Wiedemann-Rautenstrauch Syndrome

Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) is a rare autosomal recessive disorder due to biallelic variants in POLR3A, with intrauterine growth restriction, a progeroid appearance at birth, lipodystrophy and, in many, neurological decline. It belongs to the POLR3-related disease spectrum.

Pathophysiology. POLR3A encodes the largest catalytic subunit of RNA polymerase III, which transcribes transfer RNAs, ribosomal 5S RNA and other small RNAs. Variants that severely reduce function produce the neonatal progeroid picture, while milder variants cause hypomyelinating leukodystrophy later in life.

Most affected infants are small from foetal life and have little subcutaneous fat.

Survival varies, and some patients live into childhood or adolescence.

• Intrauterine growth restriction and low birth weight, with short stature and poor weight gain
• Progeroid appearance: a triangular face, a prominent forehead, sparse scalp hair, prominent scalp veins, and thin skin
• Generalised lipodystrophy with loss of subcutaneous fat, and sometimes focal fat pads
• Natal or neonatal teeth
• Large anterior fontanelle
• Developmental delay and intellectual disability
• Hypotonia, ataxia and later neurological decline
• Hypomyelination on MRI
• Feeding difficulty and gastrointestinal problems
• Hypogonadism or delayed puberty in survivors
• Respiratory infections
• Ocular findings: myopia, and optic atrophy in some

• POLR3A sequencing with deletion and duplication analysis, or exome sequencing. Biallelic variants are required.
• Parental carrier testing to confirm that variants are in trans.
• Brain MRI: hypomyelination with relative preservation of some structures.
• Skeletal and dental assessment.
• Metabolic screen: glucose, lipids, insulin and liver tests, because lipodystrophy can cause insulin resistance and steatosis.
• Endocrine assessment in older survivors, with pubertal staging and gonadotropin levels.

Differential diagnosis.

• Hutchinson-Gilford progeria and other laminopathies (LMNA)
• Néstor-Guillermo progeria (BANF1)
• Cockayne syndrome
• Marfanoid-progeroid-lipodystrophy syndrome (FBN1)
• Other lipodystrophy syndromes

• Nutrition: high energy feeds, dietitian input, and gastrostomy for failure to thrive or unsafe swallow. Monitor growth against appropriate charts.
• Skin and temperature care: protect thin skin, and avoid overheating or cold exposure.
• Dental care: early review for natal teeth and enamel problems.
• Metabolic complications: screen glucose and lipids yearly. Treat diabetes with metformin 500 mg increasing to 1000 mg twice daily (maximum 2000 mg, reduce at eGFR under 45 mL/min) in older patients, and manage severe hypertriglyceridaemia with dietary fat restriction and fenofibrate 145 mg daily.
• Neurological care: physiotherapy, orthotics, speech therapy and special education. Treat seizures with levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Respiratory care: vaccination and prompt treatment of chest infection.
• Endocrine care: assess puberty, with sex hormone replacement in hypogonadism when it is established.
• Palliative care input early, because life expectancy may be limited.
• Genetic counselling: a 25% recurrence risk in each pregnancy for carrier parents, with prenatal diagnosis available.

Special groups.

• Pregnancies with growth restriction and a family history: offer targeted prenatal testing for POLR3A variants.

Monitoring. Growth, feeding and development every 3 months in infancy. Glucose, lipids and liver tests yearly, and neurological review every 6 months.

Referral and escalation. Refer to clinical genetics, metabolic or endocrine services and palliative care. Urgent for respiratory infection, severe hypoglycaemia or loss of milestones.