Search

Background: Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females and is characterized by a period of normal development followed by severe cognitive, motor, and communication impairment. The syndrome is predominantly caused by mutations in the MECP2. This study aimed to use comprehensive multi-omic analysis to identify the molecular and metabolic alterations associated with Rett syndrome., Methods and Results: Transcriptomic and metabolomic profiling was performed using neuron-like cells derived from the fibroblasts of 3 Rett syndrome patients with different MECP2 mutations (R168X, P152R, and R133C) and 1 healthy control. Differential gene expression, alternative splicing events, and metabolite changes were analyzed to identify the key pathways and processes affected in patients with Rett syndrome. Transcriptomic analysis showed there was significant down-regulation of genes associated with the extracellular matrix (ECM) and cytoskeletal components, which was particularly notable in patient P3 (R133C mutation), who had non-random X chromosome inactivation. Additionally, significant changes in microtubule-related gene expression and alternative splicing events were observed, especially in patient P2 (P152R mutation). Metabolomic profiling showed that there were alterations in metabolic pathways, particularly up-regulation of ketone body synthesis and degradation pathways, in addition to an increase in free fatty acid levels. Integrated analysis highlighted the interplay between structural gene down-regulation and metabolic shifts, underscoring the adaptive responses to cellular stress in Rett neurons., Conclusion: The present findings provide valuable insights into the molecular and metabolic landscape of Rett syndrome, emphasizing the importance of combining omic data to enlighten the molecular pathophysiology of this syndrome., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Placental transmogrification of the lung (PTL) is a rare pulmonary condition characterized by the presence of immature placental villous structures. The etiology and molecular mechanisms underlying this disease remain largely unknown. This functional study aimed to identify the molecular signatures in the pathogenesis of PTL via comprehensive transcriptome analysis. Comparative transcriptomic assessment of PTL tissue and stromal cells showed differential expression of 257 genes in PTL tissue and 189 genes in stromal cells. Notably, several transcription factors and regulators, including FOSB, FOS, JUN, and ATF3, were upregulated in PTL tissue. Additionally, genes associated with the extracellular matrix and connective tissue, such as COL1A1, MMP2, and SPARC, were significantly altered, indicating possible fibrotic changes. Gene set enrichment analysis highlighted the role of vascular development and extracellular matrix organization, and the Activator Protein-1 (AP-1) transcription factor was significantly activated in PTL tissue. Furthermore, the analysis highlighted an overlap of 25 genes between PTL tissue and stromal cells, underscoring the importance of shared molecular pathways in the pathogenesis of PTL. Among the shared genes, JUND, COL4A2, COL6A2, IGFBP5, and IGFBP7 were consistently upregulated, highlighting the possible involvement of AP-1-mediated signaling and fibrotic changes in the pathogenesis of PTL. The present findings pave the way for further research into the molecular mechanisms underlying PTL and offer novel insights for therapeutic interventions. Given the rarity of PTL, these molecular findings represent a significant step forward in our understanding this enigmatic disease., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations., (© 2022 Wiley Periodicals LLC.)

Genetic skeletal disorders (GSDs) are clinically and etiologically heterogeneous group of disorders caused by abnormal growth and development of bone and/or cartilaginous tissues. Timely and accurate diagnosis is essential for prevention of significant comorbidities. In this study demographic, parental, prenatal and natal characteristics, and postnatal diagnostic distribution along with follow-up processes of 104 individuals with the finding of "short femur" detected in routine prenatal ultrasonography were evaluated. Of 104 patients, 19 (18.2%) were medically terminated, 12 (11.6%) were deceased during follow-up and 73 (70.2%) were still under follow-up. Diagnostic distribution of 104 patients was as follows: 77 (74%) had GSD, eight (7.7%) had chromosomal disorder, seven (6.7%) were completely normal, and 12 (11.5%) had no definite diagnosis. Long-term follow up evaluation contributed to clinical diagnosis in four patients. When grouped according to Nosology and Classification of GSDs: 2019 revision, the most frequent (n = 30, 38.5%) group was "FGFR3 chondrodysplasia group", followed by "Type 2 collagen group" (n = 7, 9%), and "Osteogenesis imperfecta and decreased bone density group" (n = 5, 6.4%). The finding of prenatally detected "short femur" represents a group of diverse diagnosis with heterogeneous etiology. GSDs are the most common etiology among fetuses with short extremity., (© 2022 Wiley Periodicals LLC.)

