Calf Hypertrophy Research Articles

Molecular diagnosis of Alpha-sarcoglycanopathies by NGS in seven Moroccan families and report of two novel variants.

Limb-girdle muscular dystrophies constitute a heterogeneous group of neuromuscular diseases, both clinically and genetically. Limb-girdle muscular dystrophy by alpha-sarcoglycan deficiency or LGMD R3 α-sarcoglycan-related is a subtype of the autosomal recessive sarcoglycanopathies caused by variants in the alpha-sarcoglycan gene (SGCA) at 17q21.33. It appears in childhood by progressive weakness of pelvic and/or scapular girdle muscles and calf hypertrophy, with a wide range of clinical inter- and intra-familial clinical variability. Our report extends the molecular spectrum of SGCA gene with the identification of variant disease causing and will help for better management of patients and genetic counseling of families. In our study, seven unrelated families presented a clinical and paraclinical picture consistent with alpha-sarcoglycanopathy. A molecular study using Next-Generation Sequencing (NGS) was carried out on them. Six different homozygous variants of the SGCA gene were identified in the patients analyzed, including four previously reported variants and two novel variants predicted to be deleterious by the prediction tools. Our results expand the spectrum of variants in Moroccan patients with sarcoglycanopathy, specifically LGMDR3, most importantly as this form is not common in the Moroccan population.

Teaching Video NeuroImage: Calf Hypertrophy and Myoedema Unravel a Diagnosis of Severe Hypothyroidism.

Teaching Video NeuroImage: Calf Hypertrophy and Myoedema Unravel a Diagnosis of Severe Hypothyroidism.

THU658 My Giant Calves Gave Up My Diagnosis: An Extreme Manifestation Of A Very Rare Syndrome With A Severe Elevation Of Tsh Levels

Abstract Disclosure: E.E. Castro Feliu: None. A. Ludena De Freitas: None. A. Torres Rodríguez: None. G. Irizarry: None. Hoffmann’s Syndrome is a rare type of hypothyroidism myopathy in adults that classically presents with muscle cramps, weakness, muscle stiffness, hyporeflexia, delay deep tendon reflexes and pseudohypertrophy. This is the case of a 55-year-old male with history of poorly controlled hypothyroidism and medication non-compliance who was admitted to our institution for non-purulent cellulitis. Vital signs were within normal limits and Body Mass Index was 41.1. Upon physical examination flat affect, periorbital edema, moon facies features and macroglossia were distinguished. Skin had a doughy texture with areas of ichthyosis at upper and lower extremities. Goiter was absent. The most remarkable finding was bilateral calf hypertrophy, with measurements of 56 cm and 55.5 cm in diameter of right and left calves respectively. There was no tenderness to calf palpation and Homan’s sign was absent. Laboratories revealed dyslipidemia with a cholesterol of 308 mg/dL, triglycerides of 782 mg/dL, HDL of 26 mg/dL and LDL of 216 mg/dL with elevated inflammatory markers including sedimentation rate of 77 mm/hr and C-reactive protein of 6.45 mg/dL. Hypothyroidism was suspected therefore thyroid studies were ordered, which was compatible with severe hypothyroidism demonstrated by a record level TSH of 523 lU/ml. Other reported levels were Free T3 0.94pg/ml, total T3 0.5 ng/ml, free thyroxine <0.07 ng/dL, thyroid peroxidase <4, and thyroglobulin AB 19 IU/ml. Hoffmann’s Panel was confirmatory for this diagnosis reporting elevated levels of CPK 1509 U/L, LDH serum of 383 U/L and aldolase of 9.2 u/L. Ultrasound of the neck was non-contributory. Patient received antibiotic therapy for his skin infection and was also treated with IV Levothyroxine, which was prescribed orally upon discharge. Myopathy may be present in patients with longstanding untreated hypothyroidism in which pseudohypertrophy may occur, sometimes involving calf muscles (gastrocnemius). Hoffmann’s Syndrome is associated with changes in muscle fiber type from fast twitch type II to slow twitch type I and alteration of oxidative muscle enzyme activity with deceased calcium ATPase activity of fast twitch type II fibers leading to delayed relaxation. Biopsy of the affected muscle may reveal fiber necrosis, atrophy, hypertrophy with increased number of nuclei and increased connective tissue. Most cases of Hoffmann’s Syndrome improve after treatment with Levothyroxine, therefore, implementing this management on time can be curative. This case highlights the importance of considering this diagnosis when muscle dystrophies are studied and myopathic disorders are suspected, even in the absence of overt manifestations of hypothyroidism. Presentation: Thursday, June 15, 2023

