Wiedemann-Rautenstrauch Syndrome

Disease Overview

Summary

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare genetic disorder. It is characterized by an aged appearance at birth (old man look), growth delays that start before birth (prenatal) and continue after birth, as well as a deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy).

WRS is caused by changes (variants) in the POLR3A gene. Inheritance is autosomal recessive.

There is no specific treatment, but early diagnosis and coordinated care can help manage the symptoms and improve the quality of life for affected individuals and their families.

Introduction

Wiedemann-Rautenstrauch syndrome is classified under the progeroid syndromes, which are a group of very rare genetic disorders characterized by clinical features of aging at an early age. Several features of aging are evident at birth, so it is referred to as a neonatal progeroid condition.

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Synonyms

• neonatal progeroid syndrome
• neonatal pseudo-hydrocephalic progeroid syndrome of WRS
• Rautenstrauch-Wiedemann syndrome

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Signs & Symptoms

There are only a few reports of people affected with Wiedemann-Rautenstrauch syndrome (WRS). The reported signs and symptoms include:

• Aged appearance where babies look older than they are, with thin, fragile and wrinkled skin (old man appearance)

• Deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy) with normal amounts of subcutaneous truncal fat and marked loss of fat from the face and distal extremities that result in:
  • Skin that appears unusually thin, fragile, dry, shiny, wrinkled and aged
  • Veins and muscles appearing abnormally prominent, particularly those of the forehead
    • As the children age, abnormal deposits of fat may accumulate under the skin (subcutaneous) in lower (caudal) areas of the body, particularly around the buttocks, the areas around the genitals and the anus (anogenital area) and the area between the ribs and the hips (flanks)
  • In infants and children, the abdomen may appear unusually large and prominent
• Bone thinning (osteopenia) that may predispose to bony fractures due to a defect of the cells that form new bone (osteoblasts) and cartilage cells

• Growth delays starting prenatally (especially during the last three months of the pregnancy) and continuing after birth
• Difficulty gaining weight and growing as expected (failure to thrive)
• Feeding difficulty as some babies and young children have trouble swallowing and may need special feeding methods to ensure proper nutrition (this worsens the growth failure even more)

• Abnormal skull and facial bones:
  • Large soft spot on the skull, wide gaps between skull bones and a prominent forehead in babies
  • Small facial bones
    • The head and facial differences lead to a head that appears unusually large (pseudohydrocephalus)
  • Distinctive facial abnormalities that may include:
    • Face that may be small compared to the head
    • Unusually small mouth (microstomia)
    • Prominent chin
    • Drooping eyelids
    • Lower eyelids that are turned outward (ectropion), exposing the membranes (conjunctivae) that line the eyelids as well as a portion of the eyeballs
    • Low-set ears that are abnormally angled toward the back of the head
    • Small, distinctively “beak-shaped” nose that becomes more pronounced with age

• Delayed or abnormal teeth development
  • Presence of only two to four front teeth (neonatal incisors) which fall out during infancy
  • Delayed or impaired tooth development (dentition)
• Unusually sparse scalp hair, eyebrows and eyelashes (hypotrichosis)
• Poor vision due to eye anomalies such as:
  • Cataract, a clouding of the lens of the eye, which is typically clear
  • Cloudy cornea, the clear outer layer at the front of the eye
  • Perforation of cornea
  • Abnormally small size of the eye (microphthalmia)
• Thin arms and legs with disproportionately large hands and feet
• Fingers and toes that might have underdeveloped or thickened nails
•  Stiff joints, especially in the shoulders, elbows and knees
• Thin bones, leading to fractures and other skeletal problems

• • Progressive developmental delays that start in young children, with severe delays in the acquisitions of new skills requiring the coordination of physical and mental activities (psychomotor delay)
• Intellectual disability which may range from mild to severe

Progressive neurological symptoms that may include:

• • Poor muscle tone (hypotonia)
  • Difficulty coordinating movements (ataxia)
  • Involuntary eye movements (nystagmus)
  • Lack of head control in babies
• Hoarse cry in babies and an unusual high-pitched voice in older children
• Recurrent respiratory infections which may result in life-threatening complications
• Cryptorchidism, a condition which one or both testes fail to descend from the abdomen into the scrotum
• Enlarged breasts (gynecomastia)
• Abnormal curvature of the spine (scoliosis)

Researchers think the neurological deterioration observed in a few people with WRS may be associated with loss of the myelin sheath from nerve fibers (demyelization) within the white substance of the brain (e.g., pure sudanophilic leukodystrophy).

Myelin is a whitish fatty substance that forms a protective wrapping or “sheath” around certain nerve fibers (axons) and serves as an electrical insulator, enabling the effective transmission of nerve impulses. “White substance” within the brain and spinal cord (central nervous system) primarily consists of bundles of myelinated nerve fibers.

Other reported brain anomalies include:

• Dandy Walker malformation, a brain anomaly that affects mostly the cerebellum, the part of the brain that controls movement
• Increased size of the cavities (ventricles) of the brain (ventriculomegaly)
• Calcification of the brain structures known as basal ganglia, which is a group of brain structures that have different roles including the body’s ability to move
• Absence (agenesis) of corpus callosum, the brain structure that joins both brain hemispheres.

