What is Wiedemann-Rautenstruch Syndrome?
Wiedemann-Rautenstrauch Syndrome was first described by Rautenstrauch and Snigula and then further delineated by Wiedemann. Patients often have what is described as pseudohydrocephalus, neonatal progeroid appearance, diminished subcutaneous fat, and neonatal teeth. The life span of affected individuals is typically less than 1 year, although there are rare reports surviving into their teens. [1] It is believed that the mutation in POLR3A gene is realted with this disease.
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POLR3A: The cause of the syndrome
The POLR3 complex is composed of 17 subunits with a molecular weight of 700KD; it is assembled in the cytoplasm and then translocated to the nucleus in a process mediated by chaperones. POLR3A is the largest subunit of the POLR3 complex. POLR3A consists of 1390 amino acids(MW 156 kDa) and, together with POLR3B, forms the catalytic core of the complex. [2]
POLR3A is considered as the major locus of autosomal-recessive WRS. Reports have shown that there is a relationship between WRS and bi-allelic POLR3A loss-of-function variants that alter splicing and/.or truncate translation.[3] |
Fig 1. The molecular structure of the POLR3 complex
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Symptoms
All affected children have had intrauterine growth retardation with subsequent failure to thrive and short stature. At birth and during infancy children have a progeroid appearance consisting of apparent macrocephaly, sparse hair, prominent scalp veins, entropion, greatly widened anterior fontanelles, malar hypoplasia, and generalised lipoatrophy. Two to four natal teeth have been present in all affected children; these teeth are eventually lost and subsequent dentition is delayed. Over time, the nose assumes a beaked appearance and caudal fat accumulation occurs.[4]
Fig2 . The patients who have the WRS
Diagnosing and treatment
Differential diagnosis includes other sudanophilic leucodystrophies, such as congenital Pelizaeus-Merzbacher disease, Sjogren-Larsson syndrome, Cockayne syndrome, sudanophilic leucodystrophy with microcephaly and pachygyria, as well as progeroid or lipoatrophy syndromes such as Hutchinson-Guildord, Berardinelli-Seip, DeBarsy, and Hallerman-Streiff syndromes. However, the striking phenotype and presence of natal teeth help distinguish this condition from others.
These children often suffer from feeding difficulties strauch noted that by the age of 4 years, one of their patients was markedly growth deficient. Children with this syndrome may also be more prone to intracranial haemorrhage, particularly after head trauma. [4] |
Fig3. The baby who has the WRS
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Inheritance
The condition is most probably inherited as an autosomal recessive trait. [4] WRS was first described by Rautenstrauch and Snigula in 1977 in two sisters and by Wiedemann in 1979 in two unrelated individuals. Subsequentlyu, Devos and colleagues reported a fifth unrelated patients born to consanguineous parents, proposed the name WRS, and suggested autosomal-recessive inheritance. [3] |
FIg4. WRS is an autosomal recessive disease
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References
1) Jay AM, Conway RL, Thiffault I, Saunders C, Farrow E, Adams J, Toriello HV. Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. Am J Med Genet A. 2016 Dec;170(12):3343-3346. doi: 10.1002/ajmg.a.37960. Epub 2016 Sep 9. PMID: 27612211.
2)Báez-Becerra CT, Valencia-Rincón E, Velásquez-Méndez K, Ramírez-Suárez NJ, Guevara C, Sandoval-Hernandez A, Arboleda-Bustos CE, Olivos-Cisneros L, Gutiérrez-Ospina G, Arboleda H, Arboleda G. Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mech Ageing Dev. 2020 Dec;192:111360. doi: 10.1016/j.mad.2020.111360. Epub 2020 Sep 22. PMID: 32976914.
3)Wambach JA, Wegner DJ, Patni N, Kircher M, Willing MC, Baldridge D, Xing C, Agarwal AK, Vergano SAS, Patel C, Grange DK, Kenney A, Najaf T, Nickerson DA, Bamshad MJ, Cole FS, Garg A. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. Am J Hum Genet. 2018 Dec 6;103(6):968-975. doi: 10.1016/j.ajhg.2018.10.010. Epub 2018 Nov 7. PMID: 30414627; PMCID: PMC6288318.
