Rothmund–Thomson Syndrome and the RECQL4 Spectrum

Autosomal recessive genodermatosis with poikiloderma beginning in infancy, ectodermal dysplasia, skeletal anomalies and predisposition to osteosarcoma; four known genes (ANAPC1, RECQL4, CRIPT, DNA2) and two RECQL4 allelic syndromes, RAPADILINO and Baller–Gerold; includes hereditary fibrosing poikiloderma (FAM111B), autosomal dominant, as the main differential diagnosis.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding descriptions

In 1868, the ophthalmologist Auguste Rothmund described, in a consanguineous Alpine community, children with a peculiar skin degeneration, growth retardation and rapidly progressive bilateral cataract [1, 3, 14]. Sources differ on the place and number: the reviews by Larizza and by Martins refer to ten children from a Bavarian village, whereas OMIM describes two related consanguineous families from the Walser valley in Austria, with four girls and one boy [3, 14, 16]. GeneReviews also places the original description in Austria and notes that western Tyrol, the region of origin of those patients, is today one of the areas with an ANAPC1 founder variant [2]. In 1923 and 1936, the English dermatologist M. Sidney Thomson described patients with similar skin changes, short stature and skeletal defects (bilateral thumb aplasia, hypoplastic radii and ulnae), but without cataract, which he called poikiloderma congenitale [2, 3, 14]. In 1957, Taylor proposed that the two descriptions corresponded to the same disease and coined the eponym Rothmund–Thomson syndrome (RTS) [3, 14]. The biological justification for this merger remains debated, because Rothmund's patients had mainly cataract and Thomson's had bone defects without saddle nose or cataract [16], a distinction that molecular genetics would later reproduce in the separation between types 1 and 2 [3].

1.2. Molecular discovery and reclassifications

In 1999, Kitao and colleagues identified, in three patients, compound heterozygous variants in the helicase gene RECQL4, newly cloned at 8q24.3, and showed that this gene explained at least part of the cases [42]. In the Houston international cohort, Wang and colleagues found that about two-thirds of patients with a clinical diagnosis had truncating RECQL4 variants and that all cases of osteosarcoma occurred in this group, which led to the division into RTS type 2 (with biallelic RECQL4 variants, skeletal anomalies and risk of osteosarcoma) and RTS type 1 (without RECQL4 variants, with ectodermal dysplasia and juvenile cataract) [3, 43]. In 2019, Ajeawung and colleagues identified, in ten patients from seven families with type 1, three of them of Amish ancestry, a recurrent deep intronic variant in ANAPC1, the gene for the largest subunit of the anaphase-promoting complex/cyclosome (APC/C) [14, 44]. In 2023 two further genes emerged: CRIPT, already associated with primordial dwarfism with microcephaly, whose carriers met the clinical criteria for RTS and also had neurodevelopmental delay and epilepsy [45], and DNA2, in Brazilian patients and in a Swiss–Portuguese sibship with generalised poikiloderma, congenital cataract and severe growth retardation [46]. OMIM, Orphanet and the recent literature designate these forms as RTS types 3 (CRIPT, #615789) and 4 (DNA2, #620819) [16, 18, 19, 28, 29, 36, 47]; entry #615789 was formerly designated "short stature with microcephaly and distinctive facies", a name still used in some databases [9].

1.3. RECQL4 allelic syndromes

Two independently described syndromes turned out to be allelic to RTS type 2. RAPADILINO syndrome was described in 1989 in Finnish patients (a sib pair and three unrelated patients), with radial defects, patellar hypoplasia, high or cleft palate, diarrhoea, joint dislocations, short stature, slender nose and normal intelligence [14, 24, 48]; RAPADILINO belongs to the "Finnish disease heritage", and in a survey of 62 Finnish patients with radial aplasia or hypoplasia, 11 had RAPADILINO [24]; in 2003, Siitonen and colleagues identified RECQL4 variants in these patients, with a Finnish founder splicing variant [49]. Baller–Gerold syndrome (BGS) originates in the descriptions by Baller (1950), of a 26-year-old woman with short stature, oxycephaly and aplasia/hypoplasia of the radii, the daughter of third cousins [25], and by Gerold (1959), of siblings with coronal craniosynostosis, aplasia of the radius and thumb and bowed ulnae; the name was coined by Cohen in 1975 [5, 12]. Since then, the term has been applied to any combination of craniosynostosis and radial defect, a usage that GeneReviews considers incorrect and that led to the inclusion in BGS of patients later reclassified as Fanconi anaemia, Roberts syndrome, Saethre–Chotzen syndrome, Pfeiffer syndrome or valproate embryopathy [12, 14, 50]. In 2006, Van Maldergem and colleagues demonstrated biallelic RECQL4 variants in two families with BGS and proposed integrating BGS into a spectrum with RTS and RAPADILINO [50].

1.4. Definition of the entities

RTS is defined clinically by poikiloderma beginning in infancy (facial erythema at 3–6 months, extension to the extensor surfaces of the limbs and the buttocks, sparing of the trunk and evolution to reticulated hyper- and hypopigmentation, telangiectasias and punctate atrophy), accompanied by ectodermal, skeletal and growth findings, and genetically by biallelic variants in ANAPC1, RECQL4, CRIPT or DNA2 [2, 14]. RAPADILINO is the RECQL4 form with radial and patellar defects and without poikiloderma [14, 35]. BGS is the RECQL4 form with craniosynostosis and radial ray defect, with poikiloderma in some patients [12]. As the clinical overlap is extensive and there is no precise genotype–phenotype correlation among the three, several authors treat them as a spectrum, whereas the 2023 nosology of skeletal disorders retains the three names [14]. Poikiloderma with neutropenia (USB1 gene) and other hereditary poikilodermas enter the differential diagnosis and are covered in section 6.

1.5. Hereditary fibrosing poikiloderma (POIKTMP)

In 2006, Khumalo and colleagues described a South African family of European ancestry in which two generations had facial poikiloderma from childhood, tendon contractures and progressive pulmonary fibrosis: the proband, aged 26, had heat intolerance and facial lesions from early childhood, Achilles tendon contractures at 9 years, operated on at 14, and a restrictive ventilatory pattern; her father and a brother died of diffuse interstitial pulmonary fibrosis at 56 and 30 years [6, 7]. The authors proposed the designation "hereditary sclerosing poikiloderma with tendon and pulmonary involvement" and separated it from the Weary form, which has linear sclerotic bands and has neither tendon contractures nor lethal pulmonary fibrosis [7]. In 2013, exome sequencing of this family and of a French child identified heterozygous missense variants in FAM111B; Sanger sequencing found them in three further probands (of Algerian, Italian and French–Moroccan origin), de novo in two of the five families and absent from 388 controls [51]. The entity was designated POIKTMP (OMIM #615704) and, in 2022, an Italian group proposed the acronym POIK-TMPL to include liver involvement, lymphoedema, pancreatic insufficiency and cancer [8].

POIKTMP belongs in this article as a direct differential diagnosis of RTS, with which it is confused in infancy: two Italian patients and the Italian patient described in 2022 first received a clinical diagnosis of RTS, with negative RECQL4 testing, before identification of FAM111B NM_198947.4:c.1879A>G p.(Arg627Gly) [8, 52]. It is the only autosomal dominant hereditary poikiloderma with a known gene [15]. GeneReviews defines it by early-onset poikiloderma with other findings, mainly contractures or muscle weakness, and a heterozygous pathogenic missense variant in FAM111B [13].

2. Molecular Genetics and Pathophysiology

2.1. Genetic classification of the class

RTS is genetically heterogeneous, and the four current types correspond to four genes with no evident common function [14, 37]. RECQL4 accounts for about 60% of patients with a clinical diagnosis, ANAPC1 for about 10%, and about 30% remained without an identified cause in 2020, before CRIPT and DNA2 were described [2]. In the Wang cohorts and in the Orphanet Journal of Rare Diseases review, the proportion of patients with RECQL4 variants was 60–65% [3, 43], and in a French series of patients referred for RECQL4 testing with suspected RTS the rate was 10 of 27 [53]. The following table summarises the class, with the features that distinguish each type.

The DNA2 gene has two further allelic disorders that do not belong to the class: progressive external ophthalmoplegia with mitochondrial DNA deletions type 6, autosomal dominant (OMIM 615156), and Seckel syndrome 8, autosomal recessive (OMIM 615807), described in patients with microcephalic primordial dwarfism without poikiloderma [10, 14]. Mitochondrial myopathy has not been described in patients with RTS type 4 or in Seckel syndrome 8 [14].

2.2. RECQL4 and the RecQ helicase family

RECQL4 has 21 exons spread over more than 6.5 kb, a coding sequence of 3627 bp and a housekeeping-type promoter, and encodes a protein of 1208 amino acids and 133 kDa [3, 12]. The helicase domain (ATP binding, amino acids 489–662, and C-terminal domain, amino acids 683–850) is encoded by exons 8 to 15 [12]. The structural peculiarity with the greatest diagnostic consequence is the presence of 13 introns shorter than 100 bp: small intronic deletions reduce the intron below the minimum size required for splicing (about 80 bp) and cause intron retention, a mechanism described by Wang and colleagues in 2002 [3, 12]. Humans have five RecQ helicases (RECQL, BLM, WRN, RECQL4 and RECQL5); biallelic variants in BLM cause Bloom syndrome and in WRN Werner syndrome, both chromosomal instability disorders with cancer predisposition and premature ageing, features shared by the RECQL4 disorders [3, 12].

The RECQL4 protein unwinds DNA with 3'→5' polarity and takes part in replication, recombination, repair, maintenance of telomeres and mitochondrial DNA, and chromosome segregation [2, 12]. Unlike the other RecQ helicases, RECQL4 is an essential gene, and the essential function lies not in the helicase activity but in the N-terminal domain homologous to Sld2, required to initiate replication (recruitment of GINS and polymerase ε to the pre-replicative complex) [14]. A study published in 2026, in a mouse model, showed that trace amounts of a 480-amino-acid N-terminal fragment, without the helicase domain, suffice to sustain replication [54]. RECQL4 also takes part in double-strand break resection through interaction with the MRN complex and CtIP, in base excision repair (with APE1 and FEN1), in the resolution of telomeric structures with TRF1, TRF2 and POT1, and in mitochondrial DNA maintenance by stabilising polymerase γ together with p53 [12, 14]. It interacts with the ubiquitin ligases UBR1 and UBR2, implicated in chromosome segregation [3, 12], and, according to a 2025 study, with the endonuclease MUS81, an interaction lost with a truncating RTS variant and required to prevent anaphase bridges and micronuclei [55]. Patient cells show numerical chromosomal instability (mosaic trisomies of chromosomes 8, 7 and 2) and structural instability (isochromosomes of the same chromosomes), without the increase in sister chromatid exchanges that defines Bloom syndrome, and they accumulate oxidative lesions [3, 14]. Expression of RECQL4 in rapidly proliferating tissues, such as growing bone and skin, is the proposed explanation for the distribution of manifestations; in the Recql4-deficient mouse, generalised bone disease results from reduced osteogenesis [3, 56].

2.3. ANAPC1, CRIPT and DNA2

ANAPC1 encodes APC1, the scaffold subunit of the APC/C, an E3 ubiquitin ligase that drives the metaphase–anaphase transition (with CDC20, through degradation of securin and cyclin B) and the maintenance of G1 phase (with Cdh1) [2, 14, 34]. The recurrent variant c.2705-198C>T activates a 95-bp pseudoexon, generates premature termination codons subject to nonsense-mediated decay, reduces the protein and prolongs interphase in fibroblasts; mice heterozygous for a null allele have more cataract [44]. The ClinGen expert panel records the mechanism as probable loss of function [34]. DNA2 encodes a nuclear and mitochondrial nuclease/helicase that cleaves long RPA-coated 5' flaps during Okazaki fragment maturation, degrades reversed replication forks in a controlled manner with WRN and carries out long-range resection of double-strand breaks with WRN or BLM [10, 14]; in RTS type 4, the intronic splicing variant reduces the protein and impairs double-strand break repair [46]. CRIPT encodes a cysteine-rich protein that stabilises the U12 ribonucleoprotein in the minor spliceosome and links PSD-95 to microtubules at excitatory synapses [9, 14]. CRIPT- or RECQL4-deficient fibroblasts show increased senescence markers (p53, p16, p21, β-galactosidase), without mitotic errors and with no or mild sensitivity to ionising radiation, mitomycin C, hydroxyurea, etoposide and potassium bromate [45]. The hypothesis of a common mechanism is double-strand break resection or regulation of replication: RECQL4 interacts with DNA2 and CtIP, the APC/C regulates the degradation of CtIP and RECQL4 throughout the cell cycle, and DNA2 contains a U12-type intron that depends on the minor spliceosome in which CRIPT acts [14].

2.4. Variant spectrum and nomenclature

The MANE transcript of RECQL4 is NM_004260.4; GeneReviews uses NM_004260.3, with the same c. numbering for the variants checked [2, 57]. Most RECQL4 variants are frameshift or nonsense; splicing variants, many non-canonical, account for about a third, and missense variants are rare and almost always in combination with a truncating allele [3]. In the 2023 review, 76% of the alleles catalogued in the four genes (87 of 114) were large deletions or variants predicted to generate a premature termination codon or a splicing defect [14]. Complete loss of RECQL4 is lethal: only two variants have been described upstream of exon 5, never in the homozygous state, deletion of the whole gene has never been identified, and the mutant proteins retain the N-terminus [3, 12]. The table brings together the variants with clinical or population significance, normalised in VariantValidator.

2.5. Genotype–phenotype correlations

Between genes, the correlations are clear: osteosarcoma and skeletal defects are concentrated in type 2, bilateral juvenile cataract in type 1, congenital cataract and growth hormone (GH) deficiency in type 4, and neurological involvement in type 3 [2, 14]. Within RECQL4, GeneReviews does not recognise formal correlations [2], but two data points guide oncological risk: the incidence of osteosarcoma was zero in 100 person-years without a truncating variant and 0.05 per year in 230 person-years with one or two truncating variants [43, 64], and the risk appears greater when the variants affect the helicase domain [1, 12]. In RAPADILINO, the Finnish variant causes an in-frame deletion of 44 amino acids immediately before the helicase domain, preserving it; in the 14 Finns studied (9 homozygous and 5 compound heterozygous with nonsense variants in exons 5, 18 and 19), the helicase domain was never affected, which led to the hypothesis that its loss is required for poikiloderma [2, 49]. Patients with RTS and with RAPADILINO or BGS usually share only one of the two alleles, with one exception (c.1573del with NM_004260.4:c.3061C>T p.(Arg1021Trp) in one RTS and one BGS), so the combination of alleles appears to determine the phenotype, although there is no predictive rule [3]. In type 1, compound heterozygotes (intronic variant with a loss-of-function allele) had a more extensive phenotype than those homozygous for the intronic variant, with more growth deficiency treated with GH and more dental, nail, endocrine, genital and skeletal involvement [14]. In type 4, residual activity of the splicing allele is the proposed explanation for the difference from Seckel 8 primordial dwarfism [46].

2.6. Heterozygotes

Heterozygous parents have no known increase in cancer risk [3, 14]. In the largest international RTS registry, the prevalence of cancer in 123 relatives heterozygous for RECQL4 was 2.4% (3/123), with no significant difference from the age-adjusted SEER population estimate of 5.6% (P = 0.2) [65]. Pointing in a different direction, germline analysis of 5562 children with cancer (St. Jude and TARGET) identified heterozygous loss-of-function RECQL4 variants in 5 of 249 children with osteosarcoma (2.0%), an over-representation relative to 134,187 gnomAD controls (odds ratio 7.1; 95% CI 2.9–17), with c.1573del in 9 of the 24 carriers [58]. The two studies measure different things (cancer prevalence in relatives of patients and carrier frequency among children with osteosarcoma) and do not allow an absolute risk for carriers to be estimated.

2.7. FAM111B and hereditary fibrosing poikiloderma

FAM111B (11q12.1; MANE transcript NM_198947.4, protein NP_945185.1) encodes a trypsin-like serine protease with the catalytic domain in the C-terminal region, where the catalytic triad residues Ser490, His544 and Asp650 lie, and with two ubiquitin-like domains [13, 15]. It shares 46% homology with its paralogue FAM111A, whose dominant variants cause Kenny–Caffey syndrome type 2 and gracile bone dysplasia, without skin involvement [15, 66]. The physiological function is not defined; hypotheses involve DNA replication, the cell cycle and chromatin-associated proteolysis [13, 66].

The disease mechanism remains under discussion and the sources support different models. GeneReviews and the 2015 series suggest a dominant-negative effect, supported by the absence of deletions and truncating variants in patients [13, 67]. In cell lines, Hoffmann and colleagues showed that patient variants increase the intrinsic proteolytic activity of FAM111B and reproduce the cellular toxicity of hyperactive FAM111A, indicating a gain of function [66]. Kliszczak and colleagues observed that loss of FAM111B shortens telomeres, alters nuclear shape and increases micronuclei and ultrafine DNA bridges, without a repair defect, and that the mutant protein accumulates at the nuclear envelope [68]. In fibroblasts from patients with NM_198947.4:c.1879A>G p.(Arg627Gly) and c.1883G>A p.(Ser628Asn), Vignard and colleagues found less FAM111B protein with normal messenger RNA, accumulation of ubiquitin conjugates, proteasome remodelling and a type I interferon signature, proposing ubiquitin–proteasome system dysfunction as the central mechanism and as a functional biomarker for classifying variants of uncertain significance (VUS) [15]. Lymphocytes from two Italian patients showed spontaneous chromosomal instability greater than that of controls [52]. The common tissue outcome is fibrosis and fatty replacement of the skin, muscle, pancreas, liver and lung [7, 13].

The pathogenic variants are missense variants clustered in two hotspots: group 1, at residues 416–434, upstream of the catalytic domain, and group 2, at residues 621–629, within the protease domain and the D-box (destruction box) sequence; the only exception is an in-frame deletion of one amino acid [15, 69]. No intragenic deletions or duplications have been described, and dosage analysis has an expected yield of zero [13].

In the 2025 series, the variant of a German–Irish–Norwegian family is described as c.1880G>C p.(Arg627Gly); in NM_198947.4, the change c.1880G>C translates to p.(Arg627Thr), so one of the two terms in the publication is incorrect and the variant was not included in the table [15]. A de novo frameshift variant was described in an African American adolescent with a progressive osseous heteroplasia phenotype, without poikiloderma; it is an isolated case and its relationship with POIKTMP has not been established [73].

Genotype–phenotype correlations are preliminary. In Arowolo's review of 36 cases, variants within the protease domain were more often associated with pulmonary fibrosis (47% versus 13%), cirrhosis (26% versus 7%), myopathy (53% versus 20%) and contractures (55% versus 7%) than those outside it, and the two fatal pancreatic cancers occurred in this group [69]. In the 2025 cohort of 41 patients, severe muscular forms (surgery or loss of ambulation) occurred in 5 of 24 patients in group 2 and in 0 of 16 in group 1 (p = 0.14), pulmonary involvement in 10 of 20 versus 2 of 13 (p = 0.28), and the three pancreatic adenocarcinomas and the three cases of severe liver disease occurred in group 2, without statistical significance [15]. GeneReviews also states that codon 621 variants appear milder than those at codons 625, 627 and 628 [13]. Penetrance is described as complete for the skin signs, with marked intrafamilial variability [13]. In a South African cohort of 131 patients with systemic sclerosis, no pathogenic FAM111B variants were found, which separates the genetic disease from common scleroderma [74].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limits

Most knowledge about RTS comes from reviews of published cases and from two Houston series: the cohort of 41 patients of Wang and colleagues (2001), recruited through dermatology, ophthalmology, genetics and oncology, aged between 9 months and 42 years and with male predominance (28 boys, 13 girls), and the 2003 cohort of 33 genotyped patients [43, 75]. The frequency figures that follow refer to these series or to literature reviews, both subject to selection bias towards the most severe cases or those with cancer; they are not population rates. The natural history data refer to patients without targeted treatment, because there is no disease-modifying treatment.

3.2. Skin

The rash usually begins between 3 and 6 months (in some descriptions up to 10 months and, occasionally, up to 2 years), with erythema, oedema and sometimes blisters on the cheeks and face [2, 14]. It then extends to the extensor surfaces of the limbs, later to the flexor surfaces, and to the buttocks, characteristically sparing the trunk and abdomen [2, 3]. Over months to years, the acute phase gives way to the chronic phase, with reticulated hyper- and hypopigmentation, telangiectasias and punctate atrophy, which constitute the poikiloderma and persist for life [2]. In the Smith review, 89% of patients had poikiloderma by 2 years, 20% had blisters before the poikiloderma and 35% photosensitivity [1, 3]. Sun exposure worsens the erythema in some patients, although the poikiloderma is also evident in unexposed areas [1, 14]. Hyperkeratotic lesions, sometimes verrucous, mainly palmoplantar, occur in about a third [1, 2]. In atrophic areas hypopigmentation may predominate [76]. Café-au-lait macules may appear later, and calcinosis cutis and porokeratosis are rare [2, 3]. On dark skin, the rash is harder to recognise: an African American and Puerto Rican boy had the poikiloderma of his limbs interpreted as psoriasiform dermatitis until exome sequencing, at almost 5 years [77].

3.3. Hair, nails and teeth

In the cohort of 41 patients, scalp hair was sparse, brittle, fine or absent in 50% and eyelashes and/or eyebrows were sparse in 73% [3]. Alopecia may be complete in the second or third decade and also affects the beard, pubic and axillary hair; hair may turn grey prematurely [1, 3]. Nails are small and dystrophic in about a third, with frequent pachyonychia [1, 3]. Dental anomalies, estimated in 27–59% of patients, include microdontia, rudimentary teeth, abnormal crowns, agenesis and supernumerary teeth, delayed or ectopic eruption, enamel defects, short roots and caries (40% in Smith) [1–3]. RTS is among the systemic diseases associated with early-onset periodontitis, and the short roots tend to resorb [3].

3.4. Growth and endocrinology

Most patients are born at term with low weight and length for gestational age and remain below the 5th centile, in a proportionate and symmetrical manner; at least two-thirds have low birth weight and linear growth deficiency [2, 3]. GH is generally normal in type 2, with isolated cases of deficiency [2, 3]. GH deficiency was frequent in type 1 (5 of 10 patients, 6 treated with GH; in the original series, the five boys had short stature treated with GH and cryptorchidism [17]) and in type 4 (6 of 6, 5 treated), where it was associated with hypothyroidism in 5 of 6 [14]. Hypogonadism or delayed puberty occurred in 28% in the Smith review, fertility is reduced in both sexes, but pregnancies and paternities have been described [1, 2]. Precocious puberty, treated with a gonadotrophin-releasing hormone analogue [78], and gynaecomastia with low testosterone [79] have also been described.

3.5. Skeleton and bone metabolism

In the review of the world literature, 68% of patients had visible skeletal anomalies (frontal bossing, saddle nose, long bone anomalies) [3]. In a series of 28 patients with a skeletal survey and RECQL4 testing, 21 (75%) had at least one significant anomaly, many without clinical expression: abnormal metaphyseal trabeculation with longitudinal and transverse striations, brachymesophalangy, thumb aplasia or hypoplasia, osteopenia, radial head dislocation, radial aplasia or hypoplasia and patellar ossification defects; three had a destructive bone lesion (osteosarcoma), and the anomalies correlated significantly with the presence of RECQL4 variants [80]. In the cohort of 41 patients, 20% had radial defects [75]; in 12 patients with confirmed RTS type 2, skin lesions were present in 100%, growth retardation in 83% and skeletal manifestations in 75% [16]; and in the 2023 comparative table radial ray defects appeared in 14 of 40 patients with RECQL4 and in none of the patients with DNA2 [14]. In a study of 29 patients (NCT01304407), areal bone mineral density was reduced, and RECQL4 variants and low density correlated with fractures [56, 81]. Delayed ossification of the patella may be mistaken for absence in infancy [12].

3.6. Eyes

Cataract is typically bilateral, subcapsular and rapidly progressive; in older series it affected up to 50% of patients, with onset between 3 and 7 years, but in the cohort of 41 patients it was present in only 2 (6%) [2, 3, 75]. The difference is explained by the genetic composition of the series: juvenile cataract was present in 10 of 10 patients with ANAPC1 and in 0 of 26 with RECQL4, and most European descriptions of early cataract probably correspond to type 1 [2, 14]. In type 4, the cataract is congenital (6 of 7) and associated with microphthalmia (4 of 7), corneal opacity (5 of 7), glaucoma and, in isolated patients, Peters anomaly and optic atrophy, and the skin shows photosensitivity with blisters [14, 19]; in type 3 retinal pigmentary changes predominate (4 of 6) [14]. Other changes described are corneal atrophy or sclerosis, congenital glaucoma, retinal atrophy, coloboma, iris dysgenesis, strabismus and blue sclerae [1, 3].

3.7. Digestive and respiratory systems and immunity

Feeding difficulties, chronic vomiting and diarrhoea are frequent in infancy (17% in the cohort of 41), sometimes require tube feeding and usually resolve in childhood [2, 75]. Malformations such as oesophageal or pyloric stenosis, anal atresia or stenosis, anteriorly placed anus, annular pancreas and rectovaginal fistula are rare [1, 3, 78]. Bronchiectasis has been described in patients without neutropenia [3]. Immunity is usually normal, but there are reports of humoral immunodeficiency, IgG4 deficiency, low IgG and IgA with herpetic encephalitis, and combined immunodeficiency [2]. In 2026 the first severe combined immunodeficiency in BGS was described (T lymphocytes 28–71/µL, NK 4–23/µL), detected by newborn screening for T-cell receptor excision circles (TREC); culture in thymic organoids showed an intrinsic defect of haematopoietic cells [59]. The review of that case brings together four previous patients with immunodeficiency in RECQL4 disorders, all with hypogammaglobulinaemia and NK-cell deficiency [59].

3.8. Blood

Isolated anaemia, neutropenia, progressive leucopenia, microcytic anaemia requiring transfusion, myelodysplasia, aplastic anaemia and leukaemia have been described [2, 3]. A preterm infant with RECQL4 variants, a radial defect and an ectopic kidney presented at birth with cytopenias, circulating myeloblasts and a somatic monosomy 7 clone (43.5% of marrow cells at 2 months) with megakaryocytic dysplasia consistent with myelodysplastic syndrome; the clone regressed spontaneously and was undetectable at 13 months, with recovery of counts [62]. It is the second known case of acquired monosomy 7 in a RECQL4 syndrome and the first with regression [62].

3.9. Neurodevelopment and hearing

Intelligence is normal in most patients with types 1 and 2 (intellectual disability in 6 of 202 patients in one review and in 3% in Smith) [1, 3]. Developmental delay or intellectual disability were recorded in 4 of 27 patients with RECQL4, 2 of 10 with ANAPC1, 2 of 7 with DNA2 and in all 6 with CRIPT, who also had seizures in 4 of 6 [14]. In a Turkish series of 6 patients with the same RECQL4 variant, all had microcephaly and learning difficulties [61]. Sensorineural deafness is rare [3, 61].

3.10. Cancer

Cancer is the main determinant of survival [1]. In the cohort of 41 patients, 13 (32%) had osteosarcoma, and 22 of the 28 without osteosarcoma were younger than 15 years, still within the age of risk [75]. The prevalence of osteosarcoma cited in reviews is about 30%, with a median age at diagnosis of 10–11.5 years (mean of 14 years in case reviews, versus 17 years in sporadic osteosarcoma) [2, 3, 14, 82]. The 2024 AACR update cites an estimated probability of osteosarcoma of about 50% by 20 years and over 60% by 40 years in type 2, based on a review by Lu and colleagues [37]. Osteosarcoma in RTS is located mainly in the femur and tibia and is of the conventional (osteoblastic) type, like sporadic osteosarcoma [3, 82]; multicentric forms (ten cases described up to 2010) account for 17.9–25.6% of osteosarcomas in RTS, versus 0.4–10% in sporadic disease [3]. Osteosarcoma has been observed only in patients with RECQL4 (6 of 43 in the 2023 comparative table), but patients with the other genes are young and follow-up is short [14]; in the 2003 series, all 11 patients with osteosarcoma had at least one truncating variant [43]. In a Hong Kong series published in 2025, two of three patients with RECQL4-related RTS had osteosarcoma [83].

Skin carcinomas (squamous cell, basal cell and Bowen disease) have an estimated prevalence of 5% and a mean age of 34.4 years, earlier than in the general population, also on non-sun-exposed skin, and occur in types 1 and 2 [1–3]. Three Brazilian siblings from a consanguineous family, with poikiloderma and bilateral cataract, developed cutaneous squamous cell carcinoma between 35 and 48 years on unexposed surfaces [2]. Amelanotic melanoma, malignant fibrous histiocytoma, fibrosarcoma, Hodgkin and non-Hodgkin lymphomas, acute myeloid leukaemia, myelodysplasia, gastric carcinoma and malignant eccrine poroma have been described, as well as patients with multiple primaries (one with 11 basal cell carcinomas and another with anaplastic lymphoma at 9 years, diffuse large B-cell lymphoma and osteosarcoma at 14 and lymphoblastic leukaemia at 21) [2, 3]. Two patients developed lymphoma 8 and 9 years after treatment for osteosarcoma; follow-up is too short to quantify the risk of a second neoplasm [2].

3.11. RAPADILINO

RAPADILINO is characterised by pre- and postnatal growth retardation, near-constant radial ray defects, patellar hypoplasia or aplasia, high or cleft palate, joint dislocations, infantile diarrhoea of unknown cause with poor weight gain, a long slender nose and normal intelligence; cervical spine segmentation defects have been described [2, 14]. There is no poikiloderma, alopecia or loss of eyelashes, but the absence of poikiloderma can only be stated after 1 year [12]. In the long-term follow-up of 15 Finnish patients carrying c.1390+2del, 6 (40%) developed lymphoma (4, all before 35 years) or osteosarcoma (2) [14, 35].

3.12. Baller–Gerold

BGS is suspected at birth from the combination of craniosynostosis and upper limb anomaly [12]. The coronal suture is the most affected, alone or with the metopic, lambdoid and sagittal sutures, and results in brachycephaly or turricephaly, proptosis, a prominent forehead and large fontanelles [4, 12]. In the Smith review, craniosynostosis and absent or hypoplastic thumb were present in 100%, radial aplasia or hypoplasia in 77%, short and curved ulna in 68%, low-set and rotated ears in 64%, micrognathia in 50%, gastrointestinal anomalies (imperforate or anteriorly placed anus) in 40%, urogenital anomalies (ectopic, hypoplastic, dysplastic or absent kidney, persistent cloaca) in 35% and heart defects (ventricular septal defect, tetralogy of Fallot, dextrocardia, subaortic hypertrophy) in 25% [5]. Final height is about 4 standard deviations below the mean [5, 12]. Patellar hypoplasia becomes evident in childhood and may cause genu recurvatum and knee instability [12]. Poikiloderma, when it appears, begins in the first years with erythema of the face and limbs [12]. Sources differ on development: Smith reports intellectual disability in 50% of patients followed beyond infancy, whereas GeneReviews considers that most, if not all, patients with RECQL4 variants have normal intelligence, without formal studies [5, 12]. In the Smith review, 20% of live-born infants died unexpectedly in the first year, a figure that GeneReviews does not reproduce and that comes from series in which some patients were later reclassified into other entities [4, 5, 50]. A child with severe BGS developed a midline NK/T-cell lymphoma at 2 years and 5 months [12, 14]. Two Japanese fetuses with biallelic RECQL4 variants had severe hypoplasia of the forearms and legs, one with pulmonary hypoplasia and neonatal death from respiratory failure, showing that the spectrum includes perinatally lethal forms [84]. At the other extreme, a Korean newborn with bilateral humeroradial synostosis, mild thumb hypoplasia and patent cranial sutures had the diagnosis of BGS established by rapid genome sequencing at 12 days [63].

