Wiedemann–Rautenstrauch syndrome

Rare autosomal recessive neonatal progeroid syndrome caused mainly by POLR3A variants

Wiedemann–Rautenstrauch syndrome
Synonyms	Wiedemann-Rautenstrauch syndrome, WRS, neonatal progeroid syndrome, neonatal pseudo-hydrocephalic progeroid syndrome, congenital pseudohydrocephalic progeroid syndrome, progeroid syndrome neonatal
Pronounce	N/A
Specialty	Medical genetics, Pediatrics, Neonatology, Endocrinology, Neurology
Symptoms	Aged appearance at birth, intrauterine growth restriction, failure to thrive, lipoatrophy, sparse hair, prominent scalp veins, triangular face, feeding difficulties, hypotonia, developmental delay
Complications	Feeding failure, recurrent infections, aspiration, severe growth failure, developmental disability, bone fragility, early death in severe cases
Onset	Prenatal and neonatal
Duration	Lifelong
Types	N/A
Causes	Usually biallelic pathogenic variants in POLR3A
Risks	Family history, parental carrier status, consanguinity
Diagnosis	Clinical findings, growth history, dysmorphology examination, genetic testing, molecular confirmation of POLR3A variants
Differential diagnosis	Hutchinson-Gilford progeria syndrome, Marfan lipodystrophy syndrome, Cockayne syndrome, mandibuloacral dysplasia, progeroid syndrome, lipodystrophy
Prevention	Genetic counseling, carrier testing when familial variants are known, prenatal or preimplantation genetic testing in selected families
Treatment	Supportive care, nutritional support, feeding therapy, management of complications, developmental therapies, multidisciplinary follow-up
Medication	No disease-specific curative medication
Prognosis	Variable; often poor in severe neonatal cases, but survival into childhood or adulthood has been reported
Frequency	Very rare
Deaths	N/A

Wiedemann–Rautenstrauch syndrome (WRS), also called neonatal progeroid syndrome, is a very rare genetic disorder characterized by a progeroid or aged appearance beginning at birth, severe prenatal and postnatal growth restriction, reduced or absent subcutaneous fat, distinctive craniofacial features, feeding difficulties, hypotonia, and variable developmental delay or intellectual disability. It is considered a neonatal form of progeroid syndrome.Wiedemann-Rautenstrauch syndrome(link). MedlinePlus Genetics.Wiedemann-Rautenstrauch Syndrome(link). National Organization for Rare Disorders.

WRS is most commonly caused by biallelic pathogenic variants in the POLR3A gene, which encodes the largest subunit of RNA polymerase III. RNA polymerase III is required for synthesis of several important noncoding RNAs, including transfer RNAs and ribosomal RNA components. Disruption of this enzyme complex affects growth, development, fat distribution, and multiple organ systems.POLR3A gene(link). MedlinePlus Genetics."Further delineation of Wiedemann-Rautenstrauch syndrome caused by biallelic variants in POLR3A".Clinical Genetics.2024;PMC:10958179.

Overview

Wiedemann–Rautenstrauch syndrome is a congenital disorder, meaning that features are present before birth or at birth. Affected infants often have marked intrauterine growth restriction, low birth weight, an aged facial appearance, prominent scalp veins, sparse scalp hair, reduced fat beneath the skin, a relatively large-appearing head, and feeding problems. The term "progeroid" refers to the aged appearance, not to true accelerated aging in the same sense as all forms of adult aging.

The disorder is extremely rare. Earlier literature described only a few dozen affected individuals, but molecular diagnosis has improved recognition. The clinical spectrum is variable. Some infants die in early infancy because of severe feeding problems, infections, aspiration, or multisystem complications, while other affected individuals have survived into adolescence or adulthood.

Terminology

• Wiedemann–Rautenstrauch syndrome - Preferred eponym for this neonatal progeroid syndrome.
• WRS - Abbreviation for Wiedemann–Rautenstrauch syndrome.
• Neonatal progeroid syndrome - Descriptive term emphasizing aged appearance at birth.
• Neonatal pseudo-hydrocephalic progeroid syndrome - Older descriptive name referring to apparent macrocephaly and progeroid appearance.
• Congenital pseudohydrocephalic progeroid syndrome - Another historical term.
• Progeroid syndrome - Group of disorders with features resembling premature aging.
• Lipoatrophy - Loss or deficiency of fat tissue.
• Lipodystrophy - Abnormal distribution or absence of adipose tissue.

Cause

WRS is usually caused by pathogenic variants in POLR3A. The POLR3A gene provides instructions for the largest subunit of RNA polymerase III, an enzyme complex involved in transcription of several forms of RNA.

