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Byline: T. Bilgen, I. Keser, E. Mihci, S. Haspolat, S. Tacoy, G. Luleci Background: Detection of the (CGG)n repeats in the FMR1 gene that cause the fragile X syndrome (FXS), [...]

Koolen-de Vries syndrome (KdVS) is a rare multisystemic disorder caused by a microdeletion on chromosome 17q21.31 including KANSL1 gene or intragenic pathogenic variants in KANSL1 gene. Here, we describe the clinical and genetic spectrum of eight Turkish children with KdVS due to a de novo 17q21.31 deletion, and report on several rare/new conditions. Eight patients from unrelated families aged between 17 months and 19 years enrolled in this study. All patients evaluated by a clinical geneticist, and the clinical diagnosis were confirmed by molecular karyotyping. KdVS patients had some common distinctive facial features. All patients had neuromotor retardation, and speech and language delay. Epilepsy, structural brain anomalies, ocular, ectodermal, and musculoskeletal findings, and friendly personality were remarkable in more than half of the patients. Hypertension, hypothyroidism, celiac disease, and postaxial polydactyly were among the rare/new conditions. Our study contributes to the clinical spectrum of patients with KdVS, while also provide a review by comparing them with previous cohort studies., (© 2023 Wiley Periodicals LLC.)

Objectives: To determine the demographic, clinical, and genetic profile of Turkish Caucasian PCD cases., Methods: Targeted next-generation sequencing (t-NGS) of 46 nuclear genes was performed in 21 unrelated PCD cases. Sanger sequencing confirmed of potentially disease-related variations, and genotype-phenotype correlations were evaluated., Results: Disease-related variations were identified in eight different genes (CCDC39, CCDC40, CCDC151, DNAAF2, DNAAF4, DNAH11, HYDIN, RSPH4A) in 52.4% (11/21) of the cases. The frequency of variations for CCDC151, DNAH11, and DNAAF2 genes which were highly mutated genes in the cohort was 18% in 11 patients. Each of the remaining gene variations was detected once (9%) in different patients. The variants, p.R482fs*12 in CCDC151, p.E216* in DNAAF2, p.I317* in DNAAF4, p.L318P and p.R1865* in DNAH11, and p.N1505D and p.L1167P in HYDIN gene were identified as novel variations. Interestingly, varying phenotypic findings were identified even in patients with the same mutation, which once again confirmed that PCD has a high phenotypic heterogeneity and shows individual differences., Conclusion: This t-NGS panel is potentially helpful for exact and rapid identification of reported/novel PCD-disease-causing variants to establish the molecular diagnosis of ciliary diseases., (© 2022. Dr. K C Chaudhuri Foundation.)

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

SMA is a neuromuscular disease and occurs primarily through autosomal recessive inheritance. Identification of deletions in the SMN1 gene especially in the exon 7 and exon 8 regions (hot spot), are used in carrier testing. The exact copy numbers of those exons in the SMN1 and SMN2 genes in 113 patients who presented with a pre-diagnosis of SMA were determined using MLPA method. We aimed to reveal both the most common copy number profiles of different SMA types. It was found that the frequency of homozygous deletions in SMN1 was 15.9%, while heterozygous deletions was 16.9%. The most common SMN-MLPA profile was 0-0-3-3. In the cases with homozygous deletion, SMA type III diagnosis was observed most frequently (44%), and the rate of consanguineous marriage was found 33%. Two cases with the same exonic copy number profile but with different clinical subtypes were identified in a family. We also detected distinct exonic deletion and duplication MLPA profiles for the first time. We created "the SMA signature" that can be added to patient reports. Furthermore, our data are important for revealing potential local profiles of SMA and describing the disease in genetic reports in a way that is clear and comprehensive., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Acromesomelic dysplasia type Maroteaux (AMDM, OMIM #602875) is an autosomal recessive disorder characterized by severe short stature, shortened middle and distal segments of the limbs, redundant skin of fingers, radial head subluxation or dislocation, large great toes and cranium, and normal intelligence. Only the skeletal system appears to be consistently affected. AMDM is caused by biallelic loss-of-function variants in the natriuretic peptide receptor B (NPRB or NPR2, OMIM #108961) which is involved in endochondral ossification and longitudinal growth of limbs and vertebrae. In this study, we investigated 26 AMDM patients from 22 unrelated families and revealed their genetic etiology in 20 families, via Sanger sequencing or exome sequencing. A total of 22 distinct variants in NPR2 (14 missense, 5 nonsense, 2 intronic, and 1 one-amino acid deletion) were detected, among which 15 were novel. They were in homozygous states in 19 patients and in compound heterozygous states in four patients. Parents with heterozygous NPR2 variants were significantly shorter than the control. Extra-skeletal abnormalities, including global developmental delay/intellectual disability, nephrolithiasis, renal cyst, and oligodontia were noted in the patient cohort. The high parental consanguinity rate might have contributed to these findings, probably associated with other gene variants. This study represents the largest cohort of AMDM from Turkey and regional countries and further expands the molecular and clinical spectrum of AMDM.

