Hartsfield syndrome

Hartsfield Syndrome: A Comprehensive Medical Review

Introduction

Hartsfield syndrome (also known as Hartsfield-Bixler-Demyer syndrome or holoprosencephaly-ectrodactyly-cleft lip/palate syndrome; OMIM #300571) is an extremely rare genetic disorder characterized by the unique combination of holoprosencephaly (HPE), ectrodactyly (split hand/foot malformation), and cleft lip/palate, with variable endocrine abnormalities and developmental delays. First described by Hartsfield in 1984, the syndrome represents one of the most severe phenotypic manifestations of FGFR1 gene dysfunction.^{[1][2][3][4][5]}

According to Orphanet (ORPHA:2117), MedlinePlus (NIH), and GeneReviews, Hartsfield syndrome affects approximately 35 individuals documented in medical literature to date, with a striking male predominance (approximately 80% of cases). The syndrome is caused by dominant or recessive mutations in the FGFR1 gene (fibroblast growth factor receptor 1) located on chromosome 8p11.23.^{[2][4][5][6][1]}

Hartsfield syndrome represents the most severe end of the FGFR1-related disorder spectrum, which ranges from isolated hypogonadotropic hypogonadism through Kallmann syndrome to the profound multi-system abnormalities seen in Hartsfield syndrome. The discovery of FGFR1 as the causative gene in 2013 by Simonis et al. revolutionized understanding of this rare condition.^[3][7][2]

Etiology and Genetics

Genetic Basis

Hartsfield syndrome is caused by pathogenic variants in the FGFR1 gene:^[4][1][2]

Gene and Chromosomal Location:

• Gene: FGFR1 (Fibroblast Growth Factor Receptor 1)
• Chromosomal location: 8p11.23
• Inheritance patterns:
  • Most commonly autosomal dominant (de novo mutations)
  • Rarely autosomal recessive (homozygous mutations)
• Protein product: Fibroblast Growth Factor Receptor 1 (FGFR1)^[1][2][4]

FGFR1 Protein Function:
According to molecular biology studies, FGFR1 is a receptor tyrosine kinase essential for multiple developmental processes:^[3][4]

• FGF signaling: Interacts with fibroblast growth factors (FGFs) to trigger intracellular signaling cascades
• Cell division: Regulates cell proliferation and differentiation
• Embryonic development: Critical for brain, craniofacial, and limb development
• Organ systems: Brain midline structures, hypothalamo-pituitary axis, hand/foot development^[2][3]

Molecular Mechanisms

Types of FGFR1 Mutations:
According to comprehensive genetic studies:^[7][2][3]

1. Heterozygous Kinase Domain Mutations (Most Common):

• Location: Intracellular tyrosine kinase domain
• Mechanism: Dominant-negative effect
• Functional impact:
  • Mutations near ATP-binding site or coordinating magnesium
  • Unable to bind ATP or perform kinase activity
  • Form inactive dimers with wild-type receptors
  • Interfere with normal FGFR1 signaling
• Clinical severity: Associated with most severe Hartsfield syndrome phenotypes^[7][2][3]

2. Homozygous Extracellular Domain Mutations (Rare):

• Location: Extracellular FGF-binding domain
• Mechanism: Loss of ligand binding
• Inheritance: Autosomal recessive
• Functional impact: Complete loss of FGFR1 activation
• Clinical presentation: Severe phenotype^[8][2]

3. Heterozygous Extracellular Domain Mutations (Very Rare):

• Location: Extracellular domain
• Mechanism: Not fully understood
• Clinical presentation: Can cause typical Hartsfield syndrome
• Novel finding: Expands understanding of mutation spectrum^[9][8]

Pathophysiology

Dominant-Negative Mechanism:
According to functional studies by Hong et al. (2016):^[7]

• Normal FGFR1 signaling: Requires receptor dimerization, ligand binding, ATP binding, and trans-phosphorylation
• Dominant-negative effect: Mutant receptors form dimers with wild-type receptors but cannot activate signaling
• “Frozen inactive” dimers: Unable to proceed with phosphorylation and downstream signaling
• Severe phenotype: Loss of both normal and mutant allele function explains severity
• Correlation: Dominant-negative mutations correlate with most severe Hartsfield syndrome presentations^[7]

Developmental Consequences:
Disrupted FGFR1 signaling affects multiple developmental processes:^[2][3]

Brain Development:

• Prosencephalon division: Failure of forebrain to divide into hemispheres
• Midline structures: Abnormal development of corpus callosum, olfactory bulbs
• Hypothalamus/pituitary: Malformation of hypothalamo-pituitary axis
• Timing: Critical period in first trimester^[3][7]

Limb Development:

• Apical ectodermal ridge (AER): FGF signaling essential for AER maintenance
• Limb bud outgrowth: Disrupted proximodistal and anteroposterior patterning
• Central ray development: Specific loss of middle digits
• Timing: Critical period weeks 4-8 of gestation^[2][3]

Craniofacial Development:

• Neural crest migration: Abnormal facial prominence fusion
• Palatal shelf fusion: Defective midline fusion
• Cranial suture formation: Premature or delayed fusion^[1][3]

Clinical Presentation

Demographics and Epidemiology

According to published literature and rare disease databases:^[5][6][1]

Prevalence and Incidence:

• Global cases: Approximately 35 documented cases worldwide
• Prevalence: Fewer than 1 in 1,000,000 individuals
• Gender: Strong male predominance (approximately 80% males)
• Ethnic distribution: All reported cases sporadic, no ethnic clustering^[10][5][1]

Mortality:

• Severe forms: Most patients are stillborn or die in infancy
• Moderate forms: Survival into childhood and occasionally adulthood
• Life expectancy: Depends on severity of holoprosencephaly and associated anomalies^[5][10][1]

Core Clinical Features

Hartsfield syndrome presents with a distinctive triad plus variable additional features:^[4][1][3]

Triad of Major Features

1. Holoprosencephaly (HPE) Spectrum:

The central feature involving abnormal brain development:^[11][4][1]

Severity Classification:

• Alobar HPE (Most severe): Complete failure of hemispheric division
  • Single ventricle
  • Fused thalami
  • Absent corpus callosum
  • Absent interhemispheric fissure
  • Cyclopia (single central eye) with proboscis
  • Usually lethal before or soon after birth^[4][1]
• Semi-lobar HPE (Intermediate): Partial hemispheric division
  • Posterior separation of hemispheres
  • Fused anterior frontal lobes
  • Rudimentary interhemispheric fissure
  • Moderate to severe facial abnormalities^[1]
• Lobar HPE (Mildest): Mostly divided hemispheres
  • Separation of most structures
  • Fusion limited to frontal cortex
  • Mild facial anomalies
  • Better prognosis^[3][1]

Milder Midline Anomalies:
Part of HPE spectrum:^[1][3]

• Arhinencephaly: Absence of olfactory bulbs and tracts
• Corpus callosum agenesis: Complete or partial absence
• Septooptic dysplasia: Absent septum pellucidum with optic nerve hypoplasia
• Single central maxillary incisor: Solitary upper front tooth^[1]

2. Ectrodactyly (Split Hand/Foot Malformation):

Characteristic limb malformation affecting hands and/or feet:^[11][4][1]

Clinical Features:

• Median cleft: Deep V-shaped or U-shaped split down center of hand/foot
• Missing central rays: Absence of one or more central digits (typically 2nd, 3rd, 4th)
• Variable severity: Ranges from shortened middle finger to reduction to single ray (“lobster claw”)
• Syndactyly: Fusion of remaining digits common
• Bilateral or unilateral: Can affect one to four limbs
• Asymmetry: Different severity in different limbs^[11][4][1]

Distribution:

• All four limbs: Most common presentation
• Upper limbs only: Occasional
• Lower limbs only: Rare
• Unilateral: Uncommon^[10][1]

3. Cleft Lip and/or Palate:

Present in over half of reported cases:^[3][1]

• Cleft palate alone: Most common
• Cleft lip with cleft palate: Frequent
• Unilateral or bilateral: Variable presentation
• Complete or incomplete: Ranges from soft palate only to complete cleft^[5][1]

Endocrine Abnormalities

Common due to hypothalamo-pituitary dysfunction:^[8][4][1]

Pituitary Hormone Deficiencies:

Central Diabetes Insipidus:

• Mechanism: ADH (vasopressin) deficiency
• Symptoms: Excessive urination (polyuria), excessive thirst (polydipsia)
• Risk: Hypernatremic dehydration if untreated
• Frequency: Reported in approximately 40% of cases^[10][1]

