A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Megalencephalic leukoencephalopathy with subcortical cysts protein-1: A new calcium-sensitive protein functionally activated by endoplasmic reticulum calcium release and calmodulin binding in astrocytes.

BACKGROUND: MLC1 is a membrane protein highly expressed in brain perivascular astrocytes and whose mutations account for the rare leukodystrophy (LD) megalencephalic leukoencephalopathy with subcortical cysts disease (MLC). MLC is characterized by macrocephaly, brain edema and cysts, myelin vacuolation and astrocyte swelling which cause cognitive and motor dysfunctions and epilepsy. In cultured astrocytes, lack of functional MLC1 disturbs cell volume regulation by affecting anion channel (VRAC) currents and the consequent regulatory volume decrease (RVD) occurring in response to osmotic changes. Moreover, MLC1 represses intracellular signaling molecules (EGFR, ERK1/2, NF-kB) inducing astrocyte activation and swelling following brain insults. Nevertheless, to date, MLC1 proper function and MLC molecular pathogenesis are still elusive. We recently reported that in astrocytes MLC1 phosphorylation by the Ca2+/Calmodulin-dependent kinase II (CaMKII) in response to intracellular Ca2+ release potentiates MLC1 activation of VRAC. These results highlighted the importance of Ca2+ signaling in the regulation of MLC1 functions, prompting us to further investigate the relationships between intracellular Ca2+ and MLC1 properties. METHODS: We used U251 astrocytoma cells stably expressing wild-type (WT) or mutated MLC1, primary mouse astrocytes and mouse brain tissue, and applied biochemistry, molecular biology, video imaging and electrophysiology techniques. RESULTS: We revealed that WT but not mutant MLC1 oligomerization and trafficking to the astrocyte plasma membrane is favored by Ca2+ release from endoplasmic reticulum (ER) but not by capacitive Ca2+ entry in response to ER depletion. We also clarified the molecular events underlining MLC1 response to cytoplasmic Ca2+ increase, demonstrating that, following Ca2+ release, MLC1 binds the Ca2+ effector protein calmodulin (CaM) at the carboxyl terminal where a CaM binding sequence was identified. Using a CaM inhibitor and generating U251 cells expressing MLC1 with CaM binding site mutations, we found that CaM regulates MLC1 assembly, trafficking and function, being RVD and MLC-linked signaling molecules abnormally regulated in these latter cells. CONCLUSION: Overall, we qualified MLC1 as a Ca2+ sensitive protein involved in the control of volume changes in response to ER Ca2+ release and astrocyte activation. These findings provide new insights for the comprehension of the molecular mechanisms responsible for the myelin degeneration occurring in MLC and other LD where astrocytes have a primary role in the pathological process.

Megalencephaly secondary to a novel germline missense variant p.Asp322Tyr in AKT3 associated with growth hormone deficiency and central hypothyroidism: A case report.

Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of age: growth hormone (GH) deficiency responsible for growth delay and central hypothyroidism. After 6 months of GH treatment, intracranial hypertension was noted, confirmed by the observation of papilledema and increased intracranial pressure, requiring the initiation of acetazolamide treatment and the discontinuation of GH treatment. This is the second reported patient described with megalencephaly and AKT3 gene variant associated with GH deficiency . Other endocrine disorders have also been reported in few cases with hypothyroidism and hypoglycemia. Pituitary deficiency may be a part of the of megalencephaly phenotype secondary to germline variant in the AKT3 gene. Special attention should be paid to growth in these patients and search for endocrine deficiency is necessary in case of growth retardation or hypoglycemia.

Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon-level Array, and RNA sequencing.

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.

PTEN hamartoma tumor syndrome: Clinical and genetic characterization in pediatric patients.