Catel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1-8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg330Gln) and c.326G > C (p.Trp109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS., Competing Interests: Declaration of competing interest Claudia Gonzaga-Jauregui is a full-time employee of the Regeneron Genetics Center from Regeneron Pharmaceuticals Inc. and receives stock options as part of compensation. All other authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing., Methods: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups., Results: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups., Conclusions: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

Craniosynostosis consists of premature fusion of one or more cranial sutures and can be seen as part of a syndrome or diagnosed as nonsyndromic (isolated). Although more than 180 craniosynostosis syndromes have been identified, 70% of the cases are diagnosed as nonsyndromic. On the other hand, genetic causes of the cases are mostly unknown and the overall frequency of the genetic diagnosis is around 25%. In this study, we used targeted Next Generation Sequencing (NGS) analysis to identify the genetic variations of two craniosynostosis cases. We have identified two different truncating mutations, a known NM&#95;207036.1:c.778&#95;779delAT;p.(Met260Valfs*5) and a novel NM&#95;207036.1:c.1102&#95;1108delTCACCTC;p.(Pro369Glnfs*26) TCF12 variants. Additionally, upon physical examination of these two cases, we have observed some shared clinical similarities as well as differences such as bilateral simian crease and hidden cleft palate. This is the first study that reports the TCF12 mutations in Turkish patients with coronal suture synostosis., (© 2019 Wiley Periodicals, Inc.)

Craniosynostosis is a pathologic craniofacial disorder and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of nonossified mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, and visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens, and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes have been linked to craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be nonsyndromic, formed without any additional anomalies. More than 50 nuclear genes that relate to craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. As craniosynostosis is a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetic analysis, epigenetic or environmental factors, or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic and environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose/Aim of the study: Acquired partial lipodystrophy (APL) is a rare disease characterized by selective loss of adipose tissue. In this study, we aimed to present a subset of patients with APL, who developed severe metabolic abnormalities, from our national lipodystrophy registry., Materials and Methods: Severe metabolic abnormalities were defined as: poorly controlled diabetes (HbA1c above 7% despite treatment with insulin more than 1 unit/kg/day combined with oral antidiabetics), severe hypertriglyceridemia (triglycerides above 500 mg/dL despite treatment with lipid-lowering drugs), episodes of acute pancreatitis, or severe hepatic involvement (biopsy-proven non-alcoholic steatohepatitis (NASH))., Results: Among 140 patients with all forms of lipodystrophy (28 with APL), we identified 6 APL patients with severe metabolic abnormalities. The geometric mean for age was 37 years (range: 27-50 years; 4 females and 2 males). Five patients had poorly controlled diabetes despite treatment with high-dose insulin combined with oral antidiabetics. Severe hypertriglyceridemia developed in five patients, of those three experienced episodes of acute pancreatitis. Although all six patients had hepatic steatosis at various levels on imaging studies, NASH was proven in two patients on liver biopsy. Our data suggested that APL patients with severe metabolic abnormalities had a more advanced fat loss and longer disease duration., Conclusions: We suggest that these patients represent a potential subgroup of APL who may benefit from metreleptin or investigational therapies as standard treatment strategies fail to achieve a good metabolic control.

