Wiedemann–Rautenstrauch Syndrome and POLR3A-Related Disorders

Neonatal progeroid syndrome due to biallelic variants in POLR3A (and, with limited evidence, in POLR3B and POLR3GL*), part of the spectrum of RNA polymerase III-related disorders. POLR3-related hypomyelinating leukodystrophy (4H), spastic ataxia due to hypomorphic* POLR3A and the striatal form belong to the group of hypomyelinating leukodystrophies; Hutchinson–Gilford progeria, Werner syndrome, Cockayne syndrome, marfanoid–progeroid–lipodystrophy syndrome and the hereditary cutis laxa syndromes are part of the differential diagnosis. Fontaine progeroid syndrome (SLC25A24), the main neonatal differential, is covered alongside WRS.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding descriptions

In 1977, Thomas Rautenstrauch and Friedemann Snigula described two sisters who showed from birth the signs they attributed to progeria: very small size, almost complete absence of subcutaneous fat with accumulation of adipose tissue in the caudal region, triangular face, prominent scalp veins, very wide fontanelles and neonatal teeth [21]. One of the sisters died at 5 years; the other was followed up to 16.5 years, by which time she had lost all her teeth and developed spasticity, ataxia and an aged appearance, and she died at 17 years without an identified cause [21]. In 1979, H.-R. Wiedemann described two unrelated patients with a picture he recognised as overlapping and proposed the existence of a distinct neonatal progeroid syndrome of autosomal recessive inheritance [1, 28]. In 1981, Devos and colleagues reported a fifth patient, the child of consanguineous parents (double second cousins), with absent subcutaneous fat and paradoxical accumulation over the buttocks, anogenital region and flanks, sparse scalp hair, eyebrows and eyelashes and a "pseudohydrocephalic" head; these authors proposed the eponym Wiedemann–Rautenstrauch syndrome (WRS) and recessive inheritance [1, 21]. Autopsy of this patient, who died at 5.5 years, showed a pure sudanophilic leukodystrophy [1].

1.2. Clinical heterogeneity and the 2017 delineation

After the original descriptions, another 46 patients were published with a diagnosis of WRS or with a picture considered very similar, and phenotypic variability made the diagnosis uncertain [21]. In 2017, Paolacci and colleagues re-evaluated the 51 published patients, using the patients of Rautenstrauch and Snigula and of Wiedemann as the standard: the diagnosis was confirmed in 15, with sufficient data and photographs, was considered suggestive but indeterminate in 12 and was probably another condition in 24; adding three unpublished patients, the group of patients with a reliable diagnosis rose to 18 [21]. The delineation a few years earlier of the lipodystrophic type of Marfan syndrome (variants in the penultimate exon of FBN1) allowed a group of patients with neonatal lipodystrophy and marfanoid features to be removed from the WRS group [21, 22]. The 2017 cohort established the core signs that are still used as the clinical reference and that are described in section 3 [21].

1.3. Molecular discovery

In 2016, Jay and colleagues identified by exome sequencing, in a female infant with the characteristic phenotype, two variants in POLR3A, the gene for the largest subunit of RNA polymerase III: the intronic variant NM_007055.4:c.1909+18G>A and the nonsense variant NM_007055.4:c.2617C>T p.(Arg873Ter) [29]. The patient died at 7 months of respiratory complications, and the authors called for replication in other patients before considering the gene causal [23, 29]. Confirmation came in 2018, in three independent studies: Wambach and colleagues described seven North American patients aged 0 to 21 years with biallelic POLR3A variants that truncate the protein or alter splicing [22]; Paolacci and colleagues studied 15 patients from 12 families, with biallelic variants in 8 families and monoallelic variants in 4, mainly in deep intronic regions, and concluded that only certain combinations of compound heterozygous variants produce WRS [1, 24]; Lessel and colleagues, in a series of 14 children with juvenile progeroid syndrome without a variant in LMNA or ZMPSTE24, found biallelic POLR3A variants in two and a single variant in a third patient with an identical phenotype [23]. Since then, WRS has been listed in OMIM as an entity with a known molecular basis (264090, POLR3A, AR inheritance) [1, 15].

1.4. Nomenclature and place in the POLR3 spectrum

The term neonatal progeroid syndrome is synonymous with WRS, and OMIM uses the symbol WDRTS [1]. Biallelic POLR3A variants had been known since 2011 as the cause of hypomyelinating leukodystrophy 7 (HLD7), with or without oligodontia and hypogonadotropic hypogonadism, so WRS became allelic to that leukodystrophy and to the adolescent-onset spastic ataxia described in 2017 [22, 30, 31]. The pooled analysis published in 2025 groups these entities under the designation RNA polymerase III-related disorders (POLR3-RD), which includes genes for several subunits (POLR3A, POLR3B, POLR1C, POLR1D, POLR3D, POLR3E, POLR3F, POLR3GL, POLR3H and POLR3K) and clinical categories such as hypomyelinating leukodystrophy (HLD), hereditary spastic paraplegia and spastic ataxia (HSP/SA), striatal forms (SVF), isolated cerebellar atrophy (ICA), ataxia with spasticity and demyelinating neuropathy (ASDN), isolated hormonal disorders (IHD), WRS, Treacher Collins syndrome and endosteal hyperostosis with oligodontia (EHO) [4].

1.5. Entities within scope

The central entity is WRS due to biallelic POLR3A variants, which accounts for 35 of the 38 patients with WRS gathered in the 2025 international database [4]. Three patients with WRS and POLR3B variants were included in the same database, with weaker evidence, and one patient with a homozygous nonsense POLR3GL variant was described as a neonatal progeroid syndrome variant [3–5]. The other disorders of the POLR3 class enter the article as allelic disorders and as differential diagnoses. The progeroid syndromes unrelated to RNA polymerase III that are confused with WRS in the newborn are covered in section 6. Fontaine progeroid syndrome, autosomal dominant and caused by de novo SLC25A24 variants, is the entity most often confused with WRS in the newborn: two of the five patients in the series that identified the gene had initially received a diagnosis of WRS [32]. Because of its clinical proximity, its genetics, clinical features, diagnosis, management, counselling and follow-up occupy subsections 2.9, 3.11, 5.6, 6.4, 7.11, 8.5, 9.5 and 11.4, and a published case completes section 10 [7, 8].

2. Molecular Genetics and Pathophysiology

2.1. RNA polymerase III and the POLR3A subunit

The nuclear genome is transcribed by three RNA polymerases: RNA polymerase I (Pol I) synthesises the large ribosomal RNAs, Pol II transcribes messenger RNAs and Pol III synthesises transfer RNAs (tRNA), 5S ribosomal RNA and other non-coding RNAs [30]. Pol III is a 17-subunit complex, constitutively expressed, which transcribes more than 200 non-coding RNAs from at least 500 loci: all tRNAs, 5S rRNA, U6 snRNA, 7SK and 7SL RNAs, RNase P and MRP, vault RNAs and transcripts derived from Alu elements, involved in transcription, RNA processing and translation [4, 6, 9, 22]. Some of these RNAs, such as 7SK and 7SL, regulate Pol II activity, so Pol III dysfunction can also alter genes transcribed by Pol II [21]. POLR3A encodes the RPC1 subunit, the largest of Pol III (1390 amino acids), which together with RPC2 (encoded by POLR3B, 1133 amino acids) forms the catalytic centre of the enzyme and contributes the DxDGD motif that coordinates magnesium; the gene has 31 exons [6, 9]. RPC1 also acts as a cytosolic DNA sensor in innate immunity against intracellular bacteria and DNA viruses [9].

2.2. Hypomorphism and functional dosage

Complete loss of Pol III is incompatible with life: the Polr3a−/− mouse dies in the embryonic period, whereas the heterozygous Polr3a+/− mouse reproduces and has no abnormalities at 12 months [22]. In gnomAD, with about 135,000 individuals, there are no people with two frameshift or nonsense POLR3A variants, and in POLR3 leukodystrophy no patient has two null variants [6, 22]. The disorders of the class therefore result from hypomorphic variants that reduce without abolishing Pol III function, and severity tracks residual activity: WRS lies at the severe end, with genotypes including at least one null or equivalent allele, and spastic ataxia at the mild end, with an intronic variant that disturbs splicing only partially [4, 9]. Reduced POLR3A lowers the total tRNA pool and dysregulates the transcription of several non-coding RNAs, but the mechanism linking a ubiquitous polymerase to a phenotype concentrated in myelin, teeth, bone, adipose tissue and the endocrine axes remains unclear [21, 30].

