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Molecular Syndromology Jun 2024Gorlin syndrome is a rare, autosomal dominant multi-systemic disorder with a predisposition to the development of cancers such as medulloblastoma and nevoid basal cell...
INTRODUCTION
Gorlin syndrome is a rare, autosomal dominant multi-systemic disorder with a predisposition to the development of cancers such as medulloblastoma and nevoid basal cell carcinoma. Heterozygous pathogenic variants in are responsible for 90% of Gorlin syndrome cases. Pathogenic variants in cause overstimulation of the sonic hedgehog signaling pathway, which plays a role in the development of embryonic structures and tumorigenesis. Clinical major and minor diagnostic criteria for Gorlin syndrome have been determined. Odontogenic keratocyst (OKC) is the most common reason for medical admission in Gorlin syndrome. In this article, it is aimed to draw attention to the fact that patients with Gorlin syndrome are not very rare in our country and the variability in phenotypic and dysmorphic findings may be a clue for the diagnosis.
METHODS
Exome sequencing was performed on the Illumina NextSeq550 System platform by using the Ion Ampliseq exome RDY kit for Illumina. Sanger sequencing was performed accordingly for the other affected individuals in both families.
RESULTS
In this study, the clinical and molecular findings of 9 Gorlin syndrome patients from three unrelated families are presented. Macrocephaly, calcification of falx cerebri, palmar-plantar pits, rib anomalies, and OKC were detected in decreasing order in more than half of the patients. A novel heterozygous frameshift variant in family 1, a nonsense previously reported variant in family 2, and a novel heterozygous splice-site variant in family 3 were detected.
CONCLUSION
Gorlin syndrome should be kept in mind in patients presenting with macrocephaly, palmoplantar pits, and OKC history. Careful examination of all family members is essential in the timely diagnosis of other affected individuals with minor phenotypic findings.
PubMed: 38841331
DOI: 10.1159/000535407 -
Asian Journal of Endoscopic Surgery Jul 2024Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs,...
Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs, underdeveloped lungs, and thoracic hypoplasia. Neonates with TD develop severe respiratory problems due to thoracic hypoplasia and require respiratory management for survival. Despite the resolution of respiratory problems, long-term survival cases are rare. Previous studies have reported that surgical procedures in patients with TD are limited to those necessary for survival, including tracheostomy, laminectomy, and ventricular shunt. A 1-year-old boy with TD was treated with laparoscopic herniorrhaphy. To the best of our knowledge, this is the first report of TD treated with laparoscopic procedure.
Topics: Humans; Male; Laparoscopy; Hernia, Inguinal; Herniorrhaphy; Thanatophoric Dysplasia; Infant
PubMed: 38839103
DOI: 10.1111/ases.13325 -
Frontiers in Genetics 2024Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder. A retrospective analysis predicted that the live birth prevalence of SRS in Estonia...
Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder. A retrospective analysis predicted that the live birth prevalence of SRS in Estonia is 1:15,886 [Yakoreva et al., Eur J Hum Genet, 2019, 27(11), 1649-1658]. The most common causative genetic mechanism in the proband is loss of paternal methylation in the imprinted control region 1 (ICR1) at 11p15.5 chromosome. A few studies suggested that inherited or loss-of-function alterations of the gene, including the whole-gene deletion and intragenic pathogenic variants, could cause a rare type of SRS. To date, less than 20 unrelated -related SRS cases have been reported, and the clinical information about these cases is limited. We report the first prenatal case of SRS with 8q12 deletion (including the gene). The fetus presented with intrauterine growth retardation, small for gestational age, relative macrocephaly at birth, and a protruding forehead. Unlike classical SRS cases, the fetus had micrognathia and did not show body asymmetry. We hope that the literature review in this study provides new insights into genotype-phenotype relationships of -related SRS.
PubMed: 38826801
DOI: 10.3389/fgene.2024.1387649 -
European Journal of Human Genetics :... Jun 2024Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have...
Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.
PubMed: 38824261
DOI: 10.1038/s41431-024-01642-7 -
American Journal of Medical Genetics.... May 2024Pathogenic variants of polycomb repressive complex-2 (PRC2) subunits are associated with overgrowth syndromes and neurological diseases. EZH2 is a major component of...
