Kosaki Overgrowth Syndrome: Report of a Family with a Novel PDGFRB Variant.

Heterozygous activating missense variants of PDGFRB are associated with the phenotype of Kosaki overgrowth syndrome (KOGS). Here, we present a family including a father and 2 siblings with a novel variant, c.2567A>T (p.Asn856Ile), localized in the cytoplasmic tyrosine kinase domain, exhibiting a KOGS phenotype. The coarsening of the facial features, enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. There were no signs of thin/fragile skin, premature aging appearance, myofibroma, white matter findings, and intellectual disability in any of them. Corneal pterygium and evidence of cerebral vasculopathy were only detected in the father. One sibling exhibited café-au-lait spots. Posterior fossa enlargement was revealed only in one sibling. KOGS is an extremely rare overgrowth syndrome. No familial cases of KOGS have been reported so far. Hereby, we demonstrated that the features of KOGS can show mild intrafamilial variability, and the risk of vascular complications may arise with age.

From cataract to syndrome diagnosis: Revaluation of Warburg-Micro syndrome Type 1 patients.

Warburg-Micro syndrome (WARBM) is a rare autosomal recessively inherited neuro-ophthalmologic syndrome. Although WARBM shows genetic heterogeneity, the pathogenic variants in RAB3GAP1 were the most common cause of WARBM. In this study, we aimed to evaluate the detailed clinical and dysmorphic features of seven WARBM1 patients and overview the variant spectrum of RAB3GAP1 in comparison with the literature who were referred due to congenital cataracts. A previously reported homozygous variant (c.2187_2188delGAinsCT) was identified in three of these patients, while the other four had three novel variants (c.251_258delAGAA, c.2606+1G>A, and c.2861_2862dupGC). Congenital cataract and corpus callosum hypo/agenesia are pathognomonic for WARBM, which could be distinguished from other similar syndromes with additional typical dysmorphic facial features. Although there is no known phenotype and genotype correlation in any type of WARBM, RAB3GAP1 gene analysis should be previously requested as the first step of genetic diagnosis in clinically suspicious patients when it is not possible to request a multi-gene panel.

Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis.

BACKGROUND: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

Overview of the Pulmonary Manifestations in Patients with Autosomal Recessive Cutis Laxa Type IC.

Background: Autosomal recessive cutis laxa type IC (ARCL1C) is characterized by cutis laxa accompanied by pulmonary, gastrointestinal, urinary, musculoskeletal involvement caused by biallelic mutations in latent transforming growth factor-beta binding protein 4 (LTBP4) gene. The overall prognosis is poor, and most patients die in infancy because of severe pulmonary emphysema (PE). Aim: We aimed to evaluate 3 ARCL1C patients, 2 of whom are still alive and in their childhood period, from 2 unrelated families with novel LTBP4 mutations, to demonstrate the clinical variability of pulmonary involvement. Materials and Methods: Three children who were molecularly confirmed by LTBP4 sequencing analysis were comprehensively reviewed in terms of pulmonary manifestations through chest examination, lung function tests (LFTs), chest X-ray, and thorax computed tomography. Results: Family 1 (c.3740A>G LTBP4 mutation): A 5-year-old male patient with pulmonary artery stenosis (PAS) presented with persistent cough and exhibited mild restriction on LFT. Family 2 (c.2T>G LTBP4 mutation): Radiographic examinations revealed PE in a 7-year-old female patient who was operated for diaphragmatic hernia. She had recurrent bronchiolitis and pulmonary infections. LFT revealed both obstructive and restrictive pattern. Her cousin also had respiratory distress with the onset of the newborn period and died due to bilateral pneumothorax in early infancy. Conclusion: The variable severity of pulmonary findings was shown in these patients. It should also be kept in mind that there could be intrafamilial variability of systemic manifestations. Although obstructive lung disease is expected to be seen in ARLC1C patients, restrictive LFT patterns may also be detected as a result of comorbidities such as diaphragmatic hernia and PAS.

Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey.

Autosomal recessive ataxias (ARAs) are a heterogeneous group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar tract, and/or the sensory tracts of the spinal cord. This study is aimed at establishing molecular classification and phenotypic correlation of childhood-onset ARAs in Southeast Anatolia of Turkey. Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015-2018 were selected for the study. Seventeen different, clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%), 12 of which were noted to be unreported variants. Among these 33 families, 24 had ATM-related (72.72%), four had SACS-related (12.12%), three had COQ8A-related (9.09%), and two had APTX-related (6.06%) pathogenic variants. The c.3576G>A (p.K1192=) was the most common homozygous pathogenic ATM variant (33.33%) that was associated with milder phenotype of ataxia telangiectasia (AT) with the onset of age of 3. Patients with SACS variants demonstrated developmental delay and progressive ataxia before the age of 3. Slowly progressive ataxia and intellectual disability were the common clinical manifestations of the patients with homozygous c.1396delG (p. E466Rfs*11) pathogenic variant in COQ8A. Homozygous APTX c.689T>G (p.V230G) pathogenic variant was identified in two patients who had chief complaint of ataxic gait onset after puberty. The most common types of ARAs in this region are AT- and Charlevoix-Saguenay-type spastic ataxia. ATM gene analysis should be performed foremost on children presenting early-onset ataxia from Southeastern Anatolia. If there is a concomitant peripheral neuron involvement, SACS gene analysis should be preferred. This valuable data will be a guide for the first step molecular diagnostic approach before requesting the NGS panel for ARA.

Esophageal Atresia and Thenar Hypoplasia Associated with Asymmetric Crying Face.