• POLR3A - Main gene associated with classic Wiedemann–Rautenstrauch syndrome.
• RNA polymerase III - Enzyme complex involved in producing transfer RNA, 5S ribosomal RNA, and other small RNAs.
• Transfer RNA - RNA molecule needed for protein synthesis.
• Ribosomal RNA - RNA component of ribosomes.
• Transcription - Process of making RNA from DNA.
• Biallelic variant - Pathogenic variants affecting both copies of a gene.
• Loss-of-function variant - Genetic change that reduces or eliminates gene function.
• Compound heterozygous - Two different pathogenic variants, one in each gene copy.
• Homozygous - Same pathogenic variant in both gene copies.

POLR3A variants that cause WRS are thought to impair RNA polymerase III assembly or function. Because RNA polymerase III is important in many tissues, reduced function can affect growth, fat development, craniofacial development, neurologic function, bone maturation, and endocrine-metabolic pathways.Wiedemann-Rautenstrauch syndrome(link). MedlinePlus Genetics.

Related genes and expanding spectrum

Most confirmed classic cases are linked to POLR3A. However, some reports suggest a broader RNA polymerase III-related phenotypic spectrum.

• POLR3GL - Rare variants have been reported in a patient with a neonatal progeroid phenotype overlapping WRS.
• POLR3B - Associated mainly with POLR3-related leukodystrophy rather than classic WRS.
• POLR1C - Associated with POLR3-related leukodystrophy and Treacher Collins syndrome 3 in different contexts.
• POLR3-related leukodystrophy - Related group of disorders involving hypomyelination, dental anomalies, and endocrine features.

A reported POLR3GL-associated neonatal progeroid phenotype expands the possible molecular spectrum, but POLR3A remains the principal gene for classic WRS."A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL".European Journal of Human Genetics.2019;28(4)

461-468.doi:10.1038/s41431-019-0539-6.PMC:7080780.

Inheritance

WRS is usually inherited in an autosomal recessive pattern.

• Autosomal recessive - Both copies of the disease-associated gene must have pathogenic variants.
• Carrier - A person with one pathogenic variant who usually does not have symptoms.
• Recurrence risk - When both parents are carriers, each pregnancy has a 25% chance of being affected.
• Genetic counseling - Helps families understand inheritance, testing, and reproductive options.
• Consanguinity - Parental relatedness can increase the chance of autosomal recessive conditions.
• Prenatal testing - Possible if familial pathogenic variants are known.
• Preimplantation genetic testing - Possible for some families using in vitro fertilization when variants are known.

Autosomal recessive inheritance: when both parents are carriers, each pregnancy has a 25% chance of being affected.

Parents of an affected child are usually unaffected carriers. Siblings may be affected, unaffected carriers, or unaffected non-carriers depending on inherited variants.

Pathophysiology

The exact mechanism linking POLR3A dysfunction to the full WRS phenotype is not completely understood. Proposed mechanisms involve reduced RNA polymerase III activity, impaired synthesis of small RNAs, abnormal cellular growth and survival, disrupted adipose tissue development, altered bone maturation, and abnormal neurologic development.

• Adipose tissue - Reduced subcutaneous fat is a major feature.
• Bone maturation - May be delayed or abnormal.
• Growth retardation - Begins before birth and continues after birth.
• Hypotonia - Low muscle tone may affect feeding and motor development.
• Neurodevelopment - Developmental delay or intellectual disability may occur.
• Endocrine system - Hormone and metabolic abnormalities have been described in some patients.
• Lipid metabolism - Abnormal fat distribution and metabolic findings can occur.
• Cellular transcription - RNA polymerase III dysfunction affects transcription of small RNAs.

Signs and symptoms

Features vary among affected individuals. Not every patient has all findings.

Growth and body composition

• Intrauterine growth restriction - Poor growth before birth.
• Low birth weight - Common at delivery.
• Postnatal growth failure - Poor growth after birth.
• Failure to thrive - Difficulty gaining weight and growing.
• Short stature - May occur in survivors.
• Lipoatrophy - Deficiency or absence of subcutaneous fat.
• Lipodystrophy - Abnormal fat distribution.
• Thin limbs
• Disproportionately large-appearing hands and feet
• Reduced muscle bulk