3.13. Comparison between the forms

Source: table 1 of Martins and colleagues (2023), which combines unpublished data from the São Paulo group for RECQL4 with the literature for the remaining genes [14]. Among the RECQL4 syndromes, the shared features are pre- and postnatal growth retardation, chronic diarrhoea and patellar hypo- or aplasia; the radial defect is near-constant in RAPADILINO and BGS and less frequent in RTS; poikiloderma is present in RTS and in part of BGS, but not in RAPADILINO; craniosynostosis defines BGS and is rare in RTS; alopecia and absent eyelashes and eyebrows belong to RTS [1, 12].

3.14. Life expectancy

In the absence of cancer, life expectancy appears normal, although follow-up data are limited; metastatic osteosarcoma is the main cause of death described [2, 3, 14].

3.15. Hereditary fibrosing poikiloderma (POIKTMP)

The largest compilation is that of Vignard and colleagues (2025): 41 patients, 4 new, 5 with long-term follow-up in Nantes and 32 from the literature, with a mean age of 26 years at the last examination, 18 of paediatric age and 22 male; not all signs were sought in all patients, so denominators vary [15]. The frequencies are not population natural history, because they derive from reports with publication bias.

In the text of the same publication, exocrine pancreatic insufficiency is given as 67% and liver disease as 50%, values that do not match those in the authors' table; the table, with numerators and denominators, is the reference used [15]. In Arowolo's review (36 cases), the frequencies were 94% for poikiloderma, 86% for alopecia, 75% for hypohidrosis, 56% for lymphoedema, 33% for pulmonary restriction or fibrosis and 28% for exocrine pancreatic insufficiency [69].

Skin and appendages. The poikiloderma (erythema of the cheeks, atrophy, telangiectasias and mottled pigmentation) appears in the first months, mainly on the face, worsens transiently with sun and improves with age [13]. It is associated with chronic erythematous and scaly lesions of the limbs, mild lymphoedema of the lower or upper limbs, sometimes complicated by cellulitis, digital sclerosis and mild palmoplantar keratoderma [13]. Biopsy shows epidermal atrophy, collagen sclerosis and elastic degeneration with elastic globules in the papillary dermis [7, 13].

Muscle and tendons. The contractures, most frequent in the triceps surae, shorten the Achilles tendons and cause varus feet; the biceps and the wrist extensors are also affected [13]. Weakness begins in the proximal muscles of the lower limbs and is accompanied by atrophy and sometimes scoliosis [13]. In the 2015 series, creatine kinase was normal in 3 of 8 patients and mildly raised in 5 (maximum 500 IU/L), and electromyography was normal or myopathic [67]. Muscle magnetic resonance imaging shows diffuse fatty infiltration of the legs with relative sparing of tibialis posterior and of the anterior compartment of the thighs, in particular vastus lateralis, with relative sparing of the posterior compartment, and may demonstrate involvement in asymptomatic patients [13, 67]. Biopsy shows extensive fatty infiltration, fragmented fascicles with normal or atrophic fibres with central nuclei and, sometimes, a secondary reduction in calpain [67].

Lung. In the 2015 series, all patients whose respiratory function was assessed had a restrictive pattern, partly due to respiratory muscle weakness; progressive interstitial fibrosis was not observed in children and occurred in 3 of 6 adults, who died at 30, 40 and 56 years, two of them 3 to 4 years after the first symptoms (progressive dyspnoea and dry cough) [67]. The histological pattern in the original family was usual interstitial pneumonia, with fibrosis of the oesophagus and mediastinal lymph nodes [6, 7]. A 44-year-old Japanese man had interstitial pneumonia with an unclassifiable pattern at autopsy [72].

Pancreas and liver. Exocrine pancreatic insufficiency begins in childhood, manifests as steatorrhoea and diarrhoea, with a risk of fat-soluble vitamin deficiency, and is confirmed by low faecal elastase; computed tomography showed severe pancreatic atrophy in one patient and autopsy of the original family extensive fatty infiltration of the pancreas [13, 67]. In a review of 30 patients, 11 had liver disease, from raised transaminases to fibrosis on biopsy; biopsies showed micro- and macrovesicular steatosis, lymphocytic ductulitis and loss of bile ducts, and one patient died of cirrhosis at 17 years [8]. The 44-year-old Japanese man had cirrhosis and died after severe hepatic encephalopathy [72].

Cancer. Three pancreatic adenocarcinomas have been described in adults, all with group 2 variants: at 64 years (French family of 2017), at 32 years and at 48 years (father of a patient in the 2025 series), which corresponds to 13% of the adults in the cohort, according to the authors [8, 15]. There is no age-specific risk estimate, and the number of adults followed is small.

Other systems. Renal failure, short dental roots, agenesis and enamel hypoplasia, hypoparathyroidism, hypothyroidism, cholelithiasis and splenomegaly in early childhood, and a motor axonal neuropathy in a 47-year-old woman have been described [15]. A 9-year-old boy with chronic mucocutaneous candidiasis, hypoparathyroidism, a Sjögren-like syndrome and pneumonitis had the variant NM_198947.4:c.1292T>C p.(Phe431Ser) de novo and had no pathogenic AIRE variants [70]. Cognitive development is normal [13]. Clinical expression depends on age: the skin dominates in infancy, contractures and myopathy in childhood and adolescence, and pulmonary fibrosis and pancreatic cancer in adulthood [52, 85].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the prenatal period, ultrasound may show forearm reduction defects, limb shortening and brachycephaly; in BGS, these findings identified affected fetuses from 14 weeks in at-risk pregnancies [2, 12]. A small thymus, growth restriction and craniosynostosis were the prenatal signs of the BGS case with severe combined immunodeficiency [59]. In the newborn, the combination of craniosynostosis and a thumb or radial defect suggests BGS, and a radial defect with patellar hypoplasia suggests RAPADILINO, especially in families of Finnish origin [4, 12]. A low TREC newborn screening result in a newborn with a radial defect should prompt consideration of a RECQL4 disorder among the syndromic causes of T lymphopenia [59, 62]. In the infant, the sign that leads to the diagnosis of RTS is facial erythema between 3 and 6 months, which extends to the limbs and buttocks and spares the trunk, especially when associated with low weight, feeding difficulties, vomiting or diarrhoea [2, 86]. In the child, established poikiloderma with sparse hair, eyelashes and eyebrows, dental and nail anomalies and proportionate short stature complete the picture [2]. Bilateral cataract in a child with poikiloderma points to RTS (type 1 if juvenile, type 4 if congenital and with microphthalmia and severe short stature) [14, 87].

4.2. Osteosarcoma as the presentation

Several patients were diagnosed only after osteosarcoma [3]. RTS should be considered in any child or adolescent with osteosarcoma, especially if there are skin changes, short stature or a radial defect, alongside other predisposition syndromes such as hereditary retinoblastoma, Li–Fraumeni syndrome and Werner syndrome [3, 47].

4.3. Warning and emergency signs

The signs that require immediate assessment are persistent bone pain, swelling or a mass in a limb, limping and pathological fracture (osteosarcoma) [1, 2, 37]; lymphadenopathy, unexplained fever or weight loss, especially in RAPADILINO and BGS (lymphoma) [12]; a skin lesion of unusual colour or texture that does not heal or that grows (skin carcinoma) [2]; pallor, bleeding or recurrent infections (cytopenias, myelodysplastic syndrome) [2, 62]; loss of visual acuity or leucocoria (cataract) [2]; and, in the infant, opportunistic infections such as Pneumocystis jirovecii pneumonia, which prompted the diagnosis of combined immunodeficiency in a patient with RTS [59]. There is no specific newborn screening; diagnosis through newborn screening has occurred only indirectly, through T lymphopenia [59].

4.4. When to suspect POIKTMP

POIKTMP should be considered in an infant with facial poikiloderma in the first 6 months, hypotrichosis and hypohidrosis with heat intolerance, especially if limb lymphoedema, chronic eczematous lesions, Achilles tendon contractures from 2 years, muscle weakness, steatorrhoea or raised transaminases appear [13, 67]. Suspicion is strengthened when a patient with a clinical diagnosis of RTS has negative RECQL4 testing and vertical inheritance or a sporadic case [8, 52]. In the adult, the combination of pulmonary fibrosis with a history of childhood poikiloderma, contractures and pancreatic insufficiency points to FAM111B [38, 67]. The signs that require rapid assessment are progressive dyspnoea and dry cough (fibrosis that may be fatal within 3 to 4 years), jaundice, ascites or gastrointestinal bleeding (advanced liver disease), fever in an infant with hypohidrosis, cellulitis over a limb with lymphoedema and, in the adult, weight loss or jaundice (pancreatic adenocarcinoma) [8, 13, 15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated scored criteria for a "definite", "probable" or "possible" diagnosis [3]. GeneReviews establishes the diagnosis in the presence of the classic rash (onset, extension and appearance described in section 3.2) and/or biallelic pathogenic variants in ANAPC1 or RECQL4 [2]. When the rash is atypical in appearance, distribution or pattern of onset and extension, a diagnosis of probable RTS requires two of the following findings: sparse hair, eyelashes or eyebrows; proportionate short stature; gastrointestinal disturbance in childhood (chronic vomiting and diarrhoea); dental anomalies (rudimentary or hypoplastic teeth, enamel defects, delayed eruption); dysplastic nails; hyperkeratosis, mainly plantar; bilateral juvenile cataract; skeletal anomalies (radial and ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation); and cancers (cutaneous and osteosarcoma) [2]. The 2023 review presents these criteria as a general requirement of poikiloderma with at least two additional findings [14]. For BGS, GeneReviews proposes suspicion in the presence of the combination of coronal craniosynostosis (confirmed by radiography or, preferably, computed tomography with three-dimensional reconstruction), radial ray defect (with radiography for minor forms), growth restriction and poikiloderma [12]. For RAPADILINO, the main criterion discriminating it from RTS is the absence of poikiloderma in a patient with a radial and patellar defect [14, 35].