The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis., (© 2022 by The American Society of Hematology.)

The objectives are to explore the demographic and polysomnographic features of children with Down syndrome and to determine the predictive factors associated with severe sleep apnea. A total of 81 children with Down syndrome referred for full-night polysomnography were analyzed. In addition, parental interviews were performed for each child. Data were available for 81 children, with a mean age of 4.8 years. Severe obstructive sleep apnea was determined in 53.1%. Age, sex, exposure to second-hand smoke, clinical findings, anthropometric features, and the presence of comorbidities were not predictors of severe obstructive sleep apnea. Children who were exposed to second-hand smoke had more sleep-related symptoms. Even in children without symptoms, the prevalence of severe obstructive sleep apnea was 40%. Moreover, 86% of parents had no previous information regarding possible sleep breathing disorders in their children. Clinically significant central apnea was present in 10 patients (12.3%).Conclusion: Our results demonstrate that severe obstructive sleep apnea is common in children with Down syndrome, even in children without a history of symptoms of sleep apnea. It is not possible to predict patients with severe apnea; thus, screening of children with Down syndrome beginning from young ages is very important. Central apneas could be a part of the spectrum of sleep abnormalities in Down syndrome., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63 ∗ ), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs ∗ 95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs ∗ 95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2 Leu381Hisfs ∗ 95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2 -/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Kohlschütter-Tönz syndrome (OMIM 226750) is a rare disorder with autosomal recessive inheritance among epileptic encephalopathy syndromes. To date, only 31 Kohlschütter-Tönz syndrome families have been reported in the literature. Early-onset epilepsy, progressive global developmental delay, and amelogenesis imperfecta are the main components of the syndrome. Mutations in ROGDI (MIM 226750) and SLC13A5 (MIM 615905) are responsible for Kohlschütter-Tönz syndrome. Here, we report on the clinical and molecular characteristics of 3 individuals from 2 families, all harboring the same homozygous novel deleterious variant in ROGD1 , along with a long-term follow-up and review of the literature. Although the phenotypic features are almost consistent in Kohlschütter-Tönz syndrome, overlooking dental findings and diverse degrees of variability in clinical findings makes diagnosis challenging occasionally. Because there is a limited number of reported patients, identification of new patients and delineation of clinical and molecular findings will increase the awareness of clinicians and enable establishing genotype-phenotype correlations.

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. 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.

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype- and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition., (© 2021 Wiley Periodicals LLC.)

Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by osteosclerosis and platyspondyly. DOS is genetically heterogeneous and causally associated with mutations in three genes, SLC29A3, CSF1R, and TNFRSF11A. TNFRSF11A has been known as the causal gene for osteopetrosis, autosomal recessive 7, and is recently reported to cause DOS in three cases, which show a complex genotype-phenotype relationship. The phenotypic spectrum of TNFRSF11A-associated sclerosing bone dysplasia remains unclear and needs to be characterized further in more cases with molecular genetic diagnosis. Here, we report another TNFRSF11A-associated DOS case with a homozygous missense mutation (p.R129C). The mutation effect is different from the previous three cases, in which truncated or elongated RANK proteins were generated in isoform specific manner, thus enriching our understanding of the genotype-phenotype association in TNFRSF11A-associated sclerosing bone dysplasia. Besides DOS, our case presented with intracranial extramedullary hematopoiesis, which is an extremely rare condition and has not been identified in any other sclerosing bone dysplasias with molecular genetic diagnosis. Our findings provide the fourth case of TNFRSF11A-associated DOS and further expand its phenotypic spectrum.

