Molecular Syndromology最新文献

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. Due to significant bilateral corneal opacification, penetrating keratoplasty was performed on both eyes. Histopathologic examination of the corneal buttons showed disorganized collagen fibers with heterogenous thickness and many granule-containing keratocytes with excessive cytoplasm. Despite receiving enzyme replacement therapy, in vivo confocal microscopy revealed characteristic vacuoles in the basal epithelium and corneal stroma 96 months after transplantation. High resolution anterior segment optical coherence tomography demonstrated hyperreflective opacities superficial and deeper in the stroma which was consistent with recurrence of host disease in the graft.

Conclusion: To the best of our knowledge, this is the first documented Hurler-Scheie syndrome case of recurrence after penetrating keratoplasty demonstrated by in vivo confocal microscopy. Additionally, this patient manifested severe ocular involvement of MPS which might be an explanation of the progressive course of corneal opacification after transplantation.

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. Pure partial trisomy 6p cases are even rarer and may occur as a result of a marker chromosome, tandem or inverted duplication, and interchromosomal insertion.

Case presentation: In this study, we evaluated the physical characteristics and genetic data of a 2-year-old girl with developmental delay and facial dysmorphic features. Dysmorphology assessment revealed the presence of a prominent forehead, short and narrow palpebral fissures, blepharoptosis, convex nasal ridge, hemangioma on the left eyelid, high-arched palate, retromicrognathia, and low-set ears. The patient‧s G-banded karyotype was 46,XX,der(2)t(2;6)(q37.3;p22.1). Upon SNP-array analysis, aimed to determine the origin of the extra chromosomal material detected in chromosome 2 of the patient, there was a de novo 27.5-Mb duplication at 6p, arr[GRCh37] 6p25.3p22.1(204,909_27,835,272)×3, interpreted to be pathogenic.

Conclusion: We present this case report to clarify the clinical findings of a rare chromosomal anomaly, discuss the genes that may be related to the phenotype and contribute to the literature in terms of knowledge regarding genotype-phenotype correlation.

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.106+1delG), revealed through exome sequencing (ES). After 2-year treatment with hydrocortisone, skin hyperpigmentation was improved. Patient 2 initially presented with hyponatremia. Low cortisol levels and high levels of ACTH were subsequently detected; he was subjected to a hydrocortisone treatment during which he experienced repeated hypoglycemic attacks and pigmentation. ES revealed the same mutation as in patient 1 in MRAP (c.106+1delG), thus he was diagnosed with FGD type 2. After 6 years of age, his symptoms remarkably improved, and there was no episode of hypoglycemia. Patient 3 mainly presented with hyperpigmentation, hypoglycemic attack, and tall stature. Laboratory findings were normal except for low serum cortisol levels and high ACTH levels. She was diagnosed with FGD type 1 as ES revealed a novel homozygous mutation in MC2R (c.712C>A, p.His238Tyr). After nearly 2 years of hydrocortisone replacement therapy, the excessive growth was reduced to near normal, and the skin color returned to normal.

Conclusions: Three patients were diagnosed with FGD (one with FGD type 1 and two with FGD type 2). They all presented with hyperpigmentation and hypoglycemia; however, compared with patient 1, the clinical manifestations of patient 2 were more complicated. Patient 3 had later onset and taller stature than patients 1 and 2. A novel mutation in patient 3 expands the mutation spectrum of MC2R.

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).

Objective: The aim of this study was to assess the patients‧ phenotypic features for syndromic disorders and evaluate the use of molecular testing to clarify the clinical diagnosis.

Method: The patients were recruited for genetic testing with written informed consent. Genomic DNA from venous blood was sequenced and potential variants were identified via targeted next-generation sequencing. Their phenotypic features were compared with other CFCS cases carrying pathogenic variants in the same gene.

Results and discussion: One patient had a de novo variant (c.370C>T; p.P124S) in MAP2K1 and presented with mild and typical features which do not significantly affect her quality of life. The second patient presented with severe features, including failure to thrive, feeding difficulties, epileptic spasms, septal hypertrophy, and global developmental delay, and developed chronic lung disease and sequelae from multiple infections. She had a severe disease course and severe global developmental delay. The discovery of a de novo variant (c.371C>A; p.P124Q) in MAP2K1, which had been reported in another patient with a similar phenotype, clarifies her clinical diagnosis. Her presentations add to existing reports that support expanding the CFCS phenotype to include features previously thought to be more suggestive of CS.

Conclusion: The genetic findings for the 2 patients affirm the use of identified gene mutations to confirm the clinical diagnosis of syndromic disorders and add to the phenotypic spectrum of CFCS.

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.

Methods: Participants were recruited during 2010 in the intensive care unit of a pediatric hospital. MMs and regions of chromosome 22 were screened by SALSA MLPA Probemix P245 Microdeletion Syndromes-1A kit for detection of copy number variations (CNVs).