2.3. Cellular mechanisms studied in WRS

Cellular studies are preclinical and small. In fibroblasts from a Colombian patient with WRS and the variant NM_007055.4:c.3772_3773del p.(Leu1258GlyfsTer12) (article notation c.3772_3773delCT; confirmed in VariantValidator), Báez-Becerra and colleagues observed reduced normal mRNA and protein, increased mutant protein in the nucleus, increased nucleolar number and area, activation of phosphorylated p53 and phosphorylated H2AX, and premature senescence [10, 33]. Induced pluripotent stem cells (iPSC) obtained from a Russian patient showed increased expression of mutant POLR3A during reprogramming, nucleolar abnormalities, nucleolar sequestration of the telomerase RNA component (TERC) and absence of telomere elongation; fibroblasts derived from these iPSC showed, from early passages, increased senescence-associated β-galactosidase activity and p16, with telomere shortening [34, 35]. A 2006 study cited by OMIM found no change in telomere-dependent replicative lifespan in fibroblasts from another patient [1]. In zebrafish, polr3a mutants have hypoplasia of neural crest-derived craniofacial cartilage and bone, without altered embryonic cell proliferation or survival, with cell death at the larval stage, reduced tRNA transcription and ribosome biogenesis and activation of tp53; inhibition of Tp53 alone does not correct the defect [36].

2.4. Variant spectrum in POLR3A-related WRS

The variants described in WRS are of diverse types: nonsense variants, start-loss variants, canonical and non-canonical splicing variants, deep intronic variants, synonymous variants with an effect on splicing, a 3' untranslated region variant and missense variants of high predicted impact [4, 22, 24]. The POLR3-RD database gathers 32 unique POLR3A variants associated with WRS (10 missense, 10 splicing and 6 nonsense) in 29 genotypes [4]. Many lie in introns, outside the regions captured by conventional exome sequencing, which explains why the aetiology of WRS remained unknown until 2016 [23, 24]. The following table gathers the variants with a studied functional effect or that are recurrent, normalised in VariantValidator to the MANE Select transcript NM_007055.4; the c. numbering coincides with that of publications using NM_007055.3 [10, 22].

The c. and p. notations in the table were confirmed in VariantValidator on GRCh38 with the MANE Select transcript; the notation p.(Tyr637CysfsTer23) for NM_007055.4:c.1909+18G>A is the consequence described in the original article from the aberrant transcript, whereas VariantValidator, which does not predict the splicing effect, returns p.? [10, 29].

2.5. Genotype–phenotype correlation

In the Wambach series, all seven patients had variants that alter splicing or truncate translation on both alleles, and the authors proposed that biallelic null or splicing genotypes are associated with WRS, whereas genotypes with biallelic missense variants, or missense in trans with null variants, are associated with leukodystrophy [22]. Paolacci and colleagues identified recurrent haplotypes exclusive to WRS and concluded that no single functional domain explains the variability, specific combinations of compound variants being required [24]. The 2025 analysis, with 38 WRS patients, refined the model: of the 29 genotypes associated with WRS, 10 (34.5%; 13 patients) affect the initiation codon or introduce premature termination, 5 (17.2%; 9 patients) have only missense variants, 7 (24.1%; 8 patients) have only splicing variants, 1 is homozygous for a synonymous variant and 7 (24.1%; 8 patients) are multiallelic, with c.1909+22G>A and c.3337-11T>C in cis [4]. All WRS genotypes include at least one allele of more severe effect; in genotypes with only missense variants, the SIFT, PolyPhen-2 and AlphaMissense scores of the more severe allele are significantly more deleterious than in variants not associated with WRS (SIFT W = 6355.5, p = 1.23 × 10⁻⁹; PolyPhen-2 W = 5507.5, p = 1.62 × 10⁻⁴; AlphaMissense t = 3.022, p = 0.0138), although the authors consider bioinformatics insufficient to draw conclusions [4]. Genotypes repeated in more than one patient always produced the same diagnostic category [4].

The behaviour of the intron 14 variants illustrates the effect of allelic context. c.1909+22G>A is present in all 93 patients with HSP/SA in the 2025 database, in trans with another variant and without a second variant in cis; homozygosity for this variant is considered to cause no or minimal disease, because there are 10 homozygotes in gnomAD; when it is in cis with c.3337-11T>C and there is a pathogenic variant on the other allele, the result is WRS [4]. The neighbouring c.1909+18G>A is not associated with HSP/SA, causes leukodystrophy in the homozygous state (9 patients) and WRS in compound heterozygosity with a null variant (2 patients) [4, 22]. The intron 13 variants c.1771-6C>G and c.1771-7C>G define the striatal forms; in trans with a protein-truncating variant they cause a severe striatal form (13 of 13 patients), which can mimic WRS [4, 39].

2.6. POLR3B and POLR3GL

In 2021, Wu and colleagues described a 6-year-old Chinese child, with a progeroid phenotype and an affected fetus in the following pregnancy, compound heterozygous for POLR3B NM_018082.6:c.2191G>C p.(Glu731Gln) and NM_018082.6:c.3046G>A p.(Val1016Met), absent from gnomAD and classified by the authors themselves as variants of uncertain significance (VUS) [3, 10]. The 2025 database adds a patient homozygous for POLR3B NM_018082.6:c.1625A>G p.(Asn542Ser), a variant also observed in compound heterozygosity in isolated cerebellar atrophy [4, 10]. OMIM does not list WRS among the POLR3B phenotypes (November 2024 revision), which are HLD8 (AR) and demyelinating Charcot–Marie–Tooth disease type 1I (AD) [12]. POLR3GL encodes a subunit of a dissociable Pol III subcomplex, with POLR3C and POLR3F, important for transcription initiation; biallelic splicing variants cause axial endosteal hyperostosis, oligodontia, short stature and mild facial dysmorphism (OMIM 619234), and a homozygous nonsense variant, NM_032305.3:c.358C>T p.(Arg120Ter), with mRNA decay suggested by RNA studies, was described in a female infant with a neonatal progeroid syndrome phenotype without lipodystrophy [5, 10, 11, 44].

2.7. Allelic disorders and other disorders of the class

2.8. Inheritance, penetrance and modifiers

POLR3A-related WRS is transmitted in an autosomal recessive manner; in all patients studied with parental samples the variants were in trans, and heterozygotes are asymptomatic [6, 22]. The presence of complex alleles (two variants on the same chromosome) requires segregation analysis to establish phase: 18 of 551 patients (3.3%) in the POLR3-RD database had more than one variant in cis [4]. Severity varies between siblings, but the similarity of age at death in small groups of affected siblings suggests a genetic influence, and the role of modifier genes, POLR3A polymorphisms and Pol III interactors remains open [21]. In a patient with WRS and anaemia, the anaemia was attributed to concomitant biallelic FANCA variants, a reminder of the possibility of a second molecular diagnosis [40].

2.9. Fontaine progeroid syndrome: molecular genetics of SLC25A24

The SLC25A24 gene (1p13.3; MANE Select transcript NM_013386.5, protein NP_037518.3; OMIM 608744) encodes SCaMC-1 (short calcium-binding mitochondrial carrier 1), also called APC1, an inner mitochondrial membrane carrier that exchanges ATP-Mg or ADP for phosphate in an electroneutral and reversible manner and maintains the matrix adenine nucleotide pool [7, 48]. The protein has a calcium-sensitive N-terminal regulatory domain, followed by six transmembrane helices; reduced expression in cell lines increases susceptibility to oxidative stress, calcium overload and cell death dependent on the mitochondrial permeability transition pore [7]. OMIM places the gene at 1p13.3 in the phenotype–gene relationships table, although the entry text refers to 1p36; GeneReviews, VariantValidator (NC_000001.11, about 108.16 Mb) and case reports confirm 1p13.3 [7, 8, 10, 19].

All known pathogenic variants affect codon 217, in exon 5, at the end of the first transmembrane helix and within the conserved motif of the mitochondrial carrier family [7, 48]. There are two: NM_013386.5:c.650G>A p.(Arg217His), genomic NC_000001.11:g.108157481C>T, and NM_013386.5:c.649C>T p.(Arg217Cys), genomic NC_000001.11:g.108157482G>A, both confirmed in VariantValidator on the MANE Select transcript (the gene is on the minus strand, which explains the base swap between genomic and cDNA notations) [7, 10]. In the Ehmke series, c.650G>A was present in four of the five patients and c.649C>T in one; in the Writzl series, c.650G>A in three of the four patients and c.649C>T in one patient; none of the variants is listed in ExAC, gnomAD or 1000 Genomes, and all arose de novo [8, 32, 48]. A review table published in 2019 writes the cysteine variant as c.649G>T, a notation incompatible with the reference sequence; the correct form is c.649C>T [10, 49]. In a Japanese patient, the c.649C>T variant was classified as pathogenic with ACMG/AMP criteria PS2, PM1, PM2 and PM4, as applied by the authors [20].

The mutant protein has normal stability in fibroblasts, which rules out haploinsufficiency as the mechanism. In the fibroblasts of Ehmke's patients, mitochondria showed swelling, worsened by hydrogen peroxide and reproduced by overexpression of the mutant cDNA; matrix ATP content was lower than in controls and membrane potential rose under oxidative stress, without reduction of mitochondrial DNA copy number, which led the authors to propose a pathological gain of function [32]. Writzl and colleagues predicted, by molecular dynamics simulation, that both substitutions narrow the substrate cavity and disturb carrier dynamics, and observed in fibroblasts altered mitochondrial morphology, slower proliferation, hyperpolarisation of the mitochondrial membrane and reduced oxygen consumption linked to ATP synthesis [48]. In a Japanese female newborn with c.649C>T and neonatal lactic acidosis, autopsy showed in muscle complex I activity of 11.9% and complex IV activity of 25.3% of normal, values that met the criteria for mitochondrial respiratory chain disease [20]. The proposed mechanism explains lipoatrophy and skeletal hypoplasia, but not hypertrichosis or microphthalmia, and no animal models have been published [19, 49].

