Atypical presentations of RECQL4-related syndromes.

RECQL4-related syndromes are a group of rare cancer-predisposition syndromes caused by biallelic pathogenic/likely pathogenic variants (PV/LPV) in the DNA helicase gene, RECQL4. Genetic testing is typically prompted by the presence of one or more hallmark clinical features, and in the absence of such manifestations, diagnosis may be delayed or even missed. We describe five patients with biallelic germline mutations in RECQL4 who presented atypically, without the hallmark clinical manifestations of this syndrome. Three of these patients developed osteosarcoma, underscoring the importance of recognizing atypical presentations of Rothmund-Thomson syndrome (RTS) to allow for early awareness and surveillance for cancer.

A Chinese patient with Rothmund-Thomson syndrome.

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.

Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence.

PURPOSE: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789). METHODS: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts. RESULTS: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate. CONCLUSION: CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.

A case of Rothmund-Thomson syndrome originally thought to be a case of Bloom syndrome.

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.

Rothmund-Thomson syndrome investigated by two nationwide surveys in Japan.

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.

Rothmund-Thomson syndrome: a case series from a tertiary pediatric hospital in Mexico.

BACKGROUND: Rothmund-Thomson syndrome, also known as congenital poikiloderma, is a rare autosomal recessive genodermatosis with onset in early childhood that affects at a multisystem level. CASE REPORTS: Case 1. A 4-year-old male patient, consanguineous parents, 26-year-old brother with a probable diagnosis of Rothmund-Thompson syndrome. He presented with adactyly of the right thumb, hypoplasia of the left thumb, delayed growth and psychomotor development. At 3 months, he presented rough, dry, sparse hair and erythematous lesions on the face, leaving hyperpigmented and hypopigmented spots with a reticulated pattern. We detected hypoacusis, skeletal alterations, narrow chin, short stature, severe malnutrition, and chronic and asymptomatic hypodontia. Genetic sequencing showed a mutation for the RECQL4 gene, for which a multidisciplinary follow-up was provided by the genetics, gastroenterology, nutrition, endocrinology, stomatology, audiology, orthopedics, rehabilitation, ophthalmology and oncology services. Case 2. A 2-year-old female patient presented facial erythema that spread to the arms and legs at 3 months; skin biopsy showed poikiloderma. She was evaluated by the endocrinology service and followed up for short stature and hypogonadism. A genetic study was not performed. CONCLUSIONS: Rothmund-Thomson syndrome is characterized by atrophy. Only a few cases are reported in the literature. We present two cases of Rothmund-Thomson syndrome, emphasizing its clinical and dermatological characteristics.

INTRODUCCIÓN: El síndrome de Rothmund-Thomson, también conocido como poiquilodermia congénita, es una rara genodermatosis autosómica recesiva de inicio en la infancia temprana y afectación multisistémica. CASOS CLÍNICOS: Se describen dos casos de pacientes con síndrome de Rothmund-Thomson. Caso 1. Paciente de sexo masculino de 4 años de edad, padres consanguíneos, hermano de 26 años con diagnóstico probable de síndrome de Rothmund-Thompson. Presentó adactilia del pulgar derecho, hipoplasia de pulgar izquierdo, retraso en el crecimiento y retraso del desarrollo psicomotor. A los 3 meses de edad mostraba pelo áspero, seco y escaso, y lesiones eritematosas en la cara, las cuales dejaron manchas hiperpigmentadas e hipopigmentadas con patrón reticulado. Se detectaron hipoacusia, alteraciones esqueléticas, mentón estrecho, talla baja, desnutrición grave e hipodontia crónica y asintomática. La secuenciación genética resultó con mutación para el gen RECQL4, por lo que se dio seguimiento multidisciplinario por los servicios de genética, gastroenterología, nutrición, endocrinología, estomatología, audiología, ortopedia, rehabilitación, oftalmología y oncología. Caso 2. Paciente de sexo femenino de 2 años de edad que a los 3 meses de vida inició con eritema facial que se diseminó a los brazos y la piernas; la biopsia de piel reportó poiquilodermia. Se encuentra en seguimiento por el servicio de endocrinología por talla baja e hipogonadismo. No se realizó estudio genético. CONCLUSIONES: El síndrome de Rothmund-Thomson se caracteriza por atrofia. Existen pocos casos reportados en la literatura. Se presentan dos casos de síndrome de Rothmund-Thomson, enfatizando sus características clínicas y dermatológicas.

Novel pathogenic variants in the RECQL4 gene causing Rothmund-Thomson syndrome in three Chinese patients.

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.

Inherited skin disorders presenting with poikiloderma.

Poikiloderma is a skin condition that combines atrophy, telangiectasia, and macular pigment changes (hypo- as well as hyperpigmentation). It is often mistaken for mottled pigmentation by general practitioners or nondermatology specialists. Poikiloderma can be a key presenting symptom of Rothmund-Thomson syndrome (RTS), dyskeratosis congenita (DC), hereditary sclerosing poikiloderma (HSP), hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP), xeroderma pigmentosum (XP), Bloom syndrome (BS), Kindler syndrome (KS), and Clericuzio-type poikiloderma with neutropenia (PN). In these conditions, poikiloderma starts early in life, usually before the second or third year. They may also be associated with photosensitivity and other significant multi-organ manifestation developed later in life. Poikiloderma could indicate the presence of a genetic disorder with potentially serious consequences. Poikiloderma almost always precedes more severe manifestations of these genodermatoses. Prompt diagnosis at the time of presentation could help to prevent complications and mitigate the course of the disease. This review discusses these to help the practicing clinician manage patients presenting with the symptom. To further facilitate early recognition, this paper also proposes a simple diagnostic algorithm.

