McCusick syndrome

Overview

McCusick syndrome, also referred to as Oto-palato-digital syndrome type II (OPD II), is a rare X-linked genetic disorder characterized by abnormalities in the development of the bones, face, palate, and auditory system. It was first described by Dr. Victor A. McKusick and colleagues and is considered a more severe form of the oto-palato-digital spectrum disorders, which include OPD type I and OPD type II.

Individuals with McCusick syndrome typically present with a combination of distinctive craniofacial features, cleft palate, conductive hearing loss, short stature, limb deformities, and developmental delay. OPD II is often more severe in males due to the X-linked mode of inheritance, while carrier females may show mild or no symptoms.

Causes

McCusick syndrome is caused by mutations in the FLNA gene (filamin A gene), located on the X chromosome (Xq28). The FLNA gene encodes the filamin A protein, which plays a crucial role in cytoskeletal organization and signal transduction in developing tissues, particularly during skeletal morphogenesis.

The condition is inherited in an X-linked dominant pattern:

• Males with the mutation typically exhibit the full, severe phenotype.

• Females who carry the mutation may be mildly affected or asymptomatic due to X-chromosome inactivation (lyonization).

The same gene is also implicated in other conditions, such as periventricular nodular heterotopia and OPD type I, but McCusick syndrome (OPD II) is distinct due to its more severe presentation.

Symptoms

The clinical manifestations of McCusick syndrome affect multiple body systems and are typically more pronounced in males. Common symptoms and features include:

• Craniofacial abnormalities:

  • Prominent forehead (frontal bossing)

  • Hypertelorism (wide-spaced eyes)

  • Broad nasal bridge

  • Downslanting palpebral fissures

  • Micrognathia (small jaw)

• Oral and palatal anomalies:

  • Cleft palate

  • High-arched palate

  • Dental crowding or malalignment

• Auditory system involvement:

  • Conductive hearing loss due to ossicle malformations

• Skeletal abnormalities:

  • Short stature

  • Broad and shortened fingers and toes (brachydactyly)

  • Camptodactyly (permanently bent fingers)

  • Limb bowing or joint contractures

  • Chest deformities (pectus carinatum or excavatum)

• Other features:

  • Developmental delay or intellectual disability (varies in severity)

  • Possible respiratory difficulties due to chest wall anomalies

  • Gastrointestinal anomalies in rare cases

Females with a mutation in the FLNA gene may show some of the above signs, particularly facial and skeletal differences, but are typically less severely affected.

Diagnosis

Diagnosis of McCusick syndrome involves a combination of clinical evaluation, imaging studies, and genetic testing. Diagnostic procedures include:

• Clinical evaluation: Assessment of craniofacial structure, skeletal anomalies, and developmental milestones.

• Radiographic imaging:

  • X-rays of the hands, feet, spine, and skull to identify bone deformities

  • Chest X-rays to assess thoracic structure

• Hearing assessment: Audiometry or otoacoustic emissions testing to evaluate for conductive hearing loss.

• Genetic testing:

  • Sequencing of the FLNA gene to identify pathogenic variants

  • Testing is especially useful for confirming diagnosis and for genetic counseling

• Family history: Examination of family pedigree can help identify potential carriers or at-risk individuals.

Early diagnosis is important for timely management and to anticipate complications.

Treatment

There is no cure for McCusick syndrome, but management is multidisciplinary and focuses on relieving symptoms, supporting development, and improving quality of life. Treatment options include:

• Hearing management:

  • Use of hearing aids for conductive hearing loss

  • Surgical correction of middle ear ossicles in selected cases

• Speech and feeding support:

  • Speech therapy for language development, particularly in children with cleft palate

  • Feeding therapy for infants with palatal abnormalities

• Orthopedic interventions:

  • Physical therapy for joint mobility and muscle strength

  • Surgical correction of severe skeletal deformities

• Dental care:

  • Orthodontic treatment for malocclusion or crowded teeth

• Developmental support:

  • Early intervention programs for children with developmental delay

  • Special education resources as needed

• Genetic counseling: Recommended for affected families to understand recurrence risks and implications for future pregnancies.

Prognosis

The prognosis for individuals with McCusick syndrome varies depending on the severity of symptoms and the extent of organ system involvement. Most individuals can achieve an improved quality of life with early diagnosis, supportive care, and tailored interventions.

Hearing loss, orthopedic issues, and speech difficulties can be managed effectively, although developmental delay may present long-term challenges. In some severe cases, particularly those with respiratory or feeding complications, prognosis may be guarded.

Ongoing monitoring and multidisciplinary care are essential to address evolving health needs, optimize outcomes, and support both the individual and their family throughout life.