Craniofacial features

• Aged facial appearance at birth
• Triangular face
• Apparent macrocephaly or pseudohydrocephalus
• Prominent scalp veins
• Wide anterior fontanelle
• Sparse scalp hair
• Sparse eyebrows and eyelashes
• Hypotrichosis
• Malar hypoplasia - Underdeveloped cheekbones.
• Small or underdeveloped facial bones
• Beaked or prominent nose
• Low-set ears
• Posteriorly rotated ears
• Ectropion - Outward turning of eyelid.
• Entropion - Inward turning of eyelid, reported in some individuals.
• Small chin or micrognathia
• Natal teeth or early teeth in some cases
• Delayed tooth eruption in others

Feeding and gastrointestinal features

• Feeding difficulty
• Poor sucking
• Swallowing difficulty
• Gastroesophageal reflux
• Vomiting
• Poor weight gain
• Need for tube feeding in some infants
• Aspiration risk
• Constipation in some cases

Neurologic and developmental features

• Hypotonia
• Developmental delay
• Delayed motor milestones
• Delayed speech
• Variable intellectual disability
• Seizures in some cases
• Abnormal tone or movement in some individuals
• Brain imaging abnormalities in some reports
• Hearing or vision concerns in selected cases

Eye findings

• Nystagmus
• Ectropion
• Entropion
• Decreased tear protection due to eyelid abnormalities
• Refractive errors in some patients
• Corneal exposure risk when eyelid closure is incomplete

Skeletal findings

• Osteopenia
• Delayed bone age
• Thin bones
• Joint stiffness in some cases
• Contractures in some cases
• Small fingers and toes
• Underdeveloped nails
• Bone fragility in selected patients

Endocrine and metabolic features

Some individuals have metabolic or endocrine abnormalities, though findings vary.

• Abnormal lipid metabolism
• Altered fat distribution
• Possible insulin or glucose abnormalities in selected cases
• Growth failure
• Delayed skeletal maturation
• Possible hormone abnormalities in reported cases

Diagnosis

Diagnosis is based on clinical findings, dysmorphology evaluation, growth history, and molecular genetic testing.

Clinical diagnosis

A clinical diagnosis may be suspected in a newborn or infant with:

• Severe intrauterine and postnatal growth restriction
• Aged or progeroid appearance at birth
• Marked loss of subcutaneous fat
• Prominent scalp veins
• Apparent macrocephaly or pseudohydrocephalus
• Triangular face and craniofacial dysmorphism
• Sparse hair
• Feeding difficulty
• Hypotonia
• Developmental delay or neurologic findings
• Autosomal recessive family pattern

Genetic testing

Genetic testing is the preferred method for confirmation.

• Gene panel - May include progeroid syndromes, lipodystrophy, growth disorders, or leukodystrophy-related genes.
• Exome sequencing - Useful when the diagnosis is unclear.
• Genome sequencing - May detect variants missed by targeted testing.
• POLR3A sequencing - Main molecular test for suspected classic WRS.
• Deletion and duplication analysis - May be considered when sequencing finds only one pathogenic variant.
• Variant interpretation - Requires correlation with clinical phenotype and inheritance.
• Parental testing - Confirms whether variants are inherited in trans.
• Genetic counseling - Recommended after diagnosis.

Prenatal diagnosis

WRS may be suspected prenatally when ultrasound shows severe growth restriction or unusual craniofacial features, but most cases are diagnosed after birth.

• Prenatal ultrasound - May show intrauterine growth restriction or craniofacial differences.
• Fetal growth restriction - Important prenatal clue.
• Chorionic villus sampling - Possible when familial variants are known.
• Amniocentesis - Possible when familial variants are known.
• Preimplantation genetic testing - Option for some families with known variants.

Evaluation after diagnosis

A multidisciplinary evaluation helps identify complications and care needs.

• Pediatric genetics evaluation
• Neonatology or pediatric assessment
• Nutrition and feeding evaluation
• Swallow study if aspiration is suspected
• Developmental assessment
• Neurology evaluation when seizures, tone abnormalities, or developmental concerns are present
• Ophthalmology evaluation
• Hearing evaluation
• Skeletal survey or bone health evaluation when indicated
• Endocrinology evaluation when growth or metabolic concerns are present
• Cardiac evaluation if clinically indicated
• Renal or abdominal imaging if anomalies are suspected

Differential diagnosis

WRS overlaps clinically with other progeroid, lipodystrophy, and congenital growth disorders.