Most children with WRS die in early childhood but survival to the third decade has been reported.

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Causes

Wiedemann-Rautenstrauch syndrome is caused by variants 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 molecule that is made from DNA. RNA polymerase III helps make 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 variants that cause Wiedemann-Rautenstrauch syndrome lead to production of abnormal subunit proteins that may prevent assembly of the RNA polymerase III enzyme or result in an RNA polymerase III that is not able 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 variants result in the specific signs and symptoms of Wiedemann-Rautenstrauch syndrome is unknown.

WRS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

WRS is extremely rare, affecting males and females equally across different ethnic and racial groups. About 40 patients with WRS have been reported in the medical literature from the first case reported in 1977 until 2022.

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Disorders with Similar Symptoms

The following disorders share some common features with WRS.

Hutchinson-Gilford Progeria Syndrome (HGPS) has some common features with WRS such as premature aging (progeria), growth delays, low weight and characteristic facial features. However, babies with HGPS have a small face, underdeveloped jaw and prominent eyes, as well as hair loss on the scalp, eyebrows and eyelashes and prominent scalp veins. Joint stiffness, repeated fractures, aged skin appearance and dental problems are common. In addition, intelligence is normal but affected people develop severe arteriosclerosis, which can be life-threatening. HGPS is caused by a variant in the LMNA gene.

Hallermann-Streiff syndrome has some common features with WRS, such as craniofacial differences, small mouth, beak-like nose and short stature. However, people with Hallermann-Streiff syndrome usually have normal intelligence and distinctive features including a small, wide head (microcephaly and brachycephaly), underdeveloped lower jaw and eye issues like congenital cataracts and microphthalmia (small eyes).

De Barsy Syndrome has some common features with WRS, such as aged appearance at birth, short stature and craniofacial differences as well as intellectual disability and hypotonia but patients also have distinctive symptoms such as loose skin (cutis laxa), continual involuntary movements (athetosis), large misshapen ears, thin lips and sparse hair.

Cockayne syndrome has some common features with WRS, such as growth disability, progeroid appearance, craniofacial differences, short stature and beaked nose, as well as neurological deterioration and movement disorders, Distinctive symptoms may include sensitivity to sunlight, small head (microcephaly), sunken eyes and hearing loss.

There are other congenital disorders that can present with similar symptoms such as growth delays, craniofacial malformations, intellectual disability and progressive neurological and neuromuscular issues. However, these conditions often have unique symptoms or physical findings that help differentiate them from WRS. Accurate diagnosis is crucial for proper management and treatment.

Other conditions that doctors should consider when making the diagnosis include 4H leukodystrophy and adolescent-onset progressive spastic ataxia, which are also caused by variants in the POLR3A gene. WRS may also resemble endosteal sclerosis-cerebellar hypoplasia syndrome caused by variants in the POLR3B gene. Additionally, other diagnoses to consider are Nestor-Guillermo progeria syndrome, Fontaine syndrome, SHORT syndrome and Marfan syndrome lipodystrophy type.

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Diagnosis

Doctors may suspect WRS based in premature aging or progeroid features since birth. It can sometimes be suspected before birth through ultrasound if growth delays and other signs are present. Imaging tests such as X-rays and MRIs, can help doctors to identify characteristic abnormalities.

Genetic testing identifying the POLR3A gene variants can confirm the diagnosis. Prenatal genetic diagnosis is possible if the specific POLR3A gene variants have previously been identified in a family member.

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Standard Therapies

There is no cure or specific treatment. General supportive care including help in coping with the progressive nature of the disorder is indicated. The treatment of Wiedemann-Rautenstrauch syndrome is directed toward the specific symptoms that are apparent in each affected person.

Treatment may require the coordinated efforts of a team of specialists who should work together to care for the patient. Pediatricians, specialists who assess and treat disorders of the nervous system (neurologists), physical therapists and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment, which should focus on managing symptoms and supporting the child’s overall health. It may include:

• Special feeding techniques including tube feeding may be necessary
• Regular monitoring to prevent and treat respiratory infections

Genetic counseling is recommended to help families understand the condition and the risks for future children.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/.
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [progeroid appearance, neurological abnormalities, intellectual disability, etc.].)

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References

TEXTBOOK

Pivnick EK. Neonatal Progeroid Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:238-39.

JOURNAL ARTICLES

Ghamry MA, Salah R, Galal EI, Henin S, Dobs M. A Case of Wiedemann-Rautenstrauch syndrome with fatal hyperkalemic renal failure. Cureus. 2022 Sep 19;14(9):e29320. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484294/

Shawky RM et al. Neonatal progeroid syndrome (Wiedemann Rautentrauch syndrome in an Egyptian child with premature loss of teeth and café au lait skin patches. Egyptian Journal of Medical Human Genetics. 2012;13;227-231.

Arboleda G, et al. Neonatal progeroid syndrome (Widemann-Rautenstrauch syndrome) report of three affected sibs. Am J Med Genet A. 2010;155:1712-1715.

Hou JW. Natural course of neonatal progeroid syndrome. Pediatr Neonatol 2009;50(3):102–9.

Arboleda G, Ramírez N, Arboleda H. The neonatal progeroid syndrome (Wiedemann-Rautenstrauch): a model for the study of human aging?. Exp Gerontol. 2007;42(10):939-943. doi:10.1016/j.exger.2007.07.004

O’Neill B, et al. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am J Med Genet A 2007 July 1;143A(13):1421-30.

O’Neill B, Simha V, Kotha V, Garg A. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am J Med Genet A. 2007 Jul 1;143 (13):1421-30.

Jäger M et al. In vitro osteogenic differentiation is affected in Wiedemann-Rautenstrauch-Syndrome (WRS). In Vivo.2005 Sept-Oct;19(5):831-6.

Arboleda H and Arboleda G. Follow-up study of Wiedemann-Rautenstrauch syndrome: long term survival and comparison with Rautenstrauch’s patient “G”. Birth Defects Res A Clin Mol Teratol. 2005 Aug;73(8):562-8.

Hoppen T et al. Siblings with neonatal progeroid syndrome (Wiedemann-Rautenstauch). Klin Padiatr. 2004 Mar-Apr;216(2):70-1.

Cao H and Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedeman-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet. 2003; Vol 48,Number 5,271-274.

Thorey F, et al. Kyphoscoliosis in Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome). Z Orthop Ihre Grenzgeb. 2003;141:341-4.

Korniszewski L, et al. Wiedemann-Rautenstrauch (neonatal progeroid) syndrome: new case with normal telomere length in skin fibroblasts. Am J Med Genet. 2001;103:144-8.

Korniszewski L et al. Wiedemann-Rautenstrauch (neonatal progeria) syndrome: New case with normal telomere length in skin fibroblasts. Am J Med Genet. 2001: October 1;103(2): 144-148.

Pivnick EK, et al. Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: report of five new cases and review. Am J Med Genet. 2000;90:131-40.

Hoppen T, et al. Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): case report and review of the literature. Klin Padiatr. 2000;212:71-76.

Abdel-Salam GM, Czeizel AE. A new case of neonatal progeroid syndrome with agenesis of corpus callosum. Genet Couns 1999;10(4):377–81.

Stoll C, et al. Wiedemann-Rautenstrauch syndrome. A case report and review of the literature. Genet Couns. 1998;9:119-24.

Courtens W, et al. A probable case of Wiedemann-Rautenstrauch syndrome or neonatal progeroid syndrome and review of the literature. Clin Dysmorphol. 1997;6:219-27.

Arboleda H, et al. Wiedemann-Rautenstrauch neonatal progeroid syndrome: report of three new patients. J Med Genet. 1997;34:433-37.

Bitoun P, et al. The Wiedemann-Rautenstrauch neonatal progeroid syndrome: a case report and review of the literature. Clin Dysmorphol. 1995;4:239-45.

Rautenstrauch T, et al. Neonatal progeroid syndrome (Wiedemann-Rautenstrauch). A follow-up study. Klin Padiatr. 1994;206:440-43.

Mazzarello P, et al. Enzymes of DNA metabolism in a patient with the Wiedemann-Rautenstrauch progeroid syndrome. Ann N Y Acad Sci. 1992;663:440-41.

Castineyra G, et al. Two sibs with Wiedemann-Rautenstrauch syndrome: possibilities of prenatal diagnosis by ultrasound. J Med Genet. 1992;29:434-36.

Toriello HV. Wiedemann-Rautenstrauch syndrome. J Med Genet. 1990;27:256-57.

Hagadorn JI, et al. Neonatal progeroid syndrome: more than one disease? Am J Med Genet. 1990;35:91-94.

Rudin C, et al. The neonatal pseudo-hydrocephalic progeroid syndrome (Wiedemann-Rautenstrauch). Report of a new patient and review of the literature. Eur J Pediatr. 1988;147:433-38.

Martin JJ, et al. The Wiedemann-Rautenstrauch or neonatal progeroid syndrome. neuropathological study of a case. Neuropediatrics. 1984;15:43-48.

Devos EA, et al. The Wiedemann-Rautenstrauch or neonatal progeroid syndrome. Report of a patient with consanguineous parents. Eur J Pediatr. 1981;136:245-48.

Wiedemann HR. An unidentified neonatal progeroid syndrome: follow-up report. Eur J Pediatr. 1979;130:65-70.

Rautenstrauch T, et al. Progeria: a cell culture study and clinical report of familial incidence. Eur J Pediatr. 1977;124:101-11.

INTERNET
Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. 2003 Dec 12 [Updated 2023 Oct 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1121/ Accessed August 6, 2024.

Wiedemann-Rautenstrauch syndrome. Orphanet. June 2021. https://www.orpha.net/en/disease/detail/3455 Accessed August 6, 2024.

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