There is no clinically relevant genotype–phenotype correlation between p.(Arg217His) and p.(Arg217Cys): with the same variant, the course ranges from death in the first hours of life to survival to 45 years [7, 48, 50]. The authors of the two founding series attribute this variability to other mitochondrial function genes and to epigenetic or environmental factors, hypotheses not yet tested [8]. No allelic disorders of SLC25A24, causal loss-of-function variants or intragenic deletions or duplications associated with the syndrome are known [7]. The two entities share no known molecular pathways: WRS results from biallelic loss of function of the largest subunit of RNA polymerase III, and Fontaine syndrome from a monoallelic variant with a dominant effect in a mitochondrial carrier [7, 22].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Sources of natural history data

The clinical description of WRS rests on three types of source, which should not be mixed. The first is the cohort of 18 patients with a reliable clinical diagnosis gathered by Paolacci and colleagues in 2017, which includes patients described since 1977, without molecular confirmation at the time [21]. The second is the series with molecular confirmation published from 2016 onwards, with 1 to 15 patients each (Jay, Wambach, Paolacci 2018, Lessel, Temel, Kovalskaia, Khan and others) [22–24, 29, 38, 42, 43]. The third is the 2025 international POLR3-RD database, which gathers 38 patients with WRS and allows genotype analyses but does not describe individual clinical course [4]. There are no prospective natural history studies; the series include patients receiving intensive supportive care (gastrostomy, orthopaedic surgery, ventriculoperitoneal shunt), so survival data reflect treated disease and different eras.

3.2. Frequency of manifestations in the 2017 clinical cohort

Source: Paolacci and colleagues, table 2; denominators vary because not all patients had the information recorded [21].

3.3. Prenatal and postnatal growth

Growth restriction begins in utero and is detectable on ultrasound, sometimes from the 24th week, with an abnormal skull shape reported in three of the seven patients of Wambach [22, 38]. Birth weight is low for gestational age in most patients (15 of 18 below the 3rd centile in the clinical cohort), with length and head circumference less affected; in the Wambach series weights ranged from 960 g at 30 weeks to 2400 g at 38 weeks, and prematurity was frequent (30 to 38 weeks) [21, 22]. The postnatal deficit is more marked in weight than in length and head size, which creates relative macrocephaly or pseudohydrocephalus (a head that looks large with a circumference normal for age) [22, 28]. Growth deficiency persists despite gastrostomy feeding: two adults in the Wambach series measured 130 cm and 135 cm and weighed 30 kg and 26 kg; a patient in the 2017 cohort measured 85 cm (−8.5 standard deviations, SD) and weighed 8300 g (−6 SD) at 10 years, with a body mass index of 8.7 kg/m²; the Russian patient measured 103 cm (standard deviation −3.41) and weighed 10.35 kg at 7.5 years, with a body mass index of 9.71 kg/m² [21, 22, 38]. There are exceptions: a boy in the Wambach series had weight and height between the 10th and 50th centiles at 5 years [22].

3.4. Skull, face and eyes

The skull has frontal and parietal bossing, wide fontanelles with wide sutures that may persist, and hypoplasia of the facial bones gives the triangular shape [21, 28]. Scalp hair, eyelashes and eyebrows are sparse, the veins of the scalp and forehead are visible, the eyes are deep-set and the eyeballs appear low-set, with the lower eyelid covering part of the cornea, an appearance Paolacci attributes to the absence of orbital fat; one patient pulled down her lower eyelid with her hand in order to see [21]. The nose is small and beaked, sometimes with a convex bridge, the mouth is small, with a thin upper vermilion and downturned corners, the chin is pointed and the ears are small, malformed or low-set [21, 28]. Ocular anomalies include entropion, inverted eyelashes, corneal opacity and scarring, astigmatism, myopia or hypermetropia, nystagmus, nocturnal lagophthalmos, small optic discs, hyperpigmented retina or pigmentary retinopathy and, occasionally, cataract [21, 22, 28, 38].

3.5. Dentition

Neonatal teeth are one of the most constant signs (17 of 18 patients; usually two, up to four), and they frequently fall out in the first days or months [21, 38]. Delayed or absent eruption follows: hypodontia or oligodontia, total absence of the permanent dentition in two adults of the Wambach series and only three permanent molars in a third; a 17-year-old patient had no teeth at all [21, 22]. The dental spectrum is shared with POLR3 leukodystrophy and with CHES, which underlines the dependence of odontogenesis on Pol III activity [21, 39].

3.6. Adipose tissue, skin and metabolism

Generalised reduction of subcutaneous fat is present in the neonatal period in almost all patients (18 of 18 in the clinical cohort), with localised accumulations over the posterior iliac region, the buttocks and the lumbosacral region and, less frequently, the axillae, fingers, feet, neck, suprapubic region and genitalia [21, 22, 28, 38]. In the Wambach series, the localised fat over the posterior iliac region was present at birth and became less evident with age [22]. A study with MRI and dual-energy X-ray absorptiometry in two girls, cited by OMIM, showed normal truncal fat and marked fat loss in the face, distal extremities and paravertebral and lateral gluteal regions, with reduced fat mass and lean mass, and proposed that fat loss is regional and not generalised [1]. The skin is thin, dry, translucent and wrinkled, with visible veins, and may have a sclerodermatous appearance; keloids, severe eczema in childhood, acanthosis nigricans and hirsutism in adolescence have been described [21, 22, 28]. Metabolic changes appear mainly in survivors: hypertriglyceridaemia in 3 of 5 patients assessed (up to 32 mmol/L in one patient, against a reference range of 0.31 to 1.14 mmol/L), hepatic steatosis, insulin resistance and insulin-treated diabetes from 12 years in one patient [21, 28].

3.7. Musculoskeletal system

The hands and feet are large, with long fingers; joint contractures (knees, ankles, hips, elbows, wrists and interphalangeal joints) are frequent and may prevent walking; dislocation or absence of the patella, congenital fractures of the tibia and fibula, kyphosis, scoliosis, pectus excavatum, osteopenia or osteoporosis and metaphyseal widening have been described [22, 23, 28, 38]. Radiology shows hypoplastic facial bones, a partially ossified atlas, thin ribs, square iliac bones, trident acetabula and irregular metaphyseal plates, with osteopenia associated with increased urinary deoxypyridinoline in survivors [28]. A Russian patient had a Chiari type 1 malformation, a posterior defect of the foramen magnum and spina bifida of C1 [38].

3.8. Nervous system

Development is variable. In the clinical cohort, 7 of 10 patients assessed had intellectual disability, usually severe according to Smith, but three children had normal development, and in the Wambach series a 13-year-old patient was attending mainstream school with good performance, while four other preschool children were making progress [21, 22, 28]. Hypotonia, poor head control, intention tremor and truncal ataxia are frequent, and neurological signs (tremor, dystonia, hypertonia and ataxia) typically appear at the end of the first year or in childhood and progress: one patient developed tremor at 6 years and hypertonia at 9, with loss of the ability to sit; another lost the ability to walk at 9 years with cerebellar signs, weakness and paraesthesiae of the feet [21, 22, 28]. MRI showed hypomyelination in 2 of 7 patients assessed in the clinical cohort, perisylvian polymicrogyria in one patient and hydrocephalus requiring a ventriculoperitoneal shunt at 6 months in another, and diffuse demyelination, ventricular dilatation with cortical atrophy and Dandy–Walker malformation are reported [21, 22, 28]. Autopsy of the Devos patient showed sudanophilic leukodystrophy [1]. Seizures have been described in a minority [21].

3.9. Respiration, feeding and other systems

Feeding difficulties and recurrent respiratory infections, including aspiration pneumonia, are frequent, and four of the seven patients of Wambach needed a gastrostomy [22, 28]. Severe perinatal respiratory problems, laryngomalacia, congenital heart defects (murmur, dysplastic and stenotic pulmonary valve), ureteropelvic junction stenosis with hydronephrosis, cryptorchidism, rectal prolapse, absent mesentery or mesocolon, thyroglossal duct cyst, papillary thyroid carcinoma at 20 years, hypothyroidism, hyperprolactinaemia or low prolactin, secondary amenorrhoea, thrombocytosis and sensorineural or conductive deafness with recurrent otitis have been described [21–23, 28].