Pathogenic variants of polycomb repressive complex-2 (PRC2) subunits are associated with overgrowth syndromes and neurological diseases. EZH2 is a major component of PRC2 and mediates the methylation of H3K27 trimethylation (H3K27me3). Germline variants of EZH2 have been identified as a cause of Weaver syndrome (WS), an overgrowth/intellectual disability (OGID) syndrome characterized by overgrowth, macrocephaly, accelerated bone age, intellectual disability (ID), and characteristic facial features. Germline variants of SUZ12 and EED, other components of PRC2, have also been reported in the WS or Weaver-like syndrome. EZH1 is a homolog of EZH2 that interchangeably associates with SUZ12 and EED. Recently, pathogenic variants of EZH1 have been reported in individuals with dominant and recessive neurodevelopmental disorders. We herein present sisters with biallelic loss-of-function variants of EZH1. They showed developmental delay, ID, and central precocious puberty, but not the features of WS or other OGID syndromes.
PubMed: 38814056
DOI: 10.1002/ajmg.a.63726 -
Revista de Neurologia Jun 2024Pathogenic variants in BRWD3 gene have been described as a rare cause of syndromic X-linked intellectual disability. Its phenotype shows neurodevelopmental delay with...
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.
Topics: Humans; Megalencephaly; Male; Gene Deletion; Intellectual Disability; Mental Retardation, X-Linked; Phenotype; Child; Bromodomain Containing Proteins; Transcription Factors
PubMed: 38813790
DOI: 10.33588/rn.7811.2024057 -
Clinics and Practice May 2024Tatton-Brown-Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the gene, which is an important participant in epigenetic...
Tatton-Brown-Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton-Brown-Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the , leading to the formation of a premature stop codon-NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton-Brown-Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the gene significantly increases the risk of developing acute myeloid leukemia.
PubMed: 38804405
DOI: 10.3390/clinpract14030073 -
Taiwanese Journal of Obstetrics &... May 2024
Detection of digynic triploidy in a second-trimester fetus presenting syndactyly, relative macrocephaly, intrauterine growth restriction, cardiomegaly, pericardial effusion, Dandy-Walker malformation, double bubble sign and single umbilical artery on prenatal ultrasound and a false negative...
Topics: Humans; Female; Pregnancy; Ultrasonography, Prenatal; Pregnancy Trimester, Second; Pregnancy Trimester, First; Dandy-Walker Syndrome; Adult; Cardiomegaly; Fetal Growth Retardation; Pericardial Effusion; Megalencephaly; Single Umbilical Artery; Triploidy; Abnormalities, Multiple; False Negative Reactions; Noninvasive Prenatal Testing
PubMed: 38802216
DOI: 10.1016/j.tjog.2024.03.014 -
American Journal of Medical Genetics.... May 2024Osteopathia Striata with Cranial Sclerosis (OSCS) is a rare genetic condition primarily characterized by metaphyseal striations of long bones, bone sclerosis,...
Osteopathia Striata with Cranial Sclerosis (OSCS) is a rare genetic condition primarily characterized by metaphyseal striations of long bones, bone sclerosis, macrocephaly, and other congenital anomalies. It is caused by pathogenic variants in AMER1, a tumor suppressor and a WNT signaling repressor gene with key roles in tissue regeneration, neurodevelopment, tumorigenesis, and other developmental processes. While somatic AMER1 pathogenic variants have frequently been identified in several tumor types (e.g., Wilms tumor and colorectal cancer), whether OSCS (i.e., with AMER1 germline variants) is a tumor predisposition syndrome is not clear, with only nine cases reported with tumors. We here report the first case of neuroblastoma diagnosed in a male child with OSCS, review all previously reported tumors diagnosed in individuals with OSCS, and discuss potential tumorigenic mechanisms of AMER1. Our report adds to the accumulating evidence suggesting OSCS is a tumor predisposition condition, highlighting the importance of maintaining a high index of suspicion for the associated tumors when evaluating patients with OSCS. Importantly, Wilms tumor stands out as the most commonly observed tumor in OSCS patients, underscoring the need for regular surveillance.
PubMed: 38801192
DOI: 10.1002/ajmg.a.63709 -
International Journal of Molecular... May 2024Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians.... (Review)
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.
Topics: Humans; Megalencephaly; Fingers
PubMed: 38791606
DOI: 10.3390/ijms25105567