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Congenital nephrogenic diabetes insipidus (NDI) is a rare cause of hypernatremia in newborns. Central diabetes insipidus (CDI) is the main differential diagnosis in NDI, however NDI responds poorly to desmopressin acetate (DDAVP) treatment, while this is the mainstay of CDI management. Therefore, early and correct diagnosis of NDI is important to avoid the complications of inappropriate therapy. We report a newborn with hypernatremia and hypotonic polyuria. The patient was initially responsive but subsequently unresponsive to intranasal DDAVP treatment in terms of both urine output and serum sodium levels. A novel hemizygous missense mutation (c.632T>C, p.L211P) in the gene was found in both the baby and his mother, and the diagnosis of congenital NDI was established. After hydrochlorothiazide treatment and hypo-osmolar formula were given, urine volume was decreased, and serum sodium levels were normalized. Early recognition and appropriate management of NDI may prevent complications of hypernatremic dehydration in young infants.

ObjectiveSystemic autoinflammatory diseases (SAIDs) may not always present with typical clinical findings of a monogenic disease. We aimed to genetically screen and diagnose these clinically unclassified patients by next-generation sequencing (NGS) analysis.MethodA total of 64 patients who had clinical findings of a periodic fever syndrome but did not meet the clinical diagnostic criteria for any SAID or had clinical findings for more than one monogenic SAID were identified as “clinically unclassified SAIDs.” NGS panel analysis, including 16 genes, was performed in these patients. Patients, who could not be classified as one of the defined SAID after the result of the NGS gene analysis, were identified as “undefined SAID.”ResultsThe most common autoinflammatory symptoms in unclassified SAID patients were abdominal pain (60.9%), arthralgia (48.4%), urticarial rash (43.8%), myalgia (40.6%), oral aphthae (28.1%), and conjunctivitis (20.3%), respectively. In the result of the NGS gene panel screening, pathogenic, likely pathogenic variants, or VUS (variants of uncertain significance) were detected in 36 of 64 patients in at least one gene in the NGS panel. A total of 15 patients were diagnosed with a monogenic SAID according to both phenotypic and genotypic data; 12 patients as FMF, two patients as FCAS, and one patient as TRAPS, respectively. A total of 49 patients who did not meet the classification criteria including genetic results for a monogenic SAID were followed as undefined SAID.ConclusionsThe classification criteria described for SAIDs so far unfortunately do not cover all patients with signs of periodic fevers. The NGS gene panel appears to be a useful diagnostic tool for some of the patients with clinically unclassified SAID findings.Key Points• The classification criteria described for SAIDs do not cover all patients with signs of periodic fevers• The use of the undefined SAID nomenclature will benefit clinicians for diagnosis and initiating early treatment• The NGS panel appears to be a useful diagnostic tool in patients with clinically unclassified SAIDs

Introduction/objectivesThe clinicians initially prefer to define patients with the systemic autoinflammatory disease (SAID)’s based on recommended clinical classification criteria; then, they confirm the diagnosis with genetic testing. We aimed to compare the initial phenotypic diagnoses of the patients who were followed up with the preliminary diagnosis of a monogenic SAID, and the genotypic results obtained from the next-generation sequence (NGS) panel.MethodSeventy-one patients with the preliminary diagnosis of cryopyrin-associated periodic fever syndrome (CAPS), mevalonate kinase deficiency (MKD), or tumor necrosis factor-alpha receptor-associated periodic fever syndrome (TRAPS) were included in the study. The demographic data, clinical findings, laboratory results, and treatments were recorded. All patients were examined by NGS panel analysis including 16 genes. The genetic results were compared with the initial Federici score to determine whether they were compatible with each other.ResultsThirty patients were initially classified as MKD, 22 as CAPS, and 19 as TRAPS. The frequency of clinical manifestations was urticarial rash 57.7%, diarrhea 49.2%, abdominal pain 47.8%, arthralgia 45%, oral aphthae 43.6%, myalgia 32.3%, tonsillitis 28.1%, and conjunctivitis 25.3%, respectively. After NGS gene panel screening, 13 patients were diagnosed with CAPS, 8 with MKD, 7 with familial Mediterranean fever, 5 with TRAPS, and 2 with NLRP12-associated periodic syndrome. The remaining 36 patients were genetically identified as undefined SAID since they were not classified as one of the defined SAIDs after the result of the NGS panel.ConclusionsWe have demonstrated that clinical diagnostic criteria may not always be sufficient to establish the correct diagnosis. There is still low accordance between clinical diagnoses and molecular analyses. In the case of a patient with a preliminary diagnosis of a monogenic SAID with the negative result of target gene analysis, other autoinflammatory diseases should also be kept in mind in the differential diagnosis.Key Points• Monogenic autoinflammatory diseases can present with different clinical manifestations.• The clinical diagnostic criteria may not always be sufficient to reach the correct diagnosis in autoinflammatory diseases.• In the case of a patient with a preliminary diagnosis of a monogenic SAID with the negative result of target gene analysis, other autoinflammatory diseases should be kept in mind in the differential diagnosis.

