Premature aging syndromes are a group of ultra-rare heterogeneous hereditary diseases that manifest predominantly in childhood and are characterized by accelerated aging of the organism. Despite differences in pathogenesis, the diseases are characterized by multisystem changes, including lesions of the musculoskeletal system, which are represented by multiple joint contractures, deformations of the spine and limbs, and changes in bone structure. The examination data of 6 patients were analyzed: 5 children (3 boys and 2 girls) with pediatric progeria (Hutchinson-Gilford syndrome) (4 patients with classic genotype of pediatric progeria (c.1824 C>T in the LMNA gene) and 1 child with a non-classical (c.1968+1G>A in the LMNA gene)) and one girl with neonatal progeria (Wiedemann-Rautenstrauch syndrome) (c.3337- 11T>C/ c.3677T>C in the POLR3A gene). The diagnosis was made at the age of 1.9 (1.5; 4.3) years (Me (25%; 75%)). Patients were under the supervision of a pediatric endocrinologist, examined by an orthopedic traumatologist, radiologic studies, and densitometry of the lumbar spine were performed. The age at the time of the initial examination was 6.0 (3.5; 7.2) years, and at the time of the repeated examination — 7.6 (7.5; 9.3) years. Bone and joint changes in Hutchinson-Gilford syndrome were represented by contractures of interphalangeal joints of fingers and toes, wrist, elbow, hip, knee, and ankle joints, and flat-valgus feet; in a patient with a nonclassical genotype of pediatric progeria, these changes were diagnosed at the first examination at 1 year 6 months of age, which confirms the severe course of the disease in this genotype. In 2 older patients (7 years 5 months and 9 years 10 months) coxa valga on 2 sides with development of aseptic necrosis of the femoral head and closed dislocation of the left femur were also diagnosed. In neonatal progeroid syndrome, musculoskeletal lesions were manifested as multiple contractures of large and small joints and spinal deformity. Bone age either corresponded to the chronologic age or lagged behind by 18 (15; 26) months All patients were diagnosed with osteoporosis according to densitometry (Z-criterion: -3.4 (-3.0; -3.8)); no fractures were recorded. The revealed changes in bone tissue and musculoskeletal system in our patients correspond to the features described in the world literature in patients with Hutchinson-Gilford and Wiedemann-Rautenstrauch syndromes. The similarity of pathologic changes indicates the similarity of phenotypes of diseases included in the group of premature aging syndromes.

Background: Pathogenic biallelic variants in POLR3A have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann–Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Case presentation: Here, we present the detailed clinical course of a 20-year-old woman who presented with developmental delays, neurological deficits, metabolic abnormalities, and sleep disturbances. She was born to non-consanguineous parents and had an elder sister who usually behaved. Laboratory studies demonstrated low or undetectable LH and FSH levels and abnormally low estradiol levels. MRI showed leukoencephalopathy characterized by white matter lesions and brain atrophy. Homozygous missense mutation c.2984C>T (p.Thr995Ile) was found in POLR3A, which codes for the largest subunit of RNA polymerase Ill. Conclusions: POLR3A-induced leukodystrophy is relatively rare and not well understood, making it challenging to diagnose and easy to overlook. The prognosis for this disease is generally poor, significantly impacting the quality of life of affected individuals. Since Pol III-related leukodystrophies shows various combination of neurologic and non-neurologic features, additional report will help to bring crucial information concerning this molecular diagnosis, the prediction of the disease and practical consequences for genetic counseling.

BACKGROUND: Wiedemann-Rautenstrauch Syndrome (WRS) is a neonatal progeroid syndrome for which biallelic pathogenic variants in RNA polymerase III subunit A (POLR3A) have recently been described. POLR3 is a 17 subunits protein complex responsible for the transcription of short RNAs including all the transfer RNAs (tRNAs), the 5 S subunit of ribosomal RNA, the short nuclear RNA U6, among other regulatory RNAs. OBJECTIVE: We aim to evaluate the impact of POLR3A pathogenic variants on the relative expression of the short nuclear RNA U6 and on the differential profile of intron retention RNA U6, p53 isoforms and in fibroblasts derived from patients with WRS and control fibroblasts. METHODS: RNA was extracted by the TRIzol method; intron retention analysis was performed by using IRFinder from an mRNA sequencing (RNA-Seq) platform; P53 isoforms, short nuclear RNA U6 and additional genes related to cell senescence were measured by RT-PCR. RESULTS: No significant differences were found in the percentage of intron retention (control: 7.8%, WRS1 : 6.3%and WRS2 : 8.14%). Genes showing higher intron retention profile in both groups were mainly related to RNA binding pathways, cell cycle regulation, positive regulation of transcription, positive regulation of inflammatory pathways, negative regulation of apoptosis, RNA transcription, mitochondria, and regulation of translation initiation. However, in WRS fibroblasts the genes with more intron retention were those related to the immune response and mitochondrial function; while in control those related to the response to oxidative stress had the most introns retained. WRS1 showed higher expression of short nuclear RNA U6 compared to control and WRS2; while both WRS cells showed higher expression of p53β and lower percentage of Δ133p63α, consistent with a higher expression of the cellular senescence markers p16 and p21. CONCLUSIONS: These results demonstrated the important role of POLR3A in the maintenance of cellular homeostasis and highlight its potential role in cell senescence in WRS.

Синдром Видемана-Раутенштрауха (неонатальный прогероидный синдром) — ультраорфанное заболевание из группы синдромов преждевременного старения с аутосомно-рецессивным типом наследования, ассоциированный с мутациями в генах POLR3A, POLR3B и POLR3GL, кодирующих РНК-полимеразу III. Частота заболевания в настоящее время неизвестна. Мы представляем первое в Российской Федерации клиническое описание пациента 7 лет 6 месяцев с синдромом Видемана-Раутенштрауха (компаунд-гетерозиготные мутации в гене POLR3A) с прогероидными чертами, адентией, задержкой роста (SDS роста -3,41, SDS скорости роста -2,47), дефицитом массы тела (SDS ИМТ -6,20) и генерализованной липодистрофией. В статье представлено наблюдение пациента на протяжении 1,5 года, рассмотрен мировой опыт динамического наблюдения пациентов с неонатальным прогероидным синдромом, дифференциальная диагностика, а также даны рекомендации по ведению пациентов с данным заболеванием. Учитывая отсутствие на сегодняшний день специфического лечения, пациенты наблюдаются многопрофильной командой врачей.

Aim. Аnalysis and synthesis of the literature data on the problem of differential diagnosis of neonatal progeroid syndrome. Key points. One of the rarest representatives of premature aging syndromes is neonatal progeroid syndrome (Wiedemann–Rautenstrauch syndrome). It is an ultra-orphan disease with autosomal recessive type of inheritance, associated with a mutation in the POLR3A, POLR3B, POLR3GL genes and characterized by congenital lipodystrophy and premature aging. The disease manifests from the first days of life: low body length and weight at birth, pronounced phenotypic features (pseudohydrocephaly, progeroid facial features, generalized lipodystrophy, neonatal incisors). Severe bronchopulmonary and skeletal damage is seen over the course of life, and average life expectancy ranges from 7 months to 2 years but can reach 27 years. The differential diagnosis is made with Hutchinson–Gilford syndrome (progeria), which clinical signs manifest at 1.5-2 years of age, and with Marfan-progeroid lipodystrophy, Fontaine syndrome, and Sekkel syndrome. Conclusion. Early diagnostics is necessary for predicting the course of the disease, selection of treatment, and determining of further management. Keywords: neonatal progeroid syndrome, Wiedemann–Rautenstrauch syndrome, premature aging syndromes

Neonatal-progeroid syndrome known as Wiedemann Rautenstrauch syndrome (WRS) is an extremely rare, autosomal recessive disorder. Neonatal progeroid disease characterized by progeroid appearance growth retardation, lipodystrophy, an unusual face (triangular shape, sparse hair, small mouth, macrocephaly, pointed jaw), thin skin, hard and thick joints and dental anomalies (newborn tooth; hypodontics). A 5-year-old boy case diagnosed with hypodontics is presented. In this case, a child prosthesis was performed to facilitate the nutrition of the patient and to increase the quality of life.

CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3. In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients' fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients' fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence. The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

ObjectiveTo expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.MethodsWe performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [1H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.ResultsThe patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant.ConclusionsMutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate.

The extracellular matrix microenvironment of adipose tissue is of critical importance for the differentiation, remodeling and function of adipocytes. Fibrillin-1 is one of the main components of microfibrils and a key player in this process. Furin processing of profibrillin-1 results in mature fibrillin-1 and releases the C-terminal propeptide as a circulating hunger hormone, asprosin. Mutations in the fibrillin-1 gene lead to adipose tissue dysfunction and causes Marfan syndrome, marfanoid progeroid lipodystrophy syndrome, and neonatal progeroid syndrome. Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils. Circulating asprosin on the other hand is secreted primarily by white adipose tissue under fasting conditions and in obesity. It increases hepatic glucose production and drives insulin secretion and appetite stimulation through inter-organ cross talk. This review discusses the metabolic consequences of fibrillin-1 and fibrillin-1-derived asprosin in pathological conditions. Understanding the dynamic role of fibrillin-1 in the adipose tissue milieu and of circulating asprosin in the body can provide novel mechanistic insights into how fibrillin-1 may contribute to metabolic syndrome. This could lead to new management regimens of patients with metabolic disease.

Genetic studies of patients with neonatal progeroid syndrome led to the discovery of the novel fasting-induced, glucogenic, and orexigenic hormone named asprosin, the C-terminal cleavage product of profibrillin. Upon secretion, asprosin travels to the liver, where it exerts a glucogenic effect through OR4M1, an olfactory G-protein-coupled receptor. It also crosses the blood-brain barrier to stimulate appetite-modulating neurons in the arcuate nucleus of the hypothalamus, exerting an orexigenic effect via an as yet unidentified receptor. Specifically, it stimulates appetite by activating orexigenic AgRP neurons and inhibiting anorexigenic POMC neurons. Studies have also focused on the therapeutic potential of inhibiting asprosin for treatment of obesity and type 2 diabetes, both of which are characterized by high levels of circulating asprosin. It has been shown that anti-asprosin monoclonal antibodies reduce blood glucose, appetite, and body weight, validating asprosin as a therapeutic target. Current work aims to uncover key features of the asprosin biology such as the identification of its neuronal receptor, identification of the secretion mechanism from adipose tissue, and development of anti-asprosin monoclonal antibodies as diabetes and obesity therapies.

Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome

Wiedemann-Rautenstrauch syndrome (WRS) is a rare autosomal recessive disorder that includes premature aging phenotype at birth. The condition is also known as a neonatal progeroid syndrome. Up to now only a few published case reports have been documented. The syndrome is characterized by progeroid appearance, decreased subcutaneous fat, hypotrichosis, macrocephaly, and in some natal teeth. We describe a new patient with features of bilaterally pelvicalyceal ectasia and partial syndactyly on 2th and 3th toes, not previously described, to our knowledge.

A female, 26months old with features supporting the diagnosis of neonatal progeroid syndrome was presented. She had prenatal and postnatal growth failure, generalized lipoatrophy except for fat pads in the suprabuttock areas, triangular face, pseudohydrocephalous, sparse scalp hair and eyebrows, prominent scalp veins, greatly widened anterior fontanels, and moderate mental retardation. The patient had also some features not reported previously as premature loss of milk teeth, large mouth, atrophic gums, protruded lower jaw, and café aulait skin patches on lower limbs. Nail dystrophy was also detected. She had local depression of the left parietal bone on CT brain, white matter demyelination in MRI brain, and high level of cholesterol.

Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome (NPS), is an extremely rare genetic disorder characterised by an aged appearance at birth. About thirty cases have been reported in the literature. The authors report first Indian baby with Wiedemann-Rautenstrauch syndrome with the lowest birth weight documented in such a patient, who is still surviving at 24 months. This ethnicity has not been reported previously in literature.

We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed a novel de novo heterozygous deletion, c.8155_8156del2 in exon 64. The severe generalized lipodystrophy in this patient with progeroid features has not previously been described in other patients with MFS and FBN1 mutations. We did not find a mutation in genes known to be associated with congenital lipodystrophy (APGAT2, BSCL2, CAV1, PTRF-CAVIN, PPARG, LMNB2) or with Hutchinson-Gilford progeria (ZMPSTE24, LMNA/C). Other progeria syndromes were considered unlikely because premature greying, hypogonadism, and scleroderma-like skin disease were not present. Our patient shows striking similarity to two patients who have been published in this journal by O'Neill et al. [O'Neill et al. (2007); Am J Med Genet Part A 143A:1421-1430] with the diagnosis of neonatal progeroid syndrome (NPS). This condition also known as Wiedemann-Rautenstrauch syndrome is a rare disorder characterized by accelerated aging and lipodystrophy from birth, poor postnatal weight gain, and characteristic facial features. The course is usually progressive with early lethality. However this entity seems heterogeneous. We suggest that our patient and the two similar cases described before represent a new entity, a subgroup of MFS with overlapping features to NPS syndrome.

Natural Course of Neonatal Progeroid Syndrome

The neonatal progeroid syndrome (Wiedemann–Rautenstrauch): A model for the study of human aging?

Neonatal progeroid syndrome (NPS), also known as Wiedemann-Rautenstrauch Syndrome, is a rare autosomal recessive disorder characterized by accelerated aging and lipodystrophy from birth. Affected children have extreme intrauterine growth retardation, poor postnatal weight gain, and characteristic facial dysmorphic features such as a triangular shape, pinched nose, pseudohydrocephalus with wide fontanelles and prominent subcutaneous (sc) veins. Generalized loss of sc fat has been reported as a cardinal feature; however, the pattern of fat loss and its association with insulin resistance and its metabolic complications have not been systematically studied. The aim of the current study was to examine body fat distribution and body composition in two girls with NPS using anthropometric measures, whole-body magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry (DEXA), and to assess metabolic complications such as hyperinsulinemia and dyslipidemia. Both the girls (aged 17 years and 10 years, respectively) had generalized paucity of sc fat on physical examination. However, measurements of skin-fold thickness revealed that sc fat was decreased over the extremities, but preserved over the chest and abdomen. MRI studies confirmed the presence of normal amounts of sc truncal fat, and marked loss of fat from the face and distal extremities. Striking fat loss was also noted in the paravertebral and lateral gluteal regions. Interestingly, body composition analysis with DEXA scan revealed a marked reduction in both the fat and lean tissue mass. Fasting glucose, lipids and insulin levels were not elevated. We conclude that patients with NPS do not have generalized lipodystrophy as previously reported, but fat loss is confined to the face, distal extremities, and possibly the paravertebral and lateral gluteal regions. Metabolic abnormalities related to insulin resistance are also uncommon in this condition.

Propofol infusion syndrome during anaesthesia for scoliosis surgery in an adolescent with neonatal progeroid syndrome