Considerable Phenotypic Overlap Research Articles

P20 A Rare Case of Hereditary Mucoepithelial Dysplasia With Long Term Follow Up

Abstract This 28-year old woman initially presented at 2 years of age with patchy alopecia, perianal erythema and widespread rough skin. Prior to her first birthday she was diagnosed with bilateral corneal ulceration and was treated initially with soft contact lenses. She had no features of ichthyosis or hyperkeratosis and teeth, nails and eyelashes were normal. The hair loss progressed with involvement of the eyebrows. On examination, there was widespread keratosis pilaris, perianal and vulval erythema and angular cheilitis. Light microscopy of the cut hair was essentially normal. A clinical diagnosis of hereditary mucoepithelial dysplasia was made at that time. She recently underwent genetic testing which has confirmed the diagnosis. She is now registered blind and wears a wig. Her IQ is normal. Hereditary mucoepithelial dysplasia (HMD; OMIM 158310) is a rare autosomal dominant genodermatosis characterised by chronic mucosal lesions associated with keratitis, non-scarring alopecia, keratosis pilaris and psoriasiform perineal intertrigo. A novel causative heterozygous pathogenic variant c.1580G>T (p.Arg527Leu) was identified in our patient in the sterol regulatory element-binding factor 1 (SREBF1) gene. This is involved in promoting the transcription of lipogenes that are associated with epidermal cholesterol and fatty acid biosynthesis. HMD is allelic with autosomal dominant IFAP showing considerable phenotypic overlap and should be considered in patient with congenital hypotrichosis.

A Different Way to Think About Syndromes of Hereditary Colorectal Cancer.

Hereditary colorectal cancer is an increasingly complex field in which the commoner syndromes are being augmented by rarer genetic presentations contributing to familial polyposis and colorectal cancer. Coming to grips with the complexity is difficult because of the phenotypic and genotypic overlap between syndromes. This study aimed to describe a new way of thinking about syndromes of hereditary colorectal cancer based on their embryonic tissue of origin. Articles were searched through PubMed and MEDLINE. The terms "hereditary colorectal cancer," "syndromes of hereditary colorectal cancer," and "hereditary polyposis" were used to direct the search. Primarily endoderm-derived syndromes were different from mesoderm-derived syndromes in their genetics, molecular biology, histology, and clinical course. There is considerable phenotypic and genotypic overlap between syndromes, even when considering embryonic tissue of origin. Thinking about hereditary syndromes of colorectal cancer from the perspective of embryonic tissue of origin provides a fresh look at phenotype and genotype that opens new areas of exploration. ANTECEDENTES:El cáncer colorrectal hereditario es un campo cada vez más complejo donde los síndromes más comunes se ven aumentados por presentaciones genéticas más raras que contribuyen a la poliposis familiar y al cáncer colorrectal. Hacer frente a esta complejidad resulta difícil debido a la superposición fenotípica y genotípica entre los síndromes.OBJETIVO:En este artículo, describimos una nueva forma de pensar sobre los síndromes de cáncer colorrectal hereditario en función del origen de su tejido embrionario.FUENTES DE DATOS:Se realizaron búsquedas de artículos en Pubmed y Medline.SELECCIÓN DE ESTUDIOS:Se utilizaron los términos "cáncer colorrectal hereditario", "síndromes de cáncer colorrectal hereditario", "poliposis hereditaria" para dirigir la búsqueda.RESULTADOS:Principalmente los síndromes derivados del endodermo fueron diferentes a los síndromes derivados del mesodermo en su genética, biología molecular, histología y curso clínico.LIMITACIONES:Existe una superposición fenotípica y genotípica considerable entre los síndromes, incluso cuando se considera el tejido de origen embrionario.CONCLUSIÓN:Pensar en los síndromes hereditarios del cáncer colorrectal desde la perspectiva del tejido embrionario de origen proporciona una nueva mirada al fenotipo y al genotipo que abre nuevas áreas de exploración. (Traducción-Dr Osvaldo Gauto ).

