Malan Syndrome

Malan syndrome is an overgrowth syndrome with intellectual disability caused by deletion or loss-of-function variants of NFIX at 19p13.2. It is distinct from Marshall-Smith syndrome, which results from dominant negative NFIX variants.

Pathophysiology. NFIX is a transcription factor of the nuclear factor I family that regulates neural and muscle development. Haploinsufficiency leads to overgrowth and developmental impairment.

Most cases are de novo.

Anxiety and neurological complications such as Chiari malformation need targeted follow up.

• Postnatal overgrowth with tall stature and macrocephaly, and advanced bone age
• Intellectual disability from mild to moderate, with speech delay
• Facial features: a long face, a prominent forehead, a long narrow chin, and downslanting fissures
• Hypotonia and joint laxity
• Anxiety, attention problems, autism features and sleep problems
• Seizures in a minority
• Brain MRI findings: Chiari I malformation, ventriculomegaly, and corpus callosum anomalies
• Scoliosis
• Eye problems: myopia, strabismus
• Congenital heart disease, and kidney anomalies in some
• Feeding difficulty in infancy and later constipation

• NFIX sequencing with deletion and duplication analysis, and chromosomal microarray for 19p13.2 deletions.
• Parental testing to confirm de novo origin.
• Brain MRI, with craniocervical junction views for Chiari malformation.
• Spine radiography.
• Echocardiography and renal ultrasound.
• Ophthalmology and developmental assessment.

Differential diagnosis.

• Sotos syndrome (NSD1)
• Weaver syndrome and Cohen-Gibson syndrome
• Marshall-Smith syndrome (NFIX, dominant negative)
• Tatton-Brown-Rahman syndrome (DNMT3A)
• Marfan syndrome and Beckwith-Wiedemann spectrum

• Neurological care: MRI of the brain and craniocervical junction at diagnosis. Refer a symptomatic Chiari malformation (headache, cough headache, neck pain, brainstem or cerebellar signs) to neurosurgery.
• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Anxiety and behaviour: cognitive and behavioural therapy, sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily, and 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 for ADHD.
• Sleep: melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Scoliosis: yearly spine review, bracing for curves of 20 to 40 degrees, and surgery for progressive curves over 40 degrees.
• Eye care: correction of myopia and treatment of strabismus.
• Cardiac and renal care: treat structural anomalies.
• Development and education: early intervention, speech therapy, occupational therapy and special education.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue mental health care, and plan transition and supported living.

Monitoring. Growth, development and behaviour every 6 to 12 months. Spine and eye review yearly, and repeat neuroimaging when new neurological symptoms occur.

Referral and escalation. Refer to clinical genetics, paediatric neurology and neurosurgery. Urgent for progressive headache, ataxia, swallowing difficulty or prolonged seizures.