4)Toriello HV. Wiedemann-Rautenstrauch syndrome. J Med Genet. 1990 Apr;27(4):256-7. doi: 10.1136/jmg.27.4.256. PMID: 2325106; PMCID: PMC1017029.
2)Báez-Becerra CT, Valencia-Rincón E, Velásquez-Méndez K, Ramírez-Suárez NJ, Guevara C, Sandoval-Hernandez A, Arboleda-Bustos CE, Olivos-Cisneros L, Gutiérrez-Ospina G, Arboleda H, Arboleda G. Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mech Ageing Dev. 2020 Dec;192:111360. doi: 10.1016/j.mad.2020.111360. Epub 2020 Sep 22. PMID: 32976914.
3)Wambach JA, Wegner DJ, Patni N, Kircher M, Willing MC, Baldridge D, Xing C, Agarwal AK, Vergano SAS, Patel C, Grange DK, Kenney A, Najaf T, Nickerson DA, Bamshad MJ, Cole FS, Garg A. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. Am J Hum Genet. 2018 Dec 6;103(6):968-975. doi: 10.1016/j.ajhg.2018.10.010. Epub 2018 Nov 7. PMID: 30414627; PMCID: PMC6288318.
4)Toriello HV. Wiedemann-Rautenstrauch syndrome. J Med Genet. 1990 Apr;27(4):256-7. doi: 10.1136/jmg.27.4.256. PMID: 2325106; PMCID: PMC1017029.
Image Reference
Fig 1. Báez-Becerra CT, Valencia-Rincón E, Velásquez-Méndez K, Ramírez-Suárez NJ, Guevara C, Sandoval-Hernandez A, Arboleda-Bustos CE, Olivos-Cisneros L, Gutiérrez-Ospina G, Arboleda H, Arboleda G. Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mech Ageing Dev. 2020 Dec;192:111360. doi: 10.1016/j.mad.2020.111360. Epub 2020 Sep 22. PMID: 32976914.
Fig 2. Wambach JA, Wegner DJ, Patni N, Kircher M, Willing MC, Baldridge D, Xing C, Agarwal AK, Vergano SAS, Patel C, Grange DK, Kenney A, Najaf T, Nickerson DA, Bamshad MJ, Cole FS, Garg A. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. Am J Hum Genet. 2018 Dec 6;103(6):968-975. doi: 10.1016/j.ajhg.2018.10.010. Epub 2018 Nov 7. PMID: 30414627; PMCID: PMC6288318.
Fig 3. Toriello HV. Wiedemann-Rautenstrauch syndrome. J Med Genet. 1990 Apr;27(4):256-7. doi: 10.1136/jmg.27.4.256. PMID: 2325106; PMCID: PMC1017029.
Fig 4. https://en.wikipedia.org/wiki/Wiedemann–Rautenstrauch_syndrome
Fig 2. Wambach JA, Wegner DJ, Patni N, Kircher M, Willing MC, Baldridge D, Xing C, Agarwal AK, Vergano SAS, Patel C, Grange DK, Kenney A, Najaf T, Nickerson DA, Bamshad MJ, Cole FS, Garg A. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. Am J Hum Genet. 2018 Dec 6;103(6):968-975. doi: 10.1016/j.ajhg.2018.10.010. Epub 2018 Nov 7. PMID: 30414627; PMCID: PMC6288318.
Fig 3. Toriello HV. Wiedemann-Rautenstrauch syndrome. J Med Genet. 1990 Apr;27(4):256-7. doi: 10.1136/jmg.27.4.256. PMID: 2325106; PMCID: PMC1017029.
Fig 4. https://en.wikipedia.org/wiki/Wiedemann–Rautenstrauch_syndrome