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Year : 2020  |  Volume : 24  |  Issue : 1  |  Page : 5-12

Rothmund-Thomson syndrome: A review of clinical and molecular aspects

Department of Internal Medicine, Salmaniya Medical Complex, Manama, Bahrain

Date of Submission29-Jun-2019
Date of Acceptance20-Aug-2019
Date of Web Publication27-Mar-2020

Correspondence Address:
Dr. Manahel Mahmood Alsabbagh
Building 293, Road 2904, Manama 329
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdds.jdds_34_19

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Introduction: Rothmund-Thomson syndrome (RTS) is a rare genodermatosis which manifests a wide array of symptoms affecting skin and skin appendages. The first two cases were reported in 1957. Purpose: To present a comprehensive clinical and molecular perspective of RTS. Methods: A clinical review of the reported cases. Results: A variety of nonspecific symptoms make it difficult to reach an early diagnosis and to provide an appropriate counseling. Conclusion: This review highlight the major clinical variations to help reach a prompt diagnosis and take appropriate preventative measures.

Keywords: Basal cell carcinoma, fracture, RecQ helicases, squamous cell carcinoma

How to cite this article:
Alsabbagh MM. Rothmund-Thomson syndrome: A review of clinical and molecular aspects. J Dermatol Dermatol Surg 2020;24:5-12

How to cite this URL:
Alsabbagh MM. Rothmund-Thomson syndrome: A review of clinical and molecular aspects. J Dermatol Dermatol Surg [serial online] 2020 [cited 2021 Jun 12];24:5-12. Available from: https://www.jddsjournal.org/text.asp?2020/24/1/5/281418

  Introduction Top

In 1868, unilateral cataract and marmorization of the skin were first described by the ophthalmologist Rothmund; and 55 years later, Thomson described the first case of congenital poikiloderma.[1] It was not until 1957 when Taylor concluded that these two cases reported by Rothmund and Thomson represent a single syndrome currently known as Rothmund-Thomson syndrome (RTS).[2] There are two types of RTS, RTS I and RTS II, both of which have poikiloderma as a common sign however; RTS II appears to carry a higher risk of malignancy [Figure 1].
Figure 1: Clinical distinction between RTS I and RTS II

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RTS follows an autosomal recessive pattern of inheritance. It is a rare disease with around 300 reported cases. The male-to-female ratio is yet unclear with equal incidence across males and females, female predominance (2:1) and male predominance (2:1) all being reported.[3],[4] RTS is phenotypically a heterogeneous disease where multiple organs are affected complicating early infancy or in some cases, neonatal period.

The purpose of this review is to provide a comprehensive clinical and molecular perspective of RTS.

  The Clinical Presentation of Rothmund-Thomson Syndrome Top

Birth and growth

Although babies with RTS typically present cephalic and are born at term (≥37 weeks gestation) for a single fetus[5],[6],[7],[8],[9],[10],[11],[12] and fraternal twins;[13] a single report documented breech presentation delivered through a cesarean section,[7] and another two reports documented preterm delivery of a single fetus[14] and discordant twins at 36 weeks gestation.[14] Generally, fetuses with RTS are born with a low (≤2500 g)[5],[6],[7],[13] or a very low (≤1500 g)[14] birth weight. However, a normal birth weight of 2500–5000 g was reported in a few cases.[7],[9],[11]

Facial dysmorphia is commonly absent in these babies yet, patients may present with nonspecific features including small flat face, short palpebral fissure,[15] hypertelorism,[16] small low-set ears,[5],[9] depressed[17] or flat nasal bridge,[5],[14],[18] and micrognathia.[5],[19] In the context of growth, developmental delay is the second major sign of RTS, after ectodermal dysplasia.[4]

Retarded growth can be detected as early as the second trimester of pregnancy.[20] Around two-thirds[4] of children and adolescents fail to thrive (<5th percentile)[5],[7],[8],[9],[10],[12],[14],[18],[20],[21],[22],[23],[24],[25],[26],[27] and have a small (<5th percentile) head circumference.[5],[10],[14],[20],[28] Yet, normal growth was also reported.[29]

Although infancy might go uncomplicated, multiple congenital deformities necessitating surgical intervention have been reported: ventricular septal defect,[30] subglottic stenosis resulting in respiratory distress,[31] severe gastroesophageal reflux,[5],[18] annular pancreas, resulting in duodenal stenosis,[14] anteriorly placed stenotic anus,[5] and congenital right inguinal[30] or umbilical[18] hernias.