Peters plus syndrome is a rare genetic condition wherein multiple systemic involvement with distinctive facial features are manifested, whilst the hallmark is Peters anomaly, occuring from anterior segment dysgenesis. Homozygous variants in the B3GLCT gene were identified to underlie this disorder. We here report on a onemonth- old female patient with typical features characteristic of Peters plus syndrome in whom a homozygous pathogenic mutation in the B3GLCT gene was detected.

Cartilage hair hypoplasia and anauxetic dysplasia spectrum constitute a group of autosomal recessive disorders characterized by variable extent of metaphyseal to spondylometaepiphyseal involvement and various additional clinical features. Within this group, anauxetic dysplasia represents the severe end of the skeletal spectrum. However, extraskeletal features including immunodeficiency, hematological abnormalities, and hair hypoplasia are absent, despite the severe skeletal involvement. This disorder is caused by mutations in the gene encoding ribonuclease mitochondrial RNA-processing complex. We herein report on a patient with anauxetic dysplasia, who presented with severe roto-scoliosis and skeletal findings requiring surgical intervention, and in whom a homozygous RMRP mutation was detected.

Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type, is a rare autosomal recessive disorder of the skeleton characterized by disproportionate short stature with narrow chest and dysmorphic facial features. The skeletal manifestations include platyspondyly, short flared ribs, short tubular bones with abnormal metaphyses and epiphyses, severe brachydactyly, and premature stippled calcifications in the cartilage. The abnormal calcifications are so distinctive as to point to the definitive diagnosis. However, they may be too subtle to attract diagnostic attention in infancy. Homozygous variants in DDR2 cause this disorder. We report on a 5-year-old girl with the classic phenotype of SMED, SL-AC in whom a novel homozygous nonsense mutation in DDR2 was detected using exome sequencing.

Schwartz-Jampel Syndrome (SJS) type-1 (OMIM; #255800), a rare cause of skeletal dysplasia, is characterized by myotonic myopathy, chondrodystrophy, short stature, facial and eye abnormalities. SJS Type-1 develops due to variations in the HSPG2 gene which produces the \"perlecan\" molecule, one of the main proteoglycans of the basement membrane. A 6-year-old girl presented with short stature, a mask face, shrunken lips, narrow palpebral opening due to blepharospasm, stiffness of facial muscles, micrognathia, overlapping teeth, a short neck, and a bell-shaped thorax due to myotonic myopathy. She was diagnosed with SJS type-1 due to compound heterozygosity of two novel variations in the HSPG2 gene. In patients with short stature and an accompanying myotonic myopathy SJS should be considered. Compound heterozygosity may cause typical clinical findings of SJS. In case of suspicion creatinine kinase levels can be measured, and the determination of myotonia may require evaluation with electromyography. Once the diagnosis is made, patients should be carefully monitored in terms of growth, neuromuscular disorders, joints problems and bone health.

Aims: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy with multisystemic involvement and variable phenotypic features. A diagnosis is usually made through the clinical diagnostic criteria. However, the clinical diagnosis can be difficult due to the absence of clear phenotype-genotype correlation and overlapping findings with other ciliopathies. Next-generation sequencing (NGS) is a rapid and cost-effective diagnostic method for this group of diseases. Besides correct diagnosis, detection of novel variants also contributes to establishing new phenotype-genotype correlations and delineating the pathophysiology of the syndrome. Here, we aimed to present clinical and molecular findings of patients with BBS using NGS panel analysis to contribute to the genotype-phenotype correlation in this rare syndrome. Methods: We retrospectively reviewed the medical records of patients with a suspicion of BBS admitted to the Pediatric Genetics Department in Umraniye Training and Research Hospital. Patients who met the BBS clinical diagnostic criteria were included in the study. Targeted NGS analysis, including 20 genes associated with BBS, was performed on an Illumina Next-Seq-500 platform. Results: The final analyses included 6 patients (age, mean [+ or -] standard deviation: 14.3 [+ or -] 6.6 years, female: 50%). Rod cone dystrophy (100%), Polydactyly (100%), and intellectual disability (100%) were the most common findings followed respectively by obesity (83%), renal anomalies (83%), liver anomalies (67%), dental problems (67%), metabolic problems (50%), genital anomalies (33%), psychiatric disorders (33%), and sleep apnea (33%). The 5th metatarsal shortness and camptodactyly were anomalies reported for the first time in BBS. Seven variants were detected in the BBS1, BBS7, BBS5, BBS9, and MKKS, two of which were novel. BBS7 was the most common gene. Conclusions: Our study expanded the genotypic spectrum of the disease with two novel variants reported. Besides, by defining novel/rare clinical features, including camptodactyly, the fifth metatarsal, the 4th-5th metacarpal shortness, and nephrocalcinosis, it formed a source for the phenotype-genotype correlation trying to be established in the literature. Keywords: Bardet-Biedl syndrome, next-generation sequencing, phenotype-genotype correlation, variants