Growth Hormone Deficiency:

• Consequences: Short stature, delayed growth
• Severity: Variable
• Treatment: Growth hormone replacement therapy^[4][1]

Hypogonadotropic Hypogonadism:

• Mechanism: LH/FSH deficiency
• Manifestations in males:
  • Cryptorchidism (undescended testes)
  • Micropenis
  • Hypospadias
  • Delayed or absent puberty
• Manifestations in females:
  • Delayed or absent puberty
  • Primary amenorrhea
• Anosmia: May be present (Kallmann syndrome overlap)^[8][4][1]

Other Endocrine Issues:

• Temperature dysregulation: Impaired thermoregulation
• Sleep pattern abnormalities: Irregular sleep-wake cycles
• ACTH deficiency: Rare, adrenal insufficiency
• TSH deficiency: Rare, hypothyroidism^[11][1]

Neurological and Developmental Features

Developmental Delay:
Universal feature with variable severity:^[4][1]

• Mild: Borderline intellectual functioning, learning disabilities
• Moderate: Significant cognitive impairment, requires special education
• Severe: Profound intellectual disability, nonverbal, non-ambulatory, spastic
• Correlation: Severity often correlates with degree of holoprosencephaly^[11][1]

Seizures:

• Frequency: Common in severe HPE
• Types: Generalized, focal, or infantile spasms
• Management: Antiepileptic medications^[5][1]

Feeding Difficulties:

• Sucking/swallowing: Oral-motor dysfunction
• Aspiration risk: Due to cleft palate and neurological impairment
• Failure to thrive: Poor weight gain
• Gastrostomy: Often required for nutrition^[11][1]

Craniofacial Dysmorphisms

Ocular Features:

• Hypotelorism: Closely spaced eyes (with severe HPE)
• Hypertelorism: Widely spaced eyes (with milder HPE)
• Microphthalmia: Small eyes
• Coloboma: Gap in iris, retina, or optic nerve
• Ptosis: Drooping eyelids
• Down-slanting palpebral fissures: Downward slant of eye openings^[5][1][11]

Ear Abnormalities:

• Low-set ears: Below normal position
• Malformed ears: Abnormal shape or structure
• Small ears: Microtia^[5][1]

Nasal Features:

• Depressed nasal bridge: Flat nose bridge
• Single nostril: In severe HPE
• Proboscis: Tubular structure above single eye (alobar HPE)^[4][5]

Microcephaly:

• Small head circumference: Common in severe HPE
• Correlation: Reflects severity of brain malformation^[1][5]

Additional Reported Features

Skeletal Abnormalities:

• Craniosynostosis: Premature fusion of skull sutures
• Vertebral anomalies: Spinal malformations
• Radial aplasia: Absent radius bone
• Scoliosis: Spinal curvature^[5][11][1]

Cardiac Malformations:
Reported in some patients:^[11][1]

• Ventricular septal defect: Hole between ventricles
• Atrial septal defect: Hole between atria
• Patent ductus arteriosus: Persistent fetal blood vessel
• Complex cardiac anomalies: Multiple defects^[1]

Genitourinary Abnormalities:
Beyond hypogonadism:^[11][1]

• Renal anomalies: Structural kidney defects
• Urogenital malformations: Various abnormalities^[1]

Diagnosis

Clinical Diagnostic Approach

The diagnosis of Hartsfield syndrome requires recognition of the characteristic combination of features:^[6][1]

Diagnostic Criteria:
According to GeneReviews and expert consensus:^[6][1]

1. Holoprosencephaly spectrum disorder: Any severity from alobar to milder midline defects
2. Ectrodactyly spectrum disorder: Split hand/foot affecting one to four limbs
3. Additional features: Cleft lip/palate, endocrine abnormalities, developmental delay
4. Molecular confirmation: FGFR1 pathogenic variant identification

Clinical Evaluation:

Prenatal Assessment:
When suspected prenatally:^[1]

• Prenatal ultrasound: May detect severe HPE, facial abnormalities, limb malformations
• Fetal MRI: Better visualization of brain structures
• Genetic counseling: Discussion of findings and prognosis^[1]

Postnatal Evaluation:
Comprehensive assessment required:^[6][1]