The bones of the skull are held together by fibrous joints called sutures. Premature fusion of these sutures leads to a pathologic condition called as craniosynostosis. Although at least 50 nuclear genes including FGFR2, TWIST1, TCF12, and SMAD6 were identified as causative of craniosynostosis; only 25% of the patients can be genetically diagnosed. Here, we report a 3-year-old Turkish Caucasian boy with sagittal craniosynostosis with a de novo loss-of-function mutation in exon 4 of the AXIN2 gene for the first time. The patient has frontal bossing, high anterior hair line, depressed nasal bridge, bilateral epicanthus and low set ears which are correlated with his scaphocephaly. As a negative regulator of the Wnt signaling pathway which is one of the key modulators of craniosynostosis syndrome, it has been shown in model organisms that Axin2 orchestrates the regulation of beta-catenin especially in the intramembranous ossification process. This clinical report adds value to the literature that AXIN2 gene mutations could be a potential cause in human calvarial malformations, especially for the sagittal synostosis., (© 2018 Wiley Periodicals, Inc.)

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7 -/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7 -/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mucopolysaccharidosis type III (MPS III) is a neurodegenerative disorder. In MPS III patients, heparan sulfate accumulates in many tissues especially the central nervous system. There are limited data regarding bone involvement in MPS III compared to other MPS types. The aim of this study was to evaluate bone mineral density (BMD) and the prevalence of low bone mass, and to explore the association between BMD, vitamin D levels, bone fracture, and patient characteristics in MPS III. A clinical assessment and interview was held to obtain data about family history, height, weight, body mass index (BMI), nutrition, walking capacity, bone fracture, epilepsy, and medical therapy of 15 patients with MPS III. Height, weight, and BMI z scores were calculated. Laboratory tests including 25-hydroxyvitamin D (25-OH-D) were measured. BMD measurements for the lumbar spine were obtained using dual-energy X-ray absorptiometry (DXA). BMD z scores were adjusted for height-for-age z score (HAZ) to provide correction for height deficits. Lumbar spine BMD z score was low (<-1) in five patients for chronological age and normalized in two of five patients after adjustment for HAZ. Three patients continued to have low BMD; these were older than the other patients and one had a history of long bone fracture. Two of these patients were observed to have lost walking capacity at 10 and 14 years, and the other was walking with support. Six patients had deficient, and three patients had insufficient levels of 25-OH-D. Two osteoporotic patients had significantly lower levels of 25-OH-D. We found that older patients with immobility are at high risk of osteoporosis and bone fracture, and vitamin D deficiencies/insufficiencies are widely seen. We recommend monitoring BMD by DXA and checking vitamin D metabolism to assess low bone mass and fracture risk in older MPS III patients with immobility.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Context: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat., Objective: We aimed to study natural history and disease burden of various subtypes of CGL., Design: We attempted to ascertain nearly all patients with CGL in Turkey., Setting: This was a nationwide study., Patients or Other Participants: Participants included 33 patients (22 families) with CGL and 30 healthy controls., Main Outcome Measure(s): We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up., Results: Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667&#95;705delinsCTGCG, c.268delC, and c.316+1G>T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C>T, c.631delG, c.62A>T, and c.465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c.259C>T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events., Conclusions: CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.

Isochromosome 18p is a rare chromosomal disorder that occurs with a frequency of approximately one in every 180,000 live births, and affects both genders equally. MOst cases result from a de novo formation. In the literature, there are currently only a small number of reports that describe the phenotypic and clinical features of Isochromosome 18p. In this article, we report six cases that displayed the phenotypic and clinical features of Isochromosome 18p, and which were subsequently confirmed by conventional karyotyping and fluorescence in situ hybridization. We also discuss the clinical features of these patients in the context of the cases previously reported in the literature.

Mucolipidosis II or I-cell disease is a rare lysosomal enzyme hydrolase trafficking due to deficient activity of the multimeric enzyme UDP-Nacetylglucosamine-l-phosphotransferase. It is a severe inborn error of lysosomal storage that causes progressive multisystem deterioration and death within the first year of life. The diagnosis of ML II is often difficult in an infant due to clinical variety, phenotypic overlap and the enzyme analysis required. Mucolipidosis II and rickets may have similar physical, biochemical and radiographic findings in newborns. The diagnosis of Mucolipidosis II is often missed, as it may present with rickets-like picture. In this article, we describe two neonatal mucolipidosis II patients mimicking rickets, and we evaluated them by clinical, metabolic and imaging findings via literature and also emphasized the difficulties in diagnosis of this rare disease.

Interstitial deletion of chromosome 11 long arm is a rare event. In most of the interstitial deletions on the long arm of chromosome 11 both the position and the size of these deletions are heterogeneous making a precise karyotype-phenotype correlation. In only a few of the reported cases has the deletion been molecularly characterized. Our patient was a 13-year-old male presented; mental motor retardation, strabismus, myopia, retinopathy, sensorineural hearing loss, a long and triangular face, a broad forehead, hypotelorism, nasal septal deviation, a beaked nose, hypoplastic ala nasie, bilateral low-set ears, a high arched palate, crowded teeth, retrognathia, thin lips, a long neck, and sloping shoulders, hyperactive behavior, pulmonary stenosis and lumbar scoliosis. Conventional cytogenetic analysis revealed 46,XY,del(11)(q14.1-q23.3) karyotype in the patient. Array-CGH analysis of the patient's DNA revealed an interstitial deletion encompassing 33.2 Mb in the 11q14.1-q23.3 genomic region (chr11: 83,161,443-116,401,751 ; Hg19). In this report, we present a patient with an interstitial deletion on the long arm of chromosome 11 that encompassed the 11q14.1-q23.3 region; and, using array-CGH analysis, we molecularly characterized the deleted region.

Hallermann-Streiff syndrome (HSS) is a genetic disorder characterized by proportionate dwarfism, birdlike facies, hypotrichosis, skin atrophy, dyscephaly, bilateral microphthalmia, congenital cataracts, a narrow, weak, beaked nose, a hypoplastic mandible, and orodental anomalies. Occurrence is sporadic and distinct patterns of inheritance have not been found. This case report describes the dental management of a 3-year-old girl patient with HSS, who had unusual radiographic appearance of teeth. Furthermore, dental treatments and a 30-month follow-up period of the patient with this rare tooth structure malformation have been presented.

Chanarin-Dorfman syndrome is an autosomal recessive lipid storage disease characterized by non-bullous congenital ichthyosiform erythroderma, and involvement of the liver, muscles and central nervous system due to a multisystemic accumulation of neutral lipids in various types of cells. Less than 100 affected individuals have been reported worldwide, the majority from the Mediterranean and Middle-East countries, especially Turkey. We present clinical and molecular data of four affected relatives with Chanarin-Dorfman syndrome homozygous for a N209X mutation in ABHD5, and provide a short review by comparing patients with N209X homozygous mutations to patients with other ABHD5 mutations. No major clinical differences exist between individuals with an N209X mutation and those with other mutations, which argues against a genotype/phenotype correlation., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

22q11.2 deletion syndrome is a pattern of malformations resulting from abnormalities during cephalic neural crest migration and during the development of the third and fourth branchial arch. It is also known as DiGeorge syndrome, as it is most often associated with a de novo 3 Mb hemizygous 22q11.2 deletion. The recognition of similarities and phenotypic overlap between DiGeorge syndrome and other disorders associated with genetic defects in 22q11 has led to an expanded description of the phenotypic features of this syndrome. Indeed, the extent of this phenotypic variability can often make it difficult to accurately diagnose DiGeorge syndrome. Tertiary monosomy resulting from the 3:1 segregation of the respective chromosomal segments of the chromosomes involved in a balanced translocation in meiosis is rarely reported in the literature. In this report, we present a female infant with dysmorphic facial features, microcephaly, a cleft palate, unilateral membranous choanal atresia, convulsions, hypocalcemia, semilobar holoporencephaly and echocardiographic abnormalities. To the best of our knowledge, this is the first description of a newborn displaying both DiGeorge syndrome and deletion 18p syndromes.

Skeletal dysplasias (SDs) constitute a group of heterogeneous disorders affecting growth morphology of the chondro-osseous tissues. Prenatal diagnosis of SD is a considerable clinical challenge due to phenotypic variability. We performed a retrospective analysis of the fetal autopsies series conducted between January 2006 and December 2012 at our center. SD was detected in 54 (10%) out of 542 fetal autopsy cases which included; 11.1% thanatophoric dysplasia (n = 6), 7.4% achondroplasia (n = 4), 3.7% osteogenesis imperfect (n = 2), 1.9% Jarcho-Levin Syndrome (n = 1), 1.9% arthrogryposis (n = 1), 1.9% Dyggve-Melchior-Clausen syndrome (n = 1), 72.1% of dysostosis cases (n = 39). All SD cases were diagnosed by ultrasonography. In 20 of the cases, amniocentesis was performed, 4 cases underwent molecular genetic analyses. Antenatal identification of dysplasia is important in the management of pregnancy and in genetic counseling. Our data analysis showed that SD is usually detected clinically after the 20th gestational week. Genetic analyses for SD may provide early diagnosis and management.