The contribution of 7q33 copy number variations for intellectual disability.

Copy number variations (CNVs) at the 7q33 cytoband are very rarely described in the literature, and almost all of the cases comprise large deletions affecting more than just the q33 segment. We report seven patients (two families with two siblings and their affected mother and one unrelated patient) with neurodevelopmental delay associated with CNVs in 7q33 alone. All the patients presented mild to moderate intellectual disability (ID), dysmorphic features, and a behavioral phenotype characterized by aggressiveness and disinhibition. One family presents a small duplication in cis affecting CALD1 and AGBL3 genes, while the other four patients carry two larger deletions encompassing EXOC4, CALD1, AGBL3, and CNOT4. This work helps to refine the phenotype and narrow the minimal critical region involved in 7q33 CNVs. Comparison with similar cases and functional studies should help us clarify the relevance of the deleted genes for ID and behavioral alterations.

Epileptic Encephalopathy in Adams-Oliver Syndrome Associated to a New DOCK6 Mutation: A Peculiar Behavioral Phenotype.

Adams-Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb malformations of variable severity. When neurological findings are present, patients are reported as AOS variants. We describe a child with compound heterozygosity of the DOCK6 gene, aplasia cutis, terminal transverse limb defects, cardiovascular impairment, intellectual disability, and brain malformations with intracranial calcifications. He suffers from a severe refractory epileptic encephalopathy characterized by polymorphic seizures with prolonged periods of electroencephalogram (EEG), continuous epileptiform activity related to clinical inactivity, and closure of eyes with an "ON-OFF" behavior.

Different manifestations of Class II Division 2 incisor retroclination: a morphologic study.

INTRODUCTION: The aims of this study were to investigate whether there is a different transverse morphologic pattern of dental arches among patients with different manifestations of Class II Division 2 incisor retroclination and to evaluate to what extent the pattern of smaller-than-average teeth in Class II Division 2 malocclusion is common to all groups studied. This information might clarify whether different Class II Division 2 phenotypes represent a single etiology or multiple etiologies. METHODS: The sample comprised 108 subjects with Class II Division 2 malocclusions, divided into 2 groups according to the type of incisor retroclination: group I included 43 Class II Division 2 subjects with retroclination exclusively of the maxillary central incisors, and group II included 65 Class II Division 2 subjects with retroclination of the 4 maxillary incisors. Maxillary and mandibular intercanine and intermolar widths as well as mesiodistal crown dimensions of the 4 maxillary and mandibular incisors were determined from the patients' initial study models. Mean values of all variables were compared between the 2 groups by sex with analysis of variance. RESULTS: From the comparison between these 2 groups, no statistically significant differences were found for all transverse measurements (P >0.05). For all mesiodistal measurements analyzed, statistically significant differences between the groups were only found for the mean value of both maxillary lateral incisors' mesiodistal dimensions in both sexes (P <0.05). CONCLUSIONS: It is not possible to attribute a characteristic pattern of dental arch-width and incisor mesiodistal dimensions to the different manifestations of incisor retroclination in Class II Division 2 malocclusion.

Piebaldism and neurofibromatosis: state of knowledge.

Despite progress in understanding the molecular basis, the diagnosis of neurofibromatosis 1 (NF 1) is based on clinical criteria, established by the National Institute of Health (NIH) Consensus Conference in 1987. The association of NF1 and piebaldism has been reported, but some authors disagree with this co-occurrence. In the light of present knowledge, we highlight that both entities might co-exist in the same patient.

Different manifestations of class II division 2 incisor retroclination and their association with dental anomalies.

OBJECTIVE: To investigate whether there is an association between dental developmental anomalies (DDAs) and different manifestations of class II division 2 (CII/2) malocclusion incisor retroclination. DESIGN: Retrospective comparative study. SETTING: Private orthodontic practice in the regions of Lisbon and Porto, Portugal. SUBJECTS AND METHODS: The sample comprised 115 CII/2 malocclusions distributed into two groups on the basis of incisor retroclination: Group I composed of 48 CII/2 with retroclination exclusively of both maxillary central incisors; Group II composed of 67 CII/2 with retroclination of all four maxillary incisors. Using the initial orthodontic records, it was determined for each patient the presence of the following DDAs: tooth impaction, tooth agenesis, maxillary lateral incisor microdontia, tooth transpositions and supernumerary teeth. RESULTS: Fifty-five per cent of patients were diagnosed with at least one of the DDAs studied. In the total sample the prevalence rates were: 20.0% of palatal maxillary canine impaction, 27.4% of third molar agenesis, and 15.7% of maxillary lateral incisor microdontia. No patient exhibited any transposition or supernumerary teeth. The distribution of the DDAs studied by groups revealed a strong association of palatal canine impaction, tooth agenesis and maxillary lateral incisor microdontia with Group II but not with Group I. CONCLUSION: The association of DDAs with CII/2 malocclusion is not common to all types of maxillary incisor retroclination, suggesting different etiologic factors among the different manifestations of CII/2 incisor retroclination.