CAV-3-related age-dependent muscle diseases: A novel mutation in mother and son

The caveolin-3 protein encoded by the CAV-3 gene is a muscle-specific protein found in skeletal, smooth, and cardiac muscle. Caveolin-3 defects lead to several muscle diseases: rippling muscle disease (RMD), limb-girdle muscular dystrophy (LGMD1C), distal myopathy, familial hypertrophic cardiomyopathy, and asymptomatic hyper-CK-emia. While some variants that cause mutations in this gene cause a pure type of disease, some variants may appear as overlap syndromes. Even in the same variants of CAV-3 mutation, the type of muscle disease, its severity, and time of occurrence can be variable. For this reason, it should be known that CAV-3-related diseases and all overlapping diseases can be seen over time, and the patient should be followed up. We report here a 9-year- old boy and his 38-year-old mother who were investigated for asymptomatic hyper-CK-emia and diagnosed with caveolinopathy. The boy had calf hypertrophy and percussion-induced rapid muscle contraction (PIRCs). His mother had calf hypertrophy, contractions due to percussion, and proximal muscle weakness. Mother’s proximal muscles and m. gastrocnemius magnetic resonance imaging (MRI) was normal. The mother had complaints of weakness, showing slow progression starting from the second decade. Heterozygous (ENST000003cav3849.2) c.298A>T p.Ile100Phe variant in exon 2 was detected in the CAV-3 gene. This mutation is classified as pathogenic according to The American College of Medical Genetics and Genomics (ACMG) criteria (PM1, PM2, PP3, PM5). In conclusion, calves’ pseudohypertrophy and mildly raised CK without weakness can be the initial presentation of caveolinopathy. Percussion-induced muscle contractions, rather than muscle rippling, can occur at a young age. The onset of muscle weakness can be delayed during adolescence and can have a slowly deteriorating course associated with myalgia.

Relevance of Ayurveda Management in Duchenne Muscular Dystrophy to Augment the Quality of Life- A Pediatric Case Report

Muscular dystrophy is a myopathy that stakes clinical characteristics of progressive muscular feebleness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder of muscular dystrophy in children, present in early childhood, and characterized by proximal muscle weakness and calf hypertrophy in affected boys. This case aims to make Ayurveda pediatricians aware of planning a protocol for DMD. The objective is to provide instant relief in motor function to some extent and to augment the quality of life. An 11 years old boy was presented with an in ability to stand, gross muscle weakness, difficulty in movements of lower limbs, and particularly in all vigorous physical activities. He also had decreased strength, stamina, and progressive debility with positive Gower's sign, which suggested DMD. Confirmed economic treatment options are unavailable to prevent progressive illness and mortality. The family members were counselled and assured of improving their quality of life. He was started with multiple pre-panchakarma procedures of alternate Rukshan and Brihan to pacify internal Ayurveda medicines with the support of occupational therapy and physiotherapy in different sittings for three months. His CPK -creatinine kinase was 8335 U/L (NV= 55 to 170 U/L) which became4741U/L post-treatment. He could stand with support for 15 minutes on his own with ease in body movements due to a reduction in contractures & increase in the range of motions measured by the goniometer, as this genetic disease has no medicinal cure. However, by adopting a multi-dimensional integrative approach, family support, and willpower, the quality of life can be augmented to much extent. Ayurveda plays a crucial role in the drastic improvement because of panchkarma shaman procedures, medicines, Yog, physiotherapy, traction, and counselling at regular intervals for lifelong.

Suspicion of Duchenne Muscular Dystrophy in A 7-Year-Old Madurese Boy: A Rare Case Report

Introduction: Duchenne Muscular Dystrophy (DMD) is an X-linked disorder presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys associated with a functional deficiency of dystrophin. The incidence of these cases reached 1 in 3500-6000 male births. Research at RSUPN Dr Cipto Mangunkusumo (RSCM) showed that DMD is the second most frequent neuromuscular disorder in children regardless there is no prevalence data available yet in Indonesia. It is quite complicated to diagnose DMD due to the limited facilities of genetic testing and its high cost. Case Presentation: A 7-year-old boy came with the main complaint of weakness in both legs progressively two years before admission. He had to hold onto the floor and then both knees when started to stand. There was a history of motor and speech delay but family history was denied. Vital signs and nutritional status were within normal. Laboratory examination revealed significantly elevated levels of CK, ALT, and AST. The EMG result supported the presence of myopathy. Due to a lack of facilities, genetic testing or muscle biopsy could not be done. He received prednisone once a day with a 14 mg dose and was scheduled to attend regular physiotherapy. Conclusion: In a limited facilities area, the clinician should have a suspicion of DMD not only by anamnesis and clinical features, but also by considering the elevated levels of CK and myopathies on EMG.

Endoscopic Concurrent Gastrocnemius Muscle Resection and Soleus Muscle Neurectomy for Severe Muscular Calf Hypertrophy.

Selective neurectomy or muscle resection techniques for calf reduction conventionally focus on the gastrocnemius muscle. However, the underlying soleus muscle plays an important role in muscular calf hypertrophy. In the authors' experience, the results of calf reduction have been suboptimal in patients with severe muscular calf hypertrophy who underwent gastrocnemius muscle resection only. This article describes a new calf reduction method that uses concurrent gastrocnemius muscle resection and soleus muscle neurectomy using an endoscope-assisted single-incision approach in patients with severe muscular calf hypertrophy. A total of 139 patients who underwent simultaneous gastrocnemius muscle resection and soleus muscle neurectomy for severe calf hypertrophy from March of 2017 to June of 2020 were retrospectively analyzed. After combined gastrocnemius resection (mean weight per calf, 349 g) and soleus neurectomy, about 3.8 to 8.2 cm (mean, 6.4 cm) or 12.8% to 24.3% (mean, 16.6%) of the calf was reduced. Complications included cellulitis, hematoma, seroma, and mild depression ( n = 1 each). Two patients had traction injury to the sural nerve. One patient developed Achilles tendon rupture at 2 months postoperatively. No patient complained of functional impairment with respect to easy fatigability, stability, gait, or sport activities at 6 months postoperatively. This study is the first to combine gastrocnemius muscle resection with selective soleus muscle neurectomy to achieve the most efficient calf reduction for severe muscular calf hypertrophy. Therapeutic, IV.

COMPARISON BETWEEN UNIPEDAL AND BIPEDAL PLANTAR FLEXIONS USING TIME UNDER TENSION METHOD

ABSTRACT. Introduction. Bodybuilding is a sport that requires all muscle groups to be similarly developed, bringing an aesthetic physique to the observers. The development of the triceps surae may be a difficult goal to achieve for some athletes. Considering this, we chose to focus on a new training method that induces less stress in muscle groups: the time under tension. Objective. The purpose of the study was to compare exercises used for calf hypertrophy using the time under tension method and to identify the optimal situations in which this method could be used. Methods. Ten subjects, 6 male and 4 female, age of 25.7±4.9 years old, height 174.7±9.5 centimeters, body weight 82±17.8 kg and with varied levels of fitness, participated in the study. The plantar flexions were done with body weight only on one and both feet. The exercises we tested were done on a 3 second cycle: 3 seconds on the upwards movement and 3 seconds for the downwards one. The subjects performed a total of 10 repetitions for each exercise. Results. A significant statistical difference was found between the types of plantar flexion measured. This indicates that the analysis of time under tension plantar flexion should take into account the actual type of movement done. Conclusions. Time under tension method for calf muscle hypertrophy should take into consideration the movement characteristics for the focused muscle group. Our results showed that postural balance and body position can influence the force and power output of plantar flexion.

Limb-Girdle Muscular Dystrophy in Brazilian children: Clinical, histological and molecular characterization.

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic muscular disorders, involving autosomal recessive and dominant forms, that clinically are characterized by progressive muscular weakness of proximal predominance, generally starting in the pelvic girdle and, later, in the shoulder girdle, frequently associated with other clinical signs such as calf hypertrophy, joint retractions and skeletal deformities such as winging scapula and scoliosis. The distal muscles may be affected, but usually only late in the progression of the disease. Involvement of respiratory muscles and cardiac muscles is described in many forms of the disease. Different degrees of increase in the serum level of creatine kinase (CK) are observed and, sporadically, there is involvement of the central nervous system (CNS) and gastrointestinal tract . Autosomal recessive forms are far more common than autosomal dominant, particularly in children. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunohistochemical studies and the confirmatory toll is the molecular test . This retrospective study had the objective to investigate the frequency of different subtypes of limb-girdle muscular dystrophy in children from a population from a large public teaching hospital serving the country, describing the clinical and histological aspects of the different forms.