• Detailed physical examination: Documentation of all anomalies
• Neurological assessment: Tone, reflexes, developmental status
• Dysmorphology evaluation: Systematic craniofacial examination
• Endocrine screening: Pituitary hormone levels, electrolytes^[1]

Imaging Studies

Brain Imaging:
Essential for diagnosis and prognosis:^[11][1]

• Brain MRI: Gold standard for assessing brain malformations
  • Degree of hemispheric division
  • Corpus callosum integrity
  • Olfactory bulb presence
  • Pituitary anatomy
  • Ventricular configuration
• CT scan: Alternative if MRI contraindicated
• Cranial ultrasound: In neonates with open fontanelles^[1]

Skeletal Imaging:

• Hand/foot radiographs: Document bone structure and digit absence
• Skeletal survey: If additional skeletal anomalies suspected
• Spinal imaging: If vertebral anomalies present^[11][1]

Cardiac Imaging:

• Echocardiography: Screen for congenital heart defects^[1]

Laboratory Investigations

Endocrine Testing:
Comprehensive hormonal assessment:^[8][1]

• Serum sodium and osmolality: Screen for diabetes insipidus
• IGF-1 and IGFBP-3: Growth hormone status
• LH, FSH, testosterone/estradiol: Hypogonadotropic hypogonadism
• Thyroid function: TSH, free T4
• Cortisol: ACTH reserve
• Water deprivation test: Confirm diabetes insipidus if suspected^[1]

Molecular Genetic Testing

FGFR1 Gene Sequencing:
Confirmatory diagnostic test:^[6][2][1]

• Method: Complete gene sequencing of all exons and splice sites
• Detection rate: Approximately 85-90% of clinically diagnosed cases
• Variant types: Missense, nonsense, frameshift, synonymous with splice effects
• Interpretation: Requires expert assessment of pathogenicity^[9][2][1]

Additional Genetic Testing:
When FGFR1 testing negative:^[6][1]

• Chromosomal microarray: Detect copy number variants
• Exome sequencing: Identify variants in other genes
• FGF8 testing: Potential digenic inheritance (rare)^[7][6]

Differential Diagnosis

Hartsfield syndrome must be differentiated from other conditions with overlapping features:^[6][11][1]

Primary Differential Diagnoses:

1. Isolated Holoprosencephaly:

• Similarities: Brain malformation, facial anomalies
• Key differences: No ectrodactyly
• Genetic causes: SHH, ZIC2, SIX3, and other HPE genes^[3][1]

2. Isolated Ectrodactyly:

• Similarities: Split hand/foot malformation
• Key differences: No HPE, normal brain development
• Genetic causes: TP63, DLX5, DLX6, and other genes^[3][1]

3. EEC Syndrome (Ectrodactyly-Ectodermal Dysplasia-Clefting):

• Similarities: Ectrodactyly, cleft lip/palate
• Key differences: Ectodermal dysplasia (sparse hair, abnormal teeth, dry skin), no HPE
• Genetic cause: TP63 mutations^[12][11]

4. Pallister-Hall Syndrome:

• Similarities: Hypothalamic hamartoma, polydactyly, pituitary dysfunction
• Key differences: Postaxial polydactyly (not ectrodactyly), different brain malformation
• Genetic cause: GLI3 mutations^[1]

5. Kallmann Syndrome:

• Similarities: Hypogonadotropic hypogonadism, anosmia, FGFR1 mutations
• Key differences: No HPE, no ectrodactyly, milder phenotype
• Spectrum: Represents milder end of FGFR1 disorder spectrum^[2][7][3]

Management and Treatment

Treatment Philosophy

Currently, there is no curative treatment for Hartsfield syndrome, and management is entirely supportive and symptomatic:^[6][1]

Treatment Goals:

• Life support: In severely affected infants
• Endocrine management: Hormone replacement therapies
• Surgical correction: Address anatomical malformations
• Developmental support: Early intervention services
• Palliation: Comfort care when appropriate^[6][1]

Neonatal Management

Immediate Postnatal Care:
For severely affected newborns:^[1]

• Airway management: Intubation if respiratory distress
• Feeding support: Nasogastric or gastrostomy tube
• Fluid and electrolyte management: Monitor for diabetes insipidus
• Seizure management: Antiepileptic medications if needed
• Comfort care: Palliative approach for lethal forms^[5][1]

Endocrine Management

Central Diabetes Insipidus:
Lifelong treatment required:^[8][1]

