A Case Study of Early Diagnosed Angelman Syndrome: Recognizing Atypical Clinical Presentations
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Abstract:
Angelman syndrome (AS) is a rare pediatric neurological condition in which patients most commonly present with inappropriate laughter, microcephaly, speech difficulties, seizures, and movement disorders. AS can be diagnosed clinically and confirmed with genetic testing. In this case report, the patient presented with 9.3% weight loss at two days of age. Although there were multiple attempts at lactational counseling and nutritional guidance, the patient was admitted to the hospital due to failure to thrive. Due to continued global developmental delay and upper and lower extremities hypotonia by the age of nine months, the patient was referred to a neurologist. Brain MRI was negative, and genetic testing revealed 15q11.2q13.1 deletion, which is consistent with AS. Through different therapies and intervention, the patient showed slow improvements in symptoms. This case illustrates the importance of early recognition of nonspecific clinical manifestations of AS. The general management for all AS patients includes physical therapy, speech therapy, mobility support devices, education, and behavioral therapy as they progress through life. Establishing an early diagnosis has potential long-term benefits of improved quality of life and outcomes for patients via early interventions such as physical therapy starting at the age of six months to improve gross motor function. When infants present with nonspecific clinical presentations such as failure to thrive and hypotonia, clinicians should maintain a lower threshold for suspecting genetic conditions, which will facilitate early diagnosis of AS.Keywords:
Failure to Thrive
Angelman Syndrome
Microcephaly
Developmental Milestone
Failure to Thrive
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Failure to Thrive
Hepatic dysfunction
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The first girl of an unrelated couple was noted to have failure to thrive since age 3 months, generalized hypotonia and weakness, hepatomegaly, hypoglycemia, and lactic acidosis at 4 months. She was found to have severe mitochondrial DNA (mtDNA) depletion and respiratory chain complex IV deficiency in both skeletal muscle and liver but without other common mtDNA mutations. Her younger brother developed vomiting at age 3 weeks and was diagnosed as having pyloric stenosis. His skeletal muscle and liver also showed severe mtDNA depletion. He developed generalized weakness and hypotonia, hepatomegaly, and lactic acidosis at age 3 months. Both siblings died of hepatic failure and hemorrhagic complication before 6 months of age. The brother also had chemical pancreatitis, which had not been reported before in mtDNA depletion in children. Severe mtDNA depletion may present with nonspecific symptoms such as vomiting, failure to thrive, and developmental delay; multiorgan involvement such as hepatomegaly, pancreatitis, and myopathy occurs later. Mitochondrial DNA depletion should be considered in the differential diagnosis in children with developmental delay or failure to thrive of unknown etiology. (J Child NeuroL 2000;15:822-824).
Failure to Thrive
Lactic acidosis
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Background:Pompe disease is a lysosomal glycogen storage disease (GSDII) characterized by deficiency of acid glucosidase, resulting in lysosomal glycogen accumulation in multiple tissues, with cardiac and skeletal muscles being the most seriously affected. It manifests itself as a spectrum in multiple age groups including infancy, childhood and adulthood.Case Report:We present a case of infantile Pompe disease that was detected at a four month well visit in the presence of hypotonia and failure to thrive.Conclusions:Pompe disease can be diagnosed clinically by plotting growth parameters and performing developmental screening accurately. Enzyme replacement is the only available medical treatment for Pompe disease. High index of suspicion is necessary in diagnosing Pompe disease.
Failure to Thrive
Muscle Hypotonia
Growth retardation
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Microcephaly
Failure to Thrive
Ring chromosome
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Failure to thrive in the setting of profound hypotonia and multiple electrolyte derangements is a challenging constellation of findings that offers a broad differential diagnosis for providers to consider. Initial management should focus on the stabilization of the patient and correction of potential life-threatening electrolyte derangements. Once completed, the diagnosis should be sought, and in this case, many were considered and ultimately ruled out with thorough history and physical examination. Laboratory abnormalities revealed the final diagnosis of pseudohypoaldosteronism and connected the case. With proper treatment, our patient had a resolution of laboratory anomalies along with improved growth and tone.