Uloga gena modifikatora na klinički tok Dišenove mišićne distrofije

Duchenne muscular dystrophy is the most common inherited muscle disease in childhood, which has a progressive clinical course with a fatal outcome that most often occurs between the second and fourth decade of life. The disease is inherited X-linked, recessively, and in two-thirds of patients, it is transmitted from the mother, while in the remaining third of patients, it is a de novo mutation. Mutations in the dystrophin gene (DMD gene) such as deletions, duplications and small mutations can be found throughout the entire length of the gene. The disease begins between the third and fifth year of life, and the initial muscle weaknesses are clinically manifested as slower running, difficulty climbing stairs or difficulty getting up from squats. Sometimes, accidentally discovered, elevated keratin kinase values or delayed early psychomotor development milestones in a child with hypertrophic calves can initiate a diagnostic procedure in the direction of Duchenne muscular dystrophy. The disease usually has a uniform clinical course and implies a clear time sequence of events. Muscle weakness leads to loss of ambulation, then the function of the upper extremities, to complete immobility, with the evolution of dilated cardiomyopathy and respiratory insufficiency, which are the main causes of death. Certain patients show deviations from the above in terms of longer functionality and later loss of independent ambulation, later cardiomyopathy and respiratory insufficiency and vice versa. It is believed that in addition to the application of modern standards of care and treatment of patients, the clinical course is influenced by genes independent of the causal DMD gene, which affects processes in dystrophic muscle, primarily inflammation, fibrosis and fatty infiltration, through specific signaling pathways. So far, six genes have been described whose variants modify the course of Duchenne muscular dystrophy. The secreted phosphoprotein 1 (SPP1) is the first described gene whose G allele in the variant rs28357094 is associated with an earlier age of gait loss. In addition, variants in the genes described are LTBP4 (latent transforming growth factor-b binding protein 4), CD40, ACTN3 (actinin 3), THBS1 (thrombospondin 1) and TCTEX1D1 (Tctex1 domain containing 1). The aim of this paper is to present already-known genes that modify Duchenne muscular dystrophy and their influence on the clinical course of the disease.

Clinical score for early diagnosis of myotonic dystrophy type 2

IntroductionMyotonic dystrophy type 2 (DM2) is a rare, multisystemic, autosomal dominant disease with highly variable clinical presentation. DM2 is considered to be highly underdiagnosed.ObjectiveThe aim of this study was to determine which symptoms, signs, and diagnostic findings in patients referred to neurological outpatient units are the most indicative to arouse suspicion of DM2. We tried to make a useful and easy-to-administer clinical scoring system for early diagnosis of DM2-DM2 early diagnosis score (DM2-EDS).Patients and methodsTwo hundred ninety-one patients with a clinical suspicion of DM2 were included: 69 were genetically confirmed to have DM2, and 222 patients were DM2 negative. Relevant history, neurological, and paraclinical data were obtained from the electronic medical records.ResultsThe following parameters appeared as significant predictors of DM2 diagnosis: cataracts (beta = 0.410, p < 0.001), myotonia on needle EMG (beta = 0.298, p < 0.001), hand tremor (beta = 0.211, p = 0.001), positive family history (beta = 0.171, p = 0.012), and calf hypertrophy (beta = 0.120, p = 0.043). In the final DM2-EDS, based on the beta values, symptoms were associated with the following values: cataracts (present 3.4, absent 0), myotonia (present 2.5, absent 0), tremor (present 1.7, absent 0), family history (positive 1.4, negative 0), and calf hypertrophy (present 1.0, absent 0). A cut-off value on DM2-EDS of 3.25 of maximum 10 points had a sensitivity of 84% and specificity of 81% to diagnose DM2.ConclusionSignificant predictors of DM2 diagnosis in the neurology outpatient unit were identified. We made an easy-to-administer DM2-EDS score for early diagnosis of DM2.

