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This review starts off with the first germline homozygous variants of the Nucleoporin 98 gene (NUP98) in siblings whose clinical presentation recalls Rothmund–Thomson (RTS) and Werner (WS) syndromes. The progeroid phenotype caused by a gene associated with haematological malignancies and neurodegenerative disorders primed the search for interplay between caretakers involved in genome instability syndromes and Nuclear Pore Complex (NPC) components. In the context of basic information on NPC architecture and functions, we discuss the studies on the interdependence of caretakers and gatekeepers in WS and Hereditary Fibrosing Poikiloderma (POIKTMP), both entering in differential diagnosis with RTS. In WS, the WRN/WRNIP complex interacts with nucleoporins of the Y-complex and NDC1 altering NPC architecture. In POIKTMP, the mutated FAM111B, recruited by the Y-complex's SEC13 and NUP96, interacts with several Nups safeguarding NPC structure. The linkage of both defective caretakers to the NPC highlights the attempt to activate a repair hub at the nuclear periphery to restore the DNA damage. The two separate WS and POIKTMP syndromes are drawn close by the interaction of their damage sensors with the NPC and by the shared hallmark of short fragile telomeres disclosing a major role of both caretakers in telomere maintenance. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS), also known as congenital poikiloderma, is a genodermatosis that appears in infancy and is characterized by poikilodermatous changes in the skin. It is a very rare and complex genetic disorder that can present with a wide range of symptoms and affect multiple systems in the body. The syndrome is inherited in an autosomal recessive manner. A 21-year-old female patient presented to our rheumatology outpatient clinic with swelling of the hands, sclerodactyly, and stiffness of the fingers with preliminary diagnosis of systemic sclerosis. She has had deformities in her feet and hands since the age of one year. Physical examination revealed poikiloderma and extremity deformities. She also had neutropenia in her bloodstream. She was diagnosed with Rothmund Thomson syndrome after genetic test results, prescribed colchicine and followed up regularly every three months. After two years of follow-up, she was diagnosed with ovarian cancer.

