Introduction

• Definition:
  • USP7-related disorder, also known as Hao-Fountain Syndrome (HFOUS), results from pathogenic variants or deletions in the USP7 gene.
  • The USP7 gene is located on chromosome 16p13.2 and encodes ubiquitin-specific protease 7, a key enzyme regulating protein ubiquitination and recycling.
• Clinical Presentation:
  • Affects both boys and girls, with variability in severity.
  • Common features include:
    • Neurodevelopmental difficulties: Developmental delay, intellectual disability (ID), and behavioral issues.
    • Speech and language delays.
    • Seizures.
    • Hypotonia (low muscle tone).
    • MRI abnormalities.

Key Features of USP7-Related Disorders

Developmental and Behavioral Characteristics

1. Physical Development:
   • Delay in independent walking due to hypotonia and joint hyper-flexibility.
   • Approximately 44% have an abnormal gait.
2. Learning:
   • Learning difficulties often diagnosed as intellectual disability (ID).
   • Educational needs range from special education programs to mainstream schooling with an Educational Health Care Plan (EHCP).
3. Behavioral Challenges:
   • Autistic traits: Hand flapping, repetitive behaviors, skin picking.
   • Other behaviors include:
     • Aggressiveness.
     • Temper tantrums.
     • Impulsivity and compulsivity.
4. Speech:
   • Speech delays; some individuals are non-verbal.
   • Language deficits often correlate with the degree of intellectual disability.

Growth and Physical Features

1. Growth:
   • Short stature affects about one-third of individuals.
   • Potential benefit from growth hormone (GH) therapy.
2. Facial Features:
   • Minor, variable features such as deep-set eyes and a prominent nasal septum.

Medical Concerns

Neurological

1. MRI Findings:
   • Many children have unusual brain imaging results.
2. Seizures:
   • Present in 44% of cases.
   • Monitoring for seizure activity is recommended.

Vision

• Common issues include:
  • Strabismus (squint): Misalignment of eyes; treated with patching, exercises, glasses, or surgery.
  • Myopia (short-sightedness).
  • Nystagmus: Involuntary eye movements.

Gastrointestinal

• Over half of affected children experience:
  • Feeding difficulties: Reflux, vomiting.
  • Chronic constipation or diarrhea.

Genitourinary

• Boys often exhibit:
  • Hypogonadism: Small penis, underdeveloped scrotum, small or undescended testes (cryptorchidism).

Pathophysiology

• USP7 Role in Protein Recycling:
  • Functions in the MAGEL2-USP7-TRIM27 (MUST) complex to regulate:
    • Ubiquitination of WASH protein for actin nucleation and endosomal recycling.
    • Balances levels of F-actin for proper protein trafficking.
• Neurodevelopmental Impact:
  • Disruption of ubiquitination affects neuronal pathways, leading to ID, ASD, and other symptoms.

Epidemiology

• Rarity:
  • Fewer than 25 individuals documented globally as of 2021.
  • Many cases remain undiagnosed due to limited awareness and rarity of the condition.

Management Recommendations

• Therapeutic Interventions:
  • Early intervention with speech and language therapy, physical therapy, and occupational therapy.
  • Multidisciplinary approach involving:
    • Ophthalmologists for vision issues.
    • Gastroenterologists for feeding/gastrointestinal concerns.
    • Neurology/neurodevelopment teams for behavioral and seizure management.
• Investigations:
  • Brain MRI for structural abnormalities.
  • Seizure monitoring.
  • Screening for growth hormone deficiency.
• Educational Support:
  • Assessment for special educational needs (SEN).
  • Tailored plans for school and home-based support.

Clinical Features Summary

Conclusion

• USP7-related disorders, or Hao-Fountain Syndrome, represent a rare but significant cause of neurodevelopmental delays and intellectual disability.
• Early identification and multidisciplinary management can improve outcomes and quality of life.
• Greater awareness and research are needed to enhance diagnostic rates and therapeutic options.