3.10. Atypical forms and intermediate phenotypes

The spectrum of POLR3A-related WRS overlaps with that of the leukodystrophy. A 37-year-old woman homozygous for a synonymous variant with partial splicing was born with growth restriction, lipodystrophy, hypotonia and a WRS-like face, without sparse hair or prominent veins and without intellectual disability, and later developed severe growth delay, contractures, thoracic hypoplasia, scoliosis, anodontia, spastic tetraparesis, bilateral deafness, aphonia, hypogonadotropic hypogonadism and hyperintensities of the cerebellar peduncles [41]. In three consanguineous families from Oman and Saudi Arabia with homozygous missense variants, the patients described with a diagnosis of WRS had seizures, microcephaly, aspiration pneumonia (one child died at 7 months) and, on MRI, diffuse cerebral atrophy with leukodystrophy, atrophy of the corpus callosum and basal ganglia hyperintensity, a severe neurological picture approaching the striatal forms [42]. In 2026, a 4-year-old Chinese girl was described with progressive diffuse alopecia, growth delay, abnormal white matter development, severe anaemia, cutaneous laxity and myelofibrosis, with reduced POLR3A mRNA in the skin [51]. An Egyptian newborn with a WRS phenotype without molecular study died of hyperkalaemic renal failure on the third day, after a sibling with a similar picture had died in the first week [52]. The POLR3GL variant of WRS is distinguished by the absence of lipodystrophy, and POLR3B-associated WRS was described in a child with facial dysmorphism, micrognathia, congenital hip dislocation and hallux valgus [3, 5].

3.11. Fontaine progeroid syndrome: history and clinical manifestations

Before the gene was identified, the phenotype was published under several names. Gorlin, Chaudhry and Moss described in 1960 two sisters with craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of the labia majora and dental and ocular anomalies, followed by Ippel and colleagues up to 36 and 34 years; Fontaine and colleagues reported in 1977 a complex multiple malformation picture; Petty, Laxova and Wiedemann described in 1990 a congenital progeroid syndrome in a 5-year-old girl, with which they associated a 46-year-old woman published by Wiedemann; and, in 1999, two female newborns were described as lethal neonatal forms of Hutchinson–Gilford progeria [7, 8]. In 2009, Castori and colleagues delineated Fontaine–Farriaux syndrome by the triad of craniosynostosis, anonychia and extensive hypoplasia of the abdominal muscles, and in 2013 Rosti and colleagues separated patients with GCMS into two facial gestalt subgroups (group A with synophrys, stepped eyebrows and small median palatal clefts; group B with deep-set eyes) [8]. In 2017, Ehmke and colleagues (five girls diagnosed with GCMS) and Writzl and colleagues (four patients, three already published as Fontaine–Farriaux or neonatal progeria, all of whom died in the first year) found the same SLC25A24 variants, and OMIM brought the designations together as Fontaine progeroid syndrome, considering GCMS its milder form [8, 32, 48]. No patient with a clinical diagnosis of Petty syndrome yet has molecular confirmation, although several authors consider it the same entity [7].

The frequency of manifestations comes from the 13 patients with molecular confirmation gathered in the 2022 GeneReviews chapter, of whom 11 survived more than 24 hours; denominators vary because not all patients were assessed for each sign [7].

Growth is compromised from fetal life, with frequent third-trimester oligohydramnios; feeding difficulties with reflux and aspiration led to gastrostomy in three patients, and microcephaly, when present, is proportional to stature [7]. Turribrachycephaly is visible at birth and sometimes on prenatal ultrasound; the calvaria is poorly ossified in the newborn, and coronal craniosynostosis becomes evident as ossification progresses [7]. The face combines underdeveloped supraorbital ridges, a convex nasal bridge and neonatal micrognathia that evolves into relative prognathism, with protrusion of the lower lip and tongue [7]. Scalp hair is sparse in the frontotemporal region in the newborn, with a low anterior and posterior hairline, and becomes coarse, with several whorls; hypertrichosis of the back, neck and face is present at birth and persists at least through childhood [7]. The wrinkled, thin, translucent skin, with visible vessels and little subcutaneous fat, gives an aged appearance that is greatest in the infant and lessens over time [7]. Digital anomalies affect the postaxial rays more than the preaxial ones, with a mixture of normal, hypoplastic and absent nails in the same patient [7].

Cardiovascular involvement has two phases. In the first year, four patients developed pulmonary hypertension, two of them after a normal neonatal echocardiogram and before 6 months, and in at least two the hypertension coexisted with reflux and aspiration requiring fundoplication and gastrostomy; in one of them right heart pressures improved after fundoplication [7]. The structural heart defects described include patent ductus arteriosus, ostium secundum atrial septal defect, bicuspid aortic valve and dysplastic valves [7]. Later, aortic dilatation, absent on neonatal echocardiograms, appears in six of the 11 survivors, including patients without other heart disease; in a 9-year-old Korean girl the ascending aorta measured 2.7 cm (+5.0 standard deviations), and a 45-year-old Dutch woman, 142 cm tall and weighing 31 kg, presented with a 51 mm aneurysm of the ascending aorta and proximal arch with acute type A dissection [7, 49, 50]. Aortic histology in this patient showed fibrosis without cystic medial necrosis or vasculitis [50].

Motor development is slow in infancy (walking unsupported between 19 and 36 months in the four patients with data), attributed in part to muscle weakness, but cognition is normal in those who survive beyond early childhood [7, 49]. Two patients had hydrocephalus requiring a shunt, and two had brain malformations (thin corpus callosum, ventriculomegaly, dysplastic cerebellar vermis and pineal cyst in one; gyral simplification, cerebellar hypoplasia and subependymal heterotopia in another), whereas five had normal brain imaging [7]. An Irish infant also had bilateral parietal cysts and Dandy–Walker malformation [19]. Hypermetropia is frequent after the first year, and microphthalmia, iridocorneal adhesions with corneal opacity, upper eyelid coloboma and entropion have been described [7, 8, 49]. The deciduous dentition may be normal, with oligodontia, microdontia or hypodontia of the permanent dentition [7]. Six patients had severe infections, often fatal, and two had persistent leucocytosis [7]; in the Irish infant, leucoerythroblastic anaemia without haematological neoplasia and short telomeres in lymphocytes and granulocytes (between the 1st and 10th centiles) were recorded, with values below the 1st centile in memory T cells [19]. In the two published prenatal diagnoses, in the second trimester, the fetuses had most of the anomalies of the postnatal period, but not the progeroid appearance, and presented with encephalocele and nephromegaly, signs not described after birth [14].

4. Clinical Recognition and Red Flags

4.1. When to suspect

In the prenatal period, suspicion arises with early and severe intrauterine growth restriction with relative macrocephaly or an abnormal skull shape on ultrasound, particularly when there is an affected sibling; prenatal ultrasound diagnosis without knowledge of the genotype has been described but is not specific [1, 22, 38]. In the newborn, the combination of low weight, an aged appearance from birth, a large-looking head with wide fontanelles and sutures, prominent scalp veins, sparse hair, a triangular face, neonatal teeth and absent subcutaneous fat with accumulations over the buttocks or sacral region should prompt consideration of WRS [21, 28, 53]. In the infant and child, persistent growth failure despite nutritional support, early loss of the neonatal teeth followed by delayed eruption or absence of teeth, contractures and the appearance of tremor, ataxia or spasticity reinforce the hypothesis [21, 22]. In an older child or adult with an old clinical diagnosis of WRS and no molecular study, review of the diagnosis is warranted, because more than half of the patients published as WRS had another disorder or insufficient data [21].

4.2. Red flags and emergency signs

In the neonatal period, the immediate risks are respiratory (pulmonary hypoplasia, bronchopulmonary dysplasia, laryngomalacia and aspiration) and nutritional; several deaths occurred in the first weeks of life from respiratory complications, one from hyperkalaemic renal failure in a patient without molecular confirmation, and an infant in the Jay series died at 7 months from respiratory complications [21, 23, 39, 52]. Throughout childhood, dysphagia with aspiration pneumonia, hydrocephalus requiring a shunt, severe hypertriglyceridaemia and diabetes, loss of motor skills and worsening tremor or spasticity are signs that require reassessment [21, 22]. In a child diagnosed with WRS, developmental regression, dystonia and basal ganglia involvement on MRI suggest a severe striatal form of POLR3 disease rather than classic WRS, with prognostic implications [39, 54].

4.3. Newborn screening

There is no newborn screening for WRS or for the other disorders of the POLR3 class [4, 6].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated formal clinical criteria for WRS [5, 21]. The proposal of Paolacci and colleagues, built from the original patients, considers as core features very severe prenatal and postnatal growth deficiency (−2 to −9 SD), the facial signs (sparse hair, prominent scalp veins, triangular face, apparently low-set eyeballs with the lower eyelid covering part of the cornea, small mouth with thin upper vermilion, neonatal teeth and pointed chin) and generalised lipodystrophy with local fat accumulations; scalp veins, wide sutures, hypodontia and the eyelid position are very frequent, and the progressive nature manifests as increasing tremor and ataxia with age [21]. This proposal serves to guide molecular testing and does not replace identification of the genotype.

5.2. Molecular tests and algorithm

The diagnosis is established by identification of biallelic pathogenic or likely pathogenic POLR3A variants in trans, in a patient with a compatible phenotype [1, 22]. The order of investigation proposed on the basis of the sources is as follows. First, genome sequencing, or an exome with analysis of the adjacent intronic regions and a targeted search for the known intronic variants (NM_007055.4:c.1909+18G>A, c.1909+22G>A, c.3337-5T>A, c.3337-11T>C, c.1771-6C>G, c.1771-7C>G), because many WRS variants lie at positions not analysed by conventional filters [4, 23, 24]. Second, when a single variant is found, search for the second by genome sequencing, copy-number variation analysis and RNA study (reverse transcription followed by PCR, in blood, lymphoblastoid lines or fibroblasts), which demonstrated exon 26 skipping with the c.3337-5T>A and c.3337-11T>C variants and the effect of the synonymous variants [22, 23, 38, 40]. Third, parental testing to establish the phase of the variants, indispensable when there are complex alleles with two variants in cis [4, 38]. If POLR3A testing is negative in a patient with a typical phenotype, the authors of the POLR3GL description suggest analysing that gene, and the differential with FBN1, CAV1, SLC25A24, PYCR1, ALDH18A1, LMNA and ZMPSTE24 should be considered [5, 22, 23].

