Decreased level of consciousness in a toddler with overgrowth syndrome

Physicians caring for patients with rare diseases face unique challenges in managing symptoms, ordering diagnostic tests, and providing patients and families with anticipatory guidance. We describe the case of a toddler with overgrowth syndrome, and previously known ophthalmological and neurological findings, presenting with decreased level of consciousness (LOC) following a fall. We highlight the extensive workup undertaken in a patient with symptoms spanning multiple systems but lacking a unifying diagnosis. In this case, rapid whole exome sequencing identified a de novo CACNA1A gene mutation encoding a calcium channel subunit, located within chromosome region 19p13.13. We explore 19p13.13 Microdeletion Syndrome and compare our patient’s presentation to the cases described in the literature. Although our patient had several symptoms consistent with 19p13.13 Microdeletion Syndrome, others remain unexplained. This highlights the difficulty in determining a definitive diagnosis or treatment plan in the realm of rare diseases and emphasizes the need for further research into the disease process and development of novel therapies. patient presentation A 2 years 10 months old male presents to hospital with decreased LOC following an unwitnessed fall. He was found facedown by a caregiver who described unusual movements but no clear seizure activity. Emergency medical services brought him to a local community hospital, during which he required support by bag mask ventilation. The patient’s past medical history was significant for global developmental delay, chronic overgrowth of undetermined etiology (weight average for 9 year old male, and height average for 5 year old male), retinal cone dysfunction, peripherally hypopigmented fundus, hypotonia, and autistic features. Specialists involved in his care included paediatric neurology, ophthalmology, endocrinology and medical genetics at multiple academic medical institutions, yet he lacked a unifying diagnosis. Prior to the unwitnessed fall the patient had had a 3-day history of cough but had otherwise been well. Upon presentation to the local community emergency department, the patient was tachycardic and required supplemental oxygen. He required intubation for decreased respiratory effort, and was transferred to a paediatric critical care unit (PCCU) at the nearest tertiary care centre, where he remained intubated for 10 days. After successful extubation he was transferred to a general paediatric inpatient unit for further work-up and management. investigations and management On initial presentation to the PCCU, the patient was started on empiric broad-spectrum antibiotics and antiviral treatment for possible meningitis or encephalitis. Infectious workup, including cultures of urine, blood, and cerebral spinal fluid (CSF), were negative. CSF polymerase chain reaction (PCR) was negative for enterovirus and herpes. A computed tomography (CT) of the head ruled out any acute intracranial abnormality. Magnetic resonance imaging (MRI) of the head identified restricted diffusion involving parietal and occipital cortices bilaterally in a symmetrical fashion. Repeat MRI head 4 weeks later was normal. Ophthalmologic examination was unchanged from previous. Electroencephalogram (EEG) findings were nonspecific but suggested moderate to diffuse encephalopathy with left occipital spike and wave discharges associated with increased risk of focal seizures. Paediatric neurology started the patient on phenytoin and levetiracetam following seizure in the PCCU. During hospitalization, he developed moderate choreiform movements of all four limbs and oculogyric phenomena involving the upward rolling of the eyes. Phenytoin was discontinued and valproic acid started. Levetiracetam was weaned in discussion with his family due to concern that the anti-epileptic was contributing to the patient’s chorea. Although the patient was feeding orally prior to his acute change in LOC, in hospital he developed feeding intolerance on nasogastric (NG) tube feeds and ultimately required gastrostomy tube insertion. Previous genetic testing included normal chromosomal microarray, Fragile X testing, Simpson-Golabi-Behmel testing, isoelectric focusing, very long chain fatty acids, Bardet-Biedl and Alström panels, and GeneDx overgrowth panel. While in hospital, the patient was followed by the medical genetics team who recommended several additional investigations. Acylcarnitine profile and urine organic acids were normal. Skeletal survey was unremarkable with no dysplasia, metabolic bone disease, congenital malformation, or trauma identified. Muscle biopsy was performed for mitochondrial studies with results pending. Rapid whole exome sequencing identified a de novo pathogenic variant in CACNA1A, the gene responsible for calcium voltage-gated channel subunit alpha 1A. diagnosis and follow-up Despite the identification of a de novo CACNA1A gene mutation, there is an association between overgrowth syndrome and mutations in this gene region. CACNA1A loss-of-function mutations have been associated with symptoms including cognitive impair-