Asymmetric crying face (ACF) is a minor congenital anomaly that is often associated with a high rate of major malformations and may be considered an indication of a syndromic clinical presentation. Here, we report a 21-month-old male presenting with left- sided ACF, thenar hypoplasia, and esophageal atresia. Ultrasonographic images of the volar surface of the left hand evidenced the absence of muscle tissue around the thenar prominence at the level of the first metacarpal bone. No pathogenic copy number variation was detected on array-comparative genomic hybridization analysis (CGH). The association of esophageal atresia, thenar hypoplasia, and ACF has not been reported before. We discuss the possibility of a distinct association or of a sequence of anomalies associated with ACF.

Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations.

Baller-Gerold (BGS, MIM#218600) and Roberts (RBS, MIM#268300) syndromes are rare autosomal recessive disorders caused, respectively, by biallelic alterations in RECQL4 (MIM*603780) and ESCO2 (MIM*609353) genes. Common features are severe growth retardation, limbs shortening and craniofacial abnormalities which may include craniosynostosis. We aimed at unveiling the genetic lesions underpinning the phenotype of two unrelated children with a presumptive BGS diagnosis: patient 1 is a Turkish girl with short stature, microcephaly, craniosynostosis, seizures, intellectual disability, midface hemangioma, bilateral radial and thumb aplasia, tibial hypoplasia, and pes equinovarus. Patient 2 is an Iranian girl born to consanguineous parents with craniosynostosis, micrognathism, bilateral radial aplasia, thumbs, and foot deformity in the context of developmental delay. Upon negative RECQL4 test, whole exome sequencing (WES) analysis performed on the two trios led to the identification of two different ESCO2 homozygous inactivating variants: a previously described c.1131+1G>A transition in patient 1 and an unreported deletion, c.417del, in patient 2, thus turning the diagnosis into Roberts syndrome. The occurrence of a Baller-Gerold phenotype in two unrelated patients that were ultimately diagnosed with RBS demonstrates the strength of WES in redefining the nosological landscape of rare congenital malformation syndromes, a premise to yield optimized patients management and family counseling.

Vocal cord immobility as a cause of aphonia in a child with 3p13p12 deletion syndrome encompassing FOXP1 gene.

Congenital bilateral laryngeal paralysis/immobilization is an uncommon condition and has been described as isolated or accompanying to some recognizable syndromes. Heterozygous mutations in the FOXP1 gene (605515) are related with intellectual disability and, language impairment with or without autistic features. Expressive language is more affected than receptive language and more than half of the patients experience oromotor dysfunction and/or feeding difficulties. Here we report a child with severe developmental, speech delay and aphonia which was considered due to bilaterally abductor vocal cord immobility. Interstitial 8700 kbp deletion encompassing FOXP1 gene was detected on 3p13p12 chromosomal region. Although it is known that FOXP1 defects are related to abnormalities in vocal communication, FOXP1-associated laryngomalacia or vocal cord paralysis/immobilization cases have not been reported yet. The FOXP1 defects are considered to be a cause of delay in speech, and it is suggested that vocal cord evaluation should be conducted in suspicious cases.

Fetal Valproate Syndrome.

BACKGROUND: There have been several reports of congenital malformations in the offspring of mothers who took valproic acid (VPA) during pregnancy as a treatment for epilepsy. METHODS: Herein, we describe four cases with typically similar facial features of fetal valproate syndrome accompanied to minor skeletal abnormalities. RESULTS: The first case was a 16-month-old girl, presenting with facial dysmorphism, and finger abnormalities. Her mother took VPA (1500 mg/d) up to the 10th gestational week and at a dosage of 1000 mg/d through the pregnancy. The second patient was 5-year-old boy with speech disability, bilateral cryptorchidism, facial dysmorphism, and finger abnormalities whose mother took VPA (1000 mg/d) through pregnancy. The third 19-month-old patient was the brother of the second patient who had facial dysmorphism, bilateral cryptorchidism, and finger abnormalities. His mother also took VPA (1000 mg/d) through pregnancy. The fourth 3-year and 6 month-old boy with minor facial dysmorphism and sternum deformity was exposed to VPA (500 mg/d) in utero. CONCLUSION: In conclusion, there is a recognizable spectrum of abnormalities in some infants exposed to VPA without dose-depence and the common facial dysmorphic features and minor skeletal abnormalities that may occur within the both low and high dose VPA use.

Identification of SLC22A5 Gene Mutation in a Family with Carnitine Uptake Defect.

Primary systemic carnitine deficiency is caused by homozygous or compound heterozygous mutation in the SLC22A5 gene on chromosome 5q31. The most common presentations are in infancy and early childhood with either metabolic decompensation or cardiac and myopathic manifestations. We report a case of 9-year-old boy with dysmorphic appearance and hypertrophic cardiomyopathy. Tandem MS spectrometry analysis was compatible with carnitine uptake defect (CUD). His sister had died due to sudden infant death at 19 months. His second 4-year-old sister's echocardiographic examination revealed hypertrophic cardiomyopathy, also suffering from easy fatigability. Her tandem MS spectrometry analyses resulted in CUD. We sequenced all the exons of the SLC22A5 gene encoding the high affinity carnitine transporter OCTN2 in the DNA. And one new mutation (c.1427T>G → p.Leu476Arg) was found in the boy and his sister in homozygous form, leading to the synthesis of an altered protein which causes CUD. The parent's molecular diagnosis supported the carrier status. In order to explore the genetic background of the patient's dysmorphic appearance, an array-CGH analysis was performed that revealed nine copy number variations only. Here we report a novel SLC22A5 mutation with the novel hallmark of its association with dysmorphologic feature.