Musculoskeletal symptoms may be due to noninflammatory causes, including genetic disorders. We aimed to examine the final genetic diagnosis in patients who presented with musculoskeletal complaints to the rheumatology department. Patients who presented to the Department of Pediatric Rheumatology and were referred to the pediatric genetic department between January 2015 and May 2019 were evaluated retrospectively. A total of 60 patients, 19 boys (31.66%), with a mean age of 12.46 ± 1.41 years were included in the study. The total consanguinity rate was 25%. The most common (29.5%) cause of referral to the pediatric genetic department was the presence of skeletal anomalies (such as camptodactyly, clinodactyly, and short stature) with accompanying joint findings. Approximately one-third of the patients (n: 19) were diagnosed and followed up by the pediatric genetics department. The diagnoses of patients were as follows: camptodactyly, arthropathy, coxa vara, and pericarditis (CACP) syndrome (n: 3); trichorhinophalangeal syndrome (n: 1); progressive pseudorheumatoid dysplasia (n: 2); LIG4 syndrome (n: 1); H syndrome (n: 1); spondyloenchondrodysplasia (SPENCD) (n: 3); and nonspecific connective tissue disorders (n: 8). In the differential diagnosis of patients who are referred to the Department of Pediatric Rheumatology with complaints of the musculoskeletal system, genetic disorders should also be considered., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

3M syndrome is a rare autosomal recessive genetic disorder characterized by severe growth retardation, dysmorphic facial features, skeletal dysplasia, and normal intelligence. Variants in CUL7, OBSL1, and CCDC8 genes have been reported to be responsible for this syndrome. In this study, the clinical and molecular findings of four 3M syndrome cases from three families are presented. All cases had growth retardation, relative macrocephaly, and typical dysmorphic facial features. Their neurological developments were normal. Sequencing of CUL7, OBSL1, and CCDC8 genes revealed two different novel homozygous variants in CUL7 in Families 1 and 3 and a previously reported homozygous pathogenic variant in OBSL1 in Family 2. In conclusion, a comprehensive dysmorphological evaluation should be obtained in individuals presenting with short stature and in such individuals with typical facial and skeletal findings, 3M syndrome should be considered. Our report expands the genotype of 3M syndrome and emphasizes the importance of thorough physical and dysmorphological examination., (© 2020 Wiley Periodicals LLC.)

The genetic etiology of collagen VI related muscular dystrophies is heterogenous. Genomic deletions in one allele involving COL6A2 or both COL6A1 and COL6A2 unmasking a pathogenic variant in the second nondeleted allele have been described in the etiology. We aimed to report the clinical and molecular findings of a 13-year-old boy with ring chromosome 21 who presented to our clinic with easy fatigability, muscle weakness, and waddling gait. Phenotypic delineation along with chromosomal microarray analysis and DNA sequencing were performed. Affymetrix CytoScan Optima array platform and DNA sequencing revealed a 2,202 kb de novo deletion at 21q22.3, including COL6A1 and COL6A2 , and a novel heterozygous variant at position c.2875G > A;p.(Glu959Lys) in COL6A2 , respectively. Before his admission to our center, the patient was evaluated for hypotonia elsewhere when he was 15 months old. He was diagnosed with ring chromosome 21 on peripheral blood karyotype analysis; however, no further assessment was performed at that time. He had normal growth with mild dysmorphic facial features, distal laxity, gastrocnemius hypertrophy, proximal muscle weakness, increased lordotic posture with mild flexion contractures at the knees, and gait disturbance. Although the phenotype does not fit into classical Ullrich congenital muscular dystrophies, muscle magnetic resonance imaging (MRI) revealed a complementary pattern consistent with collagen VI related myopathies. Genetic testing confirmed the clinical diagnosis as well. This patient yet represents another example of the effect of large genomic deletions leading to recessive disorders through unmasking a pathogenic variant in the second nondeleted allele., Competing Interests: None., (Thieme. All rights reserved.)

Mowat-Wilson syndrome (MWS) is a rare autosomal dominant syndrome characterized by distinctive facial features, congenital heart defects, Hirschsprung disease, genitourinary anomalies, various structural brain anomalies, and intellectual disability. Pathogenic mutations that result in haploinsufficiency in the ZEB2 gene cause MWS. In this study, we aimed to evaluate the clinical features and molecular analysis results of 4 MWS patients. All patients were examined by an expert clinical geneticist. Dysmorphological abnormalities were recorded. Data including demographic, clinical, and laboratory findings were obtained from hospital records. ZEB2 gene analysis was performed using a Sanger sequencing method. All patients had typical facial features of MWS such as widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes. Four different heterozygous mutations were identified; 2 mutations were frameshift (c.246_247delGGinsC, c.980_980delG), 1 was nonsense (c.2083C>T), and 1 was splice site (c.808-2A>G). Two of them (c.246_247delGGinsC, c.980_980delG) have not been previously reported in the literature. By defining 2 novel mutations, this study contributes to the molecular spectrum of MWS, while also providing a further insight for genetic counseling. It also demonstrates the importance of dysmorphological examination in clinical diagnosis., Competing Interests: All authors declare that they have no conflict of interest., (Copyright © 2020 by S. Karger AG, Basel.)

Congenital cataract, which refers to lenticular opacity diagnosed at birth or more commonly during the first year of life, is one of the leading causes of childhood blindness. Molecular understanding of the disease pathogenesis has evolved thanks to many studies based on modern technologies. In this study, we aimed to identify and discuss the molecular etiology of nonsyndromic or nonmetabolic bilateral congenital cataract by whole-exome sequencing (WES). Patients with bilateral congenital cataract presumed to be isolated after metabolic and genetic evaluation were enrolled in the study. All patients underwent detailed ophthalmological examination and bilateral cataract surgery. DNA samples of the probands, parents, and available affected family members were analyzed by WES. Variants were validated and confirmed by Sanger sequencing in all probands and in available affected family members. A total of 4 patients (3 girls and 1 boy) were recruited. Two patients had nuclear, 1 patient had total, and 1 patient had combined lamellar and sutural cataract. One family had consanguinity. A heterozygous c.215+1G>A mutation in CRYBA1 , heterozygous c.432C>G (p.Tyr144Ter) mutation in CRYGC , heterozygous c.70A>C (p.Pro24Thr) mutation in CRYGD , and a heterozygous c.466G>A (p.Gly156Arg) mutation in CRYBB3 were detected. All these mutations were confirmed by Sanger sequencing in selected affected individuals. The current study identified all causative mutations of congenital cataract in the crystalline genes. The results confirmed that WES is a very useful tool in the investigation of the diseases with heterogeneous genetic background., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Several endocrine disorders have been defined in patients with Costello syndrome (CS). In this report, we describe a patient with CS accompanied by a clinical picture of hyperinsulinemic hypoglycemia responsive to diazoxide treatment. A 41-day-old female patient with a birth weight of 3,600 g was referred for atypical facial features and swallowing dysfunction. She had a weight of 4,000 g (-0.8 SDS), a length of 50 cm (-2.4 SDS), and a head circumference of 38 cm (0.2 SDS). The clinical findings were suggestive of a genetic syndrome, mainly a RASopathy or Beckwith-Wiedemann syndrome. Whole exome sequencing revealed a de novo heterozygous missense variant in the HRAS (NM_001130442) gene in exon 2: c.35G>C; p.(Gly12Ala), establishing the molecular diagnosis of CS. The patient developed symptomatic hypoglycemia (jitteriness and sweating) at the age of 13 months. The patient's serum glucose was 38 mg/dL with simultaneous serum insulin and C-peptide levels, 2.8 μIU/mL and 1.8 ng/mL, respectively. Hyperinsulinism was suspected, and an exaggerated glucose response was detected in a glucagon test. Blood glucose monitoring indicated episodes of fasting hypoglycemia and postprandial hyperglycemia. Diazoxide of 10 mg/kg/day was initiated in 3 doses for hyperinsulinemic hypoglycemia, which resolved without new episodes of postprandial hyperglycemia. The patient deceased at the age of 17 months due to cardiorespiratory failure in the course of severe pneumonia complicated with pulmonary hypertension and hypertrophic cardiomyopathy. Several genetic syndromes including CS are associated with endocrinologic manifestations including abnormal glucose homeostasis. Although the frequency and underlying mechanisms leading to hyperinsulinemic hypoglycemia are yet unknown, hypoglycemia in CS responds well to diazoxide., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Introduction: Sengers syndrome is an autosomal recessive disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. The causative AGK mutations have been identified with whole exome sequencing., Clinical Report: We report on a 9-month-old infant with episodic lactic acidosis who died before a definitive diagnosis could be established. Postmortem genomic autopsy revealed a novel homozygous NM_018238: c.1215dupG; p.Phe406Valfs*4 mutation in AGK (OMIM 610345) confirming the diagnosis of Sengers syndrome., Conclusion: This report provides further evidence that reverse genetics is a useful approach in patients who do not manifest the hallmark features of known and recognizable syndromes.