Introduction: Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive disorder that has been reported in all ethnicities, with several identifiable pathogenic variants. There have been reported cases indicating that RTS may lead to low birth weight in fetuses, but specific data on the fetal period are lacking. Genetic testing for RTS II is currently carried out by identifying pathogenic variants in RECQL4. Methods: In order to determine the cause, we performed whole‐genome sequencing (WGS) analysis on the patient and his parents. Variants detected by WGS were confirmed by Sanger sequencing and examined in family members. Results: After analyzing the WGS data, we found a heterozygous nonsense mutation c.2752G>T (p.Glu918Ter) and a novel frameshift insertion mutation c.1547dupC (p.Leu517AlafsTer23) of RECQL4, which is a known pathogenic/disease‐causing variant of RTS. Further validation indicated these were compound heterozygous mutations from parents. Conclusion: Our study expands the mutational spectrum of the RECQL4 gene and enriches the phenotype spectrum of Chinese RTS patients. Our information can assist the patient's parents in making informed decisions regarding their future pregnancies. This case offers a new perspective for clinicians to consider whether to perform prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This review focusing on gender differences in the incidence of soft tissue and bone sarcomas. Sarcomas are rare cancers arising from mesenchymal tissues, which are different from the epithelial tissues and originate from the embryonic mesodermal layer. These cancers can be classified into bone or soft tissue sarcomas. Most sarcomas occur without known causes; however, certain genetic syndromes and environmental factors are known to be associated with these malignancies. Studies have indicated a male predominance in sarcoma incidence, which is also seen in other cancers like colorectal and lung cancers. Notably, childhood sarcomas exhibit significant gender differences, with a stronger association with the male sex, particularly in soft tissue sarcomas. The biological reasons for these sex differences are not well understood, and this review seeks to shed light on these underlying factors to aid in prevention and treatment strategies. Sarcomas, uncommon malignancies, stem from mesenchymal tissues, distinct from epithelial tissues, originating in the embryonic mesodermal layer. These sarcomas have been categorized as either bone or soft tissue sarcomas, depending on their originating tissue. The majority of sarcomas occur sporadically with their etiology being unknown, but there are several, well-established genetic predisposition syndromes and some environmental exposures associated with specific sarcomas. Recently, many studies have shown that sarcomas, in analogy with colorectal, skin, head and neck, esophageal, lung, and liver carcinomas, also have a male sex predilection. Significant gender differences have already been observed in childhood sarcomas. Among the tumors strongly associated with the male sex, childhood sarcomas have been identified as being particularly sensitive to the biological differences between the sexes, with special regard to soft tissue sarcomas. As the biological mechanisms underlying the sex differences in the incidence of soft tissue sarcomas remain largely unexplored, this review aims to highlight the factors underlying these differences to inform prevention and treatment. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS), also known as congenital poikiloderma, is a genodermatosis that appears in infancy and is characterized by poikilodermatous changes in the skin. It is a very rare and complex genetic disorder that can present with a wide range of symptoms and affect multiple systems in the body. The syndrome is inherited in an autosomal recessive manner. A 21-year-old female patient presented to our rheumatology outpatient clinic with swelling of the hands, sclerodactyly, and stiffness of the fingers with preliminary diagnosis of systemic sclerosis. She has had deformities in her feet and hands since the age of one year. Physical examination revealed poikiloderma and extremity deformities. She also had neutropenia in her bloodstream. She was diagnosed with Rothmund Thomson syndrome after genetic test results, prescribed colchicine and followed up regularly every three months. After two years of follow-up, she was diagnosed with ovarian cancer. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short stature, sparse hair, eyebrows/eyelashes, nail dysplasia, and skeletal abnormalities. While classically associated with mutations in the RECQL4 gene, which encodes a DNA helicase involved in DNA replication and repair, three additional genes have been recently identified in RTS: ANAPC1, encoding a subunit of the APC/C complex; DNA2, which encodes a nuclease/helicase involved in DNA repair; and CRIPT, encoding a poorly characterized protein implicated in excitatory synapse formation and splicing. Here, we review the clinical spectrum of RTS patients, analyze the genetic basis of the disease, and discuss molecular functions of the affected genes, drawing some novel genotype-phenotype correlations and proposing avenues for future studies into this enigmatic disorder. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short stature, sparse hair, eyebrows/eyelashes, nail dysplasia, and skeletal abnormalities. While classically associated with mutations in the RECQL4 gene, which encodes a DNA helicase involved in DNA replication and repair, three additional genes have been recently identified in RTS: ANAPC1, encoding a subunit of the APC/C complex; DNA2, which encodes a nuclease/helicase involved in DNA repair; and CRIPT, encoding a poorly characterized protein implicated in excitatory synapse formation and splicing. Here, we review the clinical spectrum of RTS patients, analyze the genetic basis of the disease, and discuss molecular functions of the affected genes, drawing some novel genotype-phenotype correlations and proposing avenues for future studies into this enigmatic disorder.

The Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive disease associated with poikiloderma, telangiectasias, sun-sensitive rash, hair growth problems, juvenile cataracts and, for a subset of some RTS patients, a high risk of cancer, especially osteosarcoma. Most of the RTS cases are caused by biallelic mutations of the RECQL4 gene, coding for the RECQL4 DNA helicase that belongs to the RecQ family. Cellular and post-radiotherapy radiosensitivity was reported in RTS cells and patients since the 1980s. However, the molecular basis of this particular phenotype has not been documented to reliably link the biological and clinical responses to the ionizing radiation (IR) of cells from RTS patients. The aim of this study was therefore to document the specificities of the radiosensitivity associated with RTS by examining the radiation-induced nucleo-shuttling of ATM (RIANS) and the recognition and repair of the DNA double-strand breaks (DSB) in three skin fibroblasts cell lines derived from RTS patients and two derived from RTS patients’ parents. The results showed that the RTS fibroblasts tested were associated with moderate but significant radiosensitivity, a high yield of micronuclei, and impaired DSB recognition but normal DSB repair at 24 h likely caused by a delayed RIANS, supported by the sequestration of ATM by some RTS proteins overexpressed in the cytoplasm. To our knowledge, this report is the first radiobiological characterization of cells from RTS patients at both molecular and cellular scales.