Genetic contributions to transdiagnostic symptom dimensions in patients with major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions “Depression”, “Negative syndrome”, “Positive formal thought disorder”, “Paranoid-hallucinatory syndrome”, and “Increased appetite” in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with “Positive formal thought disorder”, the PRS for SZ was positively associated with “Paranoid-hallucinatory syndrome”, and the PRS for BD was negatively associated with “Depression”. The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e−6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions.

Cox Proportional Hazards Deep Neural Network Identifies Peripheral Blood Complete Remission (PB-CR) to be at Least Equivalent to Morphologic CR in Predicting Outcomes of Patients Treated with Azacitidine - a Prospective Cohort Study By the AGMT

Background Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) are multiclonal diseases demonstrating considerable biologic, phenotypic, genetic, and clinical overlap. In recognition of this continuum, these diseases are often treated similarly. Achievement of complete remission (CR)/CR-incomplete (CRi) is deemed the major outcome associated with improved overall survival (OS), and is often used as primary endpoint in clinical AML trials, whereas red blood cell transfusion independence is often the endpoint used in MDS trials. Expert opinions questioning these endpoints are cumulating [Sekeres M, Leukemia 2019, 570; Kim N, BJH 2021, 1137; Chandhok N, Leuk Lymphoma 2022, 1], as are reports indicating that achievement of CR/CRi may not be necessary for prolonged OS in patients treated with azacitidine [Pleyer L, Annals Hematol 2014, 1825; Schuh AC, ASH 2015, P575; Pleyer L, ASH 2015, P3752; Pleyer L, ASH 2019, P3387]. All response criteria for MDS, CMML and AML require bone marrow evaluations (BME), which are only performed in ~50% of patients outside of clinical trials [Dinmohamed A, Leuk Res 2015, 177; Pleyer L, ASH 2019, P3387], indicating the real-world need for internationally accepted response endpoints that do not necessitate repeated BME. We thus introduced peripheral blood CR (PB-CR), defined as Hb ≥11.0 g/dL, PLT ≥100 and <450 G/L, ANC ≥1.0 G/L, WBC ≥1.5 and <10.0 G/L, monocytes ≤1.0 G/LPB blasts=0%, no growth factors, no transfusions). In 1441 patients treated with azacitidine, multivariate survival modelling adjusted for 17 baseline covariates, indicated that PB-CR is at least as good a predictor of OS as CR [Pleyer L, ASH 2019, P3387]. Aims To compare the predictive value of CR or CR/CRi versus PB-CR. Methods Data from 1441 patients receiving 13971 cycles of azacitidine included in the Austrian Azacitidine Registry NCT01595295 was used for expanded analyses. The endpoints OS, time to next treatment (TTNT) and time on treatment (TOT) were defined as described previously [Pleyer L, Lancet Haematology 2021, e135]. Only data from patients who had a BME during treatment, and for whom all 17 baseline variables remaining in the final Cox model [Pleyer L, ASH 2019, P3387] were available, were analyzed (n=624). DeepSurv, a Cox proportional hazards model parametrized by a deep neural network [Katzman J, BMC Med Res Meth 2018, 24], was used to assess the predictive value of CR, CR/CRi and PB-CR. The network architecture is depicted in Fig 1. To assess whether CR or CR/CRi has greater predictive value than PB-CR, model performance was evaluated on randomly corrupted (i.e. destroyed) data. Either CR, CR/CRi or PB-CR responses were randomly permutated 1000 times, thus removing the information content from the respective variable and allowing investigation of the resulting drop in model performance using the concordance index (C-index). The average validation C-index for each response type of the corrupted datasets was generated with 5-fold cross-validation (Fig 2), stratified by sex, age </≥75 years and diagnosis. Validation C-index pairs for each of the 1000 permutations were compared by Wilcoxon signed-rank test. Bonferroni-correction for multile testing was performed. Results Random permutations of the PB-CR response resulted in signficantly higher performance loss than random permutations of the response types CR or CR/CRi, indicating that PB-CR has significantly more information content than either CR or CR/CRi. The C-indices with "intact PB-CR and permutated CR (or CR/CRi) were significantly higher than for "intact CR (or CR/CRi) and permutated PB-CR", with p<0·0001 for the endpoints TOT, TTNT and OS (Fig 3). Results remained consistent irrespective of the choice of inner network architectures. Conclusions In the largest cohort of azacitidine treated patients reported to date, survival modelling with a neural Cox regression revealed a higher information content for PB-CR as compared to either CR or CR/CRi for all time-to-event endpoints analyzed. Presence of PB-CR can thus identify patients with adequate response to non-intensive therapies without repeated BM assessments. Incorporation of PB-CR as secondary endpoint in clinical trials would be ideal to confirm these results. We aim to analyse whether these findings can be recapitulated in MDS, CMML and AML patients receiving other treatments and welcome collaborations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adverse Reactions to Biologic Medications Used in Allergy and Immunology Diseases.

