Hadziselimovic Syndrome

Hadziselimovic Syndrome: A Comprehensive Medical Review

Introduction

Hadziselimovic syndrome, more formally known as microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, is an extraordinarily rare genetic disorder characterized by a distinctive constellation of prenatal growth retardation, microcephaly, characteristic facial features, cardiac malformations, and skeletal abnormalities. First described in the medical literature, this syndrome represents one of the rarest known congenital multiple malformation syndromes, with fewer than ten cases reported in the scientific literature to date.^[1]^[2]

According to Orphanet, the European reference portal for information on rare diseases and orphan drugs, Hadziselimovic syndrome is classified under the category of rare syndromes with cardiac malformations, highlighting the significant cardiovascular involvement that characterizes this condition. The syndrome is also recognized by the National Institutes of Health Genetic and Rare Diseases Information Center (GARD), emphasizing its importance as a distinct clinical entity requiring specialized medical attention.^[3]^[1]

The condition demonstrates the complex interplay between genetic factors and embryonic development, affecting multiple organ systems during critical periods of fetal growth. The syndrome’s rarity and severity make it a significant challenge for both diagnosis and management, requiring multidisciplinary expertise and comprehensive genetic counseling.

Etiology and Pathophysiology

Genetic Basis and Inheritance Pattern

The underlying genetic mechanism of Hadziselimovic syndrome remains largely unclear, though current evidence suggests both autosomal recessive and X-linked recessive patterns of inheritance may be involved. According to available genetic databases, the syndrome has been assigned the OMIM (Online Mendelian Inheritance in Man) code #612946, reflecting its recognition as a distinct genetic entity.^[4]^[2]^[5]^[6]

The limited number of reported cases has made it challenging to establish definitive inheritance patterns. However, the occurrence of affected dizygotic twins born to consanguineous parents strongly suggests an autosomal recessive mode of inheritance in at least some cases. This pattern indicates that both parents must be carriers of the mutated gene for their children to be affected, with a 25% recurrence risk for each subsequent pregnancy.^[2]

Pathophysiological Mechanisms

The pathophysiology of Hadziselimovic syndrome involves disrupted embryonic development affecting multiple organ systems during critical developmental windows. The syndrome appears to result from defects in early morphogenetic processes, particularly those occurring between the 6th and 8th weeks of gestation when cardiac, skeletal, and craniofacial structures are forming.^[7]^[2]

Developmental Timing and System Involvement:

The simultaneous involvement of cardiac, skeletal, and facial structures suggests that the underlying genetic defect affects fundamental developmental pathways active during early embryogenesis. This timing explains the characteristic features of:

Cardiac conotruncal malformations (6-8 weeks gestation)
Limb bud development abnormalities (5-7 weeks gestation)
Craniofacial morphogenesis defects (6-9 weeks gestation)
Neural tube closure and brain development (3-4 weeks gestation)^[2]^[7]

Clinical Presentation

Core Clinical Features

Hadziselimovic syndrome presents with a characteristic tetrad of clinical manifestations affecting growth, neurological development, facial appearance, and multiple organ systems:^[1]^[2]

1. Prenatal and Postnatal Growth Retardation:

Low birth weight despite appropriate gestational age
Persistent short stature falling below the 5th percentile
Failure to thrive in infancy and childhood
Proportionate growth restriction affecting both length and weight ^[1]^[2]

2. Microcephaly and Neurological Features:

Significant microcephaly present from birth
Developmental delay and intellectual disability
Hypotonia (decreased muscle tone)
Global developmental delays affecting motor and cognitive milestones ^[2]^[1]

3. Distinctive Craniofacial Features:

Low anterior hairline
Hypotelorism (closely spaced eyes)
Thick, prominent lips with characteristic carp-shaped mouth
High-arched palate
Low-set ears
Micrognathia (small jaw)
Coarse facial features ^[1]^[2]

4. Cardiac Malformations:

Conotruncal heart defects as the predominant cardiac abnormality
Tetralogy of Fallot is the most commonly reported cardiac lesion
Other complex congenital heart diseases may be present
Cyanosis and exercise intolerance may be evident ^[2]^[1]

Skeletal and Limb Abnormalities

Upper Limb Malformations:

Hypoplastic thumbs (underdeveloped thumbs)
Hypoplastic first metacarpals
Possible radial deficiencies
Short fingers with possible syndactyly
Limited range of motion in affected joints ^[1]^[2]

Additional Skeletal Features:

Possible hypoplastic radius and ulna
Joint contractures
Delayed bone age
Possible scoliosis or other spinal abnormalities ^[2]