5.3. Limitations of testing

A negative exome result does not exclude WRS. In the Wambach series, three patients were studied only by Sanger sequencing of POLR3A and the authors acknowledge that deep intronic variants may have been missed; POLR3A deletion and duplication analysis was negative in the only patient in whom it was performed [22]. In the Lessel series, a patient with an identical phenotype had only one variant (NM_007055.4:c.3G>T), and the second could be deep intronic, a copy-number variant, a balanced translocation or a regulatory variant [23]. In four patients of the Paolacci series only one variant was found, and lack of material prevented further studies [24]. Splicing prediction programs do not predict the clinical severity of non-canonical intronic variants, and missense predictions are not enough to classify a genotype as causing WRS without functional study [4]. The classification of novel missense variants, such as the POLR3B variants described in WRS, often remains VUS [3].

5.4. Report content and interpretation

The report should state the gene, the transcript with version (NM_007055.4 for POLR3A), the HGVS c. and p. nomenclature, zygosity, the phase of the variants (in trans, or in cis in the case of complex alleles), the classification according to the standards of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and functional RNA data, where available [4, 10]. Two biallelic VUS, or a pathogenic variant with a VUS, do not establish the diagnosis [6]. Interpretation benefits from knowledge of genotype–phenotype correlations: a genotype with c.1771-6C>G or c.1771-7C>G points to a striatal form, c.1909+22G>A alone in trans to HSP/SA, and the same allele in cis with c.3337-11T>C to WRS [4]. In the 2025 database, nomenclature was normalised in VariantValidator and pathogenicity assessed according to ACMG/AMP with manual curation [4].

5.5. Prenatal and preimplantation diagnosis

Once the two pathogenic variants in the family have been identified, prenatal diagnosis and preimplantation genetic testing are possible, as for the other POLR3 disorders [6]. In the Chinese family with POLR3B variants, the fetus of the following pregnancy had the same variants and a similar ultrasound phenotype [3]. Without a known genotype, ultrasound may show early growth restriction and skull abnormalities, but these findings are not specific [22, 38].

5.6. Diagnosis of Fontaine progeroid syndrome

There are no consensus clinical diagnostic criteria [7]. Suspicion rests on the association of prenatal and postnatal growth restriction, thin sagging skin with little fat, turribrachycephaly with a wide anterior fontanelle and craniosynostosis, hypertrichosis, sparse low-set hair, umbilical hernia with hypoplastic abdominal musculature, short distal phalanges with cutaneous syndactyly and abnormal nails, and hypoplasia of the labia majora or cryptorchidism; radiographs show a poorly ossified calvaria and short distal phalanges, and computed tomography (CT) confirms craniosynostosis [7]. The diagnosis is established by identification of a heterozygous pathogenic or likely pathogenic SLC25A24 variant; a variant of uncertain significance at another codon neither confirms nor excludes the diagnosis [7].

When the phenotype is suggestive, SLC25A24 sequencing, alone or in a craniosynostosis or skeletal dysplasia panel, identified the variant in 13 of 13 patients; no deletions or duplications have been described, and copy-number analysis has no known yield [7]. When the hypothesis has not been raised, exome or genome sequencing, preferably as a trio, allows the diagnosis and documents de novo occurrence [7, 19]. In published cases, the diagnostic pathway included a karyotype and ATP6V0A2 sequencing for suspected cutis laxa before targeted sequencing of exon 5 at 8 years, trio exome sequencing at 5 months and, in a female newborn with lactic acidosis, a panel of 367 nuclear mitochondrial disease genes that included SLC25A24 [19, 20, 49]. These variants are not detected by microarray, and a panel without SLC25A24 leaves the disease undiagnosed [20, 49].

In the prenatal period, severe symmetrical growth restriction, oligohydramnios, brachycephaly and genital and intracranial anomalies are the signs described; exome or genome sequencing of fetal or post-mortem samples established the diagnosis in two fetuses with a normal karyotype and microarray [14, 19]. The report should state the transcript NM_013386.5, the HGVS notation, zygosity, the ACMG/AMP class and the parental study; when a variant is absent from the parents' blood, a parental study sensitive to low-level mosaicism has implications for counselling, as in the family in which paternal mosaicism was detected [7, 14].

6. Differential Diagnosis

6.1. Principles

The differential diagnosis of WRS has two axes. The first is that of the progeroid and lipodystrophic syndromes of neonatal onset, which share the aged appearance, the wide fontanelle, prominent veins and lack of fat, and which accounted for most of the erroneous WRS diagnoses in the literature [7, 21, 22]. The second is that of the other POLR3 disorders, which share the dental and neurological changes and, in the severe forms, can mimic WRS [21, 39]. On the first axis, the features that most favour WRS are neonatal teeth with later loss of the dentition, the absence of distal limb anomalies, sparse hair, marked prenatal restriction and local fat accumulations over the buttocks and sacral region [7, 21].

6.2. Neonatal progeroid syndromes unrelated to Pol III

The most frequent distinction in practice is from the entities due to heterozygous de novo variants in FBN1, CAV1 and SLC25A24, which accounted, in the University of Texas Southwestern series, for two of eight patients with a clinical diagnosis of WRS, whereas two had POLR3A variants and two remained undiagnosed [22]. The phenotype of FBN1 lipodystrophy includes growth restriction, prematurity and an aged appearance at birth, but preserves fat over the breasts and iliac region and adds joint hyperlaxity, arachnodactyly and severe myopia [22]. Fontaine syndrome is distinguished by craniosynostosis, hypertrichosis and distal phalangeal anomalies, and the aged appearance lessens with age [7]. In a series of 14 juvenile progeroid patients without LMNA variants, biallelic PYCR1 variants were the most frequent cause (8 patients), and in the first years they mimicked Hutchinson–Gilford progeria through the triangular face, sparse hair, thin skin with veins and lipodystrophy; prenatal restriction, brain anomalies and improvement over time separated them from progeria, and only 14% had wrinkled skin before 1 year [23]. Hutchinson–Gilford progeria syndrome has no prenatal growth restriction, and sclerodermatous skin, alopecia and acro-osteolysis point to LMNA [7]. The distinction has therapeutic consequences: lonafarnib (Zokinvy®) is approved by the US Food and Drug Administration (FDA) for Hutchinson–Gilford progeria and for processing-deficient progeroid laminopathies (LMNA with accumulation of progerin-like protein, or biallelic ZMPSTE24), and the label expressly states that it is not indicated for other progeroid syndromes, which includes WRS [62]. The Oxford Desk Reference also records the overlap of WRS with AR cutis laxa associated with congenital disorders of glycosylation and with progeroid-type Ehlers–Danlos syndrome in the assessment of a large fontanelle [53].

6.3. Differential diagnosis within the POLR3 class

Typical POLR3 leukodystrophy is distinguished by age at onset, the absence of a progeroid phenotype and lipodystrophy, the MRI pattern and the progressive course, whereas WRS has a neonatal picture with severely compromised growth [6, 21]. The severe striatal form, associated with NM_007055.4:c.1771-7C>G together with a protein-truncating variant, can be confused with WRS: in the Indian patient published as WRS in 2021, birth was at term with normal weight, the triangular face was noticed only at 15 months, when there was cachexia, and regression, dystonia and pyramidal signs predominated, with death at 18 months; of the six patients with this severe form, 4 died before 3 years, 3 had laryngomalacia and all had dystonia [39, 63]. A Korean boy with NM_007055.4:c.1771-6C>G and c.1805T>C (published designation, without the protein stated; the reference base at c.1805 of transcript NM_007055.4 is G, so the notation cannot be mapped), published as WRS with atypical brain involvement, was born weighing 3.1 kg, was practically bedridden at 40 months and had progressive cerebral atrophy with basal ganglia hyperintensity, a picture that fits the same group [4, 54]. CHES, now included in HLD8 due to POLR3B, shares with WRS the abnormal dentition (neonatal teeth in 3 of 6 patients) and growth delay, but lacks the facial signs and lipodystrophy and has endosteal osteosclerosis [16, 21, 45]. The Bone Dysplasias atlas attributes CHES to POLR3A; the primary sources and OMIM identify POLR3B [16, 45, 60].

6.4. Distinguishing WRS from Fontaine progeroid syndrome

The two syndromes share prenatal growth restriction, a wide fontanelle, thin skin with visible veins and scarcity of fat, and confusion is documented in both directions: two of Ehmke's five patients had an initial diagnosis of WRS, and in the Dallas and St. Louis series some of the patients with a clinical diagnosis of WRS had FBN1, CAV1 or SLC25A24 variants [22, 32]. As early as 1990, Petty and colleagues separated their patient from WRS by the absence of neonatal teeth, of large hands and feet with long tapering fingers, of developmental delay and of neurological involvement [8].

In the newborn, the most useful data are palpation or CT of the skull (craniosynostosis and deficient ossification in Fontaine syndrome, wide sutures without synostosis in WRS), examination of the nails and distal phalanges, hair distribution and the presence of neonatal teeth [7, 21]. The distinction changes follow-up: Fontaine syndrome requires surveillance of pulmonary hypertension and the aorta and usually carries a low recurrence risk, whereas WRS requires neurological and metabolic surveillance and carries a 25% recurrence risk [6, 7].

7. Treatments and Risk Management Strategies

7.1. Sources of recommendations and principles

There is no guideline, consensus or clinical trial dedicated to WRS, and there is no treatment directed at the cause [4, 64]. The recommendations available for the POLR3 class come from the GeneReviews chapter on POLR3 leukodystrophy, written by experts and last updated in May 2017, before the association between POLR3A and WRS was confirmed; it does not have the status of a formal guideline and has no ClinGen actionability assertion [6, 9]. Management of WRS therefore rests on the supportive care described in patient series and on extrapolation, declared as such, of the recommendations for the neurological, dental, endocrine and swallowing features of POLR3 leukodystrophy, which share the same molecular basis [6, 21, 22]. The multidisciplinary team recommended for the class includes paediatric neurology, clinical genetics, physiotherapy, occupational therapy, speech and language therapy, neuropsychology, physical and rehabilitation medicine, dentistry, endocrinology, ophthalmology, otorhinolaryngology and general practice [6, 30].

7.2. Initial assessment after diagnosis

The table brings together the assessments recommended for POLR3 leukodystrophy, plus those arising from the manifestations described in WRS. The origin column distinguishes GeneReviews recommendations from extrapolation from the series.

7.3. Nutrition and swallowing

Weight deficiency persists despite nasogastric tube and gastrostomy feeding, and a patient in the 2017 cohort had a body mass index of 8.7 kg/m² at 10 years with ongoing feeding problems [21, 22]. In POLR3 leukodystrophy, dysphagia varies over the course of the same day, probably owing to cerebellar incoordination worsened by fatigue, and it progresses, possibly requiring gastrostomy; foods with a choking risk should be avoided [6]. These observations apply by extrapolation to patients with WRS who develop cerebellar signs. The severe hypertriglyceridaemia described in survivors warrants lipid monitoring and dietary and pharmacological treatment according to usual practice; the sources consulted do not describe specific treatment of dyslipidaemia in WRS [21].

7.4. Neurological symptoms

Seizures, spasticity and dystonia are treated according to usual practice, with monitoring to prevent complications and improve quality of life [6, 30]. Sialorrhoea, frequent in POLR3 leukodystrophy, is managed with oromotor and behavioural rehabilitation, anticholinergics, botulinum toxin injections and, in severe cases, surgical rerouting of the parotid and submandibular ducts, with or without excision of the sublingual glands [6]. Hydrocephalus may require a ventriculoperitoneal shunt, as in a patient in the Wambach series operated on at 6 months [22].

7.5. Orthopaedics, rehabilitation, teeth and sense organs

Contractures and dislocations have been treated with physiotherapy and surgery: patellar realignment at 7 and 26 months in one patient, hamstring lengthening with knee capsulotomy at 6 years and hip release at 8 years in another [22]. Absence of the permanent dentition requires follow-up by dentistry and, when necessary, orthodontics and prosthetic rehabilitation [6, 22]. Entropion, corneal opacity and refractive errors require ophthalmological follow-up; conductive deafness due to recurrent otitis was treated with ventilation tubes and moderate deafness with hearing aids [21, 22]. Sex hormone and growth hormone deficiency, when present, is treated by individual decision, according to the GeneReviews chapter on POLR3 leukodystrophy; the sources consulted do not describe the use of growth hormone in WRS [6].

7.6. Drugs and regulatory status

There is no drug authorised for WRS or for any other POLR3 disorder by the FDA or the European Medicines Agency (EMA), and a search of ClinicalTrials.gov identified no interventional trials [64]. The drugs used are those of usual practice for common symptoms (antiepileptics, muscle relaxants, anticholinergics, botulinum toxin, insulin), with no disease-specific dose.

7.7. Ongoing trials and studies

There are no therapeutic trials to compare, and the absence of registered trials in the search does not prove that no studies are in preparation.

7.8. Developments in the last 12 months and level of evidence

Between October 2025 and October 2026 there was no authorisation, regulatory opinion or therapeutic trial for WRS. The developments are in research: (a) published human study — Ramos and colleagues described 11 patients from 8 families with monoallelic POLR3A missense variants, de novo or with dominant transmission, and early-onset progressive sensorimotor polyneuropathy with intermediate to demyelinating conduction velocities, without white matter changes, with global reduction of tRNAs in patient cells, which establishes a second inheritance pattern for POLR3A [13]; (b) preclinical study — the CRISPR-dCas13Rx system identified that 20% of the exonic regions of POLR3A with pathogenic missense variants alter splicing, and antisense oligonucleotides derived from active guides improved correct splicing of exon 14 and exon 26 variants in cell lines [66]; (c) preclinical study — zebrafish polr3a model with craniofacial hypoplasia and tp53 activation [36]; (d) preclinical studies in iPSC and fibroblasts derived from a patient with WRS, with nucleolar abnormalities, telomere dysfunction and accelerated senescence [34, 35]; (e) case reports — WRS with cutis laxa and myelofibrosis in China and WRS with the variant NM_007055.4:c.2707G>A p.(Gly903Arg) in Colombia, analysed only in silico [51, 67]; (f) shortly before this period, in July 2025, the retrospective cohort study of the international POLR3-RD database was published, providing the genotype–phenotype correlations of section 2 [4]. Antisense oligonucleotides targeting splicing variants are a line of research and not an available clinical option.

7.9. Agents and circumstances to avoid

In POLR3 leukodystrophy, GeneReviews recommends avoiding dopamine D2 receptor blockers (neuroleptics such as haloperidol and risperidone and antiemetics such as metoclopramide), because they worsen extrapyramidal signs, and foods with a choking risk [6]. In patients with WRS and cerebellar or dystonic signs or dysphagia, the same precaution applies by extrapolation. Lonafarnib should not be used outside its labelled indications [62].

7.10. Perioperative care, pregnancy and transition

Patients with WRS undergo several procedures (gastrostomy, ventriculoperitoneal shunt, orthopaedic surgery, tonsillectomy, ventilation tubes, nephrectomy), but the sources consulted do not describe specific anaesthetic complications or perioperative recommendations particular to the syndrome [21, 22]. The micrognathia, mandibular hypoplasia and craniocervical junction malformation described in some patients warrant prior assessment of the airway and cervical spine, by analogy with general recommendations for patients with craniofacial dysmorphism; this indication is an extrapolation [22, 38]. The sources do not describe pregnancies in women with WRS; menarche occurred at 11 and 13 years in two patients, with irregular cycles and secondary amenorrhoea [21, 22]. Two adults aged 20 and 21 years in the Wambach series lived with some assistance or independently, and transition to adult care should include metabolic and endocrine surveillance; papillary thyroid carcinoma was diagnosed at 20 years in one of these patients, an isolated observation that does not allow an oncological risk to be estimated [21, 22].

7.11. Management of Fontaine progeroid syndrome

There are no clinical guidelines, trials or targeted treatment for Fontaine syndrome; the 2022 GeneReviews chapter, written by experts, is the reference for initial assessment, treatment of manifestations and surveillance, and a search of ClinicalTrials.gov for SLC25A24, Fontaine progeroid syndrome and GCMS returned no registered studies in October 2026 [7, 64]. Lonafarnib (Zokinvy®) has no indication, because the FDA label restricts it to Hutchinson–Gilford progeria and processing-deficient progeroid laminopathies [62].

Craniofacial surgery is decided case by case: in a 7-year-old Hungarian girl, frontofacial advancement by internal distraction, performed for functional and psychosocial reasons, was complicated by a necrotising soft tissue infection of the scalp [8]. In a Korean girl, syndactyly of the fourth and fifth fingers, bilateral upper entropion and umbilical hernia were corrected at 4 years, with later recurrence of the hernia, and growth hormone and low-dose corticotropin stimulation tests, performed because of short stature, were normal [49]. Regarding the aorta, the 45-year-old woman with dissection successfully underwent supracoronary replacement of the ascending aorta and partial arch replacement, under deep hypothermic circulatory arrest with bilateral antegrade cerebral perfusion; the authors recommend aortic screening in all patients with GCMS or Fontaine syndrome [50]. In a Spanish boy, aortic dilatation progressed despite treatment with a beta-blocker, and there are no data to support a pharmacological choice for the aortopathy of this syndrome [7].