Expanding the Clinical and Genetic Spectrum of Caveolinopathy in Korea

Purpose: Caveolinopathy is a disease caused by caveolin-3 (CAV3) mutations that shows a wide clinical spectrum, including isolated hyperCKemia and limb-girdle muscular dystrophy. While recent advances in next-generation sequencing (NGS) have enabled earlier diagnosis of this disease, it remains difficult to predict the clinical course of each patient.Methods: This study summarizes the clinical presentations of 13 genetically confirmed caveolinopathy patients in four Korean families. Genetic diagnosis was performed using NGS technologies for probands and Sanger sequencing for the other family members.Results: Four coding mutations were found (p.Val103_Val104del, p.Asp28Glu, p.Pro105Leu, and p.Arg27Gln), and each family showed autosomal dominant inheritance. While all 13 cases had hyperCKemia, only five of them showed some myopathic features including ankle contracture, calf hypertrophy, exercise intolerance, and muscle cramping. This high proportion of asymptomatic cases suggests both that these mutations may be associated with a mild phenotype and that caveolinopathy may be an underdiagnosed disease.Conclusion: This study extends our understanding of caveolinopathy; in particular, the findings suggest the need to consider caveolinopathy in patients with incidental findings of CK elevation. NGS may be a useful method in the differential diagnosis of such cases.

Clinical and Genetic Studies of Limb Girdle Muscular Dystrophy: Reports of Two Cases

Limb girdle muscular dystrophy (LGMD) presents with weakness and wasting of muscles, initially appear at proximal group of pelvic and shoulder girdles and inherited by an autosomal recessive disorder mainly and rarely autosomal dominant trait. We report two young girls of limb girdle muscular dystrophy (LGMD), who presented with gradual onset of weakness in proximal muscle of all four limbs. There was positive family history in one girl. Neurological examination revealed pseudo hypertrophy of both calves, hypotonia in all four limbs, muscle power diminished, more on proximally. All deep tendon reflexes were diminished with planters bilateral flexors. Gower sign was positive and winging of scapula was also present. Electromyography (EMG) showed myopathic pattern. Both had elevated creatinine phosphokinase levels and finally genetic study confirmed the diagnosis. J Enam Med Col 2020; 10(3): 190-194

Single Incision Endoscope-Assisted Gastrocnemius Muscle Resection for Calf Hypertrophy: Analysis of 300 Cases.

Muscular calf hypertrophy can cause severe psychological distress. Total or subtotal resection of the gastrocnemius muscle results in significant calf reduction. However, both techniques require a second incision of 5 and 2 cm, respectively, at the posterior mid-calf. The resultant mid-calf scar is more difficult to conceal when wearing short skirts or pants. The authors sought to describe the technique of endoscope-assisted gastrocnemius muscle resection to obviate the need for a mid-calf scar and to review the outcomes of patients who underwent this procedure. A retrospective study of 300 patients in a single center in Taiwan who underwent endoscope-assisted subtotal resection of the gastrocnemius muscle for hypertrophic muscular calves, between March 2015 to June 2019, were included in this study. The combined weight of the resected gastrocnemius muscle ranged from 156 to 484 g per calf (mean = 276 g). The mean maximal calf circumference was 36.1 cm preoperatively and 30.9 cm postoperatively. The calf reduction achieved was 3.0 to 8.1 cm (mean = 5.2 cm), or 8.9% to 19.8% (mean = 14.4%). The complications were minor, and the rate was low (2%). As for the popliteal fossa scar, 6 patients underwent further treatment of their hyperpigmented or hypertrophic transverse scar. There were no complaints of impaired leg function regarding gait or sports activities 3 to 6 months postoperatively. At present, gastrocnemius muscle resection remains unrivaled in its ability to achieve calf reduction. The surgery is now much more appealing to patients as a result of employing the endoscope-assisted technique to obviate the mid-calf scar.

Techniques and Applications of Lower Extremity Feminization and Masculinization.

Significant differences exist between feminine and masculine lower extremities, and this region contributes to gender dysphoria in transgender and nonbinary individuals. A systematic review was conducted for primary literature on lower extremity (LE) gender affirmation techniques as well as anthropometric differences between male and female lower extremities, which could guide surgical planning. Multiple databases were searched for articles before June 2, 2021 using Medical Subject Headings. Data on techniques, outcomes, complications, and anthropometrics were collected. A total of 852 unique articles were identified: 17 met criteria for male and female anthropometrics and 1 met criteria for LE surgical techniques potentially applicable to gender affirmation. None met criteria for LE gender affirmation techniques specifically. Therefore, this review was expanded to discuss surgical techniques for the LE, targeting masculine and feminine anthropometric ideals. LE masculinization can target feminine qualities, such as mid-lateral gluteal fullness and excess subcutaneous fat in the thigh and hips. Feminization can target masculine qualities like a low waist-to-hip ratio, mid-lateral gluteal concavity, calf hypertrophy, and body hair. Cultural differences and patient body habitus, which influence what is considered "ideal" for both sexes, should be discussed. Applicable techniques include hormone therapy, lipo-contouring, fat grafting, implant placement, and botulinum toxin injection, among others. Due to lack of existing outcomes-based literature, gender affirmation of the lower extremities will rely on application of an array of existing plastic surgery techniques. However, quality outcomes data for these procedures is required to determine best practices.

