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Objective: Oculoauriculovertebral spectrum (OAVS) is a genetically and clinically heterogeneous disorder that occurs due to a developmental field defect of the first and second pharyngeal arches. Even though recent whole exome sequencing studies (WES) have led to identification of several genes associated with this spectrum in a subset of individuals, complete pathogenesis of OAVS remains unsolved. In this study, molecular genetic etiology of OAVS was systematically investigated., Design/setting/patients: A cohort of 23 Turkish patients with OAVS, referred to Hacettepe University Hospital, Department of Pediatric Genetics from 2008 to 2018, was included in this study. Minimal diagnostic criteria for OAVS were considered as unilateral microtia or hemifacial microsomia with preauricular skin tag. The cohort was clinically reevaluated for craniofacial and extracranial findings. Molecular etiology was investigated using candidate gene sequencing following copy number variant (CNV) analysis. WES was also performed for 2 of the selected patients., Results: Patients in the study cohort presented similar demographic and phenotypic characteristics to previously described patients in the literature except for a higher frequency of bilaterality, cardiac findings, and intellectual disability/developmental delay. CNV analysis revealed a possible genetic etiology for 3 patients (13%). Additional WES in 1 of the 2 patients uncovered a novel heterozygous nonsense variant in Elongation factor Tu GTP-binding domain-containing 2 ( EFTUD2 ) causing mandibulofacial dysostosis with microcephaly (MFDM), which clinically overlaps with OAVS., Conclusion: Detailed clinical evaluation for any patient with OAVS is recommended due to a high rate of accompanying systemic findings. We further expand the existing genetic heterogeneity of OAVS by identifying several CNVs and a phenotypically overlapping disorder, MFDM.

Objectives: X-linked adrenoleukodystrophy (X-ALD), is a peroxisomal inborn error of metabolism caused due to the loss of function variants of ABCD1 gene that leads to accumulation of very long chain fatty acids (VLCFAs) in several tissues including the neurological system. Childhood cerebral X-ALD (CCALD) is the most common and severe form of X-ALD, if left untreated. Allogenic hematopoietic stem cell transplantation (HSCT) is the only available therapy that halts neurological deterioration in CCALD. We present 12 patients with several subtypes of X-ALD that were followed-up in a single center., Methods: Data of 12 patients diagnosed with X-ALD were documented retrospectively. Demographics, age of onset, initial symptoms, endocrine and neurological findings, VLCFA levels, neuroimaging data, molecular genetic analysis of ABCD1 gene, and disease progress were documented., Results: Mean age of initiation of symptoms was 7.9 years and mean age of diagnosis was 10.45 years. Eight patients had the CCALD subtype, while two had the cerebral form of AMN, one had the adult form of cerebral ALD, and one patient had the Addison only phenotype. The most common initial symptoms involved the neurological system. Loes scores varied between 0 and 12. Seven patients with CCALD underwent HSCT, among them three patients died. The overall mortality rate was 25%., Conclusions: Patients with X-ALD should be carefully followed up for cerebral findings and progression, since there is no genotype-phenotype correlation, and the clinical course cannot be predicted by family history. HSCT is the only available treatment option for patients with neurological deterioration., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients., Methods: This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method., Results: Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients., Conclusion: We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype-phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1. Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition. Kyphoscoliosis and seizures frequently accompany and autistic features might be another feature as recent studies also implicate. HERC1 mutations should be considered in differential diagnosis of severe intellectual disability and behavioural problems, particularly in patients testing negative for fragile X and KANSL1 mutations., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)