Wiedemann–Rautenstrauch syndrome

Wiedemann–Rautenstrauch syndrome
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Alternate names

Wiedemann-Rautenstrauch syndrome; Progeroid syndrome neonatal; Wiedemann Rautenstrauch syndrome

Definition

Wiedemann–Rautenstrauch (WR) syndrome [ˈviːdəman ˈʁa͜ʊtən.ʃtʁa͜ʊx] , also known as neonatal progeroid syndrome, is a rare autosomal recessive progeroid syndrome. There have been over 30 cases of WR.

Neonatal progeroid syndrome is a rare genetic syndrome characterized by an aged appearance at birth. Other signs and symptoms include intrauterine growth restriction, feeding difficulties, distinctive craniofacial features, hypotonia, developmental delay and mild to severe intellectual disability. In most cases, affected infants pass away before age 7 months, but rare reports exist of survival into the teens or early 20s. WR is associated with abnormalities in bone maturation, and lipids and hormone metabolism.

Cause

Wiedemann-Rautenstrauch syndrome is caused by mutations in a gene called POLR3A. This gene provides instructions for making the largest piece (subunit) of an enzyme called RNA polymerase III. This enzyme is involved in the production (synthesis) of ribonucleic acid (RNA), a chemical cousin of DNA. RNA polymerase III helps synthesize several forms of RNA, including those that assemble protein building blocks (amino acids) into working proteins. This process is essential for the normal functioning and survival of cells in tissues throughout the body.

The POLR3A gene mutations that cause Wiedemann-Rautenstrauch syndrome lead to production of abnormal subunit proteins. The abnormal subunits may prevent assembly of the RNA polymerase III enzyme or result in an RNA polymerase III with impaired ability to synthesize RNA. Reduced function of the RNA polymerase III molecule likely affects development and function of many parts of the body, but how the POLR3A gene mutations result in the specific signs and symptoms of Wiedemann-Rautenstrauch syndrome is unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The signs and symptoms of neonatal progeroid syndrome vary but may include:

• Subcutaneous lipoatrophy (deficiency or absence of the fat layer beneath the skin) which gives infants an aged appearance at birth
• Intrauterine growth restriction
• Failure to thrive
• Feeding difficulties
• Distinctive craniofacial features such as a triangular face; large skull with wide anterior (front) fontanelle; small, underdeveloped facial bones; natal teeth; low-set, posteriorly (towards the back) rotated ears, ectropion; and/or unusually sparse scalp hair, eyebrows, and eyelashes
• Thin arms and legs with disproportionately large hands and feet
• Small fingers and toes with underdeveloped nails
• Osteopenia (low bone density)
• Horizontal nystagmus
• Developmental delay
• Mild to severe intellectual disability

Presentation

Affected individuals exhibit intrauterine and postnatal growth retardation, leading to short stature and an aged appearance from birth. They have physical abnormalities including a large head (macrocephaly), sparse hair, prominent scalp veins, inward-folded eyelid (entropion), widened anterior fontanelles, hollow cheeks (malar hypoplasia), general loss of fat tissues under the skin (lipoatrophy), delayed tooth eruption, abnormal hair pattern (hypotrichosis), beaked nose, mild to severe mental retardation and dysmorphism.

Diagnosis

A diagnosis of neonatal progeroid syndrome is made based on the presence of characteristic signs and symptoms. Rarely, a diagnosis may be suspected before birth if concerning features are viewed on ultrasound; however, most cases are diagnosed shortly after birth.

Differential diagnosis

Marfan lipodystrophy syndrome (MFLS) has sometimes been confused with Wiedemann–Rautenstrauch syndrome, since the Marfanoid features are progressive and sometimes incomplete.

MFLS is caused by mutations near the 3'-terminus of FBN1 that cause a deficiency of the protein hormone asprosin and progeroid-like symptoms with reduced subcutaneous white adipose tissue.

Treatment

Because neonatal progeroid syndrome affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment varies based on the signs and symptoms present in each person. For example, a feeding tube may be recommended in infants with feeding difficulties who have trouble putting on weight.

History

WR was first reported by Rautenstrauch and Snigula in 1977; and the earliest reports made subsequently have been by Wiedemann in 1979, by Devos in 1981, and Rudin in 1988.

External links

Classification	ICD-10: E34.8 OMIM: 264090 DiseasesDB: 32103
External resources	Orphanet: 3455