Results: MMS were detected in 11 from 207 patients (5.3%). Heterozygous deletion in the 22q11.2 chromosome region was the most prevalent CNV (5 from 11 patients). Also, atypical RTDR1 deletion and 22q11.2 duplication were detected. MLPA was able to reveal microdeletions in SNRPN and NF1 genes in patients with a normal karyotype and FISH.

Conclusion: Our study reports the prevalence and variability of genomic alterations associated with MMS in CHD pediatric patients. The results by MLPA are of great help in planning and specialized care.

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. No pathogenic copy number variations were revealed by amniocentesis with chromosomal microarray analysis (CMA). Heterozygous variants in HNF1B were detected in all 3 fetuses by further investigation with exome sequencing (ES). Two pregnancies were terminated, and one was continued to term.

Discussion and conclusion: Because of the known high frequency of HNF1B aberrations in fetal hyperechogenic kidneys, HNF1B screening should be an integral part of prenatal diagnosis for such fetuses. ES should be recommended following or concurrently with CMA for rapid prenatal detection. The ES results would improve the diagnostic yield and are beneficial in guiding counseling and management.

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. Juvenile-onset NCL has been classically referred to as Batten disease. By far the most prevalent NCL is CLN3-associated disease. It is an autosomal recessive condition that is usually caused by mutations in the ceroid-lipofuscinosis, neuronal 3 (CLN3) gene. CLN3 encodes battenin, a ubiquitously expressed transmembrane protein of unknown function that is associated with cellular homeostasis and neuronal survival. The initial clinical symptom of CLN3-associated NCL is central vision loss, which is usually detected between 4 and 9 years of age. Seizures typically begin early in the second decade of life, and affected individuals rarely live beyond their mid-20ies.

Case presentation: Herein, we describe a 16-year-old patient with CLN3-related juvenile NCL with a preliminary diagnosis of Niemann Pick Type C disease. The proband showed characteristic clinical signs, including epilepsy, ataxia, psychomotor regression, dementia, and visual impairment with an unusual elevation of lyso-sphingomyelin-509 (Lyso-SM-509; 812 nmol/L, normal 1-33 nmol/L). A homozygous NM_001042432.2(CLN3):c.233dup (p.Thr80fs) variant was detected at exon 4 of CLN3. Diagnosis of NCL was difficult due to the pronounced elevation of LysoSM-509.

Discussion: LysoSM-509 is a biomarker which is elevated especially in Niemann Pick Type C. We can consider that a high LysoSM-509 level might be also an indicator of NCL, especially NCL type 3.

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. Whole exome sequencing (WES) coupled with Sanger sequencing was performed for molecular diagnosis. Further, 3D protein modeling was performed to see the effect of variant on protein structure.

Results: WES identified a novel homozygous missense variant (c.178T>C; p.Tyr60His) in the ANK3 gene. In silico analysis and 3-dimensional (3D) protein modeling supports the deleterious impact of this variant on the encoding protein, which compromises the protein‧s overall structure and function.

Conclusion: Our finding supports the clinical and genetic diversity of the ANK3 gene as a plausible candidate gene for ID syndrome. Intelligence is a complex polygenic human trait, and understanding molecular and biological pathways involved in learning and memory can solve the complex puzzle of how cognition develops. Intellectual disability (ID) is defined as a deficit in an individual‧s learning and adaptive behavior at an early age of onset [American Psychiatric Association, 2013]. It is one of the major medical, and cognitive disorders with a prevalence of 1-3% in the population worldwide [Leonard and Wen, 2002]. ID often exists with other disabling mental conditions such as autism, attention deficit hyperactivity disorder, epilepsy, schizophrenia, bipolar disorder, or depression. Almost half of the cases appear to have a genetic explanation that ranges from cytogenetically visible abnormalities to monogenic defects [Flint, 2001; Ropers, 2010; Tucker-Drob et al., 2013]. Intellectual disability is a genetically heterogeneous condition, and more than 700 genes have been identified to cause ID alone or as a part of the syndrome. Research in X-linked ID has identified more than 100 disease-causing genes on the X chromosome that play a role in cognition; however, research into autosomal causes of ID is still ongoing [Vissers et al., 2016].

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. Endocrine evaluations revealed low serum parathyroid hormone, low cortisol, and high ACTH. Echocardiography showed moderate to severe mitral regurgitation and LV systolic dysfunction. Serum pro-brain natriuretic peptide (pro-BNP) level was high (2,348 pg/mL). Adrenal insufficiency, hypoparathyroidism, and enamel dysplasia suggested APS1. A novel homozygous variant in the AIRE gene, NM_000383, p.Cys322Arg (c.964T>C) confirmed the diagnosis. Calcium, calcitriol, and hydrocortisone treatments were started. Serum pro-BNP level returned to normal, and LV systolic function improved.

Conclusion: Here, we present a case of adrenal insufficiency and hypoparathyroidism associated with LV systolic dysfunction whose cardiac findings improved completely with hydrocortisone and calcitriol treatments. Our case is the second reported case of APS1 presenting with LV dysfunction.