• Desmopressin (DDAVP): Synthetic vasopressin analog
  • Intranasal spray, oral tablets, or sublingual
  • Dosing: Individualized based on response
• Monitoring: Serum sodium, urine output, osmolality
• Caution: Risk of water intoxication with overtreatment^[1]

Growth Hormone Deficiency:

• Recombinant growth hormone: Subcutaneous injections
• Dosing: Weight-based, typically 0.3 mg/kg/week divided into daily doses
• Monitoring: Growth velocity, IGF-1 levels
• Duration: Until growth plates close^[4][1]

Hypogonadotropic Hypogonadism:

• Males:
  • Testosterone replacement at puberty
  • Surgical orchiopexy for cryptorchidism
  • Hypospadias repair
• Females:
  • Estrogen replacement at puberty
  • Progesterone for menstrual cycling
• Fertility: May require assisted reproductive techniques^[8][1]

Other Endocrine Support:

• Thyroid hormone: If TSH deficiency
• Hydrocortisone: If ACTH deficiency
• Multidisciplinary: Pediatric endocrinologist management^[1]

Surgical Management

Cleft Lip/Palate Repair:
Standard surgical protocols:^[1]

• Cleft lip repair: Typically 3-6 months of age
• Cleft palate repair: Usually 9-18 months of age
• Speech therapy: Post-operative intervention
• Orthodontic care: Long-term dental management^[1]

Hand/Foot Reconstruction:
Complex orthopedic surgery:^[11][1]

• Goals: Improve function and appearance
• Techniques:
  • Web space deepening
  • Digit creation from available tissue
  • Syndactyly release
  • Prosthetic fitting if severe
• Timing: Individualized, multiple staged procedures
• Occupational therapy: Hand function rehabilitation^[1]

Neurosurgical Interventions:
When indicated:^[1]

• Ventriculoperitoneal shunt: For hydrocephalus
• Encephalocele repair: If present
• Craniosynostosis correction: If causing increased intracranial pressure^[1]

Cardiac Surgery:
For significant congenital heart defects:^[1]

• Timing: Based on defect severity and hemodynamic significance
• Types: Varies with specific defect^[1]

Developmental and Supportive Care

Early Intervention:
Critical for developmental outcomes:^[6][1]

• Physical therapy: Motor development, mobility
• Occupational therapy: Fine motor skills, activities of daily living
• Speech-language therapy: Communication development
• Special education: Individualized education programs^[1]

Seizure Management:
If present:^[1]

• Antiepileptic drugs: Multiple options based on seizure type
• Monitoring: EEG, medication levels
• Ketogenic diet: Consider for refractory seizures^[1]

Nutritional Support:
Essential due to feeding difficulties:^[1]

• Gastrostomy tube: Often required
• High-calorie formula: Optimize growth
• Nutritionist involvement: Monitor nutritional status
• Swallowing assessment: Speech-language pathologist evaluation^[1]

Genetic Counseling

Family Counseling:
Essential component of care:^[6][1]

• Recurrence risk:
  • De novo dominant mutations: Very low (<1%)
  • Germline mosaicism: Theoretical but rare
  • Inherited mutations: 50% recurrence
• Prenatal diagnosis: Available for future pregnancies
• Preimplantation genetic diagnosis: Option for carrier couples
• Psychosocial support: Address emotional impact on family^[6][1]

Prognosis and Long-term Outcomes

Overall Prognosis

The prognosis for Hartsfield syndrome is generally poor, correlating with severity of holoprosencephaly:^[5][6][1]

Mortality:

• Alobar HPE: Most are stillborn or die within days to weeks
• Semi-lobar HPE: May survive months to years
• Lobar HPE: Better survival, some reach adulthood
• Milder spectrum: Prolonged survival into adulthood reported^[10][1]

Severity-Specific Outcomes

Severe Form (Alobar HPE):

• Life expectancy: Days to weeks
• Developmental outcome: Not applicable given early death
• Quality of life: Severely compromised^[5][1]

Moderate Form (Semi-lobar/Lobar HPE):

• Life expectancy: Months to years, occasionally adulthood
• Developmental outcome: Severe to profound intellectual disability
• Functional status: Nonverbal, non-ambulatory, fully dependent
• Quality of life: Requires total care^[10][1]

Milder Form (Minimal HPE Spectrum):

• Life expectancy: Can reach adulthood
• Developmental outcome: Mild to moderate intellectual disability
• Functional status: Some may achieve limited independence
• Quality of life: Better with comprehensive support^[10][1]

Complications

Common Complications:

• Aspiration pneumonia: From feeding difficulties
• Seizures: Often difficult to control
• Infections: Increased susceptibility
• Hydrocephalus: Requires shunting
• Electrolyte imbalances: From diabetes insipidus^[11][1]

Research Directions and Future Perspectives

Molecular Research

Genotype-Phenotype Correlations:
Ongoing investigation:^[9][2][7]

• Mutation location: Kinase domain vs. extracellular domain effects
• Dominant-negative vs. loss-of-function: Correlation with severity
• Modifier genes: Factors influencing phenotypic variability
• Mosaicism: Role in milder presentations^[13][7]

Functional Studies:
Understanding pathogenic mechanisms:^[7]

• Zebrafish models: In vivo assessment of mutation effects
• Cell culture: Receptor trafficking and signaling studies
• Protein structure: Molecular modeling of mutant proteins
• Therapeutic targets: Identifying druggable pathways^[7]

Therapeutic Development

Future Treatment Approaches:

• Small molecule therapies: Compounds to enhance residual FGFR1 function
• Gene therapy: Future possibility for correcting mutations
• Stem cell therapy: Regenerative approaches for brain tissue
• Pharmacological chaperones: Stabilize mutant proteins^[1]

Prenatal Diagnosis and Prevention

Improved Prenatal Detection:

• Advanced ultrasound: Better visualization of brain and limb defects
• Fetal MRI: Detailed brain structure assessment
• Cell-free fetal DNA: Non-invasive prenatal testing development
• Early diagnosis: Enable informed reproductive choices^[1]

Conclusion

Hartsfield syndrome represents one of the most severe and devastating phenotypic manifestations of FGFR1 gene dysfunction, characterized by the unique combination of holoprosencephaly, ectrodactyly, and cleft lip/palate with profound endocrine and neurological consequences. Since the identification of FGFR1 as the causative gene in 2013, our understanding of this ultra-rare condition has advanced significantly, revealing the critical role of fibroblast growth factor signaling in coordinated brain, craniofacial, and limb development.

The discovery that dominant-negative mutations in the kinase domain of FGFR1 account for the most severe presentations has provided crucial mechanistic insights into disease pathogenesis. These mutations create “frozen inactive” receptor dimers that sequester normal receptors, effectively eliminating all FGFR1 signaling and resulting in profound disruption of multiple developmental processes during critical embryonic periods.

The clinical spectrum of FGFR1-related disorders—ranging from isolated hypogonadotropic hypogonadism through Kallmann syndrome to Hartsfield syndrome—illustrates how different types of mutations in the same gene can produce dramatically different phenotypes. Understanding these genotype-phenotype correlations has important implications for genetic counseling, prognosis determination, and potential therapeutic development.

The management of Hartsfield syndrome remains challenging, requiring comprehensive multidisciplinary care addressing endocrine deficiencies, anatomical malformations, developmental delays, and numerous medical complications. While life expectancy is severely limited for those with alobar holoprosencephaly, individuals with milder forms of the syndrome can occasionally survive into adulthood with appropriate supportive care.

Healthcare providers should maintain awareness of Hartsfield syndrome when evaluating infants or fetuses with the combination of holoprosencephaly and limb malformations. Early recognition enables appropriate genetic testing, accurate prognosis determination, and informed family counseling. Genetic counseling is essential for affected families, emphasizing that most cases result from de novo mutations with very low recurrence risks for future pregnancies.

Looking forward, continued research into FGFR1 function and the development of animal models will likely yield insights that extend beyond Hartsfield syndrome to broader understanding of brain and limb development. The potential for prenatal diagnosis when causative mutations are known enables informed reproductive planning for families. While curative therapies remain distant goals, improved supportive care continues to enhance quality of life for affected individuals who survive beyond infancy.

The study of Hartsfield syndrome exemplifies how investigation of rare genetic disorders can illuminate fundamental developmental processes and disease mechanisms, contributing to our broader understanding of human development and providing hope for future therapeutic interventions.

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12. https://en.wikipedia.org/wiki/Ectrodactyly–ectodermal_dysplasia–cleft_syndrome
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