Prenatal diagnosis of pulmonary arteriovenous malformations with a postnatal diagnosis of Osler-Weber-Rendu syndrome.

Hereditary Hemorrhagic Telangiectasia (HHT), commonly known as Osler-Weber-Rendu disease, is an autosomal dominant multisystemic vascular disease associated with approximately 70% of cases of pulmonary arteriovenous malformations (PAVMs). Prenatal cases of PAVMs typically present with pulmonary vein dilatation on ultrasonography. This study presents a prenatal diagnosis of PAVMs with enlarged right pulmonary vein, cardiomegaly, cystic-appearing areas in the right lung and subsequent confirmation of Osler-Weber-Rendu syndrome using autopsy and whole exom sequencing.

Junctional Epidermolysis Bullosa Linked to Homozygous Mutation in LAMC2 Gene: A Case Report With Eosinophil-Rich Inflammatory Infiltrate.

ABSTRACT: Junctional epidermolysis bullosa (JEB) is a rare, incurable, devastating, and mostly fatal congenital genetic disorder characterized by painful blistering of the skin and mucous membranes in response to minor trauma or pressure. JEB is classified roughly into 2 subtypes: JEB-Herlitz is caused by mutations on genes encoding laminin-332. The authors present a patient consulted with a suspicion of primary immunodeficiency due to skin sores that started at the age of 1 month and a history of 3 siblings who died with similar sores, who was diagnosed with JEB-Herlitz after detecting a homozygous LAMC2 gene mutation in WES analysis. Microscopic evaluation of hematoxylin and eosin-stained sections showed vesicle formation with subepidermal separation, which is accompanied by striking neutrophil and eosinophil leukocyte infiltration both in the vesicle and papillary dermis (eosinophil-rich inflammatory infiltrate). Such a histopathological finding has been rarely reported in this condition.

Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

Exploring Multiple Endocrinological Issues and Dysautonomia in a Rare Case: Hypoparathyroidism in MIRAGE Syndrome.

MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation, adrenal hypoplasia, genital anomalies, and enteropathy. In the literature, there have been rare cases of dysautonomia. We present a 6.5-year-old girl, who was first admitted to our department with short stature. On follow up, she exhibited multiple endocrinological issues, including transient hypothyroidism, primary hypoparathyroidism and dysautonomia, along with multisystem involvement. Further investigations revealed recurrent moniliasis, low IgM levels, and transient monosomy 7 in the bone marrow. Whole exome sequencing revealed a heterozygous pathogenic variant of SAMD9 (c.2159del; p.Asn720ThrfsTer35). Additional complications observed during follow-up included medullary nephrocalcinosis, hypomagnesemia, hypermagnesiuria, hypophosphatemia, decreased glomerular filtration rate, and nephrotic proteinuria. The patient also developed hyperglycemia, which was managed with low-dose insulin. This case highlights the diagnostic challenges and the diverse phenotypic presentation observed in MIRAGE syndrome.

Clinical and laboratory findings and etiologies of genetic homocystinemia: a single-center experience.

BACKGROUND: Homocysteine (Hcy) is an endogenous nonprotein sulfur-containing amino acid biosynthesized from methionine by the removal of its terminal methyl group. Hyperhomocysteinemia (HHcy) has been linked to many systemic disorders, including stroke, proteinuria, epilepsy, psychosis, diabetes, lung disease, and liver disease. The clinical effects of high serum Hcy level, also known as hyperhomocysteinemia, have been explained by different mechanisms. However, little has been reported on the clinical and laboratory findings and etiologies of genetic HHcy in children. This study aimed to examine the relationships between clinical features, laboratory findings, and genetic defects of HHcy. METHODS: We retrospectively evaluated 20 consecutive children and adolescents with inherited HHcy at the pediatric neurology division of Baskent University, Adana Hospital (Adana, Turkey) between December 2011 and December 2022. RESULTS: Our main finding is that the most common cause of genetic HHcy is MTHFR mutation. The other main finding is that the Hcy level was higher in patients with CBS deficiency and intracellular cbl defects than in MTHFR mutations. We also found that clinical presentations of genetic HHcy vary widely, and the most common clinical finding is seizures. Here, we report the first and only case of a cbl defect with nonepileptic myoclonus. We also observed that mild and intermediate HHcy associated with the MTHFR mutation may be related to migraine, vertigo, tension-type headache, and idiopathic intracranial hypertension. Although some of the patients were followed up in tertiary care centers for a long time, they were not diagnosed with HHcy. Therefore, we suggest evaluating Hcy levels in children with unexplained neurological symptoms. CONCLUSIONS: Our findings suggest that genetic HHcy might be associated with different clinical manifestations and etiologies. Therefore, we suggest evaluating Hcy levels in children with unexplained neurologic symptoms.

A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature.

Lymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αßT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency.

Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant.

Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia. To date, only four variants have been reported; one nonsense, one splice-site, and two frameshifts in five AMDP families. Here, we report the first missense variant and a second splice-site variant in PRKG2 in two patients with clinical and radiological features of acromesomelic dysplasia. Furthermore, functional studies of the novel missense variant, p.Val470Gly, revealed that it was unable to down-regulate FGF2-induced MAPK signaling and, thus, would be predicted to cause growth delay. Hence, this report expands the mutational spectrum in skeletal dysplasias associated with PRKG2 variants. In addition, we propose recognizable facial features with acromesomelic dysplasia, PRKG2 type.

Efficacy of abatacept treatment in a patient with enteropathy carrying a variant of unsignificance in CTLA4 gene: A case report.

BACKGROUND: Cytotoxic T Lymphocyte Antigen-4 (CTLA4) deficiency is a genetic defect that causes a common variable immunodeficiency (CVID) clinical phenotype. Several studies have reported an association between CTLA mutations or variants and various autoimmune diseases. Targeted therapy models, which have become increasingly popular in recent years, have been successful in treating CTLA4 deficiency. In this article, we discuss the clinical outcomes of abatacept treatment in a patient with CTLA4 and lipopolysaccharide-responsive beige-like anchor (LRBA) variants that was previously diagnosed with CVID. CASE SUMMARY: A 25-year-old female patient, who was visibly cachectic, visited our clinic over the course of five years, complaining of diarrhea. The patient was diagnosed with ulcerative colitis in the centers she had visited previously, and various treatments were administered; however, clinical improvement could not be achieved. Severe hypokalemia was detected during an examination. Her serum immunoglobulin levels, CD19+ B-cell percentage, and CD4/CD8 ratio were low. An endoscopic examination revealed erosive gastritis, nodular duodenitis, and pancolitis. Histopathological findings supported the presence of immune mediated enteropathy. When the patient was examined carefully, she was diagnosed with CVID, and intravenous immunoglobulin treatment was initiated. Peroral and rectal therapeutic drugs including steroid therapy episodes were administered to treat the immune mediated enteropathy. Strict follow-ups and treatment were performed due to the hypokalemia. After conducting genetic analyses, the CTLA4 and LRBA variants were identified and abatacept treatment was initiated. With targeted therapy, the patient's clinical and laboratory findings rapidly regressed, and there was an increase in weight. CONCLUSION: The heterozygous CTLA4 variant identified in the patient has been previously shown to be associated with various autoimmune diseases. The successful clinical outcome of abatacept treatment in this patient supports the idea that this variant plays a role in the immunopathogenesis of the disease. In the presence of severe disease, abatacept therapy should be considered until further testing can be conducted.

A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.