OBJECTIVE: The aim of this study was to provide a full characterization of a cohort of 11 pediatric patients diagnosed with PTEN hamartoma tumor syndrome (PHTS). PATIENTS AND METHODS: Eleven patients with genetic diagnostic of PHTS were recruited between February 2019 and April 2023. Clinical, imaging, demographic, and genetic data were retrospectively collected from their hospital medical history. RESULTS: Regarding clinical manifestations, macrocephaly was the leading sign, present in all patients. Frontal bossing was the most frequent dysmorphism. Neurological issues were present in most patients. Dental malformations were described for the first time, being present in 27% of the patients. Brain MRI showed anomalies in 57% of the patients. No tumoral lesions were present at the time of the study. Regarding genetics, 72% of the alterations were in the tensin-type C2 domain of PTEN protein. We identified four PTEN genetic alterations for the first time. CONCLUSIONS: PTEN mutations appear with a wide variety of clinical signs and symptoms, sometimes associated with phenotypes which do not fit classical clinical diagnostic criteria for PHTS. We recommend carrying out a genetic study to establish an early diagnosis in children with significant macrocephaly. This facilitates personalized monitoring and enables anticipation of potential PHTS-related complications.

Macrocephaly and Finger Changes: A Narrative Review.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

[Analysis of clinical features and genetic variant in a child with Cowden syndrome 1].

OBJECTIVE: To explore the genetic etiology of a child with Cowden syndrome 1 (CS1). METHODS: A child who had visited the Ningbo Women and Children's Hospital on August 26, 2022 was selected as the study subject. Clinical information of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The child, a 13-year-old boy, had manifested with severe mental retardation, hyperactivity, autistic behavior, sparse and prominent teeth, macrocephaly, and skin freckles on the penis. His mother had presented with multiple papules, hamartomatous polyps, thyroid adenoma and macrocephaly. WES results revealed that the child has harbored a nonsense c.781C>T (p.Q261*) variant of the PTEN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.781C>T variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.781C>T variant of the PTEN gene probably underlay the pathogenesis in the child and his mother. Above finding has facilitated genetic counseling for this family.

[Analysis of clinical characteristics and molecular genetics in eighteen patients with 1q21.1 microdeletion syndrome].

OBJECTIVE: To explore the clinical characteristics of 1q21.1 microdeletion by using single nucleotide polymorphism microarrays (SNP array). METHODS: Eighteen cases of 1q21.1 microdeletion syndrome diagnosed at the Longgang District Maternal and Child Health Care Hospital of Shenzhen City from June 2017 to December 2022 were selected as the study subjects. Clinical data of the patients were collected. Results of chromosomal karyotyping and SNP assay were retrospectively analyzed. RESULTS: Among the 18 cases with 1q21.1 microdeletions, 13 had a deletion between BP3 and BP4, 4 had a deletion between BP1/BP2 and BP4, whilst 1 had a proximal 1q21.1 deletion (between BP2 and BP3) involving the Thrombocytopenia-absent radius (TAR) region. The deletions had spanned from 360 kb to 3.9 Mb, which encompassed the GJA5, GJA8, CHD1L, RBM8AB and other morbid genes. In three families, the proband child has inherited the same 1q21.1 microdeletion from their parents, whose clinical phenotype was normal or slightly abnormal. The clinical phenotypes of 1q21.1 microdeletion had included cognitive or behavioral deficits in 9 cases (9/18, 50.0%), growth retardation in 8 cases (8/18, 44.4%), craniofacial deformities in 7 cases (7/18, 38.8%), cardiovascular malformations in 5 cases (5/18, 27.8%), and microcephaly in 3 cases (3/18, 16.7%). CONCLUSION: 1q21.1 microdeletion syndrome has incomplete penetrance and varied expression such as intellectual impairment, growth and development delay, and microcephaly, with a wide range of non-specific phenotypes.

[EXAMINING THE ASSOCIATION BETWEEN THE FETAL SUPRATENTORIAL BRAIN VOLUME AND THE SUBARACHNOID SPACE IN VARIOUS FETAL PATHOLOGIES USING MAGNETIC RESONANCE IMAGING].