In the Japanese female newborn with lactic acidosis, persistent pulmonary hypertension did not respond to usual therapy or to peritoneal dialysis, and an empirical supplement regimen used in mitochondrial diseases (coenzyme Q10 5 mg/kg/day, L-carnitine 100 mg/kg/day, vitamin E 10 mg/kg/day, thiamine 5 mg/kg/day, vitamin C 50 mg/kg/day and vitamin B complex) did not correct the hyperlactataemia; the patient died at 15 days [20]. This regimen is the report of an isolated case and does not constitute a recommendation. Among agents and circumstances to avoid, GeneReviews advises restricting contact sports and isometric exercise in the presence of cranial anomalies or aortic dilatation, while maintaining aerobic activity when there is no severe dilatation or other restriction [7].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

POLR3A-related WRS is autosomal recessive: the parents of a patient are usually obligate heterozygotes and asymptomatic, and each sibling has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of inheriting neither variant [6, 22]. Recurrence in siblings has been documented since the original description (two sisters) and in several families (three Colombian siblings, Palestinian siblings, a sibling pair in the Wambach series) [15, 21, 22, 68]. Severity may vary between siblings, although age at death was similar in groups of affected siblings [6, 21]. The proband's aunts and uncles have a 50% chance of being carriers, and the children of a patient would be obligate carriers; the sources do not describe offspring of patients with WRS [6]. For POLR3B and POLR3GL, the inheritance described is likewise recessive [3, 5].

8.2. Cascade testing and carriers

Carrier testing in relatives requires prior identification of both variants in the proband [6]. In complex alleles, such as NM_007055.4:c.[1909+22G>A;3337-11T>C], the carrier parent transmits both variants as a block, and testing of relatives should include both; c.1909+22G>A alone in the heterozygous state does not cause disease, and in the homozygous state is considered to cause no or minimal disease [4]. In consanguinity, the probability that the spouse of a carrier is also a carrier increases, which is relevant in the consanguineous families described in the Middle East [21, 42].

8.3. Prenatal and preimplantation diagnosis

Once the variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible, and the appropriate time to discuss risk and reproductive options is before pregnancy [6]. Serial ultrasound may show growth restriction from the second trimester, but without the genotype it does not allow the diagnosis [1, 38]. Banking of the proband's DNA is recommended when the molecular diagnosis has not been established, for future analyses [6].

8.4. Mosaicism and counselling of minors

The sources consulted do not describe germline mosaicism in WRS, which is expected in a recessive disease in which both parents are carriers. Carrier testing in asymptomatic minors has no immediate clinical utility, and counselling of young adult carriers or at-risk young adults should include the risks to offspring and reproductive options [6].

8.5. Counselling in Fontaine progeroid syndrome

Fontaine syndrome is autosomal dominant, and in all probands with a parental study published up to 2022 the variant arose de novo [7]. Testing of the parents is recommended; if the variant is not detected in the blood of either and parentage is confirmed, the risk to siblings is estimated at about 1%, because of the possibility of germline mosaicism; if a parent has the variant, the risk is 50% [7]. Mosaicism is no longer merely theoretical: in one of the two fetuses diagnosed prenatally, paternal mosaicism for the SLC25A24 variant was detected, a situation in which the recurrence risk is higher than that estimated for a de novo variant [14]. Analysis of leucocyte DNA does not exclude mosaicism confined to germ cells [7]. Recurrence in the sisters of Gorlin's original description, interpreted before the gene was discovered as recessive inheritance or X-linked dominant inheritance with male lethality, is compatible with parental gonadal mosaicism, but these patients died without molecular study [8]. Patients have no known offspring and fertility has not been assessed; the theoretical risk to the children of a patient would be 50% [7]. Prenatal diagnosis and preimplantation genetic testing can be discussed with the parents of a patient, preferably before a further pregnancy [7].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

WRS is ultra-rare: Orphanet assigns it a worldwide point prevalence below 1 per 1,000,000, a class based on the 2017 Paolacci review, and records 37 cases or families [2]. In 2017, 51 patients had been published with this diagnosis, of whom 18 were considered reliable cases [21]; in 2021, 19 families with POLR3A-related WRS had been described [63]; and the POLR3-RD database, with literature up to 31 October 2024, gathered 38 patients with WRS (35 due to POLR3A and 3 due to POLR3B) among the 551 patients in the analysis [4]. These figures are counts of published or registered cases and not incidence estimates; rarity, molecular underdiagnosis due to intronic variants and undiagnosed neonatal mortality make a population estimate impossible with the available data [23, 24].

9.2. Geographical distribution and recurrent variants

Patients with WRS have been described in the USA (Wambach series, in St. Louis and Dallas), Germany (including Rautenstrauch's original family), Russia, Turkey, Colombia, Palestine, Oman, Saudi Arabia, Egypt, India, China, Japan and Korea, and leukodystrophy due to homozygous NM_007055.4:c.1909+18G>A in a Syrian family [1, 3, 15, 22, 38, 42, 52, 54, 63]. The variant NM_007055.4:c.3337-5T>A was found in four unrelated North American patients and in two patients in the Lessel series, and gnomAD contains only one heterozygote, of European ancestry [22, 23]. The combination NM_007055.4:c.3G>T with NM_007055.4:c.*18C>T was identified in two unrelated Colombian patients and a North American boy, and the complex allele c.[1909+22G>A;3337-11T>C] in German, Palestinian and Russian patients, which suggests recurrent haplotypes, as proposed by Paolacci and colleagues [15, 24, 38]. The Middle Eastern families with homozygous missense variants reflect consanguinity [42]. In POLR3 leukodystrophy, the order of genes to test differs between French-Canadian patients (POLR3A first) and European patients (POLR3B first), because of differing variant frequencies [6].

9.3. Portugal and Brazil

The sources consulted include no patients identified as Portuguese or Brazilian. The São Paulo geneticist Débora Bertola is a co-author of the 2017 and 2018 series, but the articles do not present national data [21, 24]. The absence of data in the sources consulted does not demonstrate the absence of patients in these countries.

9.4. Reference networks and patient associations

ERN ITHACA, the European network for rare congenital malformations and intellectual disability, is the relevant network for WRS as a malformation syndrome, and ERN-RND, for rare neurological diseases, covers the leukodystrophies of the POLR3 class [25, 26]. No patient association dedicated to WRS was found; the United Leukodystrophy Foundation maintains information on 4H leukodystrophy and lists the Yaya Foundation for 4H Leukodystrophy as a partner [69].

9.5. Epidemiology of Fontaine progeroid syndrome

Orphanet classifies Fontaine syndrome with a worldwide point prevalence below 1 per 1,000,000 and records 13 cases; GeneReviews gathered, in 2022, 13 patients with molecular confirmation, and in 2025 the authors of the Japanese case counted 12 published cases [7, 18, 20]. The patients described are of Polish, Hungarian, German, Turkish, northern European, Slovenian, French, Spanish, Italian, Korean, Dutch, Irish and Japanese origin, with no founder variant: the two codon 217 variants recur in different populations, as is typical of a mutational hotspot with gain of function [19, 20, 49, 50]. The sources consulted include no Portuguese or Brazilian patients. Adults are probably underdiagnosed, because many have not had recent genetic studies [7]. ERN CRANIO, the European network for craniofacial anomalies and rare ear, nose and throat disorders, is the relevant network for craniosynostosis, and ERN ITHACA for the malformation syndrome; GeneReviews lists the Children's Craniofacial Association and the National Organization for Rare Disorders (NORD) as resources for families [7, 25, 27].

10. Illustrative Clinical Case

In 2024, Kovalskaia and colleagues published the first patient with molecularly confirmed WRS in the Russian Federation [38]. She is a girl born to healthy non-consanguineous parents, in whom intrauterine growth restriction became evident from the 24th week of gestation. She was born at 37 weeks by caesarean section, weighing 1840 g and measuring 46 cm; in the neonatal period she had absent subcutaneous fat, a hydrocephalic skull shape, a prominent venous network in all regions, micrognathia and a neonatal tooth (upper incisor) that fell out spontaneously on the second day of life. In the first year, Chiari type 1 malformation, mixed hydrocephalus and a bony defect of the posterior part of the foramen magnum were diagnosed, and her course showed severe underweight and global delay of motor, physical and language development. At 7.5 years she measured 103 cm (standard deviation −3.41), with a growth velocity of 3.64 cm/year, weighed 10.35 kg (body mass index 9.71 kg/m², standard deviation −6.20) and had the characteristic progeroid face: hydrocephalic skull with venous network, marked frontal bossing, triangular face with midface hypoplasia, sparse eyebrows and eyelashes, low-set ears, beaked nose, short philtrum, deep-set eyes, dental agenesis, scalp hypotrichosis and generalised lipodystrophy with local fat accumulations on the neck, external genitalia, coccygeal region and feet, as well as contractures of the hips and interphalangeal joints. Systemic assessment revealed retinal angiopathy, astigmatism, entropion and opacity of the left cornea, an osteoneural malformation of the craniocervical junction with spina bifida of C1 and dysarthria, scoliosis, flexion of the hands and knees, osteoporosis, reactive pancreatic changes, lymphofollicular hyperplasia of the ileum and hepatic steatosis [38]. Exome sequencing identified in POLR3A (NM_007055.4) a novel missense variant, c.3677T>C p.(Leu1226Pro), and, on the other chromosome, the complex allele with the two intronic variants c.1909+22G>A and c.3337-11T>C in cis; parental segregation confirmed the trans position, and analysis of fibroblast mRNA confirmed the effect of c.3337-11T>C on splicing and the absence of an effect of c.3677T>C, which was reclassified as likely pathogenic [10, 38]. The patient's facial phenotype is documented in figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC10887809/figure/genes-15-00180-f001/) [38]. The case illustrates three points: the diagnosis depends on searching for intronic variants that the exome captures only when they are close to exons; functional confirmation of splicing and segregation are necessary to interpret complex alleles; and management is entirely supportive and system-based. The same combination of intronic variants in cis has been found in other European and Middle Eastern families, including Rautenstrauch's original family [15]. For comparison, figure 1 of the Wambach series (https://pmc.ncbi.nlm.nih.gov/articles/PMC6288318/figure/fig1/) shows five North American patients from infancy to adulthood, with relative macrocephaly, prominent forehead, triangular face, hypertelorism, anteverted nares, bitemporal narrowing, upslanting palpebral fissures, thin lips and sparse hair [22].

