Van Maldergem Syndrome: Physical Traits, Diagnosis, and Care

Van Maldergem syndrome is a rare genetic disorder affecting multiple body systems, leading to distinctive physical features and developmental challenges. Due to its rarity, diagnosis can be complex, often requiring clinical evaluation and genetic testing. Early identification is crucial for managing symptoms and improving quality of life.

Recognized Physical Traits

Van Maldergem syndrome presents with distinct physical characteristics affecting craniofacial structure, skeletal formation, and neurological development. A defining feature is craniofacial dysmorphism, including a broad forehead, widely spaced eyes (hypertelorism), a flattened midface, a depressed nasal bridge, and low-set, dysplastic ears with overfolded helices. These traits contribute to the syndrome’s recognizable appearance and are often noted early in clinical assessments.

Skeletal abnormalities, including joint laxity and limb malformations, are common. Affected individuals may have camptodactyly, where fingers remain permanently flexed due to abnormal tendon development, and postaxial polydactyly, with extra fingers or toes on the outer side of the hands or feet. These differences can impact fine motor skills and mobility, sometimes requiring orthopedic interventions.

Neurological manifestations include microcephaly (abnormally small head circumference) and corpus callosum hypoplasia, a brain structure anomaly affecting communication between hemispheres. These contribute to developmental delays in motor coordination and cognitive function. Hypotonia (reduced muscle tone) is also prevalent, leading to challenges in achieving motor milestones such as sitting, standing, and walking.

Molecular Basis

Van Maldergem syndrome results from pathogenic variants in genes involved in cellular signaling and tissue development. The primary genes implicated are DCHS1 and FAT4, which encode proteins essential to the planar cell polarity (PCP) pathway. Disruptions in this pathway lead to widespread structural abnormalities characteristic of the syndrome.

DCHS1 encodes dachsous cadherin-related 1, a protein involved in cell adhesion and communication. It interacts with FAT4, another atypical cadherin, to regulate tissue patterning. Loss-of-function mutations in DCHS1 impair cellular alignment, particularly in neural and skeletal tissues, contributing to craniofacial dysmorphism and limb malformations. Experimental models have shown that reduced DCHS1 expression leads to abnormal skull formation and joint laxity, mirroring clinical features in patients.

FAT4 plays a broader role in PCP signaling, influencing cytoskeletal organization and cellular polarity. Pathogenic variants disrupt proper cell orientation, particularly affecting brain development. Research links FAT4 dysfunction to corpus callosum defects, a hallmark of Van Maldergem syndrome, as well as limb anomalies such as camptodactyly and polydactyly.

Inheritance Patterns

Van Maldergem syndrome follows an autosomal recessive inheritance pattern, requiring two pathogenic variants—one from each parent—for the condition to manifest. Carriers, who possess a single altered copy of the implicated gene, typically do not exhibit symptoms but have a 25% chance of passing the disorder to their offspring if both parents are carriers.

Genetic studies show affected individuals harbor biallelic mutations in either DCHS1 or FAT4, disrupting essential embryonic development pathways. These mutations result from deletions, missense variants, or nonsense mutations that impair protein function. While spontaneous mutations can occur, most cases result from inherited variants, highlighting the importance of genetic counseling for families with a history of the syndrome. Carrier identification through molecular testing can inform reproductive decisions and assess recurrence risks.

Diagnostic Methods

Diagnosing Van Maldergem syndrome requires a comprehensive approach integrating clinical evaluation and genetic testing. Due to overlapping features with other congenital disorders, physicians assess physical characteristics, developmental history, and neurological findings to establish a preliminary suspicion. Pediatricians and geneticists collaborate to document craniofacial morphology, skeletal anomalies, and motor delays, which provide early diagnostic clues. However, clinical assessment alone is rarely sufficient for a definitive diagnosis.

Genetic testing plays a central role, with whole-exome sequencing (WES) and targeted gene panels being the most effective tools. WES analyzes protein-coding regions across the genome, detecting pathogenic variants in DCHS1 and FAT4. This method is particularly useful when the clinical picture is ambiguous, identifying novel or atypical mutations. Targeted gene panels, which focus on genes associated with syndromic craniofacial and skeletal disorders, may also be used when clinical suspicion is strong.

Management Approaches

Care for individuals with Van Maldergem syndrome requires a multidisciplinary approach addressing diverse symptoms. Early intervention is key, as developmental delays and musculoskeletal abnormalities affect long-term mobility and cognitive function. Pediatric specialists, including neurologists, orthopedists, and speech therapists, develop individualized care plans. Physical therapy improves muscle tone and coordination, helping children reach motor milestones. Occupational therapy enhances fine motor skills, particularly for those with camptodactyly or joint laxity affecting hand function.

Surgical and medical interventions may be necessary depending on severity. Orthopedic procedures can correct limb deformities and improve mobility, while craniofacial surgeries may address structural anomalies affecting breathing or feeding. For significant neurological involvement, seizure management and cognitive therapies are integrated into care plans. Regular monitoring allows healthcare providers to adjust treatment strategies over time. Given the rarity of the syndrome, families may benefit from genetic counseling and support groups.

Potential Complications

The multisystem involvement of Van Maldergem syndrome increases the risk of complications affecting quality of life and long-term health. Neurological impairments, including corpus callosum abnormalities and microcephaly, can contribute to intellectual disabilities and motor coordination difficulties. Persistent hypotonia may lead to mobility and posture challenges, increasing musculoskeletal strain over time. Cognitive delays may impact learning, requiring specialized educational support.

Feeding difficulties, particularly in infancy, are another concern. Orofacial abnormalities, such as a high-arched palate or dysplastic ears, may contribute to swallowing and speech development issues. Some individuals also experience gastroesophageal reflux disease (GERD), requiring dietary modifications or medical management. Additionally, recurrent respiratory infections have been reported, possibly due to structural airway differences or immune system involvement. Long-term surveillance and proactive management are essential for optimizing health and function, emphasizing the need for coordinated care across multiple specialties.