INTRODUCTION: The subarachnoid space (SAS) is a potential space surrounding the brain where the cerebrospinal fluid (CSF) flows. Previous work demonstrated how the SAS width changes during pregnancy and measured the normal values per gestational week. OBJECTIVES: Studying the ratio between the fetal brain volume (STV) and the SAS width (SS ratio), as measured via fetal magnetic resonance imaging (MRI) in different fetal pathologies - macrocephaly and microcephaly, and studying the correlation between this ratio and the gestational week. METHODS: A retrospective study was conducted on 77 fetuses that underwent fetal MRI scans during gestational weeks 29-37, in three groups: 23 normocephaly, 27 macrocephaly, and 27 microcephaly. SAS width was measured in 10 points via fetal MRI scans, and a ratio was calculated between the width and STV. RESULTS: The SS ratio is largest in microcephaly group and smallest in normocephaly group, with the macrocephaly group between them. All comparisons were statistically significant except between the macrocephaly and normocephaly groups. There was a strong positive correlation between SS ratio and week of gestation. CONCLUSIONS: The SS ratio is statistically different between normocephalic fetuses and fetuses with macrocephaly or microcephaly. From week 29 this ratio enlarges with gestational age. DISCUSSION: The SAS affects the fetal head circumference, an important parameter of fetal growth, thus we decided to study the SS ratio in pathologies of the head circumference. Previous work demonstrated how the STV and the SAS width expand starting at a specific gestational age, thus the gestational week also affects the SS ratio. Summary: The SS ratio is affected by pathologies of the fetal head circumference and by gestational age.

[X-linked intellectual disability syndrome with macrocephaly due to BRWD3 gene deletion]. / Síndrome de discapacidad intelectual ligada a X con macrocefalia por deleción del gen BRWD3.

INTRODUCTION: Pathogenic variants in BRWD3 gene have been described as a rare cause of syndromic X-linked intellectual disability. Its phenotype shows neurodevelopmental delay with intellectual disability in all reported patients, facial dysmorphic features, macrocephaly, overgrowth and obesity. The great majority of cases yield point variants in the gene, only three large deletions including only the BRWD3 gene have been reported. The BRWD3 protein is an epigenetic reader that regulates chromatin remodeling. We report a boy with a compatible phenotype and a deletion including only this gene. CASE REPORT: Boy, without family and perinatal pathological background, with neurodevelopmental delay: psychomotor delay, speech delay and intellectual disability, macrocephaly (p > 99) and obesity. Phenotype with facial dysmorphic features: wide forehead, deep set eyes, bulbous nose, prominent ears and pointed chin. The array-CGH analysis showed a 586 kb deletion at Xq21.1 including only one gene with associated disorder, BRWD3. Afterwards, the deletion was also identified in his asymptomatic mother and sister. CONCLUSIONS: Our patient confirms that the haploinsufficiency due to BRWD3 deletion is a causal genetic mechanism of the BRWD3-related syndromic X-linked intellectual disability. It is important to recognize the phenotype for the diagnosis and follow up of the patients, and also to carry out the family genetic analysis in order to identify and give genetic counselling to the women who also have the genetic defect, because the majority of them are asymptomatic, as the mother and sister of our patient.

TITLE: Síndrome de discapacidad intelectual ligada a X con macrocefalia por deleción del gen BRWD3.Introducción. Variantes patógenas en el gen BRWD3 son la causa de un tipo poco frecuente de discapacidad intelectual sindrómica ligada a X. Su fenotipo se asocia a la alteración neuroconductual con discapacidad intelectual, dismorfia facial, macrocefalia, sobrecrecimiento y obesidad. La gran mayoría de los pacientes presenta variantes puntuales en el gen y sólo se han descrito tres casos con deleciones parciales que incluyen únicamente al gen BRWD3. Funcionalmente es un lector epigenético que regula la remodelación de la cromatina. Presentamos un varón con fenotipo compatible con una deleción que incluye sólo este gen asociado a patología. Caso clínico. Varón sin antecedentes familiares ni perinatales de interés con alteración en el neurodesarrollo: retraso psicomotor, retraso del lenguaje y discapacidad cognitiva, macrocefalia (p > 99) y obesidad. Fenotipo con dismorfia facial: frente amplia, ojos hundidos, nariz bulbosa, pabellones auriculares despegados y mentón afilado. Array de hibridación genómica comparada con deleción de 586 kb en Xq21.1, que incluye un único gen asociado a la patología, BRWD3. Posteriormente se realizó un estudio a la madre y a la hermana, asintomáticas, y ambas portan la deleción. Conclusiones. Nuestro caso confirma que la haploinsuficiencia debida a la deleción del gen BRWD3 es un mecanismo genético causal de la discapacidad intelectual sindrómica ligada a X asociada al gen BRWD3. Es importante reconocer el fenotipo para el diagnóstico y el seguimiento, así como la realización del estudio familiar para asesoramiento genético a las mujeres que porten la alteración, puesto que en la mayoría de los casos son asintomáticas, como la madre y la hermana de este paciente.