5.2. Non-molecular investigations

There is no biochemical, enzymatic or functional test that confirms a RECQL4, ANAPC1, CRIPT or DNA2 disorder [33, 34]. A skeletal survey reveals anomalies in 75% of patients, many without clinical expression, and serves both diagnosis and as a baseline for later assessments [64, 80]. Slit-lamp ophthalmological examination detects cataract, and fundoscopy the retinal changes of type 3 [9]. Chromosomal instability (mosaic trisomies and isochromosomes of chromosomes 8, 7 and 2) has no standardised method and does not serve as a diagnostic test [3]. The chromosome breakage test with diepoxybutane or mitomycin C serves to exclude Fanconi anaemia, especially in BGS, and should be repeated in fibroblasts when it is negative in blood and suspicion persists [4, 12, 62]. The absence of increased sister chromatid exchanges distinguishes RTS from Bloom syndrome [2, 3].

5.3. Genetic testing: strategy

With a suggestive phenotype, GeneReviews recommends a multigene panel including ANAPC1, RECQL4 and the genes of the differential diagnosis; if only single-gene testing is available, start with RECQL4 when there are skeletal anomalies or osteosarcoma and with ANAPC1 when there is early juvenile cataract without skeletal defects or osteosarcoma [2]. With an atypical phenotype, the exome is the most used test and the genome an alternative [2]. Since 2023, panels should also include CRIPT and DNA2 [14, 47]. In BGS, RECQL4 is sequenced first and, if only one or no variant is identified, targeted deletion/duplication analysis is performed; when the phenotype is indistinguishable from other craniosynostoses, exome or genome sequencing is preferable [12]. In a French series of 39 patients referred for RECQL4 testing, no variant was found in the 12 patients with a BGS phenotype without poikiloderma, and clinical reassessment of the negative patients with suspected RTS led to another diagnosis in 7 of 17 (poikiloderma with neutropenia, hereditary sclerosing poikiloderma, craniosynostosis–anal anomalies syndrome and porokeratosis), in addition to a chromosomal abnormality and a TWIST1 variant [53]. Smith summarises the same conclusion: the yield of RECQL4 sequencing is low in patients with craniosynostosis and radial defect without poikiloderma [5].

5.4. Limits of the tests

Sequencing detects more than 99% of known RECQL4 variants and all 14 ANAPC1 variants described up to 2020, but these proportions refer to catalogued variants and are not equivalent to clinical sensitivity, because about 30% of patients with typical clinical features remained without a molecular diagnosis [2]. There are five concrete limits. First, the most frequent ANAPC1 variant, c.2705-198C>T, lies 198 bases into the intron, outside the usual capture of panels and exomes, so a negative panel or exome does not exclude RTS type 1 [2, 34, 88]. Second, the common DNA2 variant of RTS type 4, c.588-2214A>G, also deep intronic, was identified only by genome sequencing [36, 46]. Third, small deletions in the short introns of RECQL4 (for example, the 11-bp deletion in intron 8) escape panels that do not fully cover those introns; GeneReviews recommends including the intronic regions, the Larizza review recommends RNA analysis by RT-PCR for cases with only one allele and, in a 2025 case, only the genome identified the second allele [2, 3, 62]. Fourth, multi-exon deletions, such as the homozygous deletion of exons 13–18 described in a BGS patient, require copy-number analysis or genome sequencing [12, 63]. Fifth, the coexistence of a pathogenic variant and a variant of uncertain significance (VUS), or of two VUS, neither establishes nor excludes the diagnosis; in that situation, parental testing (segregation), RNA analysis and clinical reassessment are the next steps [12]. A single heterozygous ANAPC1 variant classified as a VUS in an adult with an RTS-like phenotype does not allow the diagnosis [89]. GeneReviews recommends banking DNA from probands without a molecular diagnosis [2].

5.5. Content of the report

The report should state the gene, the reference transcript with version (for RECQL4, NM_004260.4; for ANAPC1, NM_022662.4; for DNA2, NM_001080449.3), the HGVS c. and p. nomenclature, zygosity and phase (cis or trans) when known, classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, coverage of the relevant intronic regions and the ability to detect deletions [12, 57]. For intronic and splicing variants, the notation p.? is correct when there is no RNA study [57].

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

Once the family variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [2, 12]. Ultrasound at 16–18 weeks may show forearm reduction defects, but their absence does not exclude RTS, given the variability [2]. In BGS, serial ultrasound from 14 weeks detected limb shortening, radial hypo- or aplasia and brachycephaly in at-risk pregnancies [12]. Prenatal genome sequencing allowed the diagnosis of BGS with severe combined immunodeficiency before birth [59].

5.8. Diagnosis of POIKTMP

The diagnosis is established in a proband with early-onset poikiloderma and other findings, mainly contractures or muscle weakness, and a heterozygous pathogenic missense variant in FAM111B [13]. FAM111B sequencing detected the variant in all probands of the reference series (100%), which measures the proportion of variants detectable by the method and not the clinical sensitivity in a patient with clinical suspicion; deletion and duplication analysis identified no causal variant [13]. Poikiloderma panels usually include FAM111B with RECQL4, USB1 and FERMT1, and the exome is the usual route when POIKTMP has not been considered [13]. The report should state the transcript NM_198947.4, HGVS nomenclature, zygosity, parental origin (de novo or inherited) and ACMG/AMP class; a VUS outside the two hotspots requires family segregation and phenotypic correlation, and proteasome function tests and the type I interferon signature are research tools, not validated clinical tests [13, 15].

Non-molecular investigations help to recognise and stage the disease: skin biopsy shows the sclerodermiform pattern with changes in the elastic network; muscle magnetic resonance imaging shows fatty infiltration in the pattern described in 3.15, even in asymptomatic patients; muscle biopsy shows fibro-fatty replacement; faecal elastase confirms pancreatic insufficiency; pulmonary function tests with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), supplemented by high-resolution computed tomography, assess the lung [13, 67]. Once the variant has been identified in the family, prenatal diagnosis and preimplantation genetic testing are possible [13].

6. Differential Diagnosis

6.1. Hereditary poikilodermas and other genodermatoses

Poikiloderma, the combination of hyper- and hypopigmentation, atrophy and telangiectasias, occurs in several genodermatoses, and what distinguishes RTS is the temporal and topographical pattern: facial erythema in infancy, extension to the extensor surfaces and buttocks, and sparing of the trunk [2, 3, 91]. The table brings together the differential diagnoses of GeneReviews and of the Larizza review.

Poikiloderma with neutropenia is the differential diagnosis most often confused with RTS: before USB1 testing, several patients were diagnosed as RTS, dyskeratosis congenita or Kindler syndrome [90]. It is distinguished by the rash that begins on the limbs and spreads to the trunk, by chronic neutropenia with sinopulmonary infections and bronchiectasis, by pachyonychia and by the absence of radial defects [3, 90]. Bloom syndrome, Fanconi anaemia, xeroderma pigmentosum, Kindler syndrome and ataxia-telangiectasia also enter the differential. An adult with malar erythema, sparse hair and dental anomalies and a heterozygous ANAPC1 VUS shows that the RTS-like phenotype in adults without typical poikiloderma often remains undiagnosed [89].

6.2. Craniosynostosis with radial defect (differential diagnosis of BGS)

The diagnosis of BGS should be reserved for patients with craniosynostosis and radial defect in whom Fanconi anaemia, Roberts syndrome, Saethre–Chotzen syndrome, SALL4 disorders and valproate exposure have been excluded, because most patients published under that label before 2006 had another disease [5, 14, 50]. The general diagnostic approach to longitudinal radial deficiencies rests on dedicated classifications and on an aetiological algorithm starting from the thumbs.

6.3. Differential diagnosis of RAPADILINO

In the original description, the differential diagnoses were the classic syndromes with radial defect: TAR syndrome, Holt–Oram syndrome, VATER association and Fanconi anaemia [14]. The absence of thrombocytopenia, heart defect, vertebral anomalies and chromosome breakage, the presence of patellar hypoplasia and diarrhoea, and Finnish origin point to RAPADILINO [2, 14].

6.4. Differential diagnosis of types 3 and 4

Type 3 overlaps with microcephalic primordial dwarfism (Seckel, microcephalic osteodysplastic primordial dwarfism) and type 4 with Seckel 8 primordial dwarfism, also caused by DNA2 [10, 14]. Generalised poikiloderma and congenital cataract point to RTS type 4, and neurological involvement with retinal changes to type 3 [14]. CtIP variants (Seckel and Jawad syndromes) have been described with overlapping presentations [14].

6.5. Osteosarcoma in children

In the face of a paediatric osteosarcoma, the predisposition syndromes to consider include Li–Fraumeni syndrome, hereditary retinoblastoma, Werner syndrome and RTS [3]. Heterozygous loss-of-function RECQL4 variants are over-represented in paediatric osteosarcoma, but do not constitute a diagnosis of RTS [58].

6.6. Differential diagnosis of POIKTMP

Recessive poikilodermas have no tendon contractures, myopathy or exocrine pancreatic insufficiency, which separates them from POIKTMP [13]. Vertical inheritance and the absence of RTS-type skeletal and dental defects are the other clinical discriminators [13, 67].

The differential diagnosis of familial pulmonary fibrosis centres on telomere and surfactant genes; the 2023 European Respiratory Society (ERS) statement treats the remaining genes, including the syndromic ones, as a case-by-case assessment guided by phenotype [38]. In a child with poikiloderma, contractures and myopathy, juvenile dermatomyositis and myopathies with contractures enter the clinical differential diagnosis, but the sources consulted do not compare them directly with POIKTMP.

7. Treatments and Risk Management Strategies

7.1. Principles and sources

There is no disease-modifying treatment for any of the forms in the class, nor any randomised trial in RECQL4, ANAPC1, CRIPT or DNA2 disorders [33, 34]. The available recommendations are expert consensus: the GeneReviews entries for RTS (2020 revision) and BGS (2018) [2, 12], the 2017 recommendation of the American Association for Cancer Research (AACR) childhood cancer predisposition working group for DNA repair disorders [64] and its 2024 update for genomic instability disorders [37]. No specific European guidelines were identified. Care is multidisciplinary and long-term, with genetics, dermatology, ophthalmology, orthopaedics, oncology and dentistry, and in type 1 and type 4 also endocrinology [3, 14, 64].

7.2. Assessment after diagnosis

7.3. Skin

Photoprotection (avoiding excessive sun and heat exposure, protective clothing and sunscreen) reduces worsening of the erythema and the risk of skin cancer, although carcinomas also arise on unexposed skin [1, 2, 64]. Pulsed dye laser has been used to improve the telangiectatic component, for cosmetic purposes [2, 3, 64]. The 2017 AACR recommendation allows retinoids for hyperkeratosis, relying on an extrapolation from the use of etretinate in skin neoplasms of renal transplant recipients; none of the sources consulted gives a dose, duration or specific evidence in RTS, so this is off-label use with indirect evidence [64]. Lesions suspicious for carcinoma are treated by the usual dermatological methods [2].

7.4. Eyes, teeth and skeleton

Cataract with visual impact is an indication for surgery [2, 3]. In dentistry, the short roots and the tendency to root resorption make it advisable to avoid factors that increase apical loss, such as masticatory overload, fixed prostheses, caries and periodontal disease [3]. Radial ray and thumb defects are treated with orthopaedics and occupational therapy; pollicisation of the index finger restored functional pinch in several patients without a thumb, although many children function without surgery [12]. Osteopenia and fractures warrant DXA and attention to calcium metabolism [2, 56]; the sources consulted do not describe pharmacological treatment of bone disease specific to RTS.

7.5. Craniosynostosis in BGS

Craniosynostosis is treated by neurosurgery and craniofacial surgery teams; when it is bilateral, surgery is usually performed before 6 months [12].

7.6. Growth and growth hormone

GeneReviews does not recommend GH in patients with short stature and normal GH levels, because of the theoretical potential for tumorigenesis; with documented deficiency, standard treatment is appropriate [2]. In type 1 and type 4, GH deficiency is frequent and several patients have been treated [14]; a Turkish patient with RTS type 4 had the response to recombinant GH described in 2025 [36]. The sources consulted give no dosing schedule specific to RTS: with documented deficiency, GeneReviews refers to standard treatment of GH deficiency, and the decision to treat weighs the theoretical potential for tumorigenesis that GeneReviews itself invokes [2].

7.7. Treatment of osteosarcoma and other cancers

Patients with RTS and cancer should receive standard chemotherapy and/or radiotherapy regimens, with doses modified only if significantly increased toxicity arises [2, 37]. This recommendation rests on an international series of 12 patients with osteosarcoma (median 10 years): histological response and outcome were similar to those of large series of sporadic osteosarcoma (8 alive without disease, 4 dead from cancer), but 5 patients required dose modification, mainly for mucositis with doxorubicin [82]. Survival at 5 years was 60–70%, similar to that of patients without RTS [3]. The Larizza review adds that cisplatin, to which RECQL4-deficient fibroblasts are less sensitive, may replace doxorubicin without apparently increased toxicity, and GeneReviews records patients with increased toxicity after high-dose methotrexate, with profiles varying from patient to patient [2, 3]. This practice differs from Bloom syndrome, in which the 2024 AACR update recommends dose reduction and regimens without alkylating agents [37]. The patient should be treated by paediatric oncology with experience in osteosarcoma; in BGS, GeneReviews recommends an oncologist familiar with the type of cancer [12].

7.8. Haematological disorders and immunodeficiency

Cytopenias and myelodysplastic syndrome are treated in the standard way, by a haematologist familiar with RTS; allogeneic bone marrow transplantation has been described in RTS with myelodysplastic syndrome and cord blood transplantation in RTS with combined immunodeficiency [2, 3]. In the case of spontaneous regression of a monosomy 7 clone, transplantation was postponed because of prematurity and the lack of a matched donor, and the decision to monitor instead of transplanting was presented by the authors as exceptional, to be taken only with experts in monosomy 7 predisposition syndromes [62]. In severe combined immunodeficiency, the radiosensitivity of RECQL4-deficient cells limits conditioning: a boy with BGS and severe combined immunodeficiency was treated at 6 months with an unmanipulated bone marrow infusion from an HLA-identical sibling, without conditioning, and at 11 months had normal T lymphocytes, normal TREC, a polyclonal repertoire and almost complete T and NK chimerism, while continuing immunoglobulin replacement [59]. Another patient with RTS and combined immunodeficiency received unrelated cord blood after reduced-intensity conditioning (cyclophosphamide, fludarabine and antithymocyte globulin), with grade IV acute graft-versus-host disease and complete chimerism at one year [59]. These are isolated reports, not protocols; transplantation does not correct the non-haematopoietic manifestations or the cancer predisposition [59].

7.9. Agents and circumstances to avoid

Excessive sun and heat exposure [2, 12], GH in patients without deficiency [2] and unnecessary ionising radiation should be avoided; when choosing radiographs and computed tomography, the risks and radiation-free alternatives should be discussed with the family, given the DNA repair defect [3, 37]. The sources consulted do not identify specifically contraindicated drugs.

7.10. Anaesthesia and the perioperative period

There is no anaesthetic guideline for RTS, and Orphananesthesia had no entry for the disease in August 2025 [47]. Published experience, in a case of tibial osteosarcoma resection in a 10-year-old child and in reports of anaesthesia for endoscopy and cataract surgery, identifies as problems the difficult airway (micrognathia, retrognathia, high palate, dental anomalies, frontal bossing), difficult vascular access due to forearm malformations and fragile skin, the impossibility of monitoring neuromuscular blockade at the thumb when it is absent, positioning, and protection of the skin against adhesives and pressure [47]. Preoperative assessment should include a blood count (haematological anomalies), electrolytes and hydration in patients with gastrointestinal involvement, and respiratory assessment [47]. In the reported case, the strategy of inhalational induction, videolaryngoscopy, ultrasound-guided access and epidural analgesia proceeded without complications [47].

7.11. Pregnancy, fertility and transition

Fertility is reduced in both sexes, but there are women with normal pregnancies and men with offspring [1, 2]. The sources consulted do not describe specific obstetric complications or recommendations for pregnancy. Transition to adult care should maintain dermatological surveillance, because skin carcinomas have a mean age of 34 years, as well as ophthalmological and bone follow-up [2, 3].

7.12. Regulatory status and research

A search of ClinicalTrials.gov in October 2026 found no therapeutic trials. The registered studies are observational or physiological:

There are no trials with efficacy outcomes or comparisons between treatments, so no therapeutic recommendation is supported by trial evidence. A negative registry search does not exclude unregistered studies.

The developments of the last twelve months are case reports and preclinical studies: the first report of severe combined immunodeficiency in BGS treated with marrow infusion without conditioning (case report, 2026) [59]; spontaneous regression of a monosomy 7 clone in a RECQL4 syndrome (case report, 2025) [62]; neonatal diagnosis of BGS without craniosynostosis by rapid genome sequencing (case report, 2026) [63]; founder RECQL4 variants in Turkey and Ecuador (case series, 2026) [60, 61]; the first RTS type 4 outside Brazil and Portugal (case report, 2025) [36]; the first description of anaesthesia for major orthopaedic surgery (case report, 2025) [47]; and, in a mouse model, the demonstration that an N-terminal fragment without the helicase domain suffices for replication (preclinical, 2026) [54]. None has resulted in an authorisation, regulatory opinion or change in recommendations.

7.13. Divergences between recommendations

GeneReviews, supported by the 2017 AACR recommendation, considers that imaging screening for osteosarcoma is not recommended routinely and that radiography should be performed immediately in the presence of symptoms [2, 64]. The 2024 AACR update allows that whole-body magnetic resonance imaging (WBMRI) "could be used" in patients with RECQL4 variants, after discussing with the family the uncertain benefit of early detection, the false positives caused by non-malignant skeletal anomalies and the need for general anaesthesia in young children, given that the median onset of osteosarcoma is around 10 years [37]. The two recommendations agree on the baseline skeletal survey by 5 years, family education about alarm signs and annual dermatological, ophthalmological and physical examinations [2, 37, 64]. Neither recommends imaging surveillance for type 1, type 3 or type 4, as no cases of osteosarcoma have been described in these groups [14].

7.14. Treatment of POIKTMP

There is no disease-modifying treatment and no clinical trials; the GeneReviews recommendations address the manifestations, and the remaining approaches rely on case reports and on extrapolations from other fibrosing diseases [13]. The initial assessment includes dermatological examination, physiotherapy assessment (optional muscle MRI), respiratory assessment with pulmonary function tests, faecal elastase if there is steatorrhoea, transaminases, alkaline phosphatase and gamma-glutamyltransferase, growth and nutrition, full blood count with differential, ophthalmological examination and a genetics clinic appointment [13].

Progressive pulmonary fibrosis. The 2023 ERS statement recommends antifibrotics, in accordance with international guidelines, for patients with idiopathic or progressive pulmonary fibrosis, including those with monogenic disease, and allows lung transplantation in advanced monogenic forms [38]. POIKTMP has not been studied in any trial, so the use of nintedanib (Ofev®) is a phenotypic extrapolation. The FDA label authorises it only in adults with idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung disease with a progressive phenotype and systemic sclerosis-associated interstitial lung disease, at a dose of 150 mg twice daily in adults, about 12 hours apart and with food, maximum 300 mg/day, reduced to 100 mg twice daily in mild hepatic impairment (Child–Pugh A) or to manage adverse effects, and does not recommend it in moderate or severe hepatic impairment [100]. In the EU, Ofev® has the same indications in adults and was extended, following a CHMP opinion of December 2024, to children aged 6 to 17 years with clinically significant progressive fibrosing interstitial lung disease, with weight-based dosing: 50 mg twice daily from 13.5 to 22.9 kg, 75 mg from 23.0 to 33.4 kg, 100 mg from 33.5 to 57.4 kg and 150 mg from 57.5 kg; it has not been studied below 13.5 kg [101]. The frequent liver disease in POIKTMP constrains its use, because nintedanib requires liver tests before and during treatment and is not recommended in moderate and severe forms [100, 101].

Immunosuppression. Two reports describe a response to immunosuppressants, without value as a recommendation. In a 44-year-old Japanese man, prednisolone 40 mg/day improved the symptoms and the interstitial pneumonia opacities within 2 weeks, but the patient later died after hepatic encephalopathy, bacterial pneumonia and pulmonary oedema [72]. In a 9-year-old boy with hepatitis, myositis and pneumonitis, azathioprine 2 mg/kg/day, started with normal thiopurine methyltransferase activity, resolved the cough, normalised the transaminases at 18 months and improved the skin and myalgias, until haematological toxicity appeared [70]. In pulmonary fibroses associated with short telomeres, the ERS reports a worse course with immunosuppression, a finding that has not been studied in POIKTMP [38].