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively., (© 2019 Wiley Periodicals, Inc.)

Spondyloocular syndrome is characterized by generalized osteoporosis, multiple fractures and severe ocular findings. The causative XYLT2 mutations have recently been identified with the use of whole exome sequencing. We report on two siblings with spondyloocular syndrome who presented with varying clinical severity. A novel XYLT2 missense mutation was detected in a region evolutionary conserved across the species. This report along with the previous reports demonstrates that variable expressivity may be possible even within the same family. These two siblings with a novel mutation further expand the clinical and mutational spectrum of spondyloocular syndrome., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome., (© 2019 Wiley Periodicals, Inc.)

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting., Methods: Clinicians entered clinical data in an extensive web-based survey., Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified., Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Background: Rearrangement of the 1q21 region of chromosome 1 manifests as multiple phenotypes, including microcephaly, intellectual disability, dysmorphic facial features, eye abnormalities, cardiac defects, genitourinary anomalies, autism spectrum disorder, psychiatric conditions and seizures. Herein, we describe eight patients with 1q21 deletion and duplication syndromes, and novel deletions and findings., Methods: Chromosomal microarray analysis was performed to identify the existence of copy number variation. Quantitative polymerase chain reaction was applied using specific primers for the control and 1q21 region of chromosome 1. Mutational analysis was performed in case 5 using direct genomic sequencing for exons 1-6 in RBM8A., Results: Copy number variation analysis identified seven deletions and one duplication of the 1q21 region in the eight patients. In addition, four variations were de novo, and two deletions are reported here for the first time. One of the cases (case 7) presents moderate intellectual disability and dysmorphic facial findings, whereas chromosomal microarray analysis showed that case 7 had an 889-kb deletion in the 1q21 proximal region (GPR89A, PDZK1, CD160, POLR3C and NBPF12)., Conclusion: Although the deletion in case 5 did not include the thrombocytopenia-absent radius syndrome critical region or the RBM8A gene, he had pectoral muscle hypoplasia, radius and humerus hypoplasia and short curved ribs, which are indicative of a potential thrombocytopenia-absent radius region modifier. The findings in case 7 suggest that the proximal part of the 1q21 microdeletion syndrome region might be very important for the onset of clinical manifestations. Some novel findings were observed in the presented cases, such as radius and humerus hypoplasia and brain stem hypoplasia. The presented findings expand the spectrum of 1q21 aberrations and provide evidence of genotype-phenotype correlations for this region., (© 2019 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function., (Copyright © 2019 American Society of Human Genetics. All rights reserved.)

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is an autosomal recessive skeletal dysplasia, characterized by disproportionate short stature with a short and stiff neck and trunk. SMMD is caused by inactivating mutations in NKX3-2, which encodes a homeobox-containing protein. Because of the rarity of the disorder, the diagnostic feature has not been fully established yet. We describe an affected newborn with dysmorphic facial features and severe short trunk. The patient required immediate intubation at the delivery room and duodenal atresia was detected during his course in neonatal intensive care unit. Skeletal survey revealed total absence of the ossification of the vertebral bodies, pubis, and ischia. Mainly the femora was short and broad with mild flaring of the metaphyses. The downward sloping or tented appearance of the ribs was distinctive. A diagnosis of SMMD was made on clinical and radiological grounds. Molecular analysis revealed homozygosity for a novel mutation, c.507-508delCA (p.Gly171Cysfs*55) in exon 2 of NKX3-2. The patient was operated on postnatal day 7 for duodenal atresia. In the post-operative period he developed sepsis and respiratory failure and he died on postnatal day 14. Although no neuroradiologic imaging could be performed, the findings of clubfoot, neuromuscular respiratory insufficiency requiring invasive mechanical ventilation and downward sloping or tented appearance of the ribs were suggestive of very early cervical cord compression leading to perinatal mortality. To our knowledge this patient yet represents one of the most severe postnatal phenotypes of SMMD., (Copyright © 2018. Published by Elsevier Masson SAS.)