Erythropoietic protoporphyria: a family study and report of a novel mutation in the FECH gene.

Erythropoietic protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis mostly caused by a deficient activity of the enzyme ferrochelatase (FECH), and consequent accumulation of protoporphyrin (PP) in various tissues. Clinical manifestations include a childhood onset, cutaneous photosensitivity and, sometimes, hepatobiliary disease. We report a 16-year-old male with EPP characterized by acute episodes of painful photosensitivity since early infancy, permanent changes in the photoexposed skin, microcytic anemia, thrombocytopenia, and mild hepatic dysfunction. His 18-year-old sister presented less acute symptoms with no chronic changes. Lesional biopsy disclosed perivascular deposition of PAS positive hyaline material. Rimington-Cripps test was positive and PP erythrocyte levels were >9,000 µg/L (N<1,600), but normal in their parents and younger brother. Genetic studies in both patients and their mother revealed heterozygosity for a novel mutation (c.1052delA) in FECH gene of both children, and heterozygosity for the hypomorphic allele IVS3-48T>C in all of them. This confirms the "pseudodominant" inheritance pattern usually observed, explained by the combined presence of a disabling FECH mutation and a common intronic polymorphism affecting the counterpart allele (IVS3-48T>C). Phenotypic heterogeneity for this genotype explains the divergent clinical presentation. This is the first description of a Portuguese family with EPP characterized at the molecular level.

Vascular Ehlers-Danlos syndrome: a case with fatal outcome.

A 13-year-old boy, born prematurely and hypotonic, from non-consanguineous healthy parents, was referred to our department because of easy bruising. A slightly extensible, thin and translucent skin, associated with dysmorphic facies, acrogeria, multiple ecchymoses, hypermobility of the small joints, dorsal kyphosis, genu valgum, flat feet, elongated upper limbs, and low muscle tone were all evident. A history of learning disability and bilateral inguinal hernia was present. Blood and imaging studies were unremarkable. A skin biopsy disclosed an unremarkable dermis; electron microscopy showed abnormalities in the diameter, contour, and shape of collagen fibrils/fibers. Genetic analysis revealed heterozygosity for a novel mutation in COL3A1 gene (c.3527G>A), confirming the diagnosis of vascular Ehlers-Danlos syndrome (VEDS). The patient died at 15 years of age because of aortic dissection. Vascular Ehlers-Danlos syndrome is a rare, life-threatening, autosomal dominant variant of EDS, resulting from mutations in COL3A1 gene. Affected individuals are prone to serious and potentially fatal complications, especially vascular, intestinal, and uterine ruptures. Delay in diagnosis is common, even when the clinical presentation is typical. Therefore, dermatologists should be familiar with VEDS features because the skin findings may be the first signs. Early diagnosis will improve management of visceral complications and allow early genetic counseling.

Piebaldism and neurofibromatosis type 1: family report.

Piebaldism is a rare disorder present at birth and inherited as an autosomal dominant trait. It results from a mutation in the c-kit proto-oncogene and is associated with a defect in the migration and differentiation of melanoblasts from the neural crest. Clinical manifestations and phenotypic severity strongly correlates with the site of mutation within the KIT gene. Here we report a 3-year-old boy and his 33-year-old father with leukoderma and poliosis associated with clinical criteria for Neurofibromatosis type 1. Genetic study of both revealed a p.Gly610Asp mutation in the KIT gene. This familiar mutation has not yet been reported in the literature. There are rare reports of piebaldism in association with neurofibromatosis type I.

Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation.

We report the case of a 12-year-old girl presenting at birth with erythroderma, erosions and blisters scattered over the integument. By the age of 3 she presented generalized hyperkeratotic plaques with a cobblestone pattern and a pungent odour, most prominently around flexures, scalp and palmoplantar areas. Clinical, histological and ultrastructural findings confirmed the diagnosis of epidermolytic hyperkeratosis (EHK). Molecular genetic analysis revealed a mutation in the KRT10 gene. Treatment with oral acitretin was attempted but it was discontinued due to hepatic dysfunction and marked desquamation and blistering. EHK is a rare autosomal dominant disorder of keratinization, caused by mutations in either the KRT1 or KRT10 genes. Although palmoplantar keratoderma is typically found in patients with KRT1 mutation, our patient presents EHK with palmoplantar involvement and KRT10 mutation. Moreover, a poor response to systemic retinoids was observed, contrary to what is expected in patients with KRT10 mutation. Even though management is usually unsatisfactory, some patients with this lifelong and serious condition may experience improvement with age.

Left ventricular non-compaction: a new mutation predisposing to reverse remodeling?