• Hutchinson-Gilford progeria syndrome - Classic childhood progeria caused by LMNA variants; usually not progeroid at birth in the same way.
• Marfan lipodystrophy syndrome - FBN1-related disorder with congenital lipodystrophy, marfanoid habitus, and low asprosin.
• Cockayne syndrome - DNA repair disorder with growth failure, photosensitivity, neurologic decline, and progeroid features.
• Mandibuloacral dysplasia - Progeroid disorder with skeletal and lipodystrophy features.
• Nestor-Guillermo progeria syndrome - BANF1-related progeroid disorder.
• Mandibulofacial dysostosis - Craniofacial disorders that can mimic some facial findings.
• SHORT syndrome - Short stature, hyperextensibility, ocular depression, Rieger anomaly, and teething delay.
• Berardinelli-Seip congenital lipodystrophy - Congenital generalized lipodystrophy.
• Neonatal Marfan syndrome - Severe early-onset fibrillinopathy.
• Costello syndrome - RASopathy with feeding difficulty, distinctive face, and growth problems.
• Noonan syndrome - RASopathy with growth and craniofacial features.
• Silver-Russell syndrome - Growth restriction and triangular face.
• 3-M syndrome - Severe pre- and postnatal growth restriction.
• Seckel syndrome - Growth restriction and microcephaly.
• Primordial dwarfism - Group of disorders with severe prenatal and postnatal growth restriction.
• POLR3-related leukodystrophy - Related RNA polymerase III disorder, usually with hypomyelination, dental anomalies, and hypogonadotropic hypogonadism.
• Progeroid syndrome - General category of disorders with premature-aging-like appearance.

Marfan lipodystrophy syndrome can be confused with WRS because both may feature congenital lipodystrophy and progeroid appearance. MFLS is caused by pathogenic variants near the 3' end of FBN1 and involves deficiency of the protein hormone asprosin."Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene".European Journal of Medical Genetics.2014;57(5)

230-234.doi:10.1016/j.ejmg.2014.02.012.

Treatment

There is no curative or disease-specific therapy for WRS. Treatment is supportive and directed at the individual's symptoms and complications.

Multidisciplinary care

Care often involves:

• Medical genetics
• Neonatology
• Pediatrics
• Nutrition
• Gastroenterology
• Speech-language pathology
• Neurology
• Endocrinology
• Ophthalmology
• Audiology
• Physical therapy
• Occupational therapy
• Developmental pediatrics
• Palliative care
• Social work
• Genetic counseling

Feeding and nutrition

Feeding problems are a major management priority.

• High-calorie feeding plans
• Feeding therapy
• Monitoring for aspiration
• Treatment of reflux
• Swallow study when indicated
• Nasogastric tube feeding in selected infants
• Gastrostomy tube feeding when long-term nutritional support is needed
• Monitoring of growth parameters
• Vitamin and mineral support when deficient
• Management of constipation or vomiting

Developmental support

• Early intervention services
• Physical therapy for hypotonia and motor delay
• Occupational therapy for feeding, motor skills, and adaptive function
• Speech therapy for feeding and communication
• Developmental assessment
• Individualized educational planning
• Assistive devices when needed

Bone and endocrine care

• Bone density assessment when indicated
• Vitamin D and calcium optimization
• Monitoring for fractures
• Evaluation of delayed bone age
• Endocrinology consultation for growth and metabolic concerns
• Management of lipid or glucose abnormalities when present
• Monitoring pubertal development in long-term survivors

Eye, hearing, and dental care

• Ophthalmology examination
• Treatment of eyelid abnormalities if corneal exposure occurs
• Lubricating eye drops when needed
• Hearing screening
• Dental care for natal teeth, early teeth, delayed dentition, or oral feeding concerns
• Craniofacial or dental specialty referral when indicated

Infection and respiratory care

• Immunizations according to local schedule unless contraindicated
• Prompt evaluation of fever or respiratory symptoms
• Aspiration prevention
• Treatment of recurrent pneumonia
• Airway and sleep evaluation when clinically indicated
• Family education on signs of dehydration, respiratory distress, and infection

Prognosis

The prognosis is variable and depends on severity of feeding problems, infections, respiratory complications, neurologic involvement, and access to supportive care. Historically, many affected infants died in early infancy, but longer survival into childhood, adolescence, and adulthood has been reported.

• Severe neonatal cases may have high infant mortality.
• Feeding difficulty and aspiration are major risks.
• Recurrent infection can worsen prognosis.
• Developmental delay is common among survivors.
• Some individuals survive into adolescence or adulthood.
• Long-term outcome is difficult to predict because the disorder is very rare.
• Molecular diagnosis may improve prognostic understanding over time.

Epidemiology

WRS is extremely rare. Fewer than several dozen classic cases were reported in older literature, although the number of molecularly confirmed cases has grown since POLR3A was identified. The condition affects males and females. It has been reported in families with consanguinity and in multiple affected siblings, consistent with autosomal recessive inheritance.

