Esra Kilic

The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): A review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non‐inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1‐inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti‐inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct “lip” overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti‐inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis.

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.

A novel mutation in RNU4ATAC in a patient with microcephalic osteodysplastic primordial dwarfism type I.

A Novel Mutation in RNU4ATAC in a Patient with Microcephalic Osteodysplastic Primordial Dwarfism Type I Esra Kilic,* Gökhan Yigit, Gülen Eda Utine, Bernd Wollnik, Ercan Mihci, Banu Güzel Nur, and Koray Boduroglu Faculty of Medicine, Division of Pediatric Genetics, Hacettepe University, Ankara, Turkey Institute of Human Genetics, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Faculty of Medicine, Division of Pediatric Genetics, Akdeniz University, Antalya, Turkey

Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis.

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare primordial dwarfism that is similar to Seckel syndrome. Seckel syndrome is known to be associated with various hematological abnormalities; however, hematological findings in MOPD II patients have not been previously reported. The present study aimed to describe the hematological findings in a series of eight patients with MOPD II from a single center.

A Case of 22q11.2 Deletion Syndrome with Right Microphthalmia and Left Corneal Staphyloma

Abstract Background: A microdeletion in the chromosome 22q11.2 (DiGeorge or velocardiofacial syndrome) is the most common human deletion syndrome. Patients with 22q11.2 deletion may have a wide range of ocular findings but severe ocular involvement is uncommon. Here, we describe a 2-year-old boy who had growth retardation, developmental delay, right renal agenesis, ventricular septal defect and severe bilateral ocular anomalies. Materials and methods: The systemic and ocular findings and cranial magnetic resonance imaging study results were reviewed. Fluorescence in situ hybridization analysis was performed on his peripheral blood. Results: The patient presented with the oculodigital sign. On examination, he had severe right microphthalmia with no light perception and his left eye could not fix and follow. The left eye had anterior segment dysgenesis, mild sclerocornea, corneal staphyloma and congenital aphakia. Systemic findings included growth deficiency, microcephaly, micrognathia, ventricular septal defect, atrial septal defect and right renal agenesis. Fluorescence in situ hybridization analysis of this patient was significant for a heterozygous deletion covering DiGeorge critical region 2 and spanning a 250 kb region in the 22q11.2 locus. Conclusion: The 22q11.2 deletion syndrome may be associated with severe bilateral ocular malformations including microphthalmia, sclerocornea, corneal staphyloma, anterior segment dysgenesis and congenital aphakia. Corneal staphyloma might have resulted from the oculodigital phenomenon or increased intraocular pressure.

A Diagnosis to Consider in Intellectual Disability: Mowat-Wilson Syndrome.

Mowat-Wilson syndrome is a multiple congenital anomaly and intellectual disability syndrome characterized by a unique face and various other structural and functional anomalies. The condition is caused by de novo heterozygous mutations or deletions in ZEB2 gene located at 2q22. ZEB2 encodes Sip1 protein, which acts during central nervous system development as an important transcription factor. Herein, we report on 3 novel mutations in 6 patients with the syndrome, with an overview of corresponding clinical findings. Growth retardation and Hirschsprung disease were less common in the present cohort. One patient with a novel mutation p.Y489X had no associated anomalies except the characteristic facial and neurobehavioral phenotype. Reporting new patients with novel mutations would contribute to better delineation of the syndrome and would help clinicians establish formal diagnostic criteria and genotype-phenotype correlations.

Preparation of electrospun polyurethane nanofiber mats for the release of doxorubicine

Polyurethane (PU) and doxorubicine loaded-PU nanofiber mats were prepared by the electrospinning technique. The effect of some system and process parameters including flow rate, distance from collector, and concentration of solution on the size and morphology of nanofibers was investigated. The size, morphology and drug content of nanofiber mats were followed by scanning electron microscopy (SEM). FTIR and TGA methods were used for structural and thermal characterization, and DSC was also used for determining the form of drug within nanofiber mat. Doxorubicine release kinetics were studied in two different pHs (4.5 and 7.5) for two drug content and it was observed that there is an inverse correlation between the amounts of drug loaded and released.

Polyposis deserves a perfect physical examination for final diagnosis: bannayan-riley-ruvalcaba syndrome

Hızarcıoğlu-Gülşen H, Kılıç E, Dominguez-Garrido E, Aydemir Y, Utine GE, Saltık-Temizel İN. Polyposis deserves a perfect physical examination for final diagnosis: Bannayan-Riley-Ruvalcaba syndrome. Turk J Pediatr 2017; 59: 80-83. Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal dominant inherited polyposis syndrome characterized by macrocephaly, lipomatosis, hemangiomatosis, intestinal polyposis and pigmented macules on penis. The mutation of the PTEN gene that is responsible for controlling cellular proliferation, migration and apoptosis clarifies the reason of tissue overgrowth in BRRS. Gastrointestinal tract involvement is seen 35-45% of the patients. Histologic features of polyps in BRRS resemble juvenile polyps. In this report, we describe a boy presenting with hematochezia and aggressive polyposis and finally was diagnosed as BRRS due to extra intestinal findings.

Clinical delineation of a subtype of frontonasal dysplasia with creased nasal ridge and upper limb anomalies: Report of six unrelated patients

Frontonasal dysplasias are rare congenital malformations of frontonasal process‐derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond‐shaped palpebral fissures, and downturned corners of the mouth. All had apparently normal psychomotor development. In addition, upper limb anomalies, frontonasal encephalocele, corpus callosum agenesis, choanal atresia, and congenital heart defect were observed. We identified five reports in the literature of patients presenting with the same phenotype. Exome sequencing was performed on DNA extracted from blood of two individuals, no candidate gene was identified. In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology.