Molecular Syndromology

BACKGROUND: Cardiofaciocutaneous syndrome (CFCS) is a rare genetic condition caused by mutations in BRAF , KRAS , MAP2K1, or MAP2K2 . It is characterized by ectodermal abnormalities, cardiac defects, intellectual disability, and distinct craniofacial features. CFCS falls under a group of conditions caused by mutations in the RAS/MAPK pathway called RASopathies which share many features. In particular, CFCS has significant phenotypic overlaps with Costello syndrome (CS) and Noonan syndrome (NS)...

INTRODUCTION: Hurler-Scheie syndrome is a type of mucopolysaccharidosis I (MPS). In MPS I the decreased activity of alpha-L-iduronidase lysosomal enzyme leads to glycosaminoglycan (GAG) deposition in the intra- and extracellular matrix. Excessive amounts of GAG can accumulate in most layers of the cornea, including epithelial cells, stromal keratocytes, and endothelial cells. CASE PRESENTATION: A 25-year-old female patient suffering from Hurler-Scheie syndrome with multiple ocular manifestations is reported...

INTRODUCTION: Neuronal ceroid lipofuscinoses (NCLs) are a broad class of inherited lysosomal storage disorders. Known mutations in at least 13 different genes can result in NCL with variable ages of onset, symptoms, and pathologic findings. Generally, these patients experience cognitive and motor decline, seizures, visual impairment, and premature death. Pathologically, NCL patients display heterogeneous histologic abnormalities, but consistently exhibit neuronal loss, reactive gliosis, and lysosomal accumulation of autofluorescent storage material or lipopigment...

BACKGROUND: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by glucocorticoid deficiency without mineralocorticoid deficiency. We report 3 Chinese patients with MRAP or MC2R mutations. CASE REPORTS: Patient 1 presented with hyperpigmentation. Endocrine investigations revealed low serum cortisol levels and elevated adrenocorticotropic hormone (ACTH) levels. Furthermore, low serum sodium was evident. She was diagnosed with FGD type 2 due to a homozygous mutation in MRAP (c...

INTRODUCTION: Primary adrenal insufficiency associated with cardiomyopathy has been rarely reported in children. We report a case of left ventricular (LV) systolic dysfunction related to adrenal insufficiency with autoimmune polyendocrine syndrome type 1 (APS1). CASE PRESENTATION: A 7-year-old girl presented with a loss of consciousness. She had hyperpigmentation over joints and enamel hypoplasia. Laboratory tests showed hypoglycemia, hyponatremia, hypocalcemia, and hyperphosphatemia...

INTRODUCTION: Partial trisomy 6p is a rare chromosomal anomaly, characterized by low birth weight, developmental delay, craniofacial abnormalities, feeding difficulties, congenital heart defects, and renal abnormalities. Some of the partial trisomy 6p cases reported in the literature included partial monosomy of another chromosome. This is often due to the fact that one of the parents is a balanced translocation carrier, thereby making it difficult to determine the genotype-phenotype relationship...

INTRODUCTION: Intellectual disability (ID) is a lifelong disability that affects an individual‧s learning capacity and adaptive behavior. Such individuals depend on their families for day-to-day survival and pose a significant challenge to the healthcare system, especially in developing countries. ID is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning. METHODS: Here we studied a female index patient, born to a consanguineous Pakistani couple, showing clinical symptoms of ID, ataxia, hypotonia, developmental delay, seizures, speech abnormality, and aggressive behavior...

INTRODUCTION: Cornelia de Lange syndrome (CdLS) is a rare congenital malformation characterized by distinctive facial features, short stature, and limb defects. In addition, half of the patients with CdLS exhibit repetitive self-injurious behaviors (SIBs) related to intellectual disability with autistic traits. CdLS is caused by pathogenic variants of genes encoding the cohesin complex pathway, with 70% of these variants identified in the nipped-B-like ( NIPBL ) gene. CASE PRESENTATION: We report 2 patients with CdLS who exhibited repetitive SIBs...

INTRODUCTION: FBLN5 -related cutis laxa is a very rare, autosomal recessive syndrome that is characterized by loose, wrinkled, and redundant skin, sagging cheeks, emphysema, aortic or pulmonary artery abnormalities, inguinal hernia, and diverticula of the gastrointestinal and urinary tract. CASE PRESENTATION: In this study, we report an 8-year-old Turkish girl with a novel homozygous missense variant in the FBLN5 gene, c.862G>T, p.(Asp288Tyr). Her unaffected parents were carriers of the same variant...

INTRODUCTION: HNF1B -associated diseases are a group of genetic conditions that affect the kidney as well as other organ systems. Kidney anomalies are the most common symptoms. Other defects may include early-onset diabetes, genital abnormalities, and abnormalities of pancreas and liver function. Renal involvement has emerged as the earliest finding in HNF1B disease, even in prenatal life, with the most common feature being hyperechogenic kidneys. CASE PRESENTATION: In this study, we present 3 fetuses with bilateral renal hyperechogenicity identified by ultrasound in the second trimester...

INTRODUCTION: Congenital heart disease (CHD) is the most common type of congenital defect reported to be one of the leading causes of mortality in the first year of life. Microdeletion and microduplication syndromes (MMS) are associated with cardiac malformations. Understanding which genetic factors are involved in these conditions directly impacts treatment decisions. We aimed to identify the occurrence of genetic alterations and their association with MMS in CHD pediatric patients evaluated in a reference service of Southern Brazil...

INTRODUCTION: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. METHODS: In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature...

BACKGROUND: Prolonged exposure to glucocorticoids can result in the development of Cushing's syndrome. Excess serum cortisol can occur due to several factors including exogenous steroids, pituitary and adrenal adenoma, and ectopic ACTH secretion. SUMMARY: The last 2 decades have seen significant progress in identifying new genetic and molecular mechanisms underlying hypercortisolemia. This has implicated mutations seen in a multitude of aberrant pathways that underpin the pathophysiology of Cushing's syndrome...

INTRODUCTION: Cri-du-chat syndrome is generally diagnosed when patients present a high-pitched cry at birth, microcephaly, ocular hypertelorism, and prominent nasal bridge. The karyotype is useful to confirm deletions in the short arm of chromosome 5 (5p-) greater than 10 Mb. In cases of smaller deletions, it is necessary to resort to other molecular techniques such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA) or genomic array. CASE PRESENTATION: We report a family with an atypical deletion in 5p (mother and 2 children) and variable phenotypes compared with the literature...

INTRODUCTION: Mendelian disorders of the epigenetic machinery are a growing group of disorders exhibiting several overlapping clinical features that are probably due to common abnormalities at the epigenomic level, which lead to downstream convergence at the transcriptomic level. CASE PRESENTATION: Here, we report a new case of short stature, brachydactyly, intellectual developmental disability, and seizures (SBIDDS) syndrome with a severe ocular phenotype and hypogonadism...

INTRODUCTION: 3M syndrome is an autosomal recessive disorder characterized by characteristic facial features, severe pre- and postnatal growth restriction (<-4 SDS), and normal mental development. 3M syndrome is genetically heterogeneous. Up to date, causative mutations have been demonstrated in 3 genes, cullin-7 ( CUL7 ), obscurin-like 1 ( OBSL1 ), and coiled coil domain containing protein 8 ( CCDC8 ). CASE PRESENTATION: Here, we report a patient who was referred to our clinic due to short stature and developmental delay...

INTRODUCTION: Whole-exome sequencing (WES) is becoming widely available in prenatal diagnosis. However, as with most scientific methods, WES also has its limitations. The aim of the study was to report a fetal case of RNU4ATAC -opathy which was missed by prenatal WES. CASE PRESENTATION: A 28-year-old healthy primigravida was revealed by ultrasound at 20 + 3 weeks of gestation to have a fetus with ventriculomegaly (left 15.1 mm/right 11.9 mm), hypoplastic vermis, and mild growth retardation...

INTRODUCTION: Pathogenic variants in the SLC26A2/DTDST gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of SLC26A2/DTDST -related disorders. METHODS: The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS)...

INTRODUCTION: Copy-number variations (CNVs) impacting on small DNA stretches and associated with language deficits provide a unique window to the role played by specific genes in language function. METHODS: We report in detail on the cognitive, language, and genetic features of a girl bearing a small deletion (0.186 Mb) in the 2p16.3 region, arr[hg19] 2p16.3(50761778_50947729)×1, affecting exons 3-7 of NRXN1 , a neurexin-coding gene previously related to schizophrenia, autism (ASD), attention deficit hyperactivity disorder (ADHD), mood disorder, and intellectual disability (ID)...

INTRODUCTION: Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is a rare disease with an early onset and severe phenotype. The pathogenic mechanism associated with mutations in the gene COL7A1 has been widely studied and many related cases have been reported, but prenatal cases are rare. Here, we report the prenatal diagnosis of a sporadic case of RDEB. METHODS: In this study, the fetus with abnormal skin manifestations, which were determined during a prenatal ultrasound, was evaluated based on the ultrasound and autopsy findings and the results of molecular diagnostic analyses...