Purpose of ReviewThe use of biologic therapies has risen exponentially over recent years, allowing for unprecedented disease control within numerous areas of Allergy/Immunology. With this expanded use, awareness and understanding of adverse reactions to biologic agents have also increased.Recent FindingsMultiple biologic adverse reaction phenotypes have been described, but significant overlap in clinical features across phenotypes exists. Given considerable phenotypic overlap, a targeted testing approach may not always be clear, and more recent classifications focus on management decision making using tools of diagnostic challenges and rapid drug desensitizations, guiding clinicians in developing a management plan when the exact underlying mechanism is not clearly known. With increased clinical experience with omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, tezepelumab, rituximab, and TNF-inhibitors, there is a growing appreciation to the spectrum and particularities of adverse reactions to these agents which are outlined in this review.SummaryOur understanding of the clinical presentation and management of adverse reactions to biologic medications encountered in Allergy/Immunology has grown. Opportunities remain to further define optimal diagnostic and management strategies for these reactions.

An early glimpse at azacitidine plus venetoclax for myelodysplastic syndromes

Myelodysplastic syndromes, chronic myelomonocytic leukaemia, and acute myeloid leukaemia comprise a spectrum of heterogenous myeloid diseases characterised by abnormal haematopoiesis, a block in differentiation, and haematopoietic insufficiency resulting in cytopenias. These multiclonal processes show considerable biologic, phenotypic, genetic, and clinical overlap. In recognition of this continuum, WHO has recently renamed the former category of myelodysplastic syndromes with excess blasts-2 (defined as having ≥10% and <20% bone marrow blasts) to “myelodysplastic syndromes/acute myeloid leukaemia”.

The Clinical, Myopathological, and Genetic Analysis of 20 Patients With Non-dystrophic Myotonia

IntroductionNon-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by CLCN1 or SCN4A mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.MethodsWe reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.ResultsCases included myotonia congenita (MC, 17/20) and paramyotonia congenita (PMC, 3/20). Muscle stiffness and hypertrophy, grip and percussion myotonia, and the warm-up phenomenon were frequently observed in MC and PMC patients. Facial stiffness, eye closure myotonia, and cold sensitivity were more common in PMC patients and could be accompanied by permanent weakness. Nine MC patients and two PMC patients had cardiac abnormalities, mainly manifested as cardiac arrhythmia, and the father of one patient died of sudden cardiac arrest. Myotonic runs in electromyography were found in all patients, and seven MC patients had mild myopathic changes. There was no difference in muscle pathology between MC and PMC patients, most of whom had abnormal muscle fiber type distribution or selective muscle fiber atrophy. Nineteen CLCN1 variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two SCN4A variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.ConclusionsMC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.

Phenotypic variability of syndromic craniosynostosis caused by c.833G > T in FGFR2: Clinical and genetic evaluation of eight patients from a five-generation family.

ObjectiveCraniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome. Considerable phenotypic overlap exists among these syndromes and mutations in FGFR2 may cause different syndromes. This study aims to investigate the explanation of the phenotypic variability via clinical and genetic evaluation for eight patients in a large pedigree.MethodsFor each patient, comprehensive physical examination, cranial plain CT scan with three‐dimensional CT reconstruction (3D‐CT), and eye examinations were conducted. Whole exome sequencing was applied for genetic diagnosis of the proband. Variants were analyzed and interpreted following the ACMG/AMP guidelines. Sanger sequencing was performed to reveal genotypes of all the family members.ResultsA pathogenic variant in the FGFR2 gene, c.833G > T (p.C278F), was identified and proved to be co‐segregate with the disease. Some symptoms of head, hearing, vision, mouth, teeth expressed differently by affected individuals. Nonetheless, all the eight patients manifested core symptoms of Crouzon syndrome without abnormality in the limbs, which could exclude diagnosis of Pfeiffer syndrome.ConclusionWe have established clinical and genetic diagnosis of Crouzon syndrome for eight patients in a five‐generation Chinese family. Variability of clinical features among these familial patients was slighter than that in previously reported sporadic cases.

Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance

Background: Antenatally detected occipital encephalocele and polycystic kidneys are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber syndrome which have considerable genetic and phenotypic overlap. Case reports: We describe 3 cases of antenatally diagnosed occipital encephalocele and enlarged kidneys with fetal autopsy, histopathology & exome sequencing results. A novel nonsense variant in the CEP290 gene was reported in first case (Meckel syndrome). The second case shows the importance of fetal exome where the parents were carriers for 2 ciliopathy genes (TMEM138 & SDCCAG8). Diagnosis in this case was confirmed by fetal exome sequencing (Joubert syndrome). Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance. Conclusion: We report 2 cases of Meckel syndrome with a novel variant and multiexon deletion, and 1 case of Joubert syndrome which depicts the limitations of preconceptional carrier screening in ciliopathies due to overlapping phenotypes.

Neurodevelopmental disorders-the history and future of a diagnostic concept .

This article describes the history of the diagnostic class of neurodevelopmental disorders (NDDs) up to DSM-5. We further analyze how the development of genetics will transform the classification and diagnosis of NDDs. In DSM-5, NDDs include intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Physicians in German-, French- and English-speaking countries (eg, Weikard, Georget, Esquirol, Down, Asperger, and Kanner) contributed to the phenomenological definitions of these disorders throughout the 18th and 20th centuries. These diagnostic categories show considerable comorbidity and phenotypic overlap. NDDs are one of the chapters of psychiatric nosology most likely to benefit from the approach advocated by the National Institute of Mental Health’s Research Domain Criteria project. Genetic research supports the hypothesis that ID, ASD, ADHD, schizophrenia, and bipolar disorder lie on a neurodevelopmental continuum. The identification of recurrently observed copy number variants and disruptive gene variants in ASD (eg, CDH8, 16p11.2, SCN2A) led to the adoption of the genotype-first approach to characterize individuals at the etiological level.

Protocol for the Characterization of the Cytosine-Adenine-Guanine Tract and Flanking Polymorphisms in Machado-Joseph Disease: Impact on Diagnosis and Development of Gene-Based Therapies

Polyglutamine spinocerebellar ataxias (SCAs) constitute a group of autosomal dominantly inherited neurodegenerative disorders with considerable phenotypic overlap. Definitive diagnoses rely on the detection of a mutation in each associated locus, comprising the abnormal expansion of the trinucleotide cytosine-adenine-guanine (CAG) in coding exons. Assessment of single nucleotide polymorphisms associated with the CAG expansion in the context of SCAs is also relevant for improving molecular diagnosis and for generating novel therapeutic strategies. The current study is focused on Machado-Joseph disease/SCA type 3, with the aim of developing a protocol for the accurate determination of the CAG length in exon 10 of the human ATXN3 gene and to characterize flanking polymorphisms. A single pair of primers was designed and validated, and two complementary PCR-based methods were established. In method I, PCR amplicons were cloned and sequenced, allowing the assessment of three single nucleotide polymorphisms in the vicinity of the CAG repeat (C987GG/G987GG, TAA1118/TAC1118, and C1178/A1178), which can constitute potential targets for personalized gene-based therapies. Method II combines PCR, capillary electrophoresis, and a size correction formula, enabling a time and cost-effective determination of the number of CAGs. The established protocol paves the way to overcome technical difficulties related to the molecular characterization of the CAG motif and intragenic polymorphisms in the context of Machado-Joseph disease/SCA type 3 and may prove useful when applied to other polyglutamine SCAs.