Rothmund-Thomson Syndrome (RTS) is a rare, multisystem disease accompanied by many anomalies that require careful attention from preoperative evaluation to discharge regarding anesthesia preparation and management. Due to craniofacial deformities accompanying facial abnormalities, maintaining the airway becomes a complete struggle with a race against time for survival. This case report presents the preoperative preparation and perioperative management, the risks that may be encountered, and the detailed preparation for a 7-year-old patient diagnosed with RTS and multiple system involvement. General anesthesia was administered to this patient, who had intrauterine growth retardation, nail streaking, redness of the bullae and legs, and a history of somatotropin treatment and antinuclear antibody (ANA) positivity under optimum conditions. Thanks to successful and detailed preoperative preparation and perioperative management, the patient was followed up and discharged without any complications. Although RTS is rare, the need for general anesthesia often arises due to juvenile cataracts, dental anomalies, syndactyly and other extremity anomalies in these patients whose airway management is complex. Furthermore, this increases the current risk in the population of these patients. Managing these patients with a multidisciplinary approach will reduce complications, morbidity, mortality, and length of stay.

Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse hair, eyelashes and eyebrows, short stature, variable skeletal abnormalities, dental defects, cataracts, hypogonadism, and an increased risk for cancer, especially osteosarcoma and skin cancer. RTS is caused by biallelic pathogenic variants in ANAPC1 (Type 1 RTS) or RECQL4 (Type 2 RTS). We present an African girl with Type 2 RTS caused by a nonsense variant and an intronic variant in RECQL4. The patient presented precocious puberty, which has not been previously reported in RTS and that was treated with a GnRH analog, and anal stenosis, which has only been reported once. This case highlights the need to consider deep intronic variants in patients with RTS when pathogenic variants in the coding regions and exon/intron boundaries are not identified and expands the phenotypic spectrum of this disorder. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome, a heterogeneous genodermatosis with autosomal recessive hereditary pattern, is an uncommon cancer susceptibility genetic syndrome. To date, only 400 cases have been reported in the literature, and the severity of the features varies among individuals with the condition. Here, we describe a 55-year-old male who had been diagnosed with Bloom Syndrome during childhood due to the suggestive physical features such as short stature, chronic facial erythema, poikiloderma in face and extremities, microtia and microcephaly. However, the genetic test demonstrated that the patient carried two pathogenic variants resulting in compound heterozygous in the RECQL4 gene (c.2269C>T and c.2547_2548delGT). He subsequently developed a calcaneal osteosarcoma, which was successfully treated, and has currently been oncologic disease-free for 3 years. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in RECQL4 gene and has characteristic clinical features of poikiloderma, congenital bone defects, gastrointestinal disturbances such as chronic diarrhea and vomiting, and an increased susceptibility to malignancy. A 2½-year-old Indian boy presented with reticulate hyperpigmented erythema with superimposed hypopigmented atrophic macular lesions over the cheeks and diffuse background hyperpigmentation with multiple discrete atrophic hypopigmented macules of variable size over the abdomen and extensor aspects of the forearms. X-rays suggested metaphyseal irregularity around knee joint and radioulnar synostosis. Whole-exome sequencing was suggestive of a de novo novel RECQL4 gene mutation causing RTS Type II. There is an overlapping of clinical features of the group of syndrome associated with skin lesions, skeletal, and gastric manifestations. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. This report expands the RECQL4 gene pathogenic mutations spectrum.