Second Osteosarcoma in a 16-Year-old Woman Diagnosed With Rothmund-Thomson Syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma (OS) when it is caused by concrete mutations in the RECQL4 gene. Most OSs arise sporadically, but it can also be the first manifestation of a cancer predisposition syndrome as Rothmund Thompson. The early onset, multifocality and metachronism, and a family history of the disease, may suggest a tumor predisposition syndrome. We present the case of a patient with a polymalformative syndrome, who, at 6 years of age, was diagnosed with OS in the right femur. This led to the diagnosis of a RTS type 2. She was cured and surveillance showed no sign of disease. Ten years later, the patient developed a second OS in the contralateral femur. Fortunately, she is in complete remission again after treatment. We describe our patient treatment and recommend a possible screening-surveillance for RTS type II patients.

Ophthalmic manifestations in Rothmund-Thomson syndrome: Case report and review of literature.

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.

Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome.

We present a patient with poikiloderma, severe osteoporosis and a mild intellectual disability. At the age of 9 years, this patient was proposed to suffer from a novel disease entity designated as calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnormalities (COPS) syndrome. At the age of 35, he was diagnosed with Hodgkin's lymphoma. Recently, biallelic pathogenic variants in the RECQL4 gene were detected (c.1048_1049delAG and c.1391-1G>A), confirming a diagnosis of Rothmund-Thomson syndrome (RTS). In the brother of this patient, who had a milder phenotype, a similar diagnosis was made. CONCLUSION: We conclude that COPS syndrome never existed as a separate syndrome entity. Instead, osteoma cutis may be regarded as a novel feature of RTS, whereas mild intellectual disability and lymphoma may be underreported parts of the phenotype. What is new: • Osteoma cutis was not a known feature in Rothmund-Thomson patients. • Intellectual disability may be considered a rare feature in RTS; more study is needed. What is known: • RTS is a well-described syndrome caused by mutations in the RECQL4 gene. • Patients with RTS frequently show chromosomal abnormalities like, e.g. mosaic trisomy 8.

Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders.

Rothmund-Thomson Syndrome (RTS) is a rare autosomal recessive disease which manifests several clinical features of accelerated aging. These findings include atrophic skin and pigment changes, alopecia, osteopenia, cataracts, and an increased incidence of cancer for patients carrying RECQL4 germline mutations. Mutations in RECQL4 are responsible for the majority of cases of RTS. RECQL4 belongs to RECQ DNA helicase family which has been shown to participate in many aspects of DNA metabolism. In the past several years, accumulated evidence indicates that RECQL4 is important not only in cancer development but also in the aging process. In this review, based on recent research data, we summarize the common aging findings in RTS patients and propose possible mechanisms to explain the aging features in these patients.

Síndrome de Rothmund / Rothmund syndrome

RESUMO A síndrome de Rothmund (RTS) é uma rara genodermatose, de herança autossômica recessiva. Sua incidência é desconhecida, com aproximadamente 300 casos descritos na literatura. A síndrome é determinada por eritema facial (poiquilodermia), seu marco diagnóstico, além de alterações esqueléticas, alopecia, catarata juvenil e predisposição a osteossarcoma. Neste relato, descrevemos uma paciente com esta síndrome, que foi referida ao serviço de oftalmologia por baixa visão e hiperemia ocular.

ABSTRACT Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis. While its incidence is unknown, approximately 300 cases have been reported in the literature. The syndrome typically presents with a characteristic facial rash (poikiloderma), its diagnostic hallmark, and heterogeneous clinical features including congenital skeletal abnormalities, sparse hair distribution, juvenile cataracts, and a predisposition to osteosarcoma. This is a report describing a patient diagnosed with RTS referred to us because of low vision and red eyes.

Dental management of Rothmund-Thomson syndrome with partial anodontia.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive trait disease. It is characterised by skin, eye and skeletal abnormalities. Abnormalities associated with teeth include abnormal crown and root formations, rudimentary or hypoplastic teeth, microdontia and multiple missing teeth. In the present case, there were multiple decayed primary teeth and multiple congenitally missing permanent teeth. Mandibular left primary first molar (tooth 74) was pulpally involved and obturated with mineral trioxide ggregate. Follow-up after 2 years revealed successful obturation.

Kindler's syndrome: a report of five cases in a family.

Kindler's Syndrome (KS) is a rare genodermatosis with autosomal recessive mode of inheritance. The disease results from homozygous mutations on both alleles of the FERMT-1 gene (also known as KIND-1 gene) that encodes the protein Kindlin-1 (kindlerin). Clinical features include a constellation of early infantile skin blistering and mild photosensitivity, which improves with age, and progressive poikiloderma with widespread cutaneous atrophy. The differential diagnosis of Kindler syndrome include other congenital poikilodermatous and photosensitive conditions including Bloom syndrome, Cockayne syndrome, dyskeratosis congenita, epidermolysis bullosa, Rothmund-Thomson syndrome and xeroderma pigmentosum. We herein, report the presence of the Kindler's syndrome in 5 out of 7 children of consanguineous parents. To authors' knowledge, this is the first report of Kindler's syndrome involving 5 members of a family.

[Rare hereditary tumours]. / Ritka örökletes daganatok.

Almost 5-10% of all tumours are hereditary, which manifest in tumour syndrome or neoplasmic complication of a genetic disease. We present a short introduction of some of these rare diseases through our patients with the aspect of the clinical signs, diversities and challenges. These cases indicate that the incidency of malignancies are increased at genetic diseases, it means even multiple neoplasms in the same patient. The therapy does not differ from the ordinary tumour's therapy and the results are nearly the same as in cases without genetic diseases.