SOD1 is the first identified causative gene for amyotrophic lateral sclerosis. Recently, a novel syndrome, presenting with severe childhood-onset spastic tetraplegia and axial hypotonia caused by the homozygous truncating variants in the SOD1 gene, is described. A 22-month-old boy was admitted with a loss of motor functions that began at the age of 9 months. Neurological was significant for axial hypotonia with spastic tetraplegia and hyperekplexia-like jerky movements. In WES, we found a novel homozygous variant (c.52_56del5ins154) in the SOD1 gene, resulting in a total loss of SOD1 mRNA expression in the real-time PCR analysis. Western blot analyses confirmed the lack of protein production. Erythrocyte superoxide dismutase enzymatic activity was nearly abolished. The heterozygous family members displayed reduced superoxide dismutase 1 protein expression and enzymatic activity (by about 40%), compared with the healthy control. Our study expanded the mutation spectrum of SOD1.

A novel mutation in the proteoglycan 4 gene causing CACP syndrome: two sisters report.

BACKGROUND: Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, caused by biallelic pathogenic mutations in the proteoglycan 4 (PRG4) gene, is characterized by early-onset camptodactyly, noninflammatory arthropathy, coxa vara deformity, and rarely, pericardial effusion. This syndrome can mimic juvenile idiopathic arthritis. CACP syndrome is caused by mutations in the proteoglycan 4 (PRG4) gene. To date, only 36 pathogenic mutations have been reported in this gene, but none have been reported from Azerbaijan. CASE PRESENTATION: Herein, we report two siblings presented with chronic polyarthritis, had a prior diagnosis of juvenile idiopathic arthritis, but was subsequently diagnosed as CACP syndrome with novel mutation in the PRG4 gene. CONCLUSION: Our report expands the knowledge of PRG4 mutations, which will aid in CACP patient counseling.

A Novel Pathogenic IGSF1 Variant in a Patient with GH and TSH Deficiency Diagnosed by High IGF-I Values at Transition to Adult Care

IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in the context of normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood, contrasting with an increased GH secretion in adulthood. Patients with this disorder are not detected shortly after birth if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations. A 13.2-year-old male patient was referred to pediatric endocrinology for evaluation of short stature. He was born large for gestational age into a nonconsanguineous family. During work-up for short stature, deficiencies of TSH, prolactin and GH were detected, leading to treatment with levothyroxine and GH. At 16.9 years, GH treatment was stopped and during transition to adult care, his insulin-like growth factor 1 level was above the normal range. This prompted an analysis of IGSF1, in which a novel hemizygous variant causing a stop codon at c.3559C>T (p.Q1187*) was found, confirming the diagnosis of IGSF1 deficiency syndrome. In this report, we describe his clinical and hormonal characteristics at presentation and during long-term follow-up.

Compound Heterozygous Variants in FAM111A Cause Autosomal Recessive Kenny-Caffey Syndrome Type 2

Kenny-Caffey syndrome (KCS) is a rare autosomal recessive (AR)/dominant disease characterized by hypoparathyroidism, skeletal dysplasia, dwarfism, and dysmorphism. FAM111A or TBCE gene mutations are responsible for this syndrome. Osteocraniostenosis (OCS) is a lethal syndrome with similar features to KCS, and it can be a severe form of KCS type 2 which results from the FAM111A gene mutation. The FAM111A mutation is generally characterized by the autosomal dominant transition. We present a male case having compound heterozygous variants (c.976T>A and c.1714_1716del) in the FAM111A gene with an AR inheritance pattern. Hypocalcemia developed on the second day of life. The patient and his older sister had a dysmorphic face, skeletal dysplasia, and they were diagnosed with hypoparathyroidism. Both siblings died due to septicemia. He is the first reported patient with the FAM111A mutation in Turkey. The phenotype of the patient is compatible with OCS, and the detected variants may explain the disease genetically.

Renal Involvement in H Syndrome, A Rare Cause of Diabetes Mellitus: Case Report.

