9p24.3 Deletion Syndrome

Alternate Names

• 9p24.3 Deletion Syndrome
  
• 9p short arm partial deletion (particularly in the 9p24.3 region)
  
• A subtype of 9p deletion syndrome (9p deletion syndrome / 9p‑syndrome)
  
• 9p minus syndrome (especially the “terminal deletion” type)
  
• Sometimes regarded as a subtype of Alfi syndrome (referring to the broader 9p deletion spectrum)
  

This name indicates that some or all of the genes near the terminal region (24.3) of the p arm of chromosome 9 are deleted on one copy. Within the broader framework of 9p deletion (9p deletion syndrome), the term “9p24.3 deletion syndrome” is used when the deletion breakpoint is close to 24.3.

Disorder Overview

9p24.3 Deletion Syndrome is a chromosomal abnormality in which one copy of the genes in the terminal region near 9p24.3 is lost (i.e. haploinsufficiency), leading to reduced gene dosage and a spectrum of developmental, structural, and functional abnormalities. The clinical presentation and severity vary widely depending on the exact deletion range (which genes are lost), whether additional chromosomal abnormalities are present, and individual variation. Thus, phenotypes range from mild to severe.

Deletion Range and Candidate Genes

In large‑scale studies of 9p deletions overall, many deletion breakpoints have been reported around 9p22 and 9p24, making the 9p24 region a mutational hotspot.
Within 9p24.3 deletions, there are numerous candidate genes such as DOCK8, KANK1, DMRT1, DMRT2, DMRT3, FOXD4, SMARCA2, among others.
In particular, DOCK8 and KANK1 are implicated in neurodevelopment, behavioral regulation, and immune function; their loss may be associated with neurodevelopmental disorders, seizure predisposition, and autism spectrum–like features in deletion cases.
Additionally, the DMRT gene family (involved in sexual differentiation) is of interest in cases of genital abnormalities or sex differentiation disorders. Some male (XY) cases have been reported with genital malformations associated with 9p24.3 deletion.

Clinical Features (Typical Findings)

From reported cases, the main clinical features include (but are not present in every case):

• Developmental delay, intellectual disability (moderate to severe)
  
• Delayed language development, difficulty in speech
  
• Facial dysmorphism: triangular skull (narrow frontal region), midface hypoplasia, low‑set ears, broad nasal bridge, long philtrum, thin upper lip, etc.
  
• Congenital heart defects (e.g. ventricular septal defect, atrial septal defect)
  
• Genital abnormalities / sex differentiation disorders: in male cases, underdevelopment of external genitalia, cryptorchidism, etc.
  
• Behavioral abnormalities, autism spectrum–like features, attention deficit, hyperactivity tendency
  
• Immune dysfunction predisposition, frequent infections (especially in some DOCK8 deletion cases)
  
• Others: urinary tract anomalies, limb deformities, visual abnormalities (e.g. strabismus, optic nerve developmental defects), reduced motor coordination, muscle tone abnormalities
  

Because published cases are limited, pure 9p24.3 deletion (without other chromosomal anomalies) is considered relatively rare, and is often regarded as a variant within the 9p deletion spectrum.

Epidemiology / Incidence

For the broader 9p deletion syndrome, more than 100 cases have been reported, although the true incidence is unknown.
Cases limited to 9p24.3 deletion are even fewer; only a handful have been documented in the literature.
In most cases, the deletion is de novo (new mutation), with no similar abnormality in the parents. However, in rare instances, parents may carry a balanced translocation that is passed on in an unbalanced form to offspring.

Etiology & Diagnostic Methods

Etiology / Pathogenesis

• The deletion typically arises from chromosomal breakage and aberrant recombination; the timing is presumed to be during gametogenesis or early post‑fertilization.
  
• If a parent carries a balanced chromosomal rearrangement (e.g. translocations, inversions), there is a risk that an unbalanced form may be transmitted to a child.
  
• The deletion causes haploinsufficiency, meaning that one copy of the gene is insufficient to sustain normal function, thereby disrupting development and structural formation.
  
• Interaction with genes outside the deletion region, dysregulation of gene networks, and influence of modifier genes are also considered key factors in phenotypic variability.
  

Diagnostic Methods

1. Clinical suspicion and physical examination
   Based on developmental delay, facial dysmorphism, heart defects, genital abnormalities, etc.
   
2. Karyotype (standard chromosomal analysis)
   If the deletion is large, G‑band karyotyping may detect it.
   
3. FISH (fluorescence in situ hybridization)
   Use of specific probes to check for deletion in the 9p24.3 region.
   
4. Microarray Comparative Genomic Hybridization / SNP microarray (array CGH / SNP array)
   High resolution detection of deletions or duplications, capable of identifying microdeletions.
   
5. Next‑generation sequencing (NGS) as adjunctive assay
   May be used to further characterize gene variants within the deleted region.
   
6. Parental testing / Genetic counseling
   Testing parents’ chromosomes to see if they carry balanced rearrangements, helping to assess recurrence risk and aid family planning.
   
7. Supplementary investigations
   Echocardiography, endocrine / sexual hormone assays, immune function tests, urinary system evaluation, imaging (e.g. brain MRI), etc., to assess and manage associated anomalies.
   

By this stepwise diagnostic approach, a definitive diagnosis can be reached.

Symptoms & Management

Main Symptoms / Issues

• Developmental delay, intellectual disability
  
• Delayed language development, speech difficulty
  
• Facial dysmorphism (skull shape, ear / nose / mouth morphology)
  
• Congenital heart defects
  
• Genital abnormalities / sex differentiation disorders
  
• Behavioral abnormalities, autism spectrum traits, attention deficit / hyperactivity
  
• Immune system impairment, frequent infections
  
• Visual abnormalities, nystagmus, strabismus, optic nerve hypoplasia
  
• Other anomalies: urinary system, limbs, kidney, etc.
  
• Muscle tone abnormalities, reduced motor coordination
  

Management / Therapeutic Strategies

• Developmental support / Early intervention
  Provide physical therapy, occupational therapy, speech therapy, and developmental support from infancy to maximize motor, cognitive, and language function.
  
• Management of cardiac defects
  Collaborate with cardiac specialists; if heart defects are present, consider surgical or medical management, with regular cardiac follow-up.
  
• Sex / endocrine management
  For cases with genital anomalies, perform endocrine evaluations, consider hormone replacement or surgical intervention when needed.
  
• Immune function management / Infection prevention
  Monitor immune function, and in cases of immune deficiency, implement vaccinations, infection prevention measures, and early treatment.
  
• Behavioral / psychiatric care
  Use behavioral therapy, environmental structuring, psychological support, and medications if needed to manage behavioral problems or attention deficit.
  
• Vision / hearing support
  Regular ophthalmology and otolaryngology assessments; interventions may include strabismus correction, vision correction, and assistive devices (e.g. hearing aids).
  
• Regular monitoring
  Periodically assess growth and development, cardiac/renal/urinary systems, neurodevelopment, vision/hearing, and intervene as needed.
  
• Educational / social / welfare support
  Collaborate with special education and therapy institutions, use assistive devices, day support, employment support, disability welfare systems, and caregiving structures to build a comprehensive support network.
  
• Family support
  Provide psychological support, counseling services, respite care, and early planning for future care systems for caregivers and family members.
  

Integrating these strategies to form a comprehensive, individualized support system for each patient and family is crucial.