Background: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated. Methods: In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan. Results: In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey. Conclusions: Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated. [ABSTRACT FROM AUTHOR]

Baller-Gerold syndrome (BGS, OMIM: 218600), RAPADILINO syndrome (OMIM 266280), and Rothmund-Thomson syndrome (RTS, OMIM 266280), which are caused in some cases by RECQL4 pathogenic variants, show autosomal recessive inheritance. Some refer to them collectively as RECQL4 syndromes. Most cases have been reported during infancy and childhood periods. However, there have been no reports of phenotypes resulting in a lethal course in the perinatal period. We identified two fetuses with biallelic RECQL4 pathogenic variants during the perinatal period. The two fetuses with RECQL4 syndrome showed structural abnormalities, including severely hypoplastic forearms and lower legs. One fetus also had severe pulmonary hypoplasia. One case resulted in neonatal death because of respiratory failure, and the other was artificially terminated during pregnancy. The RECQL4 pathogenic variants were identified by exome sequencing followed by Sanger sequencing. The biallelic RECQL4 pathogenic variants can induce a lethal skeletal disorder., (© 2024 Wiley Periodicals LLC.)

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in RECQL4 gene and has characteristic clinical features of poikiloderma, congenital bone defects, gastrointestinal disturbances such as chronic diarrhea and vomiting, and an increased susceptibility to malignancy. A 2½-year-old Indian boy presented with reticulate hyperpigmented erythema with superimposed hypopigmented atrophic macular lesions over the cheeks and diffuse background hyperpigmentation with multiple discrete atrophic hypopigmented macules of variable size over the abdomen and extensor aspects of the forearms. X-rays suggested metaphyseal irregularity around knee joint and radioulnar synostosis. Whole-exome sequencing was suggestive of a de novo novel RECQL4 gene mutation causing RTS Type II. There is an overlapping of clinical features of the group of syndrome associated with skin lesions, skeletal, and gastric manifestations. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. This report expands the RECQL4 gene pathogenic mutations spectrum. [ABSTRACT FROM AUTHOR]

Rothmund–Thomson syndrome (RTS) is a rare autosomal‐recessive disorder characterized by poikiloderma, short stature, sparse hair, skeletal abnormalities, and cancer predisposition. Mutations in ANAPC1 or RECQL4 have been identified to underlie RTS. Either Sanger sequencing or next‐generation sequencing (NGS) was performed for three Chinese RTS patients. Copy number variants were called by the eXome‐Hidden Markov Model using read‐depth data of NGS, and the putative heterozygous deletion was confirmed by PCR with multiple primers. The breakpoints were identified by Sanger sequencing. All patients presented with characteristic features of poikiloderma, short stature, and sparse hair, eyelashes, and eyebrows. In addition, patient 1 had intellectual disability and speech delay, and patient 2 developed osteosarcoma when she was 13 years old. Biallelic RECQL4 variants were identified in all three patients. Five of the six variants were novel, including c.119‐1G>A, c.2886‐1G>A, c.2290C>T (p.Gln764*), and c.3552dupG (p.Arg1185Glufs*42), and a gross deletion encompassing exons 6 to 10. Our study expands the genetic and clinical spectrums of RTS. Furthermore, we reported the first heterozygous gross deletion in RECQL4. [ABSTRACT FROM AUTHOR]

Abstract There are various causes of childhood poikiloderma. A proper history and clinical examination may help to get conclusion and narrow down the differentials for the causes of poikiloderma.

The article presents the discussion on term ‘dermatoglyphics' being coined by Cummins and Midlo in 1926. Topics include occurring patterns believed to be unique to an individual and remain unchanged from birth until death; and adermatoglyphia defined clinically as the congenital or an acquired loss of the epidermal ridge pattern.