Transplantation. In the Italian patient with end-stage cirrhosis, liver transplantation was considered and ruled out because of the severity of comorbidities [8]. The sources consulted do not describe lung or liver transplants in patients with POIKTMP.

Agents and circumstances to avoid. Excessive sun exposure worsens the rash and heat is poorly tolerated because of hypohidrosis [13].

Research and new developments. A search of ClinicalTrials.gov in November 2026 identified no therapeutic trials targeting POIKTMP; the 2023 North American patient was assessed under NIH natural history protocols (NCT01386437 and NCT03206099) [70]. The most recent data are preclinical: ubiquitin–proteasome system dysfunction with a type I interferon signature in patient cells (2025), proposed by the authors as a therapeutic pathway and biomarker [15], and the regulation of telomere length and the link to the nuclear pore (2023) [68]. Specific inhibition of the catalytic activity of FAM111B has been proposed as a future strategy, with early initiation, but there are no compounds in clinical study [85]. No gene therapy studies have been published in the sources consulted; the dominant mechanism, by gain of function or dominant negative effect, would make allele-specific silencing the theoretically appropriate strategy, and gene replacement would not correct the effect of the mutant allele [13, 66].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

All forms in the class are autosomal recessive [2, 12, 14]. The parents of a proband with confirmed biallelic variants are obligate heterozygotes, and molecular testing of both is recommended to confirm the phase of the variants and to calculate risk reliably; no de novo variants have been described in RTS, although they occur in recessive disorders at low frequency [2]. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier [2, 12]. The children of an affected individual are all obligate carriers, and the risk of their having affected children depends on the probability that the partner is a carrier, very low in the general population, except where founder variants exist: western Austria and the Mennonite and Amish communities for ANAPC1, Finland for the RAPADILINO variant, Ashkenazim for c.2464-1G>C, and the Brazilian and Portuguese populations for the DNA2 intronic variant [2, 14, 44, 46, 59]. The proband's aunts and uncles have a 50% chance of being carriers [2]. Consanguinity, present in the original descriptions and in many families with more than one affected member, increases the risk of recurrence in subsequent generations [3, 5].

8.2. Carriers

Heterozygotes are asymptomatic; the RTS GeneReviews entry stresses that the question has not been studied in detail [2]. In the international RTS registry, the prevalence of cancer in relatives heterozygous for RECQL4 did not differ from the general population (2.4% versus 5.6%) [65]. The over-representation of RECQL4 loss-of-function variants in children with osteosarcoma [58] does not translate into a surveillance recommendation for carriers in any of the guidelines consulted [37, 64]. Carrier testing in relatives requires prior identification of the family variants [2].

8.3. Prenatal and preimplantation diagnosis

With the family variants identified, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss these options is before pregnancy [2, 12]. The anomaly scan may detect forearm defects and, in BGS, brachycephaly from 14 weeks, but a normal scan does not exclude RTS [2, 12]. Severe fetal forms have been described, with extreme limb hypoplasia and pulmonary hypoplasia, leading to neonatal death and termination of pregnancy [84], as well as terminated pregnancies with BGS diagnosed by molecular testing [12]. Perspectives on prenatal diagnosis vary among families and professionals, and the decision is personal [12]. In patients without a molecular diagnosis, DNA should be banked [2, 12].

8.4. Counselling

Counselling should explain the genetic heterogeneity and its practical consequences: the documented risk of osteosarcoma in type 2, cataract in type 1 and type 4, neurological involvement in type 3 and the risk of lymphoma in RAPADILINO [2, 14, 35]. In a patient with a clinical RTS phenotype and negative molecular testing, the risk of osteosarcoma cannot be ruled out, because the tests may not have detected intronic RECQL4 variants [3, 62]. Young adults who are affected, carriers or at risk should be offered counselling on risks to offspring and reproductive options [2]. The sources consulted do not specifically address testing of minors in this disease; as the manifestations appear in the first year and the baseline skeletal survey is performed by 5 years, a sibling with compatible signs is assessed as a possible patient and not as a carrier [2, 64].

8.5. Counselling in POIKTMP

POIKTMP is autosomal dominant: about 50% of probands inherited the variant from an affected parent and about 50% have a de novo variant; in the 2025 cohort, 17 cases were de novo and 17 inherited [13, 15]. Each child of an affected individual has a 50% chance of inheriting the variant, and all who inherit it are expected to manifest the disease, with unpredictable severity within the family [13]. In an apparently isolated case, testing of the parents is recommended; if the variant is present in neither, the risk to siblings is estimated at about 1% owing to the possibility of germline mosaicism [13]. A parent with mild signs (for example, residual poikiloderma in adulthood) may carry the variant, so clinical examination of the parents is part of the assessment [13, 15]. Once the variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible, and counselling should be offered to affected young adults before pregnancy [13]. Counselling of adults should mention the risk of pulmonary fibrosis and the cases of pancreatic adenocarcinoma, with no validated risk estimate and no established oncological surveillance protocol [15, 69].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

There are no population prevalence studies of RTS; the prevalence and carrier frequency are unknown [2, 3]. The available figures are counts of published cases: about 300 patients in 2010 [3], fewer than 500 described in the English-language literature in 2020 [2] and, in the Orphanet count, about 500 patients with RTS, of whom about 200 with type 2 and about 100 with type 1, with a prevalence class <1/1,000,000 [33, 34]. For type 3 there were fewer than 10 published patients and for type 4 nine (eight of Brazilian or Portuguese origin and one Turkish) [9, 36]. BGS has fewer than 40 published patients and a prevalence probably below 1/1,000,000 [12]. The sex ratio varies between series (1:1, a female predominance of 1.4:1 and a male predominance of 2:1, the latter in the Houston cohort) [3, 75]. These values reflect the publication and recognition of cases and underestimate the true frequency, because patients with mild or atypical forms may go unnoticed [3].

9.2. Founder populations and geography

RTS has been described in all ethnic groups [2, 3]. The known founder effects are as follows. In Finland, the RECQL4 variant c.1390+2del has an allele frequency of 108 in 24,962 alleles in gnomAD (0.43%), much higher than in non-Finnish Europeans, and accounts for 20 of 34 alleles (59%) in the 17 published probands with RAPADILINO; the 2010 review estimated a carrier frequency of 1 in 137 in Finland [3, 14]. The ANAPC1 variant c.2705-198C>T is homozygous in Amish patients and has been associated with founders in western Austria and in Mennonite communities [2, 14, 44]. The RECQL4 variant c.2464-1G>C has a frequency of 0.31% in Ashkenazim [59]. In Turkey, c.2415_2419del was found in three unrelated families from the same region, and in Ecuador c.3236G>T p.(Ser1079Ile) was found in three unrelated patients, including one adopted in Italy [60, 61]. The c.1573del variant has a wide distribution, on a probably European haplotype [3].

9.3. Portugal and Brazil

RTS type 4 was described by a São Paulo group in six Brazilian probands and in a sibship of Swiss–Portuguese ancestry; the DNA2 intronic variant was present in all of them and in the Portuguese father of the European siblings, suggesting a common founder of Portuguese origin or one shared by the two populations [14, 46]. The same review presents unpublished data from the Brazilian group on 43 patients with RECQL4 [14], and an Ecuadorian review cites a Brazilian cohort in which 6 of 12 patients assessed had biallelic RECQL4 variants, with recurrent variants such as c.1711dup (published designation p.(Ile571Asnfs*27); in NM_004260.4, c.1711dup translates to p.(Ala571GlyfsTer12)) and deletions of exons 4 and 15 [60]. A consanguineous Brazilian family with three siblings affected by squamous cell carcinoma on unexposed skin is described in GeneReviews [2]. In Portugal, a girl of African origin with RTS type 2 was described in 2023 by teams from Hospital de Santa Maria (Lisbon) and Hospital Universitario La Paz (Madrid), both members of ERN-BOND (precocious puberty and anal stenosis), and reassessed in 2025 in relation to anaesthesia for resection of a tibial osteosarcoma (section 10) [47, 78]. No Portuguese or Brazilian prevalence data were found.

9.4. Special populations

Diagnosis is later in patients with dark skin, in whom poikiloderma may be mistaken for dermatitis [77], and in populations with limited access to molecular testing, as shown by the Ecuadorian cases diagnosed only clinically until 2012 [60]. Patients with an atypical phenotype, such as BGS without craniosynostosis or RTS type 4 with a deep intronic variant, benefited from genome sequencing and international collaborations [36, 63].

9.5. Reference networks and patient organisations

In Europe, the relevant European reference network for dermatology is ERN-Skin, whose thematic group "skin disorders associated with DNA repair defects and photosensitivity" covers this class, although the network's page does not list individual diseases [39]. For the forms with skeletal dysplasia, the Portuguese and Spanish teams that described a case of RTS type 2 belong to ERN-BOND, the European network for rare bone diseases [78]. The Rothmund-Thomson Syndrome Foundation (rtsplace.org) provides information to patients and families and is cited by GeneReviews and by the AACR recommendations [2, 37, 64]. For BGS, GeneReviews lists the Children's Craniofacial Association and the British association REACH, dedicated to upper limb differences [12]. The largest international RTS registry, analysed by researchers at Baylor College of Medicine, served as the basis for the study of cancer in heterozygotes, and the same institution conducted the bone disease study [56, 65, 81].

9.6. Epidemiology of POIKTMP

The prevalence is unknown and Orphanet classifies it as below 1/1,000,000 [32]. By 2021, 36 patients had been described, and 41 by 2025; before the 2025 series, the 37 known cases belonged to 21 families, with 16 sporadic de novo cases and 5 families with dominant transmission [15, 69]. The patients described originate from South Africa (family of European ancestry), France, Italy, Algeria, Morocco, Ireland, the Dominican Republic, Canada, Mexico, China, Japan, Germany and Norway, indicating a distribution without an identified founder population [8, 15, 51, 72]. GeneReviews considers the disease probably underdiagnosed [13]. The sources consulted do not include patients from Portugal or Brazil. In Europe, in addition to ERN-Skin, EURO-NMD, for neuromuscular involvement, and ERN-LUNG, for pulmonary fibrosis, are relevant [39–41]. Information for families is available on MedlinePlus Genetics; the sources consulted do not identify a specific patient organisation [13, 102].