Decreased level of consciousness in a toddler with overgrowth syndrome
Stephanie Fong, Alistair Scott, Dora Laczko Faculty Reviewer: Dr Tamara Van Hooren, MD, FRCPC (Department of Paediatrics) abstract Physicians caring for patients with rare diseases face unique challenges in managing symptoms, ordering diagnostic tests, and providing patients and families with anticipatory guidance.We describe the case of a toddler with overgrowth syndrome, and previously known ophthalmological and neurological findings, presenting with decreased level of consciousness (LOC) following a fall.We highlight the extensive workup undertaken in a patient with symptoms spanning multiple systems but lacking a unifying diagnosis.In this case, rapid whole exome sequencing identified a de novo CACNA1A gene mutation encoding a calcium channel subunit, located within chromosome region 19p13.13.We explore 19p13.13 Microdeletion Syndrome and compare our patient's presentation to the cases described in the literature.Although our patient had several symptoms consistent with 19p13.13Microdeletion Syndrome, others remain unexplained.This highlights the difficulty in determining a definitive diagnosis or treatment plan in the realm of rare diseases and emphasizes the need for further research into the disease process and development of novel therapies.

patient presentation
A 2 years 10 months old male presents to hospital with decreased LOC following an unwitnessed fall.He was found facedown by a caregiver who described unusual movements but no clear seizure activity.Emergency medical services brought him to a local community hospital, during which he required support by bag mask ventilation.
The patient's past medical history was significant for global developmental delay, chronic overgrowth of undetermined etiology (weight average for 9 year old male, and height average for 5 year old male), retinal cone dysfunction, peripherally hypopigmented fundus, hypotonia, and autistic features.Specialists involved in his care included paediatric neurology, ophthalmology, endocrinology and medical genetics at multiple academic medical institutions, yet he lacked a unifying diagnosis.Prior to the unwitnessed fall the patient had had a 3-day history of cough but had otherwise been well.
Upon presentation to the local community emergency department, the patient was tachycardic and required supplemental oxygen.He required intubation for decreased respiratory effort, and was transferred to a paediatric critical care unit (PCCU) at the nearest tertiary care centre, where he remained intubated for 10 days.After successful extubation he was transferred to a general paediatric inpatient unit for further work-up and management.

investigations and management
On initial presentation to the PCCU, the patient was started on empiric broad-spectrum antibiotics and antiviral treatment for possible meningitis or encephalitis.Infectious workup, including cultures of urine, blood, and cerebral spinal fluid (CSF), were negative.CSF polymerase chain reaction (PCR) was negative for enterovirus and herpes.
A computed tomography (CT) of the head ruled out any acute intracranial abnormality.Magnetic resonance imaging (MRI) of the head identified restricted diffusion involving parietal and occipital cortices bilaterally in a symmetrical fashion.Repeat MRI head 4 weeks later was normal.Ophthalmologic examination was unchanged from previous.
Electroencephalogram (EEG) findings were nonspecific but suggested moderate to diffuse encephalopathy with left occipital spike and wave discharges associated with increased risk of focal seizures.Paediatric neurology started the patient on phenytoin and levetiracetam following seizure in the PCCU.During hospitalization, he developed moderate choreiform movements of all four limbs and oculogyric phenomena involving the upward rolling of the eyes.Phenytoin was discontinued and valproic acid started.Levetiracetam was weaned in discussion with his family due to concern that the anti-epileptic was contributing to the patient's chorea.
Although the patient was feeding orally prior to his acute change in LOC, in hospital he developed feeding intolerance on nasogastric (NG) tube feeds and ultimately required gastrostomy tube insertion.
Previous genetic testing included normal chromosomal microarray, Fragile X testing, Simpson-Golabi-Behmel testing, isoelectric focusing, very long chain fatty acids, Bardet-Biedl and Alström panels, and GeneDx overgrowth panel.While in hospital, the patient was followed by the medical genetics team who recommended several additional investigations.Acylcarnitine profile and urine organic acids were normal.Skeletal survey was unremarkable with no dysplasia, metabolic bone disease, congenital malformation, or trauma identified.Muscle biopsy was performed for mitochondrial studies with results pending.Rapid whole exome sequencing identified a de novo pathogenic variant in CACNA1A, the gene responsible for calcium voltage-gated channel subunit alpha 1A.