Prevention

There is no general population prevention for WRS, but recurrence in families can be addressed through genetic counseling.

• Genetic counseling - Recommended for families with an affected child.
• Carrier testing - Possible when familial variants are known.
• Prenatal diagnosis - Available when causative variants are identified.
• Preimplantation genetic testing - Possible for some families.
• Consanguinity counseling - May be relevant in families or communities with related parents.
• Newborn evaluation - Important when there is a family history.

History

WRS was first described in the late 20th century. Rautenstrauch and Snigula reported familial cases in 1977. Wiedemann later described the syndrome in 1979, and subsequent reports clarified the neonatal progeroid phenotype. The molecular basis remained unknown until biallelic variants in POLR3A were identified in affected individuals.

• 1977 - Rautenstrauch and Snigula reported familial neonatal progeroid features.
• 1979 - Wiedemann reported an unidentified neonatal progeroid syndrome.
• 1980s–1990s - Additional cases helped define the clinical phenotype.
• 2016 - Biallelic POLR3A variants were linked to neonatal progeroid syndrome.
• 2019 onward - Reports expanded the RNA polymerase III-related progeroid spectrum.
• 2024 - Additional POLR3A variants further expanded genotype-phenotype correlations.

Patient education

Families should understand that WRS is a rare genetic condition and not caused by anything the parents did or did not do during pregnancy.

• WRS usually begins before birth with poor fetal growth.
• Affected infants often look aged because of reduced fat under the skin.
• Feeding support is often one of the most important early treatments.
• Genetic testing can confirm the diagnosis.
• Parents are usually healthy carriers when inheritance is autosomal recessive.
• Each pregnancy has a 25% recurrence risk when both parents are carriers.
• Early intervention can support development.
• Medical care should be coordinated by a multidisciplinary team.
• Fever, poor feeding, dehydration, breathing problems, or aspiration symptoms require prompt medical care.
• Genetic counseling can help with family planning.

When to seek medical care

Medical evaluation is important for infants with severe growth restriction, aged appearance, feeding difficulty, or developmental concerns.

• Poor feeding
• Recurrent vomiting
• Poor weight gain
• Signs of dehydration
• Breathing difficulty
• Choking or coughing during feeds
• Fever or signs of infection
• Seizures
• Poor muscle tone
• Developmental delay
• Eye redness or incomplete eyelid closure
• Suspected fracture
• Family history of WRS or neonatal progeroid syndrome

See also

• Progeroid syndrome
• Neonatal progeroid syndrome
• POLR3A
• RNA polymerase III
• Autosomal recessive
• Intrauterine growth restriction
• Failure to thrive
• Lipoatrophy
• Lipodystrophy
• Hypotonia
• Developmental delay
• Intellectual disability
• Marfan lipodystrophy syndrome
• Hutchinson-Gilford progeria syndrome
• Cockayne syndrome
• Mandibuloacral dysplasia
• POLR3-related leukodystrophy
• Medical genetics
• Genetic counseling
• Rare disease

Further reading

• Wiedemann-Rautenstrauch syndrome(link). MedlinePlus Genetics.
• POLR3A gene(link). MedlinePlus Genetics.
• Wiedemann-Rautenstrauch Syndrome(link). National Organization for Rare Disorders.
• Wiedemann-Rautenstrauch syndrome(link). Orphanet.
• "Further delineation of Wiedemann-Rautenstrauch syndrome caused by biallelic variants in POLR3A".Clinical Genetics.2024;PMC:10958179.
• "A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL".European Journal of Human Genetics.2019;28(4)

461-468.doi:10.1038/s41431-019-0539-6.PMC:7080780.

• "Neonatal progeroid syndrome associated with biallelic truncating variants in POLR3A".American Journal of Human Genetics.2016;PMID:27612211.
• "Wiedemann–Rautenstrauch neonatal progeroid syndrome: report of three new patients".Journal of Medical Genetics.1997;34(5)

433-437.doi:10.1136/jmg.34.5.433.PMID:9152846.PMC:1050956.

External links

• MedlinePlus Genetics - Wiedemann-Rautenstrauch syndrome
• MedlinePlus Genetics - POLR3A gene
• NORD - Wiedemann-Rautenstrauch Syndrome
• Orphanet - Wiedemann-Rautenstrauch syndrome
• OMIM - Wiedemann-Rautenstrauch syndrome
• Further delineation of WRS caused by POLR3A variants
• POLR3GL variant and neonatal progeroid syndrome
• GeneReviews - POLR3-related leukodystrophy

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