Complementary case: Fontaine progeroid syndrome with 10-year follow-up

In 2019, Ryu, Ko and Shin published the follow-up of a Korean girl born to healthy non-consanguineous parents [49]. The pregnancy proceeded without ultrasound anomalies until oligohydramnios at 26 weeks, and the child was born by caesarean section at 31 weeks and 6 days, weighing 1080 g (−1.8 standard deviations), and spent 3 months in neonatal intensive care. She had generalised lax skin, hypertrichosis, umbilical hernia, epicanthus inversus, a depressed nasal root, a low hairline, a cranial defect with a wide anterior fontanelle and soft occipital and parietal calvaria, hypoplastic nails and syndactyly of the fourth and fifth fingers of the left hand; the initial suspicion of cutis laxa led to a karyotype and ATP6V0A2 sequencing, both normal. At 4 months, head circumference was 34.3 cm (−3.8 standard deviations), radiographs showed absence of the distal phalanx of the fifth fingers and hypoplasia of the distal phalanges of the second to fourth fingers, there was mild conductive hearing loss, and brain and orbital MRI was normal. At 4 years the syndactyly, bilateral upper entropion and umbilical hernia were corrected; she remained under follow-up for esotropia and severe hypermetropia. She sat at 18 months, said her first words at 24 and walked at 36 months, but caught up to the level of her peers and was attending school with good performance. At 8 years she measured 115.0 cm (−3.0 standard deviations), weighed 15.0 kg (−4.9 standard deviations) and had a head circumference of 48.5 cm (−2.0 standard deviations), with lax wrinkled skin on the forehead and limbs, generalised hypertrichosis, microphthalmia, midface retrusion, small dysplastic ears, bifid uvula, oligodontia with malocclusion and recurrence of the umbilical hernia; growth hormone and corticotropin tests were normal. Microarray was normal and sequencing of SLC25A24 exon 5 showed the heterozygous variant NM_013386.5:c.650G>A p.(Arg217His), absent in the parents and both siblings. At 9 years, preoperative chest CT for strabismus surgery revealed dilatation of the ascending aorta (2.7 cm, +5.0 standard deviations). Figure 1 of the article shows the face with hypertrichosis and a low hairline, the hypoplastic distal phalanges with anonychia and the growth chart up to 10 years (https://pmc.ncbi.nlm.nih.gov/articles/PMC6882017/). The case illustrates the improvement of the progeroid appearance and of development with age and the late appearance of aortopathy, which warrants echocardiographic surveillance even with a normal initial echocardiogram [7, 49].

11. Prognosis and Long-Term Follow-Up

11.1. Survival

Survival data vary with the era and the inclusion criterion. OMIM, based on clinical descriptions predating molecular confirmation, reports a mean survival of 7 months, with survival into the third decade described, and Smith gives a life expectancy of about 7 months for most, with seven survivors aged between 15 months and 17 years [1, 28]. In the 2017 clinical cohort of 18 patients, 4 died in the first weeks of life, 2 in the first year, 4 between 5 and 10 years and 1 at 17 years, and 2 were alive at 20 years [21]. Recorded causes of death include respiratory complications, pneumonia, cerebral haemorrhage and exhaustion [21]. In the series with molecular confirmation, the picture is less severe: of Wambach's 7 patients and Jay's patient, only the latter died (at 7 months), and earlier reviews estimated that about 30% died before 6 years; in the three publications with current age (Lessel, Temel and Wambach), the 11 patients were alive between 11 months and 21 years [22, 39]. The 2018 Paolacci series does, however, include deaths in the first two weeks of life (4 patients), at one and a half months, at 6 months and in adolescence [39]. The difference between series may reflect ascertainment bias (living patients more available for molecular study), improved supportive care and genotypic heterogeneity, and does not allow a survival curve to be estimated.

11.2. Functional course

The neurological course is heterogeneous. Some patients develop progressive signs (tremor, dystonia, hypertonia, ataxia) from the end of the first year or in childhood, with loss of walking or of the ability to sit, and others maintain normal or near-normal development, including mainstream schooling [21, 22]. Unlike POLR3 leukodystrophy, in which neurological deterioration is the rule, most patients in the Wambach series were making developmental progress, and two adults aged 20 and 21 years lived with some assistance or independently [22]. Growth remains severely compromised, and metabolic (hypertriglyceridaemia, steatosis, insulin resistance, diabetes) and cutaneous (acanthosis, hirsutism) changes tend to become more pronounced in adolescence [21, 28].

11.3. Surveillance

There are no surveillance guidelines for WRS or for POLR3 leukodystrophy, for which GeneReviews recommends individualised monitoring [6]. The table proposes a scheme derived from the manifestations described, with the origin stated; the intervals are indicative and do not come from studies.

11.4. Prognosis and surveillance in Fontaine progeroid syndrome

Life expectancy in Fontaine syndrome is unknown and severity is bimodal [7]. Writzl's four patients died in the first year (at 7 hours and 20 hours from respiratory failure, at 6 months from pulmonary hypertension and at 7 months from sepsis); among Ehmke's five patients, one died at 20 months after a urinary tract infection and the others were alive at 5, 5.5, 7 and 14 years [8]. Cases published since include an Irish infant who died at 7 months from pulmonary hypertension and multiorgan failure aggravated by rhinovirus or enterovirus infection and a 767 g Japanese female newborn who died of sepsis at 15 days, whereas a Spanish boy was alive at 15 years and a Dutch woman at 45 [19, 20, 50, 70]. Severe fetal growth restriction and very low birth weight are associated with the lethal forms, and patients with a historical diagnosis of GCMS reached their 30s and 40s [7, 20]. In survivors, the progeroid appearance lessens, cognition is normal and the main long-term threats are aortopathy and craniofacial, ocular and auditory complications [7, 50].

Surveillance follows GeneReviews, with the aorta added according to the screening recommendation of Legué and colleagues; the intervals are not derived from cohort studies.

12. Summary and Final Considerations

Wiedemann–Rautenstrauch syndrome is an ultra-rare autosomal recessive neonatal progeroid syndrome, caused in the great majority of patients by biallelic variants in POLR3A, the gene for the largest subunit of RNA polymerase III. It is defined clinically by severe prenatal and postnatal growth restriction, relative macrocephaly with wide fontanelles and sutures, prominent scalp veins, sparse hair, a triangular face with apparently low-set eyeballs, a small mouth, a pointed chin, neonatal teeth followed by hypodontia or absence of the permanent dentition, and lipodystrophy with local fat accumulations over the buttocks and sacral region. It belongs to a spectrum of Pol III disorders that includes 4H hypomyelinating leukodystrophy, spastic ataxia, the striatal forms and, in dominant form, peripheral neuropathies due to POLR3B and POLR3A; WRS occupies the end with the least residual function, with genotypes including at least one null or severe-effect allele, and with intronic complex alleles in cis. Molecular diagnosis requires methods capable of detecting deep intronic variants (genome, RNA study) and parental testing, and the differential with the entities due to FBN1, CAV1, SLC25A24, PYCR1, ALDH18A1 and LMNA is essential, because these were the main source of erroneous diagnoses and because one of them has an approved therapy. Management is supportive and multidisciplinary, focused on nutrition, airway, orthopaedics, teeth, eyes, hearing and metabolism, with declared extrapolation of the recommendations for POLR3 leukodystrophy, including avoidance of dopamine D2 blockers. The prognosis in recent molecular series is better than in the historical descriptions, with patients alive in the third decade, but heterogeneity and ascertainment bias do not allow a survival estimate. Current lines of research are genotype–phenotype correlation in large databases, cellular and animal models and, at the preclinical stage, antisense oligonucleotides to correct POLR3A splicing defects. Fontaine progeroid syndrome, autosomal dominant due to de novo variants at codon 217 of SLC25A24, is the closest neonatal differential; it is distinguished by craniosynostosis, hypertrichosis, distal phalangeal and nail anomalies and umbilical hernia, has normal cognition in most survivors, requires surveillance of pulmonary hypertension and the aorta, and carries a low recurrence risk in siblings, except with parental mosaicism [7, 14, 50].

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