Ayurveda interventions in the management of Duchenne Muscular Dystrophy – A Review

Abstract Duchenne Muscular Dystrophy (DMD) is a heterogeneous group of inherited disorders caused due to mutation in the gene for the protein dystrophin, located on the short arm of the X chromosome in the Xp21 region. It is characterized by proximal muscle weakness, calf hypertrophy, frequently developing contractures, and loss of walking by the 2nd decade. Patients are predisposed to severe, fatal pulmonary infections and lose their lives due to dysfunction of muscles involving the respiratory system. The incidence is 1 in 5000 live boys. Objective: To review existing human case reports and clinical trials for treating Duchenne muscular dystrophy through the Panchakarma interventions. Design: The literature research comprised an electronic database from January 2000 to April 2021. The study included MEDLINE, PubMed, The Cochrane Library, Google scholar, Ayush research portal and DHARA database. Search terms were used “Duchenne muscular dystrophy”, “Ayurveda”, “Panchakarma”, “DMD” No limits were used. The search strategy was adapted for each database as necessary. Only trials on humans were included in the patient review. The study applied inclusion criteria while screening the records. Intervention: Treatment with any regimen of “Panchakarma”. Outcome measures: Number and results of studies identified in the review. Results: Seventeen articles were screened; Eight human trials met inclusion criteria. Ayurvedic Panchakarma based procedures effectively relieve the signs and symptoms and reduce the CPK level in children with DMD. There are only few studies published in Ayurveda in the management of DMD. The Conventional System of medicine and Ayurveda System of medicine are at the same level in the case of DMD for therapeutic purposes as there is no permanent cure for this disease in both systems. A combined approach should be made to manage this disease with the conventional method of medicine and Ayurveda. The integrative approach could open new hope for patients of DMD, and it is a need of time.

Syringomyelia: An Unusual Cause of Pronounced Calf Hypertrophy.

Syringomyelia: An Unusual Cause of Pronounced Calf Hypertrophy.

A rare co-occurrence of duchenne muscular dystrophy, congenital adrenal hypoplasia and glycerol kinase deficiency due to Xp21 contiguous gene deletion syndrome: case report

BackgroundContiguous gene deletion syndromes are rare genomic disorders caused by deletion of large segments of DNA resulting in co-occurrence of apparently unrelated multiple clinical phenotypes. We report a boy with contiguous gene deletion involving Xp21 genomic location.Case presentationA Sri Lankan boy with developmental delay and failure to thrive first presented at three years of age with hypovolaemia, hyperpigmentation and drowsiness. Investigations done at that time revealed hypoglycaemia, hyponatraemia, hyperkalaemia, low cortisol, low aldosterone, high ACTH and low 17-hydroxyprogesterone. He was diagnosed to have primary adrenal insufficiency.During follow-up at five years, he was noted to have progressive difficulty in walking, waddling gait, hypotonia, calf hypertrophy and positive Gower’s sign. His creatine kinase was very high, and the electromyogram showed myopathy. Genetic analysis revealed hemizygous deletion involving the final 35 exons of the dystrophin gene confirming the diagnosis of Duchenne muscular dystrophy.Further investigations revealed pseudohypertriglyceridemia, large glycerol peak on urine organic acid analysis and hemizygous deletion of the glycerol kinase gene confirming glycerol kinase deficiency. Based on the presence of Duchenne muscular dystrophy, glycerol kinase deficiency and probable congenital adrenal hypoplasia along with genetic confirmation of deletions involving dystrophin and glycerol kinase genes, the diagnosis of Xp21 contiguous gene deletion syndrome was made.ConclusionsWe report a child with contiguous gene deletion syndrome who was initially diagnosed as having isolated primary adrenal insufficiency probably due to congenital adrenal hypoplasia. Later he was confirmed to have Duchenne muscular dystrophy and glycerol kinase deficiency, as well. This case report highlights the importance of pre-emptive evaluation and identification of genetic defects when patients present with seemingly unrelated diseases that could aid in accurate diagnoses of contiguous gene deletion syndromes.