The skin and skin appendages

Signs and symptoms of the skin, hair, and nail are among the first major signs of RTS.[4] Poikiloderma manifested as telangiectasia, reticulated depigmentation, hyperpigmentation, and punctate atrophy[4] might be congenital[32] or may manifest during infancy, especially within the first 6 months of life[4],[12],[16],[22],[24],[28],[33] [Figure 2], [Figure 3], [Figure 4]. It is usually asymptomatic and may localize to photo-exposed areas; however, poikiloderma may present as a widespread rash involving the face, extensor and flexor surfaces of extremities, and the gluteal region.[4],[6],[7],[10],[11],[13],[17],[18],[21],[22],[34],[35],[36],[37],[38],[39] Although occasionally absent,[5] poikiloderma may be associated with generalized photosensitivity, usually to ultraviolet A rather than ultraviolet B,[40] atrophy, or may be preceded by erythema.[6],[8],[9],[17],[41],[42] Poikiloderma might be complicated by 1–2-cm bullae involving the face and extremities as reported in a 3-day-old girl,[8] a 5-month-old boy,[43] and a 14-year-old boy.[13] Poikiloderma has responded well to two sessions of pulsed dye laser at a wavelength of 585 nm, 2 weeks apart.[33]
Figure 2: Early facial poikiloderma, www.dermnetnz.org

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Figure 3: Palmar poikiloderma in a seven year old girl, © www.dermis.net

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Figure 4: Plantar poikiloderma in a seven year old girl, © www.dermis.net

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Keratosis, observed in one-third of cases,[4] is generally seen in palms and soles associated with fissures;[13],[16],[17],[19],[22],[23],[27],[28],[34],[44],[45],[46] yet it may localize to elbows, knees, and soles and show poor response to 5-fluorouracil as reported in a 4-year-old girl[7] or it may be associated with squamous cell carcinoma (SCC).[37],[47] Other nonspecific cutaneous manifestations include porokeratosis,[39] generalized xerosis, atrophy,[45] anhidrosis,[48] congenital capillary hemangioma of the forehead and neck associated with multiple café au lait macules,[5],[19] generalized[45] or localized[30],[49] calcinosis cutis manifesting as calcium deposits seen on histopathological examination, and recurrent digital chilblains associated with cold weather.[36]

RTS carries an increased risk of cutaneous premalignant or malignant lesions, including Bowen's disease, SCC, and basal cell carcinoma (BCC). The nonmelanoma skin cancers are seen among 5% of cases with a mean age of onset of 34.4 years.[4],[50] For instance, more than ten BCCs in addition to malignant eccrine poroma arising in a 63-year-old female patient were reported.[46] Similarly, BCC may arise in patients with a history of precancerous or cancerous squamous cell pathologies as reported in a 63-years old male.[51]

Patients with RTS may have apparently normal nails;[7],[13],[14],[21],[39] however, nail dystrophy,[16],[17],[36],[46] hypoplasia,[5],[34],[37],[52] clubbing,[12] and ridging[8] were also documented. Although these nail changes are unspecific, toenail deformity was the first manifestation of RTS in a 2-years old boy.[45]

Sparse or absent hair, prevalent among 50%–73%,[4] may be extensive to involve the scalp, eyebrows, eyelashes,[5],[7],[9],[14],[20],[28],[29],[37],[44],[46] the beard,[53] and the whole body;[38],[47] yet it may localize to the eyebrows[11],[22],[36] and eyelashes.[11],[37],[49],[54],[55] Hair loss has other rare presentations. Patients may present with a well-demarcated hairless patch localized to the nuchal furrows[49] or it might be severe, resulting in complete baldness as seen in a 17-year-old boy[30] and a 45-year-old man.[51] However, apparently normal hair growth was also reported.[10],[13],[39]


Although some patients may have normal skeletal development,[8],[14],[34],[37],[53] bone defects are a major component of RTS and are observed among 68%–75% of cases.[4] Patients commonly present with dwarfism[13],[16],[19],[22],[35],[37],[38],[39],[42],[44],[45],[47],[52],[55],[56],[57] due to metaphyseal chondrodysplasia,[30] and they often have a delayed bone age.[5],[9],[14],[16],[21],[42],[45],[55] Less commonly, individuals have a normal bone age corresponding with their chronological age.[13] In a single case, short stature was neither explained by hypothyroidism nor deficient growth hormone as the latter was supplemented for 6 years and failed to improve patient's height.[9] However, growth hormone deficiency was documented in two cases with short stature[43] one of which showed subnormal response to growth hormone replacement.[26] However, patients with RTS may have normal stature.[36],[53]

Skull and spine deformities are frequent: disproportionate craniofacial ratio,[52] dolichocephaly,[14] narrow or fused sutures that disrupt brain growth[21] and necessitate a decompressive craniotomy,[7] frontal bossing,[14],[36],[44],[46] atlanto-occipital subluxation,[45] saddle nose,[16],[28],[35],[36],[45] prognathism,[46] scoliosis,[52] kyphoscoliosis,[35] and malformation of the first sacral vertebra.[51]

The bone malformation may involve the upper and lower extremities as well. For instance, literature reported defects in the radial head,[44] a dislocated radial ray,[35] resulting in elbow contractions,[52] bowed forearms,[5] short dysmorphic[15] or curved[19] ulnae, cystic changes in distal radii and ulnae,[13] hypoplastic radii[11] and thumbs[7],[11],[13],[15],[44] [Figure 5], unilaterally or bilaterally absent radii or thumbs,[5],[15],[18],[19],[26],[38] small hands,[5],[14],[22],[28] ankylosing flexion of the right first finger,[51] brachydactyly,[24],[52] clinodactyly,[13],[19] and swan neck deformity.[45] Lower limbs defects may manifest as hip dislocation,[35] Legg-Calve-Perthes disease,[5] hypoplastic patellae,[20],[58] genus valgum,[5],[19] congenital bilateral talipes equinovarus,[23] small feet,[5],[37] malformed metatarsal bones,[51] and congenital bilaterally-overlapping second and great toes.[5]
Figure 5: Abnormal thumb,www.dermnetnz.org

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Recurrent pathological fractures[19],[30],[55],[59] or fractures with delayed[23] or nonunion[55] usually involve the weight-bearing bones including the lower tibia.[6] Reported bone pathologies which may predispose to pathological fractures include osteopenia,[9] osteoporosis,[55] and osteosarcoma with a mean age of onset of 14 years,[4],[26],[57],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73] commonly located in long bones[74] and seen in 32% of cases[75] managed with (neo) adjuvant chemotherapy combined with surgical excision[6],[76] or amputation.[10]

Blood and lymphatics

The reported hematological and lymphatic abnormalities were lymphadenopathy,[45] lethal acute myeloid leukemia,[77] nasopharyngeal nonHodgkin lymphoma,[66] progressive leukopenia due to bone marrow necrosis or myelodysplasia,[16],[17],[28],[77] transient congenital thrombocytopenia,[5] anemia[57],[78] necessitating multiple transfusions,[18] hyper immunoglobulin A (IgA),[45] hyper IgA anticardiolipin suggestive of anti-phospholipid syndrome,[39] immunoglobulin G (IgG) deficiency,[79] IgG4 deficiency,[80] C1q complete absence[81] due to a homozygous missense mutation in complement C1q C chain gene,[82] immunodeficiency,[77] and low absolute total or regulatory T-cells.[5],[48]


The neurocognitive function is variable across patients with RTS. Normal mental development was documented in some cases[5],[7],[13],[16],[20],[36],[40],[48],[54] yet mental retardation, possibly due to accelerated cerebral atrophy,[4] was observed among others.[10],[21],[27],[45],[46],[55],[83],[84] Other reported manifestations were speech and motor delay in a 4-year-old girl,[18] a surgically-excised symptomatic atypical meningioma in a 28-year-old man,[85] left-sided cerebellar signs,[46] meningitis[28] and encephalitis[79] due to immune dysfunction, bilateral deafness due to cholesteatoma,[7] unexplained hypotonia in a 14-month-old boy with normal brain computerized tomography[14] and bilateral Babinski.[46]


Juvenile cataract is typical;[21],[46],[50],[56] however, cataract may arise in early adulthood[34],[37],[39] and in some cases, the absence of cataracts has been reported.[5],[7],[9],[10],[11],[13],[16],[20],[22],[33],[35],[36],[40],[44],[54],[83],[86]

Other reported ocular problems are mild ectropion,[5] alacrimation,[33] mesodermal dysgenesis of the iris,[35],[39] persistent photophobia, horizontal nystagmus,[46] conjunctivitis, blepharitis,[21] glaucoma,[83],[87] strabismus, conjunctival subepithelial melanosis, reduced visual acuity, visual field defect,[87] and corneal subepithelial nodular scarring successfully treated with excimer laser.[88]

Oral cavity

Patients with RTS may have normal oral cavity,[14],[22] yet several reports documented multiple caries,[5],[34] brownish discoloration of teeth, teeth anomalies including hypoplastic crown and short root,[54] hypodonatia[9],[11],[57] with an onset at the age of 7 years,[45] five[29] or even at two.[12] Such anomalies may necessitate full dental prosthesis at childhood.[46] Other reported oral cavity defects were high-arched palate,[14] fragile gum with spontaneous bleeding and bifid uvula.[5] SCC of the tongue was reported in multiple cases.[34],[47],[50] In one case, the patient was managed with hemiglossectomy, Level I–III lymph node dissection and radiotherapy. The patient died 2 years later due to extensive thoracic SCC. Similarly, the second case was managed with surgical excision and radiochemotherapy; however, the patient was proved to have metastases to the lungs. The third case had the lesion excised, but follow-ups were unreported.


Pulmonary involvement is rare. However, recurrent pneumonia[21],[51] and bronchitis[16] due to immunological dysfunction[17],[48],[77] along with bronchiectasis in the presence[77] or absence of immune dysfunction or cystic fibrosis[11] have been reported.

The liver and gastrointestinal tract

The main reported anomalies of the gastrointestinal tract and visceral organs are upper esophageal stenosis,[58],[89] congenital hepatomegaly,[5] splenomegaly,[16] hepatosplenomegaly,[45] fibrocystic disease of the pancreas with subsequent increased fecal fatty acid,[42] exocrine pancreatic hypofunction with pancreatic atrophy and fatty replacement,[43] diarrhea of unknown etiology,[20] coeliac disease,[55] and rectovaginal fistula.[4]


The two reported renal pathologies were glomerulonephritis,[81] and the ectopic left kidney in the lower quadrant detected by excretory urogram.[5]


Few endocrinal defects were reported in RTS including mild hypogonadism in both males and females[19],[32],[52],[57] possibly due to gonadotropin resistance,[90] hyperparathyroidism secondary to parathyroid adenoma,[32] growth hormone deficiency,[20],[41] hypothyroidism,[41],[52] and borderline hypothyroidism.[35] However, thyroid function was reported to be normal in at least one case.[5] The acute adrenal crisis was also reported in a 26-month-old boy with RTS who presented with coma and electrolytes imbalance and interestingly, anti-adrenal antibodies were negative.[9]

Accelerated aging

RTS is considered a disease of premature aging. Hair loss, BCC, SCC, poikiloderma, mental retardation possibly due to cerebral atrophy, cataract, and osteoporosis are all well-established features of aging.[91]


Although normal karyotyping is typical,[5],[11],[16],[17],[21],[28],[47],[87] trisomy 8,[38],[92],[93],[94] mosaicism for trisomy of chromosome 2 and 8,[64] railroads of the centromere,[14] and increased breakage and gaps[9],[11] were reported in RTS. Karyotyping of fibroblasts isolated from poikiloderma showed 46, XY,17+ der(17), t (2;17)(q11;p13) pattern, suggesting chromosomal instability manifested as a rearranged chromosome 17.[95]

  The Molecular Perspective of Rothmund-Thomson Syndrome Top

RECQL4 gene, which belongs to the RecQ DNA helicase family, is located in 8q24.3 region, and consists of 6550 base pairs arranged in 21 exons. Being a DNA helicase, RECQL4 has a fundamental role during the process of DNA-damage repair, where adenosine triphosphate-dependent DNA unwinding is essential to allow the action of repairing proteins to take place. If impaired, RECQL4 loss its capability of DNA unwinding, and subsequently the damaged DNA is left unrepaired. RECQL4 helicase activity is attributed to two domains: the conserved superfamily II helicase domain and a novel adenosine triphosphate-binding domain located in the N-terminus. The carcinogenic impact of defected RECQL4 is also noted among other genes within the RecQ DNA helicase family, RECQL2 and RECQL3, where both are independently associated with gene instability and predisposition to cancer. This is also demonstrated in cases of RTS with SCC of the tongue who develop radio-sensitivity following radiotherapy. This complication is explained by the interaction between RECQL4 and poly-adenosine diphosphate-ribose polymerase-1, where both are involved in double-strand repair and base excision repair in healthy individuals. Nonetheless, RECQL4 was also found to interact with Xeroderma Pigmentosum Group A, a base excision repair factor involved in repairing ultraviolet-induced DNA damage; and Rad51, which is involved in homologous recombination and DNA repair.[4],[96],[97]

RECQL4 has other functions in DNA metabolism. For instance, its expression increases during the S phase of the cell cycle, suggesting its role in DNA replication as observed in Xenopus laevis. The xRTS gene was capable of rescuing DNA replication in RECQL4-knock out X. laevis egg extracts by recruiting and loading DNA polymerase α.[4],[96]

Mouse models were also utilized to study the function of RECQL4. Disruption of exons 5–8, which corresponds to the N-terminus, was associated with embryonic lethality. Whereas, disruption of exon 13 and exons 9–13, corresponding to the helicase domain, were associated with viable embryos in 5% and 84%, respectively, and this highlights the importance of the N-terminus. This also suggests that the deletion of five exons (9–13) results in a better protein folding and a higher enzymatic activity compared to the single exon deletion (exon 13). Apart from carrying the novel adenosine triphosphate-binding domain which exerts the helicase activity, the N-terminus was also found to be involved, along with ubiquitin ligases UBR1 and UBR2, in the formation of a stable complex essential for chromosome segregation and apoptosis. However, the exact interaction between RECQL4 and ubiquitin ligases is yet unknown.[4],[96],[98] [Figure 6] summarizes RECQL4-interacting partners and proposed cellular pathways.[96],[99]
Figure 6: RECQL4-interacting partners and proposed cellular pathways[96],[99]

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According to the National Center for Biotechnology Information, mutations within the RECQL4 gene are associated with another two syndromes that overlap with RTS: Baller-Gerold syndrome (radial ray anomalies along with coronal craniosynostosis) and radial ray defect, patellae hypoplasia or aplasia, diarrhea and dislocated joints, limb defect and little size, normal intelligence, and long nose syndrome.[100]

To date, there are 15 different mutations reported in cases of RTS: nine of which are single nucleotide variants and six are deletions, where five of them result in frameshift mutations. Four mutations are located within the noncoding region and were found to be pathogenic.[4],[100] [Figure 7] illustrates the mutations in the RECQL4 gene in RTS, their location and frequency as reported in the National Center for Biotechnology Information.
Figure 7: Reported mutations within RECQL4 gene in Rothmund-Thomson syndrome, their location and frequency[100]

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  Conclusion Top

RTS is a familial syndrome associated with BCC where patients usually present with a wide range of systemic symptoms that, if recognized early, may carry further implications for patients including surveying for cataract and osteosarcomas and taking appropriate prophylactic measures from fractures; and their families in terms of counseling and carrying preimplantation genetic diagnostic tests.


The author acknowledge Dermatology Information System (www.dermis.net) for giving the permission to republish [Figure 3] and [Figure 4]; and DermNet New Zealand (www.dermnetnz.org) for giving their permission to republish [Figure 2] and [Figure 5].

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]


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