Early diagnosis of mucopolysaccharidosis type III (Sanfilippo syndrome) in the practice of a pediatrician

Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) is a lysosomal storage disease inherited in an autosomal recessive manner, it is characterized by the accumulation of heparan sulfate in the cells of the body, which leads to the development of multiple organ failure. It occurs with a frequency of 1: 70 thousand newborns. There are 4 subtypes of the disease: A, B, C, D. Cognitive and neurological disorders are the earliest symptoms of the disease. Delay (loss) of speech development, regression of acquired skills, hyperreactivity, autistic character traits, mental retardation, sleep disturbance, epilepsy are noted; aggressive behavior is formed, the ability to move is impaired, hepatomegaly appears. There are observed the violations of other organs and systems – the organ of vision, bone, respiratory, cardiovascular systems, ENT organs, dental problems. Clinically, the subtypes of mucopolysaccharidosis III are practically indistinguishable. The average age at diagnosis is 2–6 years. Diagnostic search includes qualitative and quantitative determination of glycosaminoglycans in urine. It should be remembered that with mild variants of the disease, these indicators may be within the normal range. In the future, it is necessary to assess the activity of the corresponding enzymes in leukocytes, plasma or serum, in skin fibroblasts. Genetic testing is then performed to identify the mutation of the corresponding defective gene. Differential diagnosis should be carried out with other types of mucopolysaccharidosis, mucolipidosis, gangliosidosis, multiple sulfatase deficiency, some rheumatoid diseases.

Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study

Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient’s phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

Collagen VI-Related Myopathies: Genetic and Clinical Findings

Introduction: Collagen VI-related disorders are a group of heterogeneous muscular diseases due to mutations within the COL6A1, COL6A2, and COL6A3 genes, encoding collagen VI as an essential component of the extracellular matrix. Here, we reported four patients affected by collagen VI-related disorders with genetic variants in COL6A genes. Case Presentation: After a comprehensive clinical examination, four unrelated patients with muscular dystrophy were referred for genetic counseling. Whole-exome sequencing followed by Insilco analysis was done for one affected individual from each family. The analysis of genomic data revealed four different mutations within the COL6A1, COL6A2, and COL6A3 genes in the affected individuals. Conclusions: According to the previous reports, limb-girdle muscular dystrophy is inherited as autosomal dominant, and congenital myosclerosis phenotype is inherited in an autosomal recessive manner. Carrier testing and prenatal testing are possible if pathogenic variants are recognized in an affected family member.

Clinical experience of observation and tactics of management of a patient with ectodermal angydrotic dysplasia

The concept of ectodermal dysplasias covers a group of rare hereditary developmental anomalies that have a variety of phenotypic variants, but are characterized by common signs of underdevelopment or abnormal formation of organs and tissues derived from the ectodermal layer (skin and its derivatives - nails, hair, teeth, nervous system and sensory organs) ... Approximately 25% of ectodermal dysplasias known to date are inherited in an autosomal dominant or autosomal recessive manner; in other cases, the mode of inheritance is unclear. The syndrome is characterized by a wide range of clinical manifestations and may include additional symptoms of damage to other ectodermal, mesodermal, and endodermal structures. Ectodermal anomalies are a manifestation of disturbances in spatial-temporal coordination during the development of the epidermis. They involve genes such as EGF (epidermal growth factor), ED1 (ectodisplasin), EDAR (anhydrotic receptor ectodysplasin 1) and others that regulate the activity of genes involved in epidermal morphogenesis by activating or suppressing transcription factors (in particular, pb3; Koster). So far, only about 20% of genes have been identified that are responsible for about 200 ectodermal dysplasias of various symptoms and severity. This article describes the clinical observation of a patient with a rare disease - ectodermal anhydrotic dysplasia. The literature data on the clinical features of the course of this dermatosis, as well as the features of the course in this patient are presented.

Epidermodysplasia Verruciformis: A Case Report and a Brief Review

Epidermodysplasia verruciformis is an uncommon disorder that is transmitted in an autosomal recessive manner. It is characterized by increased susceptibility to human papillomavirus infection, which presents with hypo- or hyperpigmented macular lesions, pityriasis versicolor-like lesions, and an early tendency to transform into skin cancer. We present a case of a 40-year-old male with complaints of verrucous lesions of the hands and feet. Histopathology was suggestive of EV.

Laron syndrome: a case report

Laron syndrome (LS) is a rare, genetic disorder inherited in an autosomal recessive manner. The disease is caused by mutations of the growth hormone (GH) gene, leading to GH/insulin-like growth factor type 1 (IGF1) signalling pathway defect. A 13-month-old, male child, born of second-degree consanguineous marriage presented with short stature (57 cm, below- 3 SD) with normal head size, mild motor developmental delay, micropenis and bone age of 9 months. Basal GH was 28.7 ng/ml (normal 1-13.6 ng/ml). IGF-1 was less than 20 ng/ml (normal up to 170 ng/ml). GH stimulation test done using clonidine revealed increased levels. Post stimulation levels at 30 min, 60 min, 90 min (ng/ml) were 29.3, 37.9, 29.3 respectively, which was suggestive of resistance to GH that is laron dwarfism. Treatment is focused on improving growth and generally includes injections of insulin-like growth factor 1 (IGF-1). This case is being reported for its rarity and early detection.

TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss

Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.

Dwarfism in Tibetan Terrier dogs with an LHX3 mutation

Canine pituitary dwarfism in German Shepherd and related dog breeds has been reported to be associated with a 7-bp deletion mutation in intron 5 of the LHX3 gene. This mutation is transmitted as an autosomal recessive trait that results in dwarf dogs with significantly smaller stature and abnormal haircoat, and potentially early death. Phenotypically, affected adult dogs are proportionally dwarfs. These dwarfs also have a soft, woolly puppy coat that fails to transition into the typical adult hair coat, and marked hair loss occurs in some dogs. We report a similar manifestation of dwarfism in Tibetan Terriers with the same LHX3 mutation. Dwarf Tibetan Terrier puppies were born physically normal but failed to gain weight or to grow at the same rate as their normal littermates. The 7-bp deletion mutation of the LHX3 gene was identified in both alleles of 3 Tibetan Terrier dwarfs from 3 litters, which were biologically related. All parents of these dogs are carriers, confirming transmission of dwarfism in an autosomal recessive manner. Recognition and detection of this mutation will help in guiding future breeding plans to eventually eliminate this trait from Tibetan Terriers.

Xeroderma Pigmentosum: Important Oral Manifestations Case Report

The Xeroderma pigmentosum [XP] is a rare inherited skin disorder and transmitted in an autosomal recessive manner. The aim of the present article is to report a XP case with oral manifestations and to discuss the role of the dental professional management of this entity. A 5 year old male presented lentigos all over the skin and predominated in photoexposed areas. Oral hygiene was good and dental affection was important. No lesions were observed in the lips, tongue and the rest of the bucal mucosa but multiples teeth with cavities were observed. Antibiotic treatment was started and surgical treatment. Besides dermatological, ophtamological and neurological management, XP patients require constant dental care and follow –up in order to control the occurrence of new lesions on the lips or inside oral cavity.

A New Intronic Variant in ECEL1 in Two Patients with Distal Arthrogryposis Type 5D

Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence.