The Diagnostic Dilemma of Rothmund-Thomson Syndrome Type II: A Rare Disorder with a Novel Mutation in the RECQL4 Gene in an Indian Boy : Indian Journal of Paediatric Dermatology

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The Diagnostic Dilemma of Rothmund-Thomson Syndrome Type II: A Rare Disorder with a Novel Mutation in the RECQL4 Gene in an Indian Boy

Goyal, Manisha; Bharadia, Lalit1; Gupta, Ashok; Kotecha, Udhaya H.2

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Indian Journal of Paediatric Dermatology 23(4):p 322-324, Oct–Dec 2022. | DOI: 10.4103/ijpd.ijpd_149_21
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Rothmund-Thomson syndrome (RTS) was first described in 1868 by Auguste Rothmund in patients with poikiloderma associated with rapidly progressive juvenile cataracts. Similar patients were described later by Thomson as “poikiloderma congenitale” who had skeletal defects, however, did not have cataracts. Later, these were clubbed together by Wiliam Taylor as RTS.[1] Until now, approximately 400 patients have been reported.[2] Currently, RTS can be divided into two types (Type I and II) depending on the genetic and phenotypic heterogeneity. RTS Type I is caused by homozygous or compound heterozygous mutation in the ANAPC1 gene.[3] It is an autosomal recessive disorder and is characterized by poikiloderma, sparse hair, and bilateral juvenile cataracts. Patients may also have growth retardation and genital, skeletal, and dental abnormalities. The disorder is not associated with an increased risk of cancer. RTS Type II is caused by compound heterozygous mutation in the DNA helicase gene RECQL4.[45] It is an autosomal recessive disorder characterized by poikiloderma, congenital bone defects, and a high risk of osteosarcoma in childhood and skin cancer later in life.[4]

We report an Indian patient with the sporadic occurrence of RTS Type II detected to have a novel pathogenic variant in RECQL4 gene. The present study expands the genotype spectrum of RTS.

Case Report

A 2½-year-old boy, born of nonconsanguineous union, was brought for failure to thrive and recurrent episodes of vomiting and diarrhea. He was a full-term baby delivered by cesarean section with a birth weight of 2.25 kg. He had a mild motor developmental delay with normal cognition. There was a history of multiple hyperpigmented skin lesions without blister formation since 6 months of age. Parents noted reddening of the facial lesions on the sun exposure. He had a history of progressive bowing of legs which started at 19 months of age. At the age of 2½ years, his height was 75 cm (<3 standard deviation) with upper-to-lower segment ratio of 1.34:1. His weight was 7 kg (<3rd percentile), and his head circumference was 44.5 cm (<3rd percentile). Facial features showed hypertelorism, bilateral epicanthal folds, low set ears, and sparse scalp hair. Skin examination showed reticulate hyperpigmented erythema with superimposed hypopigmented atrophic macular lesions over the cheeks [Figure 1] and diffuse background hyperpigmentation with multiple discrete atrophic hypopigmented macules of variable size over abdomen and extensor aspects of the forearms. Hair was thin. There was phimosis on genital examination. Legs showed lateral bowing with knees wide apart. Fundus evaluation for vision and Brainstem Evoked Response Audiometry (BERA) for hearing were within the normal limits. X-rays suggested metaphyseal irregularity around knee joint and radioulnar synostosis. Biochemical analysis, such as serum calcium, inorganic phosphate, and alkaline phosphates levels, was normal. Echocardiography and ultrasound abdomen was normal. Gastroesophageal reflux disease, immunodeficiency, and cystic fibrosis were ruled out by normal upper gastrointestinal endoscopy, normal immunoglobulin levels, and a normal sweat chloride test.

Figure 1:
Poikiloderma lesion over cheek

There was no family history suggestive of similar disorder, and the parents were normal. Genetic analysis was performed by whole-exome sequencing after obtaining informed consent. Results showed homozygous missense variant c. 3197_3215del (p. Ala1066Glufs*9) in exon 19 in the RECQL4 gene, causing deletion of 19 bps. The variant was confirmed by Sanger sequencing. Parental testing was done for the same variant and found negative. It was predicted to be pathogenic by in silico prediction tools Sorting Intolerant From Tolerant (SIFT), PolyPhen-2 (HumDiv and HumVar), and mutation taster software. The p. A1066Efs*9 variant is novel (not in any individuals) in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused by a frameshift mutation, thus classified as likely pathogenic.

This deletion was neither reported in the available databases nor was observed in the parents. Thus, it was considered de novo and novel mutation.


In this study, we identified a novel likely pathogenic RECQL4 variant in an Indian patient with clinically suspected RTS, which expands the mutational spectrum of RECQL4 gene. RTS can be divided into two types, i. e., RTS Type I caused by mutations in ANAPC1 and RTS Type II by RECQL4 gene. Clinical phenotypes overlap greatly between the two types, such as poikiloderma, spare hair, and nail abnormalities. However, osteosarcoma and skeletal defects are present only in patients with RTS Type 2 and juvenile cataracts found with RTS Type 1.[2] Poikiloderma or any other skin lesion (100%) is the most common sign, followed by growth failure (83%) and skeletal abnormalities (75%) manifested in RTS Type II.[6] The characteristic finding is the cutaneous rash, which usually develops between the age of 3 and 6 months, presents as erythema and blisters, initially on the face, then gradually spreads to the extremities and to the buttocks. With time, the rash develops into a chronic form known as poikiloderma that manifested as telangiectasia, reticulated depigmentation, hyperpigmentation, and punctuate atrophy.[7]

Sparse scalp hair, eyebrows, and eyelashes and dental abnormalities such as microdontia, conical teeth, and loss of teeth can be seen.[8] Bhoyrul et al. reported an association between pili annulati (hair shaft abnormality characterized by alternating light and dark bands in the hair shaft) and RTS.[8] The hair diameter and tensile strength are usually normal, but with an increased risk of weathering and fragility. Early onset, bilateral, and subcapsular juvenile cataracts have been reported in up to 50% of cases and usually develop later in the 4th and 7th years of life.[2] However, patients with RECQL4 mutation do not typically develop cataract.

Skeletal manifestations in RTS include absent or malformed bones, fused bones, bone shortening, predisposition to fractures (osteopenia), Radial ray defect and hypoplasia or absence of the patella. Mehollin-Ray et al. reviewed a skeletal survey of 28 individuals with RTS and found that 75% had at least one major skeletal abnormality.[9] Cao et al. demonstrated a correlation between the presence of pathogenic variants in RECQL4 and low bone mineral density with a history of increased number of fractures.[10] It was postulated on the mouse model that mutated RECQL4 affects osteoblast progenitor cells and reduces the osteoid formation and hence produces osteopenia.[11]

Our proband presented with gastrointestinal symptoms such as emesis and diarrhea. The reported gastrointestinal anomalies are hepatosplenomegaly, fibrocystic disease of the pancreas with subsequent increased fecal fatty acid, upper esophageal stenosis, celiac disease, and rectovaginal fistula.[12]

Mutations in RECQL4 are reported in approximately 40%–66% of RTS patients.[11] Most of the reported mutations are truncating due to nonsense, splicing, or frameshift mutations. More than 50% of these mutations are predicted to destroy the reading frame and thus disrupt the helicase domain which is essential for gene function. Yadav et al. reported two Indian cases with novel frameshift variants in RECQL4 gene. Both had characteristic poikiloderma lesions with specific distribution and skeletal anomalies with proportionate short stature.[11] In our study, we identified a homozygous missense variant c. 3197_3215del in RECQL4 gene. Mutation in RECQL4 gene causes three allelic disorders: RTS Type II, RAPADILINO syndrome (skeletal palatal defect with gastrointestinal abnormalities), and Baller–Gerold syndrome (radial ray defects and craniosynostosis).

RAPADILINO and RTS have common clinical features of skeletal abnormalities and gastrointestinal symptoms, but RAPADILINO lacks the poikiloderma rash.[13]

Multidisciplinary management with a focus on strict photoprotection and regular screening for malignancy is needed. There is a 25% risk of recurrence in every pregnancy, and this risk can be excluded by chorionic villous sampling at around 12 weeks of gestation.[2]


Our aim is to alert the clinicians to consider RTS in any child presenting with poikiloderma and other features such as recurrent gastrointestinal symptoms and bone manifestations. This report expands the mutational spectrum of RECQL4 and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s)/guardian(s) of the patient. In the form, the parent(s)/guardian(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child/children will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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Hyperpigmented lesion; metaphyseal irregularities; poikiloderma; RECQL4 gene; Rothmund-Thomson syndrome

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