Left ventricular non-compaction (LVNC) is a rare disorder of endomyocardial morphogenesis that results in multiple trabeculations and deep intertrabecular recesses filled with direct blood flow from the left ventricular cavity. LVNC is attracting increasing interest as a model for the study of cardiomyopathies, since it is a genetically heterogeneous disorder which varies greatly in clinical presentation and age of onset. The authors present the case of a young black male with progressive congestive heart failure of 2-3 years' evolution. The investigation, which included transthoracic echocardiography (contrast and 3D), transesophageal echocardiography and cardiac magnetic resonance imaging, showed LVNC and severe aortic regurgitation, with severe left ventricular systolic dysfunction. The family history was suggestive of genetically transmitted disease and genetic study of the TAZ gene at locus Xq28 identified the mutation p.Phe128Ser (c.383T>C), the first description of this mutation in a patient with LVNC. The patient underwent aortic valve replacement, with excellent clinical evolution, regression of left ventricular dimensions and global systolic functio Aortic regurgitation (not related to LVNC) was the determining factor in the clinical expression. However, the excellent reverse remodeling that occurred after surgery highlights the heterogeneity of myocardial behavior in LVNC patients.

The Role of AKT3 Copy Number Changes in Brain Abnormalities and Neurodevelopmental Disorders: Four New Cases and Literature Review.

Microdeletions at 1q43-q44 have been described as resulting in a clinically recognizable phenotype of intellectual disability (ID), facial dysmorphisms and microcephaly (MIC). In contrast, the reciprocal microduplications of 1q43-q44 region have been less frequently reported and patients showed a variable phenotype, including macrocephaly. Reports of a large number of patients with copy number variations involving this region highlighted the AKT3 gene as a likely key player in head size anomalies. We report four novel patients with copy number variations in the 1q43-q44 region: one with a larger deletion (3.7Mb), two with smaller deletions affecting AKT3 and SDCCAG8 genes (0.16 and 0.18Mb) and one with a quadruplication (1Mb) that affects the entire AKT3 gene. All patients with deletions presented MIC without structural brain abnormalities, whereas the patient with quadruplication had macrocephaly, but his carrier father had normal head circumference. Our report also includes a comparison of phenotypes in cases with 1q43-q44 duplications to assist future genotype-phenotype correlations. Our observations implicate AKT3 as a contributor to ID/development delay (DD) and head size but raise doubts about its straightforward impact on the latter aspect of the phenotype in patients with 1q43-q44 deletion/duplication syndrome.

Genomic imbalances defining novel intellectual disability associated loci.

BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine.

DOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS. Initially, a slow-channel CMS was regarded as more probable due to prominent finger extension weakness. Accordingly, fluoxetine was started and a lengthy improvement was seen. Clinical deterioration occurred after fluoxetine withdrawal, when a c.1124_1127dup homozygous mutation was detected in DOK7 gene. Afterwards, salbutamol was started and the patient became asymptomatic. This case highlights the importance of considering CMS before an adult-onset myasthenic syndrome and suggests a benefit from fluoxetine not previously reported in DOK7-CMS.

Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome.

Alström syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alström syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease.

BCR-ABL V280G Mutation, Potential Role in Imatinib Resistance: First Case Report.

INTRODUCTION: The identification of BCR-ABL expression as the defining leukemogenic event in chronic myeloid leukemia (CML) and the introduction of BCR-ABL tyrosine kinase inhibitors in 2001 have revolutionized disease management, leading to a reduction in mortality rates and accordingly an increase in the estimated prevalence of CML. CASE REPORT: Based on medical records and clinical follow-up, the authors present the case of a Philadelphia chromosome-positive CML patient who developed resistance to imatinib. Quantitative reverse transcription-polymerase chain reaction testing revealed a V280G BCR-ABL mutation. DISCUSSION AND CONCLUSIONS: This is the first report describing a new BCR-ABL kinase domain mutation-V280G-that might be associated with resistance to imatinib. Approximately 15% to 30% of patients treated with imatinib discontinue treatment due to resistance or intolerance. More than 90 BCR-ABL mutations were detected so far, conferring variable degrees of drug resistance, with consequent clinical, therapeutic, and prognostic impact.

Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib.

Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.

Cat eye syndrome and growth hormone deficiency with pituitary anomalies: a case report and review of the literature.

Cat eye syndrome is a rare congenital disease characterized by the existence of a supernumerary chromosome derived from chromosome 22, with a variable phenotype comprising anal atresia, coloboma of the iris and preauricular tags or pits. We report a girl with cat eye syndrome, presenting short stature, with growth hormone deficiency due to posterior pituitary ectopia. Short stature is a common feature of this syndrome, and the association with a structural pituitary anomaly has been described, however growth hormone deficiency and the underlying mechanisms are rarely reported. A review on short stature and growth hormone deficiency in cat eye syndrome is conducted.

DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells.

Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.