Associated Systemic Manifestations

Ophthalmological Features:

Hypotelorism as a prominent feature
Possible epicanthal folds
Potential vision problems related to orbital abnormalities ^[8]^[2]

Genitourinary Abnormalities:

Cryptorchidism (undescended testes) may be present
Other genitourinary malformations possible
Growth hormone deficiency effects on genital development ^[5]^[1]

Dermatological Features:

Distinctive skin texture
Possible hirsutism or abnormal hair distribution
Low posterior hairline ^[1]

Diagnosis

Clinical Diagnostic Criteria

The diagnosis of Hadziselimovic syndrome is established through clinical recognition of the characteristic constellation of features, supported by appropriate imaging and genetic studies. Currently, no standardized diagnostic criteria exist due to the rarity of the condition, but diagnosis typically requires the presence of several core features:^[2]

Primary Diagnostic Features:

Prenatal-onset growth retardation with persistent short stature
Microcephaly present from birth
Characteristic facial dysmorphism including hypotelorism and thick lips
Cardiac malformations, particularly conotruncal defects
Skeletal abnormalities, especially involving the thumbs and first metacarpals ^[1]^[2]

Supporting Features:

Developmental delay and intellectual disability
Hypotonia
Additional minor malformations
Family history suggesting genetic etiology ^[2]

Imaging Studies

Comprehensive imaging evaluation should include:

Echocardiography:

Essential for documenting cardiac malformations
Assessment of Tetralogy of Fallot components:
- Ventricular septal defect
- Pulmonary stenosis
- Right ventricular hypertrophy
- Overriding aorta ^[9]

Skeletal Radiography:

Hand and wrist X-rays to document thumb and metacarpal hypoplasia
Long bone films to assess for radial/ulnar abnormalities
Bone age assessment for growth evaluation ^[2]

Neuroimaging:

Brain MRI to assess for structural abnormalities
Evaluation of brain volume and cortical development
Assessment for associated CNS malformations ^[1]

Additional Imaging:

Chest X-ray for cardiac size and pulmonary status
Abdominal ultrasound to evaluate for renal abnormalities
Ophthalmological examination for orbital measurements ^[2]

Laboratory Investigations

Genetic Testing:

Chromosomal microarray analysis to exclude microdeletions/duplications
Whole exome sequencing may be considered
Karyotype analysis to rule out chromosomal abnormalities
Targeted gene panels for syndromic conditions ^[6]^[5]

Biochemical Studies:

Growth hormone and IGF-1 levels
Thyroid function tests
Complete blood count and metabolic panel
Cardiac biomarkers if cardiac involvement suspected ^[1]

Developmental Assessment:

Comprehensive developmental evaluation
Intellectual assessment when age-appropriate
Speech and language evaluation
Occupational therapy assessment ^[2]

Differential Diagnosis

Hadziselimovic syndrome must be differentiated from other syndromic conditions with similar features:^[1]^[2]

Cornelia de Lange Syndrome:

Similar facial features and growth retardation
More prominent eyebrow synophrys
Different limb malformation patterns
Specific genetic mutations identified ^[10]

CHARGE Syndrome:

Multiple congenital anomalies
Different pattern of cardiac and sensory defects
Specific genetic cause (CHD7 mutations)^[1]

DiGeorge Syndrome/22q11.2 Deletion:

Cardiac conotruncal defects
Immunodeficiency and hypocalcemia
Characteristic facial features
Identifiable genetic deletion ^[1]

Thrombocytopenia-Absent Radius (TAR) Syndrome:

Radial defects and cardiac abnormalities
Thrombocytopenia as distinguishing feature
Different inheritance pattern ^[11]

Meckel-Gruber Syndrome:

Multiple congenital anomalies
Renal cystic disease
Posterior encephalocele
Lethal outcome ^[12]

Prenatal Diagnosis

Prenatal detection may be possible through:

Ultrasound Screening:

Growth restriction detection
Cardiac malformation identification
Skeletal abnormality visualization
Facial feature assessment ^[2]

Advanced Prenatal Testing:

Fetal echocardiography for cardiac assessment
Detailed anatomy scan
Genetic testing if familial mutation known ^[2]

Management and Treatment

Multidisciplinary Care Approach

Due to the multi-system nature of Hadziselimovic syndrome, affected individuals require comprehensive care from a specialized multidisciplinary team:^[1]^[2]

Core Specialists:

Medical geneticist (coordinator of care)
Pediatric cardiologist or adult congenital heart specialist
Pediatric endocrinologist (growth management)
Developmental pediatrician or neurologist
Orthopedic or plastic surgeon (limb abnormalities)^[2]