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.

Our understanding of the molecular basis of the genetic disorders of the skeleton has steadily increased, as the application of high-throughput sequencing technology has expanded. One of the newcomers is Spondyloepimetaphyseal dysplasia Faden-Alkuraya type. In this study, we aimed to further delineate the clinical, radiographic, and molecular findings of this entity in five affected individuals from two unrelated families. All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability. The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis. Unlike the previously reported clinical findings, all patients except one are normocephalic, and all share the clinical findings including craniosynostosis, varying degrees of intellectual disability, facial dysmorphism, and skeletal findings including pes planus, prominent heels, and pectus deformity. Interestingly one of the patients presented with a cemento-ossifying fibrous lesion of the maxilla. Whole exome sequencing revealed a novel homozygous [c.377delT] [p.Ile126fs*] frameshift mutation at exon 2 in one family, while Sanger sequencing revealed a novel homozygous splice site mutation [c.516+2T>A] at exon 4/intron 4 border of RSPRY1 in the other family. In conclusion; we provide further evidence that Spondyloepimetaphyseal dysplasia Faden-Alkuraya type is a RSPRY1-associated skeletal dysplasia with a distinctive phenotype composed of spondyloepimetaphyseal dysplasia, cono-brachydactyly, and craniosynostosis along with recognizable facial features and intellectual disability., (© 2018 Wiley Periodicals, Inc.)

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.

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

This study shares data on 417 patients with genetic disorders of skeleton including 10 fetal autopsies encountered in a 5-year period at a tertiary university hospital in Ankara, Turkey. We included patients with osteochondrodysplasias, excluding overgrowth syndromes, dysostoses, and craniofacial syndromes. When grouped according to the "International Skeletal Dysplasia Society 2010 classification" the most frequent group is "FGFR3 group" (achondroplasia). "Decreased bone density group" takes the second place, consistent with the literature. We also demonstrated, a relatively higher frequency of recessively inherited skeletal dysplasias when the diagnosis is an entity other than achondroplasia or osteogenesis imperfecta. The literature on the incidence of genetic disorders of skeleton from the Middle East and Eastern Mediterranean is limited to fetal and neonatal autopsies or birth prevelance reports. The higher rate of consanguineous marriages which increases the frequency of autosomal recessive entities makes it difficult to apply data from other parts of the world. Total consanguinity rate among parents in our study was 53% and there were regional differences. The highest (79%) was among parents from South-east Anatolia. This study is the first broad retrospective analysis of genetic disorders of skeleton from our region. We aim to provide a descriptive source for future studies and discuss our findings in comparison to reports from other parts of the world., (© 2015 Wiley Periodicals, Inc.)

Camurati-Engelmann disease is characterized by hyperostosis of the long bones and the skull, muscle atrophy, severe limb pain, and progressive joint contractures in some patients. It is caused by heterozygous mutations in the transforming growth factor β1 (TGFβ1) believed to result in improper folding of the latency-associated peptide domain of TGFβ1 and thus in increased or deregulated bioactivity. Losartan, an angiotensin II type 1 receptor antagonist, has been found to downregulate the expression of TGFβ type 1 and 2 receptors. Clinical trials with losartan have shown a benefit in Marfan syndrome, while trials are underway for Duchenne muscular dystrophy and other myopathies associated with TGFβ1 signaling. We hypothesized that due to its anti-TGFβ1 activity, losartan might be beneficial in Camurati-Engelmann disease. This report concerns a boy who presented at age 13 years with severe limb pain and difficulty in walking. Clinical and radiographic evaluation results were compatible with Camurati-Engelmann disease and the diagnosis was confirmed by mutation analysis (c.652C > T [p.Arg218Cys]). The boy underwent an experimental treatment with losartan at a dosage of 50 mg/day, orally. During the treatment period of 18 months, the intensity and frequency of limb pain decreased significantly (as shown by a pain diary), and muscle strength improved, allowing the boy to resume walking and climbing stairs. No obvious side effects were observed. We cautiously conclude that TGFβ1 inhibition with losartan deserves further evaluation in the clinical management of Camurati-Engelmann disease., (© 2014 Wiley Periodicals, Inc.)

