Microdeletion syndrome

Overview

Microdeletion syndrome refers to a group of genetic disorders caused by the deletion of a small segment of a chromosome, typically involving several contiguous genes. These deletions are usually too small to be detected by conventional karyotyping but can significantly disrupt development, growth, and organ function depending on the genes involved. Microdeletion syndromes often present with a constellation of physical, cognitive, and behavioral symptoms and are typically diagnosed in infancy or early childhood.

Common examples of microdeletion syndromes include 22q11.2 deletion syndrome (DiGeorge syndrome), Williams syndrome (7q11.23 deletion), Prader–Willi syndrome (15q11-q13 deletion of paternal origin), Angelman syndrome (15q11-q13 deletion of maternal origin), and Smith–Magenis syndrome (17p11.2 deletion). Each has distinct features but shares the common mechanism of a chromosomal deletion affecting multiple genes.

Causes

Microdeletion syndromes are caused by the loss (deletion) of a small segment of DNA on a chromosome, often involving multiple adjacent genes. These deletions can occur during the formation of egg or sperm cells (de novo) or be inherited from a parent who may have a balanced chromosomal rearrangement or mosaicism.

Several factors contribute to these deletions:

• Chromosomal instability during meiosis: Errors during recombination can lead to unequal crossover events and deletions

• De novo mutations: The majority of cases are not inherited and occur as spontaneous mutations in the affected individual

• Parental chromosomal rearrangements: In rare cases, a parent may carry a balanced translocation or inversion that predisposes to microdeletion in offspring

The severity and type of symptoms depend on the specific genes lost in the deletion and their roles in development and function.

Symptoms

Symptoms of microdeletion syndromes vary widely depending on the specific chromosome and genes involved. However, common features across many microdeletion syndromes include:

Developmental and Cognitive Features

• Global developmental delay

• Intellectual disability, ranging from mild to severe

• Speech and language delays

• Learning disabilities

Physical and Craniofacial Features

• Facial dysmorphism (e.g., flat nasal bridge, wide-set eyes, low-set ears)

• Short stature or failure to thrive

• Microcephaly (small head size) in some syndromes

Organ System Involvement

• Congenital heart defects (common in 22q11.2 deletion syndrome)

• Kidney malformations

• Immune deficiencies

• Feeding difficulties and gastrointestinal issues

Behavioral and Psychiatric Features

• Autism spectrum disorder traits

• Hyperactivity or attention deficits

• Self-injurious behavior (seen in some syndromes like Smith–Magenis syndrome)

• Psychiatric conditions such as anxiety or schizophrenia in adolescence/adulthood

The combination and severity of symptoms depend on the specific syndrome and individual variations.

Diagnosis

Due to the small size of the deletions involved, microdeletion syndromes often require advanced genetic testing for diagnosis. Diagnostic steps may include:

• Clinical examination: Identification of developmental delays, congenital anomalies, and characteristic facial or physical features

• Chromosomal microarray analysis (CMA): A high-resolution test capable of detecting small deletions and duplications across the genome

• Fluorescence in situ hybridization (FISH): Used to detect specific microdeletions when a particular syndrome is suspected

• Whole exome/genome sequencing: For cases where CMA is inconclusive or to explore additional mutations

• Parental testing: To determine whether the deletion is inherited or de novo

Early diagnosis is crucial for initiating appropriate therapies and providing genetic counseling for the family.

Treatment

There is no cure for microdeletion syndromes, and treatment focuses on managing individual symptoms through a multidisciplinary approach. Management may include:

• Early intervention: Physical, occupational, and speech therapy to address developmental delays

• Special education: Tailored educational plans to support learning

• Medical management: Addressing heart defects, immune problems, or gastrointestinal issues as needed

• Behavioral therapy: For children with autism traits, hyperactivity, or self-harming behaviors

• Psychiatric care: Monitoring and treatment of mental health conditions in older children and adults

• Genetic counseling: Providing families with information about recurrence risk and reproductive options

Support groups and family resources can also be beneficial in helping families cope with the long-term challenges associated with these syndromes.

Prognosis

The prognosis of microdeletion syndromes varies widely depending on the specific syndrome, the size and location of the deletion, and the severity of associated symptoms. Many individuals with early intervention and ongoing support can lead fulfilling lives, although some may require lifelong care.

Factors influencing prognosis include:

• The degree of intellectual disability

• Presence and severity of organ defects

• Behavioral and psychiatric manifestations

• Access to early therapeutic and educational interventions

While some microdeletion syndromes are associated with a near-normal life expectancy, others may carry risks of life-threatening complications, particularly if major organ systems are involved. Regular medical follow-up and personalized care planning are essential for maximizing quality of life.