BACKGROUND: H syndrome is a rare genodermatosis deriving from a mutation in the SLC29A3 gene and affecting numerous systems, particularly the skin. The syndrome exhibits different clinical characteristics involving several systems, most beginning with the letter "H." The most common clinical findings are cutaneous hyperpigmentation, flexion contracture in the fingers, hearing loss, short stature, insulin-dependent diabetes mellitus, heart anomalies, hepatosplenomegaly, and hypogonadism. Fewer than 150 cases have been reported so far and vast majority of them consisted with patients with Arab ethnicity. CASE PRESENTATION: We describe a patient presenting with short stature, developing diabetes mellitus at follow-ups, with homozygous deletion determined in exon 3 of the SLC29A3 gene, and diagnosed with H syndrome, reported due to the presence and rarity of renal involvement (hematuria and proteinuria). CONCLUSION: In conclusion, despite its rarity, endocrinologists, rheumatologists/nephrologists, and dermatologists need to be aware of H syndrome as a pleiotropic syndrome. H syndrome should be considered in the differential diagnosis of patients with cutaneous hyperpigmentation (particularly in the bilateral thigh and calf region) together with proteinuria/hematuria. In addition, periodic urine analysis should be performed in patients with H syndrome.

Genetic and clinical evaluation of congenital myasthenic syndromes with long-term follow-up: experience of a tertiary center in Turkey.

INTRODUCTION: Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders affecting the safety factor which required for neuromuscular transmission. Here we reported our experience in children with CMS. METHODS: We retrospectively collected the data of 18 patients with CMS who were examined in our outpatient clinic between January 2021 and January 2022. The diagnosis of CMS was based on the presence of clinical symptoms such as abnormal fatigability and weakness, absence of autoantibodies against acetylcholine receptor and muscle-specific kinase, electromyographic evidence of neuromuscular junction defect, molecular genetic confirmation, and response to treatment. RESULTS: The most common mutations were in the acetylcholine receptor (CHRNE) gene (8/18) and choline acetyltransferase (ChAT) (2/18) gene. Despite targeted gene sequencing and whole exome sequencing (WES) were underwent, we couldn't detect a genetic mutation in three out of patients. The most commonly determined initial finding was eyelid ptosis, followed by fatigable weakness, and respiratory insufficiency. Although the most commonly used drug was pyridostigmine, we have experienced that caution should be exercised as it may worsen some types of CMS. DISCUSSION: We reported in detail the phenotypic features of very rare gene mutations associated with CMS and our experience in the treatment of this disease. Although CMS are rare genetic disorder, the prognosis can be very promising with appropriate treatment in most CMS subtypes.

Mitotically Active Follicular Nodule in Early Childhood: A Case Report with A Novel Mutation in the Thyroglobulin Gene.

Dyshormonogenesis is the failure of thyroid hormone production due to a defect in thyroid hormonogenesis. Loss-of-function mutations in the thyroglobulin(TG) gene are a cause of dyshormonogenesis, leading to gland stimulation by thyroid-stimulating hormone (TSH), resulting in goiter. We report a mitotically active follicular nodule in an 11-year-old female with a novel mutation in the TG gene. The patient had been under follow-up due to congenital hypothyroidism since the neonatal period, and she had normal TSH levels. Genetic test revealed a novel compound heterogeneous mutation [c.2149C>T (p.R717*) (P.Arg717Ter) / c.5361_5362delCCinsG (p.H1787Qfs*3) (p.His1787GlnfsTer3)] in TG gene. She underwent total thyroidectomy for a thyroid nodule that was reported as Bethesda IV on FNAB and noted as suspicious for noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Pathological examination revealed a 16 mm well-demarcated follicular nodule with a solid/insular pattern. Mitotic activity and Ki67 proliferation index were unusually high (10 mitoses/2mm2 and 10% respectively). Marked cellular pleomorphism and nuclear atypia are well-known diagnostic pitfalls in patients with dyshormonogenetic goiter. However, high mitotic activity is a feature that is less emphasized in dyshormonogenetic goiter and may raise suspicion of poorly differentiated carcinoma when observed together with a solid pattern. The absence of signs of invasion, history of congenital hypothyroidism, and awareness of the presence of mutations compatible with dyshormonogenetic goiter can prevent the overinterpretation of such lesions. The risk of cancer development in the dyshormonogenetic thyroid gland is possible in childhood. The close follow-up is life-saving and prevents morbidities and mortalities.