The Barraquer-Simons syndrome or acquired parital lipodystrophy is a rare form of partial lipodystrophy characterized by gradual onset of bilaterally symmetrical subcutaneous fat loss from the face, neck, upper extremities, thorax, and abdomen but sparing the lower extremities. The patients gradually loose their subcutaneous fat in clearly demarcated, generally symmetric areas of the body over several years. Nephropathy, myopathy, deafness, epilepsy, and intellectual disability have also been described. Although the etiology is unknown, heterozygous mutations in the gene encoding one of the nuclear lamina proteins, lamin B2, have been reported in several patients. We here report on a young female patient affected by Barraquer-Simons syndrome, without accompanying renal or central nervous system involvement in whom DNA sequencing did not reveal any mutations in the genes LMNB2, LMNA, PPARG, AGPAT2, BSCL2, CAV1, PTRF, PLIN1, and CIDEC., (© 2014 Wiley Periodicals, Inc.)

Objective: This study explored the social factors affecting prenatal decision making, the impact of genetic counseling on prenatal decision making, and how genetic counseling is perceived by Turkish women., Method: A standardized questionnaire was given to 231 patients, before and after genetic counseling, at Hacettepe University Ihsan Dogramaci Children's Hospital in 2007-2008., Results: The level of education was an important factor both in prenatal decision making and in the patients' perception of genetic counseling. Decisions of pregnancy termination differed by geographic region of referral and history of healthy children but the differences were not statistically significant. The decisions were not influenced by poor obstetric history, number and sex of previous children, and disability of previous children., Conclusion: The level of education and the geographic region of referral in Turkey had an effect on the prenatal decisions and on the amount of prenatal genetic counseling received by the individuals.

Cousin syndrome, also called pelviscapular dysplasia (OMIM 260660), is characterized by short stature, craniofacial dysmorphism, and multiple skeletal anomalies. Following its description in two sibs in 1982, no new cases have been observed until the observation of two unrelated cases in 2008 who were homozygous for frameshift mutations in TBX15. We investigated an adult individual with short stature, a complex craniofacial dysmorphism, malformed and rotated ears, short neck, elbow contractures, hypoacusis, and hypoplasia of scapula and pelvis on radiographs. We identified homozygosity for a novel nonsense mutation (c.841C>T) in TBX15 predicted to cause a premature stop (p.Arg281*) with truncation of the protein. This observation confirms that Cousin syndrome is a consistent and clinically recognizable phenotype caused by loss of function of TBX15., (© 2013 Wiley Periodicals, Inc.)

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

Costello syndrome is a congenital disorder comprising a characteristic face, severe feeding difficulties, skeletal, cardiac and skin abnormalities, intellectual disability and predisposition to malignancies. It is caused by heterozygous germline HRAS mutations mostly affecting Gly(12) or Gly(13), which impair HRAS-GTPase activity and result in increased downstream signal flow independent of incoming signals. Functional analyses of rarer HRAS mutations identified in individuals with attenuated Costello syndrome phenotypes revealed altered GDP/GTP nucleotide affinities (p.K117R) and inefficient effector binding (p.E37dup). Thus, both phenotypic and functional variability associated with HRAS mutations are evident. Here, we report on a novel heterozygous HRAS germline mutation (c.187&#95;207dup, p.E63&#95;D69dup) in a girl presenting with a phenotype at the milder end of the Costello syndrome spectrum. The p.E63&#95;D69dup mutation impaired co-precipitation of recombinant HRAS with NF1 GTPase-activating protein (GAP) suggesting constitutive HRAS(E63&#95;D69dup) activation due to GAP insensitivity. Indeed, we identified strongly augmented active HRAS(E63&#95;D69dup) that co-precipitated with effectors RAF1, RAL guanine nucleotide dissociation stimulator and phospholipase C1. However, we could not pull down active HRAS(E63&#95;D69dup) using the target protein PIK3CA, indicating a compromised association between active HRAS(E63&#95;D69dup) and PIK3CA. Accordingly, overexpression of HRAS(E63&#95;D69dup) increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF, whereas AKT phosphorylation downstream of phosphoinositide 3-kinase (PI3K) was not enhanced. By analyzing signaling dynamics, we found that HRAS(E63&#95;D69dup) has impaired reagibility to stimuli resulting in reduced and disrupted capacity to transduce incoming signals to the RAF-MAPK and PI3K-AKT cascade, respectively. We suggest that disrupted HRAS reagibility, as we demonstrate for the p.E63&#95;D69dup mutation, is a previously unappreciated molecular pathomechanism underlying Costello syndrome.

