Acid Supplementation
Given the association with neural tube defects, periconceptional folic acid supplementation is recommended for women of childbearing age in affected families:[9][10][11]
- Standard recommendation: 400-800 mcg daily for all women of childbearing age
- High-risk women (previous affected pregnancy, family history): 4 mg daily starting 1-3 months before conception and continuing through the first trimester
Prognosis and Natural History
Neurological Status
The neurological abnormalities in Hemi 3 syndrome are static (non-progressive):[1][4]
- Hemihypaesthesia and hemiareflexia do not worsen over time
- This distinguishes the condition from progressive neurodegenerative disorders
- Intellectual function is typically preserved
Scoliosis
Scoliosis is progressive and represents the primary source of morbidity:[2][4][1]
- Requires ongoing monitoring throughout growth
- May require surgical correction to prevent respiratory compromise and functional disability
- Prognosis for spinal deformity depends on degree of progression and response to treatment
Life Expectancy
No specific data on life expectancy for Hemi 3 syndrome is available. Given that the neurological features are static and the primary management challenge is orthopedic (scoliosis), life expectancy is likely near-normal with appropriate management of spinal deformity and any associated neural tube defects.[2]
Functional Outcome
- With appropriate orthopedic management, affected individuals can achieve reasonable functional outcomes
- The sensory deficits require awareness and protective measures but are typically compatible with normal daily activities
- Regular follow-up is essential for monitoring scoliosis progression and managing complications
Prevention
Currently, Hemi 3 syndrome may not be preventable as a primary condition. However, several preventive strategies are relevant:[2]
Primary Prevention (General Neural Tube Defect Prevention)
- Folic acid supplementation: Adequate periconceptional folic acid intake reduces neural tube defect risk by 50-70%[10][11][9]
- Avoidance of known teratogens: Anti-epileptic drugs (particularly valproic acid), retinoic acid derivatives, and other known teratogenic agents should be avoided during pregnancy when possible[11][9]
- Glycemic control: For diabetic women, optimal glycemic control before and during early pregnancy reduces neural tube defect risk[8][9]
Secondary Prevention
- Genetic counseling for affected families
- Prenatal diagnosis to identify neural tube defects in future pregnancies
- Regular screening for associated neural tube defects in family members
Research Gaps and Future Directions
Given the extreme rarity of Hemi 3 syndrome, several important research questions remain unanswered:
- Genetic Etiology: No specific causative genes have been identified; whole-exome sequencing and genome-wide association studies may help identify genetic contributors
- Pathophysiological Mechanisms: The precise developmental mechanism leading to the asymmetric findings requires further investigation
- Natural History: Long-term follow-up studies are needed to better characterize the prognosis and outcomes
- Genotype-Phenotype Correlations: If genetic causes are identified, understanding how specific variants relate to clinical features would aid diagnosis and counseling
- Treatment Optimization: Evidence-based guidelines for scoliosis management specific to this population are lacking
Conclusion
Hemi 3 syndrome is an extremely rare congenital disorder characterized by the tetrad of hemihypertrophy (with facial sparing), hemihypaesthesia, hemiareflexia, and progressive scoliosis. First described in 1984, the syndrome is theorized to result from a defect in the dorsal lip of the neural tube or neural crest during early embryonic development. The association with neural tube defects in affected families supports this hypothesis and has important implications for genetic counseling and prenatal screening.
Clinical recognition of Hemi 3 syndrome is important for several reasons: it can be distinguished from cerebral hemiatrophy conditions, the neurological abnormalities are static (providing reassurance regarding prognosis), the scoliosis is progressive and requires monitoring and treatment, and affected families have increased risks of neural tube defects in offspring.
Management is primarily supportive, focusing on scoliosis treatment (which may require surgical correction), management of limb asymmetry, and protective measures for areas with decreased sensation. Genetic counseling is essential, and prenatal diagnosis should be offered to family members at risk for having offspring with neural tube defects.
While much remains unknown about the precise etiology and optimal management of this rare condition, awareness among clinicians facilitates appropriate diagnosis, counseling, and care for affected individuals and their families.
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