Optimization by mixture design of chitosan/multi-phase calcium phosphate/BMP-2 biomimetic scaffolds for bone tissue engineering.

The modulation of cell behavior during culture is one of the most important aspects of bone tissue engineering because of the necessity for a complex mechanical and biochemical environment. This study aimed to improve the physicochemical properties of chitosan/multi-phase calcium phosphate (MCaP) scaffolds using an optimized mixture design experiment and evaluate the effect of biofunctionalization of the obtained scaffolds with the bone morphogenetic protein BMP-2 on stem cell behavior. The present study evaluated the compressive strength, elastic modulus, porosity, pore diameter, and degradation in simulated body fluids and integrated these responses using desirability. The properties of the scaffolds with the best desirability (18.4% of MCaP) were: compressive strength of 23 kPa, elastic modulus of 430 kPa, pore diameter of 163 µm, porosity of 92%, and degradation of 20% after 21 days. Proliferation and differentiation experiments were conducted using dental pulp stem cells after grafting BMP-2 onto scaffolds via the carbodiimide route. These experiments showed that MCaP promoted cell proliferation and increased alkaline phosphatase activity, whereas BMP-2 enhanced cell differentiation. This study demonstrates that optimizing the composition of a mixture of chitosan and MCaP improves the physicochemical and biological properties of scaffolds, indicating that this solution is viable for application in bone tissue engineering.

A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase B pathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.

Correlation analysis of maternal condition during pregnancy with head circumference and autism spectrum disorder: A propensity score-matched study.

To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children's Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case-control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended.

Leukodystrophy with Macrocephaly, Refractory Epilepsy, and Severe Hyponatremia-The Neonatal Type of Alexander Disease.

INTRODUCTION: Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by GFAP mutation. Symptoms usually occur in the infantile age with macrocephaly, developmental deterioration, progressive quadriparesis, and seizures as the most characteristic features. In this case report, we provide a detailed clinical description of the neonatal type of AxD. METHOD: Next-Generation Sequencing (NGS), including a panel of 49 genes related to Early Infantile Epileptic Encephalopathy (EIEE), was carried out, and then Whole Exome Sequencing (WES) was performed on the proband's DNA extracted from blood. CASE DESCRIPTION: In the first weeks of life, the child presented with signs of increased intracranial pressure, which led to ventriculoperitoneal shunt implementation. Recurrent focal-onset motor seizures with secondary generalization occurred despite phenobarbital treatment. Therapy was modified with multiple anti-seizure medications. In MRI contrast-enhanced lesions in basal ganglia, midbrain and cortico-spinal tracts were observed. During the diagnostic process, GLUT-1 deficiency, lysosomal storage disorders, organic acidurias, and fatty acid oxidation defects were excluded. The NGS panel of EIEE revealed no abnormalities. In WES analysis, GFAP missense heterozygous variant NM_002055.5: c.1187C>T, p.(Thr396Ile) was detected, confirming the diagnosis of AxD. CONCLUSION: AxD should be considered in the differential diagnosis in all neonates with progressive, intractable seizures accompanied by macrocephaly.

Homozygous variant of MLC1 results in megalencephalic leukoencephalopathy with subcortical cysts.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene. METHODS: Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole-exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated using Sanger sequencing. RESULTS: Here, we report a new homozygous variant identified in two children from the same family in the MLC1 gene [NM_015166.4: c.838_843delinsATTTTA, (p.Ser280_Phe281delinsIleLeu)]. This variant is classified as variant of uncertain significance (VUS) according to the ACMG guidelines. Further experiments demonstrate that the newly identified variant causes a decrease of MLC1 protein levels when expressed in a heterologous expression system. CONCLUSION: Our case expands on this genetic variation and provides new evidence for the clinical diagnosis of MLC1-related MLC.

Review of published 467 achondroplasia patients: clinical and mutational spectrum.

AIM: Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease. METHODS: The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of "Achondroplasias" or "Skeleton-Skin-Brain Syndrome" or "Skeleton Skin Brain Syndrome" or "ACH" and "Receptor, Fibroblast Growth Factor, Type 3" or "FGFR3". RESULTS: Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31-53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT. CONCLUSION: ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum.

Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the KMT2E gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient's cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skipping. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in KMT2E.