Congenital poikiloderma is a rare, multisystem condition with onset in early childhood, present in numerous inherited skin disorders. Here we present a 7-year-old boy with a polymalformative syndrome associated with poikiloderma. The complex clinical data led to the diagnosis of an intermediate phenotype between Rothmund-Thomson (RTS) and Baller- Gerold (BGS) syndromes. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by defects in the skeletal system, such as bone hypoplasia, short stature, low bone mass, and an increased incidence of osteosarcoma. RTS type 2 patients have germ line compound biallelic protein-truncating mutations of RECQL4. As existing murine models employ Recql4 null alleles, we have attempted to more accurately model RTS by generating mice with patient-mimicking truncating Recql4 mutations. Truncating mutations impaired the stability and subcellular localization of RECQL4 and resulted in homozygous embryonic lethality and a haploinsufficient low-bone mass phenotype. Combination of a truncating mutation with a conditional Recql4 null allele demonstrated that the skeletal defects were intrinsic to the osteoblast lineage. However, the truncating mutations did not promote tumorigenesis. We utilized murine Recql4 null cells to assess the impact of human RECQL4 mutations using an in vitro complementation assay. While some mutations created unstable protein products, others altered subcellular localization of the protein. Interestingly, the severity of the phenotypes correlated with the extent of protein truncation. Collectively, our results reveal that truncating RECQL4 mutations in mice lead to an osteoporosis-like phenotype through defects in early osteoblast progenitors and identify RECQL4 gene dosage as a novel regulator of bone mass. [ABSTRACT FROM AUTHOR]

Rothmund–Thomson syndrome is a rare, autosomal recessive genodermatosis characterized by an early-onset poikiloderma, skeletal abnormalities, short stature, premature aging, and increased susceptibility to malignancy. We report a case of a 1-year-old male child with bullous lesions and pigmentary changes over the face and extremities. Strict photoprotection and careful surveillance for malignancy forms the mainstay of treatment. The case is being reported due to its rarity and the diagnostic dilemmas associated with it.

There are various causes of childhood poikiloderma. A proper history and clinical examination may help to get conclusion and narrow down the differentials for the causes of poikiloderma. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4 , is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication. [ABSTRACT FROM AUTHOR]

Abstract RecQL4 has been shown to be involved in DNA replication and repair, but its role in DNA damage checkpoint pathway has not been reported. Here, we show that RecQL4 plays an important role in the activation of ataxia telangiectasia mutated (ATM)-dependent checkpoint pathway in human cells. Cells depleted with RecQL4 or Rothmund-Thomson syndrome cells showed significant impairment in the activation of ATM and the downstream effector proteins such as checkpoint kinase 2 and p53 after DNA damage. This defect was recovered with the expression of wild type RecQL4 but not any mutant RecQL4 proteins with defective helicase activities. While RecQL4 failed to show any direct interaction with ATM, it stably interacted with the Mre11-Rad50-Nbs1 complex that is essential for the activation of ATM and was localized on the DNA damage foci. Thus, our results suggest that the helicase activity of RecQL4 plays an important role in the activation of ATM-dependent checkpoint pathway against DNA double strand breaks in human cells. Highlights • ATM-dependent checkpoint pathway is impaired in RecQL4-depleted cells. • The lack of helicase activity of RecQL4 is responsible for the defect in ATM activation. • Rothmund-Thomson syndrome cells are defective in ATM activation, which can be recovered via RecQL4 expression. [ABSTRACT FROM AUTHOR]

The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 5′ end resection in vivo. RECQL4 physically interacts with MRE11-RAD50-NBS1 (MRN), which senses DSBs and initiates DNA end resection with CtIP. The MRE11 exonuclease regulates the retention of RECQL4 at laser-induced DSBs. RECQL4 also directly interacts with CtIP via its N-terminal domain and promotes CtIP recruitment to the MRN complex at DSBs. Moreover, inactivation of RECQL4’s helicase activity impairs DNA end processing and HR-dependent DSBR without affecting its interaction with MRE11 and CtIP, suggesting an important role for RECQL4’s unwinding activity in the process. Thus, we report that RECQL4 is an important participant in HR-dependent DSBR.

The article presents the xeroderma pigmentosum is a group of rare inherited cancer‑prone skin conditions characterized by sever sensitivity to the DNA damaging effects of ultraviolet (UV) radiations and results in hyperpigmentation, and high risk of skin carcinoma. Topics include the proteins are involved in the repair of UV‑induced DNA damage, the removal of UV‑induced damage has associated from the DNA, and the eighth group is associated with replication of DNA containing unrepaired damage.