10. Illustrative Clinical Case

A girl of African origin, followed at Hospital de Santa Maria in Lisbon, with RTS type 2 confirmed by a nonsense variant and an intronic variant in RECQL4, was described in 2023 because of precocious puberty, treated with a gonadotrophin-releasing hormone analogue, and anal stenosis, a rare finding in RTS [78]. The authors stressed that the second allele was found only because deep intronic variants were sought after the coding regions and exon–intron boundaries had been negative [78].

At 10 years and 10 months, weighing 20 kg and measuring 123 cm (both below the 3rd centile), the patient was described again in 2025 by anaesthesiologists from the Unidade Local de Saúde de Santo António in Porto, in relation to anaesthesia for resection of an osteosarcoma of the right tibia [47]. Nine months earlier she had started to limp; radiography showed a tibial mass and, shortly afterwards, she sustained a pathological fracture in a fall. Imaging and biopsy confirmed osteosarcoma, positron emission tomography showed no metastases and she received neoadjuvant chemotherapy [47]. Examination showed short stature, bilateral aplasia or hypoplasia of the forearm bones with mesomelic shortening and bowing, absent thumbs (the right, hypoplastic, had been removed), radial deviation of the left wrist (the right surgically corrected), fifth-finger clinodactyly, dysplastic nails, overlapping toes, poikiloderma of the face, buttocks, genital region and limbs, a long face, high forehead, depressed nasal bridge, hypoplastic alae nasi, high palate, micrognathia, retrognathia and hypoplastic, conical and crowded teeth, with several extractions for caries; she had sparse hair, eyelashes and eyebrows, which disappeared with chemotherapy, and mild intellectual disability, and was on triptorelin for precocious puberty [47]. Figures 1 (upper limb anomalies and poikiloderma) and 2 (craniofacial and dental anomalies) of the article are available at https://pmc.ncbi.nlm.nih.gov/articles/PMC12666488/figure/FIG1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC12666488/figure/FIG2/ [47].

Preoperative tests and echocardiography were normal. The team anticipated a difficult airway, difficult vascular access, difficulty with positioning, skin fragility and bleeding. Inhalational induction with sevoflurane was performed before venous access, placed in a saphenous vein at the ankle; intubation with a hyperangulated-blade videolaryngoscope succeeded at the first attempt; the arterial catheter was possible only in the femoral artery, under ultrasound guidance, after failed attempts in the upper limbs; neuromuscular blockade monitoring was not possible owing to the absence of thumbs; and analgesia combined total intravenous general anaesthesia with a lumbar epidural catheter [47]. The surgery (resection with reconstruction by fibular centralisation) lasted 3 hours and 40 minutes, with an estimated blood loss of 50 mL, without instability; the patient was extubated uneventfully, monitored in an intermediate care unit and discharged on the eighth day [47].

The case brings together the elements that define risk in type 2: a severe radial ray defect, poikiloderma, dental anomalies and an osteosarcoma of the long bones at 10 years, an age close to the median described [37, 82]. The presentation with limping and pathological fracture illustrates the alarm signs that the guidelines say should be taught to families [37, 64]. The anaesthetic choices are those of a single case and do not constitute a protocol; the authors argue for the development of specific anaesthetic recommendations for RTS [47].

10.1. Complementary case: POIKTMP with end-stage liver disease

An Italian boy, the son of healthy non-consanguineous parents, had recurrent eczema and photosensitivity with a vesicular eruption from 2 months and, later, hypochromic atrophic macules on the face and neck and diffuse telangiectasias; in view of the poikiloderma, RTS was suspected, but RECQL4 testing was negative [8]. From 4 years, muscle weakness and atrophy set in, with contractures with ulnar deviation of the wrists and finger flexion and retraction of the Achilles tendons; muscle biopsies at 4 and 10 years showed progressive fibrosis and fatty infiltration, and MRI at 7 and 11 years increasing fatty replacement of the thighs and legs; he lost ambulation [8]. Leg lymphoedema appeared at 5 years, with recurrent skin infections. Liver enzymes had been abnormal since the first year; biopsy at 2 years showed a ductopenic syndrome and the one 4 years later chronic cholestasis with biliary fibrosis and micro- and macrovesicular steatosis; at 6 years he had hypersplenism due to portal hypertension, treated with variceal ligation, and from 13 years coagulopathy, hyperammonaemia and refractory ascites [8]. At 16 years he had a severe restrictive pattern (FVC 31% of predicted). Trio exome sequencing identified FAM111B NM_198947.4:c.1879A>G p.(Arg627Gly) de novo. Liver transplantation was ruled out because of the severity of comorbidities and the patient died at 17 years of liver failure; the progression of lymphoedema, contractures, cachexia and ascites is illustrated in figure 1 of the article, the liver histology in figure 2 and the ultrasound and tomographic progression to cirrhosis in figure 3 [8]. The authors proposed screening the liver from the first month of life in patients with FAM111B variants, a recommendation not included in GeneReviews, which indicates annual liver assessment [8, 13].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Without cancer, life expectancy appears normal, despite the signs of premature ageing [2, 3]. Prognosis depends on the genetic type: in type 2, osteosarcoma affects about 30% of patients, with a median onset of 10–11 years and an estimated probability of about 50% by 20 years and over 60% by 40 years, and metastatic osteosarcoma is the main cause of death [2, 14, 37]. Treated with conventional protocols, osteosarcoma in RTS has a response and survival (60–70% at 5 years) similar to those of sporadic osteosarcoma [3, 82]. Skin carcinomas (about 5%, mean of 34 years) weigh on adult life in types 1 and 2 [2]. In RAPADILINO, 6 of 15 Finnish patients had lymphoma or osteosarcoma [35]. In BGS, older series recorded unexpected deaths in the first year, and severe fetal forms may be lethal [5, 84]. Types 3 and 4 are too recent for prognostic data; one patient with CRIPT died of pneumonia in childhood [14].

11.2. Surveillance

The sources do not define intervals for surveillance blood counts or for DXA, and none recommends oncological surveillance for heterozygous carriers [2, 37, 65].

11.3. Long-term follow-up

Dermatological surveillance continues into adulthood, when skin carcinomas are concentrated, and follow-up after osteosarcoma should take into account the possibility of second neoplasms, although the risk has not been quantified [2, 3]. The team should include dermatology, ophthalmology, orthopaedics, oncology and dentistry, with lifelong follow-up [3, 64].

11.4. Prognosis and surveillance of POIKTMP

Prognosis depends on the lung, liver and pancreas. In the 2015 series, pulmonary fibrosis occurred in half of the adults assessed and caused death at 30, 40 and 56 years, in two cases 3 to 4 years after the first symptoms [67]. Liver disease led to death at 17 years in a patient with cirrhosis and contributed to the death of a man diagnosed at 44 years with interstitial pneumonia [8, 72]. The three pancreatic adenocarcinomas occurred at 32, 48 and 64 years [8, 15]. Severe myopathy, with loss of ambulation from 3 years in one patient, affected 13% of the 2025 cohort [15]. Patients with group 1 variants appear to have fewer severe complications, without statistical confirmation [15, 69]. Facial poikiloderma improves in adulthood [13].

The sources do not define surveillance for pancreatic adenocarcinoma or for pulmonary fibrosis before symptoms beyond the annual tests, and the intervals are based on expert consensus [13, 15].

12. Summary and Final Considerations

Rothmund–Thomson syndrome is an autosomal recessive genodermatosis defined by poikiloderma that begins in infancy on the face, extends to the extensor surfaces and buttocks and spares the trunk, accompanied by sparse hair, eyelashes and eyebrows, short stature and dental, nail and skeletal anomalies. It is a genetic class: type 2, due to RECQL4, is the most frequent and the only one with documented osteosarcoma, in about 30% of patients and with a median onset close to 10 years; type 1, due to ANAPC1, is associated with juvenile cataract and GH deficiency; type 3, due to CRIPT, with microcephaly, neurodevelopmental delay and epilepsy; and type 4, due to DNA2, with congenital cataract, microphthalmia and severe growth retardation, with a founder variant shared by Brazilian and Portuguese patients. RECQL4 also causes RAPADILINO, without poikiloderma and with a risk of lymphoma, and Baller–Gerold syndrome, with craniosynostosis and radial defect, in a spectrum without sharp genotypic boundaries.

The diagnosis is clinical, based on the poikiloderma, and is confirmed by molecular testing, but the most frequent ANAPC1 and DNA2 variants are deep intronic and those of RECQL4 include deletions in short introns, so a negative panel or exome does not exclude the disease and genome sequencing or RNA analysis is often required. The main differential diagnosis is poikiloderma with neutropenia due to USB1, followed by Bloom syndrome, Fanconi anaemia, dyskeratosis congenita, Kindler syndrome and xeroderma pigmentosum; in craniosynostosis with radial defect, BGS is accepted only after Fanconi anaemia, Roberts syndrome, Saethre–Chotzen syndrome, SALL4 disorders and valproate embryopathy have been excluded.

There is no disease-modifying treatment. Management rests on photoprotection, laser for telangiectasias, surgery for cataract and malformations, annual dermatological, ophthalmological and clinical surveillance, a baseline skeletal survey by 5 years in patients with RECQL4 and family education on the signs of osteosarcoma. Recommendations diverge on whole-body magnetic resonance imaging, allowed by the AACR in 2024 after shared decision-making and not recommended routinely by GeneReviews. Osteosarcoma is treated with conventional doses, monitoring for mucositis with doxorubicin, and has outcomes similar to those of sporadic osteosarcoma. The combined immunodeficiency and monosomy 7 clones described in 2025 and 2026 broaden the haematological spectrum and require transplant decisions adapted to radiosensitivity. Genetic counselling follows the recessive model, with attention to the founder populations of Finland, the Amish and Mennonite communities, Ashkenazim, Turkey, Ecuador, and Brazil and Portugal.

Hereditary fibrosing poikiloderma (POIKTMP), due to heterozygous missense variants in FAM111B, is the dominant differential diagnosis of RTS: it begins with facial poikiloderma in the first months, hypotrichosis and hypohidrosis, and is distinguished by tendon contractures, myopathy with fatty infiltration, exocrine pancreatic insufficiency and liver disease, with pulmonary fibrosis and pancreatic adenocarcinoma in adulthood. Half of the cases are de novo and the risk to offspring is 50%. Treatment is directed at the manifestations (photoprotection, thermal control, physiotherapy and surgery for contractures, pancreatin), with annual surveillance of the skin, muscle, respiratory function, liver, blood count and eyes, and nintedanib is an option by extrapolation in progressive pulmonary fibrosis.

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