diagnosis and follow-up
Despite the identification of a de novo CACNA1A gene mutation, there is an association between overgrowth syndrome and mutations in this gene region.][3][4][5][6][7] The patient was discharged with a diagnosis of encephalopathy, and started on anticonvulsive therapy.Both seizures and choreiform movement disorder were felt to most likely represent progression of his underlying diagnosis.With diminished developmental abilities and inability to orally feed, it was considered that his encephalopathy may be progressive.Community supports at discharge included occupational therapy, physical therapy, speech language pathology, and enteral feeding.Paediatric neurology, medical genetics, and community paediatrics were to continue as part of his treatment team with scheduled follow-up appointments.
In follow-up with the patient's family post-discharge, antiepileptic therapy had been weaned, and shortly following his choreiform movement disorder resolved.Though not completely back to his pre-admission baseline developmentally, his family had noted some improvements including the ability to safely tolerate some oral feed.

discussion
In 2009, a case report described a child who presented with syndromic craniosynostosis and microdeletion of chromosomal region 19p13.13. 8Another case was published in the same year of a child with psychomotor delay, overgrowth, and infantile spasms, in which the CACNA1A gene, located within region 19p13.13,][4][5][6][7] With the description of another 5 cases of 19p13.13microdeletion, each with similar presentations, including overgrowth, macrocephaly, intellectual delay and gastrointestinal problems, a unique syndrome was proposed, termed 19p13.13][10][11] Additional cases have been described of children with microdeletions spanning the 19p13.12 to 19p13.2 region (which includes the CACNA1A gene) who presented with syndromic craniosynostosis, epilepsy, and mental retardation. 12icrodeletions of neighboring region 19p13.12have been associated with similar phenotypes such as Malan syndrome (Sotos syndrome 2), which present with features such as developmental delay, macrocephaly, central nervous abnormalities, overgrowth, and cephalic malformations. 13,14[10][11] But they, and this case, present a unique opportunity for research into the roles of genes such as CACNA1A in normal physical and intellectual development.
This case report describes a 2 years 10 months old male with a unique constellation of symptoms including developmental delay, overgrowth with undetermined etiology, retinal cone dysfunction, peripherally hypopigmented fundus, hypotonia, and autistic features.On admission to hospital he was found to have seizure activity on EEG and developed choreiform movements of all four limbs and oculogyric phenomena.Through rapid whole exome sequencing, a variant in CACNA1A, the gene encoding calcium voltage-gated channel subunit alpha-1A, was identified.
3][4][5][6][7] Some of this patient's symptoms are consistent with previous reports, including developmental delay, hypotonia, and overgrowth syndrome. 2In addition, the development of seizure activity is supported by literature as CACNA1A mutations have been associated with epilepsy and febrile seizures. 1,2owever the patient had other symptoms that remain unexplained.The clear retinal findings in this patient have not been previously reported in the literature.Additionally, his movement disorder is not a previously described finding, though it's resolution post-discharge may imply it is not associated with a CACNA1A mutation.
As limited literature exists on CACNA1A loss-of-function mutations, this genetic finding brought little clarity to the underlying disease process causing the patient's symptoms.In addition, there is still much that remains unknown, including the expected longterm progression of this patient's disease.
This case report highlights the complexities parents and families of children with rare diseases often face as they search for a diagnosis.Children with rare diseases often require frequent medical visits with specialists and are subjected to many diagnostic investigations, as presented in this report.This can be both emotionally and financially stressful for families as they care for their loved one without receiving a clear definitive diagnosis or treatment plan.This is made more stressful by the fact that rare diseases are associated with high morbidity and mortality. 15,16nclusion Clinicians should be aware of the significant impact that undiagnosed medical conditions have on the lives of paediatric patients and those who care for them.Clear communication between caregivers and the healthcare team, as well as between specialists, is an essential component of care for patients with complex medical conditions where management approaches may be limited or unknown.Further study into 19p13.13Microdeletion Syndrome through basic science research into its mechanisms of pathogenesis and publication of observation and investigation of affected individuals is recommended to gain a better understanding of the role of CACNA1A in human development and lead to the development of novel therapeutics for this disorder.