Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.

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.

Skin Abnormalities in Disorders with DNA Repair Defects, Premature Aging, and Mitochondrial Dysfunction.

Defects in DNA repair pathways and alterations of mitochondrial energy metabolism have been reported in multiple skin disorders. More than 10% of patients with primary mitochondrial dysfunction exhibit dermatological features including rashes and hair and pigmentation abnormalities. Accumulation of oxidative DNA damage and dysfunctional mitochondria affect cellular homeostasis leading to increased apoptosis. Emerging evidence demonstrates that genetic disorders of premature aging that alter DNA repair pathways and cause mitochondrial dysfunction, such as Rothmund-Thomson syndrome, Werner syndrome, and Cockayne syndrome, also exhibit skin disease. This article summarizes recent advances in the research pertaining to these syndromes and molecular mechanisms underlying their skin pathologies.

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.

El embarazo en el síndrome de Rothmund-Thomson, fertilidad y manejo / Pregnancy in Rothmund-Thomson syndrome: Fertility and management

Introducción: El síndrome de Rothmund-Thomson (SRT) es un trastorno de herencia autosómica recesiva, con alteraciones endocrino-dermatológicas principalmente. Existen 300 casos a nivel mundial. Solo descrita una gestación. Descripción del caso: Paciente con SRT que consigue 2 gestaciones espontáneas, de curso normal, finalizadas mediante parto vaginal a término, naciendo 2 mujeres sanas. Discusión: La fertilidad esta disminuida debido a un hipogonadismo hipogonadotropo, sin embargo, describimos 2 gestaciones exitosas y de curso normal. El diagnóstico se realiza por hallazgos clínicos y es posible realizar estudio molecular tras técnicas de diagnóstico prenatal invasivas. Es importante un diagnóstico diferencial correcto

Introduction: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disease with endocrine and dermatological alterations. There are 300 cases worldwide, but there is only one documented case of RTS during pregnancy. Case description: A patient had two spontaneous and uneventful pregnancies, giving birth to two healthy girls through vaginal delivery at term. Discussion: Decreased fertility is due to hypogonadotropic hypogonadism. However, we describe two successful and uneventful pregnancies. Diagnosis is based on clinical findings. Molecular study is possible with invasive prenatal diagnostic techniques. The differential diagnosis is very important

Ocular manifestations of genetic skin disorders.

Genetic skin diseases, or genodermatoses, often have extracutaneous manifestations. Ocular manifestations in particular can have significant clinical implications, like blindness. Other manifestations, such as the corneal opacities that occur in X-linked ichthyosis, are asymptomatic but characteristic of a particular genodermatosis. Ophthalmologic examination can aid in diagnosis when characteristic findings are seen. The genodermatoses with ocular manifestations will be reviewed, but neurocutaneous, syndromes, genetic pigmentary disorders, and genetic metabolic diseases are not included because they are covered elsewhere in this issue.

Delayed Union of a Jones Fracture in a Patient With Rothmund-Thomson Syndrome: A Case Report and Review of the Literature.

Rothmund-Thomson syndrome is a rare autosomal recessive genodermatosis, characterized by poikiloderma, small stature, juvenile cataracts, sparse hair, skeletal abnormalities, and a predisposition to osteogenic sarcomas and skin cancers. Although numerous skeletal abnormalities have been described in patients with Rothmund-Thomson syndrome, to our knowledge, only 1 study has shown evidence of delayed fracture healing in a patient with Rothmund-Thomson syndrome. We present the case of a 13-year-old female diagnosed with Rothmund-Thomson syndrome who demonstrated delayed union of her fifth metatarsal after a Jones fracture. She was treated conservatively for 6 weeks with non-weightbearing cast immobilization and was then transitioned to a controlled ankle motion walker for an additional 4 weeks. Two months later, however, she continued to experience pain, and, on radiographic examination, the fracture remained unchanged. Therefore, with her guardian's consent, the patient elected to undergo open reduction and internal fixation of the fifth metatarsal fracture. At 8 weeks postoperatively, the patient reported a subsidence of symptoms and had returned to normal activity. With our report, we hope to increase practitioner awareness that delayed bone healing could be a possibility in patients with Rothmund-Thomson syndrome and encourage consideration of routine imaging and supplementation with calcium and vitamin D. Additionally, the present findings suggest that patients with Rothmund-Thomson syndrome could benefit from early surgical intervention, given their poor bone healing capacity and high likelihood of nonunion. Although the association between impaired bone healing and Rothmund-Thomson syndrome is rational, additional studies are needed to determine the prevalence of chronic nonunion in this patient population.

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.

RECQ DNA helicases and osteosarcoma.

The RECQ family of DNA helicases is a conserved group of enzymes that are important for maintaining genomic integrity. In humans, there are five RECQ helicase genes, and mutations in three of them-BLM, WRN, and RECQL4-are associated with the genetic disorders Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome (RTS), respectively. Importantly all three diseases are cancer predisposition syndromes. Patients with RTS are highly and uniquely susceptible to developing osteosarcoma; thus, RTS provides a good model to study the pathogenesis of osteosarcoma. The "tumor suppressor" role of RECQL4 and the other RECQ helicases is an area of active investigation. This chapter reviews what is currently known about the cellular functions of RECQL4 and how these may relate to tumorigenesis, as well as ongoing efforts to understand RECQL4's functions in vivo using animal models. Understanding the RECQ pathways may provide insight into avenues for novel cancer therapies in the future.

Poikiloderma with neutropenia: a case report and review of the literature.

Poikiloderma with neutropenia (PN, OMIM 604173) is a rare autosomal-recessive genodermatosis. Mutations in the C16orf57 gene have been recently identified as the cause. Here we describe a new case of PN in a white patient, review the literature, and point out the attention on importance of differential diagnosis.

Mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis.

Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.

[Osteosarcoma in the patella in a patient with Rothmund-Thomson syndrome]. / Osteosarkom i patella hos patienter med Rothmund-Thomsons syndrom.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis. We describe a 31-year-old male known with RTS who had a rare presentation of osteosarcoma in the patella. He initially fractured the patella, and had surgery. On suspicion infection he was treated with antibiotics several times. His condition did not improve, and a biopsy was made consequently. Pathology showed osteosarcoma. The patella was removed, but later the patient had a femur amputation. This case emphasises that patients with rare genetic defects associated with high risk of cancer must be treated by specialists.