Current and future advances in genetic testing in systemic autoinflammatory diseases.

Systemic autoinflammatory diseases (SAIDs) are a group of inflammatory disorders caused by dysregulation in the innate immune system that leads to enhanced immune responses. The clinical diagnosis of SAIDs can be difficult since individually these are rare diseases with considerable phenotypic overlap. Most SAIDs have a strong genetic background, but environmental and epigenetic influences can modulate the clinical phenotype. Molecular diagnosis has become essential for confirmation of clinical diagnosis. To date there are over 30 genes and a variety of modes of inheritance that have been associated with monogenic SAIDs. Mutations in the same gene can lead to very distinct phenotypes and can have different inheritance patterns. In addition, somatic mutations have been reported in several of these conditions. New genetic testing methods and databases are being developed to facilitate the molecular diagnosis of SAIDs, which is of major importance for treatment, prognosis and genetic counselling. The aim of this review is to summarize the latest advances in genetic testing for SAIDs and discuss potential obstacles that might arise during the molecular diagnosis of SAIDs.

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe’s syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

Rare Tauopathies.

Tauopathies are rare neurodegenerative disorders related to microtubule-associated protein tau, which functions to stabilize microtubules. Pathological changes caused by overexpression or hyperphosphorylation of tau lead to the disengagement of tau from microtubules and accumulation of toxic intracellular inclusions. Tau pathology is the underlying mechanism for several sporadic and genetic disorders. These are collectively known as tauopathies. Each tauopathy is differentiated from others by its neuropathological features such as the presence of specific isoforms of tau, type of cellular inclusions, and the regions of the brain affected. Neuropathological features, with a few exceptions however, do not correspond to distinct clinical phenotypes. There is considerable phenotypic overlap between the different tauopathies. Interaction between tau and other protein inclusions further alters the clinical phenotype.Recent advances in the development of tau biomarkers, especially the development of tau radioligands used in positron emission tomography neuroimaging, and a better understanding of biology and pathology of tau are important first steps toward the ultimate goal of accurate diagnosis and disease modification in tauopathies.

Heterogeneity in the aetiology of diabetes mellitus in young adults: A prospective study from north India.

Background & objectives:In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools.Methods:In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing.Results:Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients.Interpretation & conclusions:The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.

An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome

Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculiar facial appearance, skeletal anomalies, a variety of visceral malformations and abnormal dermatoglyphic patterns. We describe a case of Kabuki syndrome presenting with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. This report demonstrates that clinical follow-up and molecular genetic testing can be useful for establishing the correct diagnosis.

De novo exon 1 missense mutations of SKI and Shprintzen‐Goldberg syndrome: Two new cases and a clinical review

Shprintzen-Goldberg syndrome (OMIM #182212) is a connective tissue disorder characterized by craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome. SKI is a known regulator of TGFβ signaling. Therefore, like Marfan syndrome and Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome is likely caused by deregulated TGFβ signals, explaining the considerable phenotypic overlap between these three disorders. We describe two additional patients with exon 1 SKI mutations and review the clinical features and literature of Shprintzen-Goldberg syndrome.

Nondystrophic myotonia: Challenges and future directions

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Common symptoms include muscle stiffness, transitory weakness, fatigue, and pain. Although seldom life-shortening, these myotonias cause life-time disability and affected individuals cannot perform many daily activities. A notable feature of the recessive form of chloride channelopathies is the presence of transient weakness. While there has been considerable progress in skeletal muscle channelopathies with regards to identifying biophysical abnormalities, the mechanism of transient weakness remains unclear. A recent study published in Experimental Neurology (Desaphy et al., 2013) explored this question further by comparing the biophysical properties of 3 chloride channel mutations associated with recessive myotonia congenita, with varying susceptibility to transient weakness. The authors identified a variety of functional defects in channel behavior among the 3 mutations, suggesting that this variability contributes to the differing phenotypes among chloride channelopathies. This commentary discusses nondystrophic myotonias, the results of Desaphy et al., and the treatment challenges in this rare disease.

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.