Clinical phenotype characteristics and genetic analysis in children with nephronophthisis and related syndromes caused by different gene mutations / 中国当代儿科杂志

OBJECTIVES@#To improve the understanding of the clinical phenotypes and genetic characteristics of nephronophthisis (NPHP) and related syndromes in children.@*METHODS@#A retrospective analysis was performed on the medical data of eight children with NPHP and related syndromes who were diagnosed and treated in the Department of Pediatrics of the Second Hospital of Hebei Medical University, from January 2018 to November 2022. The clinical characteristics and genetic testing results were analyzed.@*RESULTS@#Among these eight children, there were five boys and three girls, with an age of onset ranging from 15 months to 12 years. All 8 children exhibited different degrees of renal function abnormalities when they attended the hospital. Among the eight children, two had the initial symptom of delayed development, two had the initial symptom of anemia, and two were found to have abnormal renal function during physical examination. The extrarenal manifestations included cardiovascular abnormalities in two children, skeletal dysplasia in two children, liver dysfunction in one child, retinitis pigmentosa in one child, and visceral translocation in one child. All eight children had renal structural changes on ultrasound, and four children had mild to moderate proteinuria based on routine urine test. Of all eight children, five had NPHP1 gene mutations and one each had a gene mutation in the NPHP3, IFT140, and TTC21B genes, and four new mutation sites were discovered.@*CONCLUSIONS@#Children with NPHP and related syndromes often have the initial symptom of delayed development or anemia, and some children also have extrarenal manifestations. NPHP and related syndromes should be considered for children with unexplained renal dysfunction, and high-throughput sequencing may help to make a confirmed diagnosis.

Interplay Between Primary Cilia and Autophagy and Its Controversial Roles in Cancer

Primary cilia and autophagy are two distinct nutrient-sensing machineries required for maintaining intracellular energy homeostasis, either via signal transduction or recycling of macromolecules from cargo breakdown, respectively. Potential correlations between primary cilia and autophagy have been recently suggested and their relationship may increase our understanding of the pathogenesis of human diseases, including ciliopathies and cancer. In this review, we cover the current issues concerning the bidirectional interaction between primary cilia and autophagy and discuss its role in cancer with cilia defect.

Bardet–Biedl syndrome: Genetics, molecular pathophysiology, and disease management.

Primary cilia play a key role in sensory perception and various signaling pathways. Any defect in them leads to group of disorders called ciliopathies, and Bardet–Biedl syndrome (BBS, OMIM 209900) is one among them. The disorder is clinically and genetically heterogeneous, with various primary and secondary clinical manifestations, and shows autosomal recessive inheritance and highly prevalent in inbred/consanguineous populations. The disease mapped to at least twenty different genes (BBS1-BBS20), follow oligogenic inheritance pattern. BBS proteins localizes to the centerosome and regulates the biogenesis and functions of the cilia. In BBS, the functioning of various systemic organs (with ciliated cells) gets deranged and results in systemic manifestations. Certain components of the disease (such as obesity, diabetes, and renal problems) when noticed earlier offer a disease management benefit to the patients. However, the awareness of the disease is comparatively low and most often noticed only after severe vision loss in patients, which is usually in the first decade of the patient’s age. In the current review, we have provided the recent updates retrieved from various types of scientific literature through journals, on the genetics, its molecular relevance, and the clinical outcome in BBS. The review in nutshell would provide the basic awareness of the disease that will have an impact in disease management and counseling benefits to the patients and their families.

Association of Joubert Syndrome and Hirschsprung Disease.

Background: Association between Joubert Syndrome and Hirschsprung disease is rare. Case characteristics: A 9-month-old girl having developmental delay and chronic constipation. Observation: Molar tooth sign on MRI brain and absence of ganglion cells in rectal biopsy specimen. Outcome: Child underwent surgical repair for Hirschsprung disease. Message: Association of these two rare entities could be explained by ciliopathy.

Identification of Two Cases of Ciliopathy-Associated Diabetes and Their Mutation Analysis Using Whole Exome Sequencing

BACKGROUND: Alstrom syndrome and Bardet-Biedl syndrome are autosomal recessively inherited ciliopathies with common characteristics of obesity, diabetes, and blindness. Alstrom syndrome is caused by a mutation in the ALMS1 gene, and Bardet-Biedl syndrome is caused by mutations in BBS1-16 genes. Herein we report genetically confirmed cases of Alstrom syndrome and Bardet-Biedl syndrome in Korea using whole exome sequencing. METHODS: Exome capture was done using SureSelect Human All Exon Kit V4+UTRs (Agilent Technologies). HiSeq2000 system (Illumina) was used for massive parallel sequencing. Sanger sequencing was used for genotype confirmation and familial cosegregation analysis. RESULTS: A 21-year old Korean woman was clinically diagnosed with Alstrom syndrome. She had diabetes, blindness, obesity, severe insulin resistance, and hearing loss. Whole exome sequencing revealed a nonsense mutation in exon 10 of ALMS1 (c.8776C>T, p.R2926X) and a seven base-pair deletion resulting in frameshift mutation in exon 8 (c.6410_6416del, p.2137_2139del). A 24-year-old Korean man had Bardet-Biedl syndrome with diabetes, blindness, obesity, and a history of polydactyly. Whole exome sequencing revealed a nonsynonymous mutation in exon 11 of the BBS1 gene (c.1061A>G, p.E354G) and mutation at the normal splicing recognition site of exon 7 of the BBS1 gene (c.519-1G>T). CONCLUSION: We found novel compound heterozygous mutations of Alstrom syndrome and Bardet-Biedl syndrome using whole exome sequencing. The whole exome sequencing successfully identified novel genetic variants of ciliopathy-associated diabetes.

Nephronophthisis

NPHP is the most common monogenic cause of CKD in children or adolescents. Extra-renal symptoms often accompany, therefore examination of retina, hearing, and skeleton is necessary in patients with CKD with insidious onset. Genes involved in NPHP-RC are mostly related in primary cilia. While genetic diagnosis is necessary for definitive diagnosis, there is no curative treatment.

Nephronophthisis

NPHP is the most common monogenic cause of CKD in children or adolescents. Extra-renal symptoms often accompany, therefore examination of retina, hearing, and skeleton is necessary in patients with CKD with insidious onset. Genes involved in NPHP-RC are mostly related in primary cilia. While genetic diagnosis is necessary for definitive diagnosis, there is no curative treatment.

Bardet-Biedl syndrome: A rare case report from North India.

The Bardet-Biedl syndrome (BBS) is a rare ciliopathic human autosomal-recessive disorder, affecting multiple organ systems. Less than 15 cases have been reported from India. The authors present a classical case of BBS presenting to dermatology outpatient with hypogonadism and features such as marked central obesity, retinal dystrophy, polydactyly, structural renal abnormalities and mental retardation, along with a brief review of the literature. This case exemplifies the need for multidisciplinary management in such cases.