AUTOIMMUNE & INFLAMMATORY NMD: EP.01 Autoimmune necrotizing myopathy with anti-signal recognition particle antibodies in the first year of life

Autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (SRP ANM) has been rarely reported in childhood. Case Reports. We report 2 patients with onset in the first years of life. Both received corticosteroids, immunoglobulins, methotrexate, hydroxychloroquine and tacrolimus. Patient 1 has clearly improved. Patient 2 was misdiagnosed as muscular dystrophy for 15 years; nevertheless, after 4 months of therapy there was mild motor improvement. Patient 1. A 6-year-old girl presented with weakness, but her parents could not recall the beginning. She had axial as well as mild to moderate limb girdle weakness. There was no systemic/skin involvement. CK levels were 2.400 UI/l. The DMD MLPA test and next-generation sequencing (NGS) did not reveal any pathogenic mutation. Muscle weakness progressed quickly in the next 3 months, suggesting an acquired myopathy, and SRP antibodies were detected. Muscle biopsy was compatible with ANM. Patient 2. A 4-year-old girl presented with weakness in lower limbs for months. Her family was consanguineous. She achieved ambulation after 18 months. She had proximal limb weakness, as well as scapular winging and calf hypertrophy. Her cognitive capacity was borderline. CK levels were >5.000U/l. MRI disclosed posterior thig involvement and focal edema, but based on the rest of clinical findings, a muscular dystrophy was suspected. Muscle biopsy performed at 5 and 10 years of age showed a dystrophic pattern with necrotic fibers and endomysial connective infiltration. Immunochemistry study for muscular dystrophies was normal. Her clinical course has progressed very slowly. She showed rigid spine and maintains independent walking. At 19 year of age, due to the negativity of the all the genetic tests performed over the time (including NGS), myositis specific autoantibodies were tested and SRP antibodies were positive. Review of the second muscle biopsy disclosed C5b-9 expression in muscle fibers. SRP ANM is under-recognized and consequently undertreated in children. Early diagnosis is crucial to improve outcome.

NEW GENES AND DISEASES: EP.304 Early onset lower limp assymmetry: a new clinical phenotype of calsequestrin mutation

Calsequestrin is a protein that handles calcium in sarcoplasmic reticulum (SR),Ca2+ transients are crucial in skeletal muscle excitation-contraction coupling. Synchronous Ca2+ release from the SR terminal cisternae into the cytoplasm and its reuptake into the SR store are granted by a structural and functional unit and their defect causes myopathy. In an 11-year-old girl, affected by lower limb asymmetry (R limb shorter of 3 cm), upper limb hypotrophy and winging scapulae were found; she had high CK:2900 U/l, her sister presented myalgias and CK:1500 U/l, the mother CK 500 U/l and grandmother had both congenital club foot. We investigated the causes of the high CK by EMG that was myopathic, muscle biopsy that showed few atrophic fibres, in ATPase rare 2C fibres, some increased NADH-TR stain at the periphery, increased central nuclei and rare basophilic fibres. We performed immunohistochemistry for dystrophin, caveolin-3, alpha-sarcoglycan, western blot for dysferlin: all normal. The girl was operated at 15 years for elongation of right femur and by epiphysiodesis left femur and the limb asymmetry was reduced to only half a centimeter: however she complained of fatiguability, especially after physical education at school, and high CK (2186 U). She presented with scoliosis, difficulty walking with calf hypertrophy. A search for the causes for hyperCKemia was done with WGS at TIGEM and resulted in detection of a pathogenetic variant of CASQ1 gene (p.ASP244Gly), coding for calsequestrin, which allowed the solution of this puzzling familial case. In 7 members of 4 Italian families with vacuolar myopathy with CASQ1 mutation calsequestrin aggregates and a similar variant was found. In CASQ1 myopathy in several cases hyperCKemia, myalgia or other vague symptoms are present: in 22 CASQ1-mutated patients from 12 families 21 sharing the same variant of our case presented symptoms in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging. In the present family, clubfoot, early onset, limb asymmetry were the predominant clinical symptoms, they could be the effect of somatic mosaicism. In this respect our patient presents an early onset and a new clinical phenotype of lower limb asymmetry that is unique. The present familial case expands the clinical phenotype of CASQ1-myopathy.