Supporting Specialists:

Ophthalmologist
Audiologist
Speech and language pathologist
Physical and occupational therapists
Nutritionist/dietitian
Social worker and genetic counselor ^[1]^[2]

Cardiac Management

Immediate Cardiac Assessment:

Comprehensive echocardiographic evaluation
Assessment of hemodynamic significance
Evaluation for cyanosis and heart failure
Cardiac catheterization if indicated ^[9]^[2]

Surgical Intervention:

Tetralogy of Fallot repair when clinically indicated:
- Complete intracardiac repair typically performed between 6-12 months
- Staged approach may be required for complex cases
- Long-term cardiology follow-up essential ^[9]

Medical Management:

Antibiotic prophylaxis for bacterial endocarditis prevention
Management of cyanotic spells if present
Heart failure management when indicated
Arrhythmia monitoring and treatment ^[9]

Growth and Endocrine Management

Growth Hormone Evaluation:

Comprehensive growth hormone stimulation testing
IGF-1 and IGFBP-3 measurements
Consideration of growth hormone therapy if deficient ^[1]

Nutritional Support:

High-calorie diet to optimize growth potential
Nutritional supplementation as needed
Feeding therapy for oral motor difficulties
Gastrostomy tube consideration in severe cases ^[2]

Endocrine Monitoring:

Regular growth velocity assessment
Bone age monitoring
Thyroid function surveillance
Pubertal development evaluation ^[1]

Developmental and Neurological Support

Early Intervention Services:

Physical therapy for motor development
Occupational therapy for fine motor skills
Speech and language therapy
Special education services ^[2]

Cognitive Support:

Intellectual disability services
Educational planning and accommodations
Behavioral interventions as needed
Transition planning for adolescents ^[1]

Seizure Management:

EEG monitoring if seizures suspected
Anticonvulsant therapy as indicated
Neurological follow-up ^[2]

Orthopedic and Surgical Management

Upper Limb Reconstruction:

Thumb reconstruction or augmentation procedures
Functional improvement surgeries
Prosthetic devices when appropriate
Hand therapy and rehabilitation ^[2]

Timing of Interventions:

Early intervention for functional improvement
Staged surgical approaches
Coordination with growth patterns
Long-term functional assessment ^[2]

Ophthalmological Care

Comprehensive Eye Examination:

Visual acuity assessment
Refractive error evaluation
Assessment for strabismus
Monitoring for complications ^[8]

Interventions:

Corrective lenses as needed
Strabismus surgery if indicated
Visual therapy and support
Regular monitoring throughout development ^[8]

Prognosis and Outcomes

Survival and Life Expectancy

The long-term prognosis for individuals with Hadziselimovic syndrome depends primarily on the severity of cardiac malformations and the degree of intellectual disability. Key prognostic factors include:^[1]^[2]

Cardiac Outcomes:

Successful repair of Tetralogy of Fallot can significantly improve long-term survival
Post-surgical cardiac function and the need for re-interventions
Risk of arrhythmias and sudden cardiac death in long-term follow-up ^[9]

Neurological Outcomes:

Degree of intellectual disability varies among affected individuals
Early intervention can optimize developmental potential
Seizure control and neurological stability ^[2]

Functional Outcomes

Growth and Development:

Persistent short stature despite treatment interventions
Intellectual disability typically ranges from mild to moderate
Some individuals may achieve semi-independent living with support ^[1]^[2]

Quality of Life Considerations:

Surgical interventions can improve functional capacity
Educational and vocational support enhance independence
Family support systems crucial for optimal outcomes ^[2]

Long-term Medical Needs

Cardiac Follow-up:

Lifelong cardiology care for congenital heart disease
Regular assessment for complications
Endocarditis prophylaxis protocols ^[9]

Growth Monitoring:

Continued endocrine follow-up through adulthood
Bone health assessment and management
Reproductive health considerations ^[1]

Epidemiology and Genetics

Prevalence and Demographics

Global Prevalence:

Extremely rare condition with fewer than 10 cases reported worldwide
No known ethnic or geographic clustering
Equal gender distribution reported in available cases ^[1]^[2]

Population Demographics:

No specific population predisposition identified
Cases reported in diverse ethnic backgrounds
Consanguinity may increase risk in some populations ^[2]

Genetic Counseling Considerations

Inheritance Patterns:

Likely autosomal recessive inheritance based on available evidence
Recurrence risk of 25% for subsequent pregnancies in affected families
Genetic heterogeneity possible with different inheritance patterns ^[2]

Family Planning:

Comprehensive genetic counseling essential
Discussion of recurrence risks
Prenatal diagnosis options when applicable
Reproductive choices and assisted reproductive technologies ^[1]

Carrier Screening:

Currently limited by lack of identified causative genes
Family history remains primary screening tool
Future genetic advances may enable carrier detection ^[2]

Research Directions and Future Perspectives

Genetic Research Priorities

Gene Discovery:

Whole exome and genome sequencing studies
Identification of causative genetic mutations
Functional studies of candidate genes
Genotype-phenotype correlation studies ^[5]

Molecular Mechanisms:

Understanding developmental pathways involved
Investigation of gene-gene and gene-environment interactions
Animal model development for mechanistic studies ^[1]

Clinical Research Needs

Natural History Studies:

Comprehensive phenotyping of additional cases
Long-term outcome studies
Quality of life assessments
Treatment response evaluations ^[2]

Therapeutic Development:

Growth hormone therapy optimization
Cardiac surgical technique improvements
Rehabilitative intervention studies
Novel therapeutic targets ^[1]

Diagnostic Advances

Improved Recognition:

Development of standardized diagnostic criteria
Clinical decision support tools
Training programs for healthcare providers ^[2]

Advanced Diagnostics:

Next-generation sequencing applications
Functional genomics approaches
Biomarker development for early detection ^[5]

Healthcare System Considerations

Specialized Care Centers

Centers of Excellence:

Multidisciplinary syndrome clinics
Coordinated care protocols
Research participation opportunities
Family support services ^[2]

Telemedicine Applications:

Remote consultation for rare disease expertise
Genetic counseling accessibility
Monitoring and follow-up services
Educational resources for families ^[1]

Economic and Social Implications

Healthcare Costs:

Significant costs associated with multiple surgeries
Lifelong medical care requirements
Specialized therapy and equipment needs
Educational and social service costs ^[2]

Family Impact:

Emotional and psychological burden
Financial implications of chronic care
Social support needs
Caregiver training and respite services ^[1]

Conclusion

Hadziselimovic syndrome represents one of the rarest and most complex genetic disorders affecting human development, characterized by a distinctive pattern of growth restriction, microcephaly, cardiac malformations, and skeletal abnormalities. The syndrome exemplifies the intricate relationship between genetic factors and embryonic development, demonstrating how single genetic defects can cause devastating multi-system disorders affecting virtually every aspect of an individual’s health and development.

The extreme rarity of this condition, with fewer than ten cases reported in the medical literature, presents significant challenges for both clinical management and research advancement. The lack of identified causative genes and unclear inheritance patterns underscore the need for continued genetic research and international collaboration to better understand the underlying mechanisms and develop targeted therapeutic approaches.

Current management relies entirely on symptomatic and supportive care, with cardiac surgery representing the most critical life-saving intervention. The multidisciplinary approach to care, emphasizing coordination between cardiology, genetics, endocrinology, and developmental specialists, has become the standard for optimizing outcomes. Early recognition and prompt intervention can significantly impact both survival and quality of life, particularly through timely cardiac surgical repair and comprehensive developmental support services.

The prognosis for individuals with Hadziselimovic syndrome depends largely on the severity of cardiac involvement and the success of surgical interventions. While intellectual disability and growth restriction typically persist, many individuals can achieve meaningful developmental progress with appropriate support and intervention. The availability of specialized care centers and multidisciplinary teams has improved outcomes, though access to such expertise remains limited due to the condition’s rarity.

Future research directions must focus on identifying the genetic basis of this syndrome through advanced genomic approaches, including whole exome and genome sequencing studies. Understanding the molecular mechanisms underlying the condition will be crucial for developing targeted therapies and improving genetic counseling capabilities. Additionally, establishing international registries and collaborative networks will be essential for advancing knowledge about natural history, optimizing treatment protocols, and supporting affected families.

Healthcare providers should maintain awareness of this syndrome when evaluating infants with unexplained growth restriction, microcephaly, and cardiac abnormalities, particularly when these features occur in combination with characteristic facial dysmorphism. Early recognition enables prompt genetic evaluation and coordinated care, potentially improving long-term outcomes for these vulnerable patients and their families.

The study of Hadziselimovic syndrome also contributes to broader understanding of human developmental biology and the genetic control of embryogenesis. As one of the rarest human genetic conditions, it serves as an important model for understanding how disrupted developmental pathways can cause complex patterns of congenital malformations, providing insights that may benefit the management of other rare genetic disorders affecting similar developmental processes.

References

Hadziselimovic Syndrome

Hadziselimovic Syndrome: A Comprehensive Medical Review

Related Posts:

Recent Post

features

Categories

Weekly Newsletter