Lujan-Fryns Syndrome

Lujan-Fryns syndrome (X-linked intellectual disability with marfanoid habitus) is an X-linked disorder in males, most often due to the recurrent MED12 variant p.Asn1007Ser. It features intellectual disability, a marfanoid body build, characteristic facies, hypernasal speech and psychiatric disease.

Pathophysiology. MED12 encodes a subunit of the Mediator complex, which links transcription factors to RNA polymerase II and regulates gene expression. The same gene produces other X-linked disorders (Opitz-Kaveggia FG syndrome and Ohdo syndrome) through different missense variants, so the phenotype depends on the position of the change.

Females who carry the variant are usually unaffected or have mild features.

Cardiac and connective tissue assessment is needed because the body build resembles Marfan syndrome.

• Intellectual disability from mild to moderate
• Tall stature, long limbs, arachnodactyly and a narrow face with a high arched palate (a marfanoid habitus without lens dislocation or aortic root dilatation in most)
• Facial features: a long narrow face, a prominent forehead, a short philtrum and a high nasal bridge
• Hypernasal speech
• Psychiatric disease: autism, hyperactivity, schizophrenia like psychosis, and mood disorders
• Agenesis or hypoplasia of the corpus callosum
• Macrocephaly in some
• Hypotonia and joint hypermobility
• Mitral valve prolapse in some
• Feeding difficulty, and sometimes cleft palate

• MED12 sequencing, with the recurrent p.Asn1007Ser variant checked first when the picture fits, or exome sequencing.
• Carrier testing of the mother and female relatives.
• Brain MRI for corpus callosum anomalies.
• Echocardiography for aortic root size and valve disease.
• Slit lamp examination for lens position.
• Psychiatric and developmental assessment.

Differential diagnosis.

• Marfan syndrome (FBN1) and Loeys-Dietz syndrome
• Homocystinuria (CBS)
• Opitz-Kaveggia FG syndrome (MED12, different variant)
• Fragile X syndrome
• Klinefelter syndrome (47,XXY) and XYY syndrome

• Cardiac care: echocardiography at diagnosis, repeated every 1 to 2 years if the aortic root or valve is abnormal, and treatment of significant mitral valve disease.
• Speech and palate: speech therapy for hypernasal speech, and surgical assessment of velopharyngeal insufficiency.
• Development and education: early intervention, special education and vocational support.
• Psychiatric care: treat anxiety and depression with sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily. For psychosis use risperidone 1 mg daily increasing to 2 to 4 mg daily (maximum 6 mg daily) with metabolic and prolactin monitoring, or olanzapine 5 mg daily increasing to 10 to 20 mg daily with weight and glucose monitoring.
• ADHD: methylphenidate 5 mg once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily after cardiac review.
• Orthopaedic care: yearly spine and chest wall review, with bracing or surgery for progressive scoliosis.
• Eye care: correction of refractive error.
• Genetic counselling: a carrier mother has a 50% chance of transmitting the variant to each child; sons are affected and daughters are carriers.

Special groups.

• Adults: monitor for psychosis, and plan supported living and employment.

Monitoring. Mental state and behaviour at each visit. Echocardiography every 1 to 2 years when abnormal, metabolic monitoring every 3 to 6 months on antipsychotics, and spine review yearly.

Referral and escalation. Refer to clinical genetics, cardiology and psychiatry. Urgent for acute psychosis, suicidal thoughts or new chest symptoms.