Mucolipidosis type III (MLIII) (MIM# 252600) is an uncommon autosomal recessive disorder that results from deficiency of the multimeric enzyme, UDP-N-acetylglucosamine-1-phosphotransferase. The enzymatic defect results in deficiencies of lysosomal degradative enzymes with concomitant intracellular accumulation of both partly degraded glycosaminoglycans and sphingolipids leading to clinical manifestations such as short stature, developmental delay and other structural abnormalities. The diagnosis is challenging since musculoskeletal presentation may mimic some of the rheumatic and metabolic disorders. We herein report on a 13-year-old adolescent who was admitted to our rheumatology clinic because of progressive joint stiffness and deformities of her hands. The clinical and radiological findings led us to the diagnosis of MLIII despite negative urinary aminoglycosyaminoglycans. Therefore we decided to check for the presence of elevated activities of alpha-mannosidase and beta-hexosaminidase A+B in the plasma which was actually the case and confirmed the clinical diagnosis ofMLIII.

Anterior segment dysgenesis comprises a spectrum of malformations arising from faulty neural crest cell migration. We report a newborn boy with partial trisomy 16q and partial monosomy 3p who presented with anterior segment dysgenesis with iris hypoplasia on the right and glaucoma on the left in association with systemic anomalies. The anterior segment dysgenesis features observed in this case have not been previously associated with partial trisomy 16q or partial monosomy 3p. Our findings support the hypothesis that an additional anterior segment dysgenesis gene may reside on chromosome 3p or 16q., (Copyright © 2012 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

Ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome is the prototype of several p63 conditions, which include ankyloblepharon, ectodermal dysplasia, clefting (AEC) syndrome, limb-mammary syndrome (LMS), Rapp-Hodgkin syndrome (RHS), ADULT syndrome, and others. All these disorders include combinations of ectodermal dysplasia, orofacial clefting and limb malformations in variable severity. A newborn patient is presented with diffuse erythematous and desquamating skin lesions and anal atresia. She also had sparse and lightly colored thin hair, deeply set eyes, hypoplastic alae nasi, and a short philtrum. Cleft lip/palate and ankyloblepharon were not present. Complete cutaneous syndactyly was present on both hands in between the third and fourth fingers. Mild ectrodactyly was evident on all four extremities in between first and second digits. There was post-axial polydactyly on both feet. Anal atresia was present and defecation occurred through a rectovaginal fistula. The patient represented an interesting overlapping clinical condition between AEC and EEC syndromes. Diffuse skin lesions with excoriation and desquamation suggest AEC syndrome, despite the absence of ankyloblepharon, however; ectrodactyly and polydactyly strongly suggest the EEC syndrome. C308Y mutation in exon 8 of TP63 gene was detected, which was previously described to lead only to EEC syndrome and not to any of the other allelic conditions. These data emphasize the large degree of clinical variability that may be seen for specific TP63 mutations., (Copyright © 2011 Wiley Periodicals, Inc.)

Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. In our study, we sequenced all 54 coding exons of the recently identified MLL2 gene in 34 patients with Kabuki syndrome. We identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located all over the gene and included three nonsense mutations, two splice-site mutations, six small deletions or insertions, and seven missense mutations. We compared frequencies of clinical symptoms in MLL2 mutation carriers versus non-carriers. MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 carriers obviously showed more frequently a typical facial gestalt (17/19) compared with non-carriers (9/15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in ten functional candidate genes (e.g. MLL, ASC2, ASH2L, and WDR5), but no convincing causative mutations could be found. Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity.