Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant.

Agammaglobulinemia represents the most profound primary antibody deficiency, stemming from early cessation of B-cell development. Deficiency in folliculin-interacting protein 1 (FNIP1) is a novel inborn error of immunity characterized by a severe defect in B-cell development, agammaglobulinemia, variable neutropenia, and hypertrophic cardiomyopathy. FNIP1 plays a critical role in B-cell development and metabolic homeostasis, establishing a metabolic checkpoint that ensures pre-B cells possess sufficient metabolic capacity to undergo division while concurrently limiting lymphogenesis due to abnormal growth. Disruption of FNIP1 functionality affects the fundamental metabolic regulators adenosine monophosphate-activated protein kinase and mTOR, culminating in a severe B-cell deficiency alongside hypogammaglobulinemia, hypertrophic cardiomyopathy, preexcitation syndrome, and intermittent neutropenia. This case report presents an 11-month-old male patient with FNIP1 deficiency who, in addition to classical features, exhibited posterior cerebellar hypoplasia.

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome.

OBJECTIVE: Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. METHODS: We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. RESULTS: The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber's congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. CONCLUSION: Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Clinical and laboratory evaluation of children with congenital hyperinsulinism: a single center experience.

OBJECTIVES: To evaluate and present the data regarding clinical, laboratory, radiological and the results of molecular genetic analysis of patients with hyperinsulinemic hypoglycemia in our clinics. METHODS: A total of 9 patients with CHI followed at Istanbul Medipol University. Data related to gender, age at presentation, birth weight, gestational age, consanguinity, glucose and insulin levels at diagnosis, treatment modalities, response to treatment, the results of genetic analysis and radiological evaluation were gathered from the files. RESULTS: The oldest age at presentation was 6 months. KATP channel mutation was detected in 55% (n: 5). Diazoxide unresponsiveness was seen in 55% (n: 5). Octreotide was effective in 3 of them. 18F-DOPA PET performed in 4 diazoxide unresponsive patients revealed focal lesion in 3 of them. Spontaneous remission rate was 66% (n:6). All the patients with normal genetic result achieved spontaneous remission. Spontaneous remission was even noted in diazoxide unresponsive patients and in patients with focal lesion on 18F-DOPA PET. CONCLUSIONS: Clinical presentation of patients with congenital hypereinsulinism is heterogeneous. Spontaneous remission rate is quite high even in patients with severe clinical presentation. It is important to develop methods that can predict which patients will have spontaneous remission. Reporting the clinical and laboratory data of each patient is important and will help to guide the management of patients with hyperinsulinemic hypoglycemia.

Clinical, Genetic, and Outcome Characteristics of Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis.

OBJECTIVE: In this study, we sought to describe the clinical, laboratory, and genetic character- istics of patients diagnosed with primary hemophagocytic lymphohistiocytosis. Thus, we aimed to evaluate the early diagnosis and appropriate treatment options for pediatric hemophago- cytic lymphohistiocytosis patients. MATERIALS AND METHODS: Medical records of 9 patients diagnosed with primary hemophago- cytic lymphohistiocytosis between November 2013 and December 2019 were analyzed retro- spectively. Clinical, genetic, and laboratory characteristics, family histories, initial complaints, physical examination findings, age at diagnosis, treatment choices, and clinical follow-up of all patients were investigated. RESULTS: The mean age at diagnosis was 11 months (range: 1.5 months to 17 years). Genetic analysis was performed in all patients, and a disease-related mutation was detected in 8 (89%) of them. Among clinical features, 6 (66%) patients had fever, 5 (56%) had splenomegaly, 4 (44%) had lymphadenopathy, 4 (44%) had skin rash, and 4 (44%) had neurological findings. Hemophagocytosis was observed in the bone marrow samples of 6 (66%) patients. Disease remission was achieved in 7 (78%) patients. Hematopoietic stem cell transplantation was per- formed in 7 (78%) patients. CONCLUSION: Hemophagocytic lymphohistiocytosis may present with different clinical symptoms that can cause a significant diagnostic delay. The only curative treatment option in primary hemophagocytic lymphohistiocytosis patients is hematopoietic stem cell transplantation. The chemotherapy should be started as early as possible, in order to achieve a disease remission. Patients should be referred to the appropriate bone marrow transplant center for hematopoi- etic stem cell transplantation as soon as they reach the disease remission.

Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.

HLA - matched related donor hematopoietic stem cell transplantation in a patient with polynucleotide kinase 3-phosphatase mutation developed acute myeloid leukemia.

BACKGROUND: PNPK gene mutations result in DNA repair disorders and have a spectrum of neurodevelopmental manifestations. To date, cancer predisposition has not been described in patients with PNKP mutations. OBSERVATION: Here, we report a patient with PNKP mutation, who developed AML at age of five and underwent reduced-intensity HSCT. CONCLUSION: Although many DNA repair disorders are known to have increased risk of malignancy, association between PNKP mutations and malignancy is not well-described. This report is the first description of a PNPK mutation patient developing a malignancy and undergoing curative HSCT.

Haploinsufficiency of the DMRT Gene Cluster in a Case with 46,XY Ovotesticular Disorder of Sexual Development

Background: Ovotesticular disorder is characterized by the presence of testicular and ovarian tissues in the same individual. Single gene mutations in SRY, SOX9, DMRT1 and DAX1 can lead to ovotesticular disorder of sexual development. Case Report: Herein, we report a 3-month-old phenotypically female baby in whom differentiated tissues of both Müllerian and Wolffian ducts were detected on pathological analysis of laparoscopic biopsy material. Chromosomal analysis observed 46,XY, der(9)t(3;9)(p25;p24) with deletion of 9p24.3p23 including the DMRT gene cluster and duplication of 3p26.3p24.3 on array comparative genomic hybridisation. Conclusion: In support of previous literature, we found that haploinsufficiency of the DMRT gene cluster leads to ovotesticular disorder of sexual development. In addition, we emphasize that array comparative genomic hybridisation is an important technique in the molecular diagnosis of ovotesticular disorder of sexual.