The article presents a case study of a 28-year-old woman presented for evaluation of a pearly papule on the forehead of several months' duration that was concerning for basal cell carcinoma (BCC). It notes that physical examination revealed hypotrichosis; numerous white cystic papules on the face, chest, and upper arms; and pitted depressions on the dorsal aspects of the hands and extensor surfaces of the elbows.

A 24-year-old male patient presented to us with diminution of vision in both eyes with watering and photophobia for the past 8 years. General physical examination showed short stature and poikiloderma. Ocular findings include photophobia with reflex tearing, dry eye, cicatricial ectropion, symblepharon approaching pupillary area of cornea, and multiple superficial punctuate erosions on the cornea. Both eyelids showed scanty meibomian glands on infrared meibography. The rest of the anterior and posterior segment was normal. The patient was treated with topical lubricants which reduced photophobia and corneal erosions. He then underwent symblepharon release with buccal mucosal grafting, which improved ectropion. Patient improved symptomatically with reduction of photophobia and improvement in vision as well.

Background Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder mainly characterized by cutaneous poikiloderma, sparse hair, short stature and skeletal defects. Deleterious mutations in the RecQ-like DNA helicase type 4 ( RECQL4 ) gene have been detected in approximately two-thirds of RTS cases. Methods Three Chinese patients from two unrelated families were enrolled for clinical evaluation. Targeted next-generation sequencing (NGS) using a custom panel consisting of 705 short-stature-related genes was performed for the probands. Variants detected by NGS were confirmed by Sanger sequencing and examined in family members. Results The probands presented with characteristic features of severe growth delay, poikiloderma mostly on the face, buttocks and extremities, sparse or absent hair, eyelashes, and eyebrows, forearm reduction defects, small hands with hypoplasia of the middle phalanx (little finger) in one of the probands, epicanthus, hypertelorism, and dental abnormalities. In addition, novel auricle features and other rare facial features, including narrow palpebral fissure, depressed nasal bridge, and small chin were exhibited. Four novel RECQL4 variants were identified, including three pathogenic frameshift variants, c.1724_1725delAC, p.His575fs*7; c.2421dupT, p.Asp808*; c.1770_1807del, p.Pro591fs*2, and one likely pathogenic missense variant, c.691G>A, p.Gly231Ser. Conclusion Our study expands the mutational spectrum of RECQL4 gene and reveals novel phenotypes observed in Chinese RTS patients. [ABSTRACT FROM AUTHOR]

Abstract: Background/Objectives: Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for many life‐threatening disorders in children. Chronic graft‐versus‐host disease (cGVHD) is a significant complication of HSCT, and its treatment is challenging. Skin is the most common organ affected in cGVHD, with protean manifestations posing a challenge in diagnosis and management. The objective was to have a better understanding of the spectrum of chronic cutaneous GVHD (cc‐GVHD) in children. Methods: Hospital records of 14 children with cc‐GVHD, registered over 9 years, were reviewed. Results: All the patients had received HSCT from related donors. Median duration between HSCT and onset of cc‐GVHD was 7.5 months. Eighty‐six percent of the patients had a prior history of aGVHD, and 14% had de novo onset of cc‐GVHD. Of 14 patients, 71% had classic cc‐GVHD. Overlap syndrome was observed in 29%. Tandem occurrence of multiple morphologies was noticed in 6 (43%) patients. Of classic cc‐GVHD, lichen planus‐like cc‐GVHD was most common (57%) followed by scleroderma‐like (29%) and poikiloderma (7%). Rare variants included eczema‐like (14%) and psoriasis‐like (7%) cc‐GVHD. Mucosal involvement was seen in 78.6% of the patients, nail involvement in 50%, and hair abnormalities in 43%. After a median follow‐up of 4.8 years, complete remission was observed in 50% and mortality in 14%. Conclusion: The study signifies the diverse nature of cc‐GVHD and indicates the need for multicenter surveys including larger number of patients to have proper insight into and develop treatment guidelines for cc‐GVHD in children. [ABSTRACT FROM AUTHOR]