Failure to Thrive
Pseudohypoaldosteronism
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Microcephaly
Facial dysmorphism
Growth retardation
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Leukotriene C4 synthase deficiency is an extremely rare fatal neurometabolic developmental disorder characterized clinically by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
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Microcephaly
Psychomotor retardation
Muscle Hypotonia
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Stromal Antigen 1 (STAG1, OMIM 604358) is a core protein of the cohesin complex (Sumara, Toth, Carramolino) that regulates chromatid separation in mitosis, gene transcription, DNA repair and DNA replication (Peters). Pathogenic variants in components of the cohesin complex are rare and referred to as cohesinopathies. A published cohort of 17 patients with STAG1 pathogenic variants (7 deletions, 8 missense and 2 frameshift) notes a neurodevelopmental phenotype (Lehalle). De novo changes were noted in 76% of the cohort, while 12% were maternally inherited and 12% were unknown. All STAG1 patients had intellectual disability/developmental delay (100%). Additional findings included IUGR (18%), neonatal feeding difficulties (53%), hypotonia (29%), facial dysmorphisms (82%), epilepsy (41%), scoliosis (12%) and abnormal brain imaging (18%) (Lehalle). The authors conclude that the pathogenic STAG1 variant most likely resulted in haploinsufficiency of the gene product and in turn disrupted gene regulation resulting in the observed phenotypes. To add to the limited knowledge regarding STAG-1 cohesinopathies, we present a patient with a novel, missense, likely-pathogenic variant. In addition, we present mechanistic evidence supporting the deleterious nature of this variant. A male infant was born via uncomplicated vaginal delivery at 35-6/7 weeks to a 27yoG4P2; late preterm induction of labor was performed for debilitating maternal headaches. A course of betamethasone was administered prior to induction. The pregnancy was otherwise uncomplicated. Family history significant for bronchiectasis in an older sister. Physical exam and newborn screen evaluation were normal at birth, but poor suck was noted immediately. The infant was discharged on day 2 of life but readmitted day 11 due to dehydration, lack of weight gain and inability to coordinate feeds. At three months, persistent difficulty with oral skills and lack of weight gain were noted. Upper GI and swallowing studies were normal. A G-tube was placed. At 4 months, a history of recurrent ear and urinary infections were noted. At 7 months, the patient was diagnosed with laryngomalacia and developed unexplained right sided Horner's syndrome. MRI brain noted an incidental Chiari 1 malformation but no acute process. Genetics consult at 7 months noted anisocoria, mild bilateral conductive hearing loss and a presacral dimple. Metabolic testing was normal for lysosomal/peroxisomal storage disorders, aminoacidopathy, congenital disorders of glycosylation, carnitine, purine and pyrimidine disorders, and pyruvic defects. Chromosomal microarray was normal. Exome sequencing (ES) trio testing through GeneDx, a CAP/CLIA-certified lab, revealed a de novo, likely pathogenic, heterozygous variant in STAG1 c.643G>A, p.V215I consistent with STAG1-related disorders. Following initial WES, he was diagnosed with non-CF bronchiectasis (negative sweat test) and low IgM and IgA levels; he has had episodes of hypoglycemia, with negative metabolic evaluation. WES reanalysis with updated phenotype was non-diagnostic. At 3 years, height is 87.6cm (2%ile), weight 12.75 kg. He has diagnoses of developmental delay including expressive speech delay, receives IVIG infusions, chest therapy and remains G tube dependent with food aversion. He receives educational services and qualified for an IEP at age 3. Our patient's variant occurred at a highly conserved amino acid region in the cohesin complex interface between STAG1 and RAD21. Although reported as likely pathogenic, the deleteriousness of the variant was questioned because the physiochemical change from valine to isoleucine is small and isoleucine occurs in lower species (yeast and fruit fly). Molecular dynamic simulation on this variant and two published deleterious STAG1 variants showed similar altered protein conformation at the RAD21 interface. This report contributes to the expanding literature for STAG1 cohesinopathy phenotypes and mechanistic evidence of the pathogenicity of the genetic variant.
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Biallelic loss-of-function variants in MED23 cause a recessive syndromic intellectual disability condition with or without epilepsy (MRT18). Due to the small number of reported individuals, the clinical phenotype of the disorder has not been fully delineated yet, and the spectrum and frequency of neurologic features have not been fully characterized. Here, we report a 5-year-old girl with compound heterozygous for two additional MED23 variants. Besides global developmental delay, axial hypotonia and peripheral increased muscular tone, absent speech, and generalized tonic seizures, which fit well MRT18, the occurrence of postnatal progressive microcephaly has been here documented. A retrospective assessment of the previously reported clinical data for these subjects confirms the occurrence of postnatal progressive microcephaly as a previously unappreciated feature of the phenotype of MED23-related disorder.
Microcephaly
Compound heterozygosity
Global developmental delay
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