Establishment of a human induced pluripotent stem cell (iPSC) line (JUCTCi018-A) from a patient with Charcot-Marie-Tooth disease type 2EE (CMT2EE) due to a homozygous c.122G > A p.(Arg41Gln) mutation in the MPV17 gene.

(Charcot-Marie-Tooth disease (CMT) is a genetic disorder affecting peripheral nerves. The human induced pluripotent stem cell (iPSC) line JUCTCi018-A was created using dermal fibroblasts from a Charcot-Marie-Tooth disease type 2EE (CMT2EE) patient with a homozygous missense mutation in the MPV17 gene (c. 122G > A, p.Arg41Gln). These fibroblasts were reprogrammed using Sendai viruses that encoded OCT4, SOX2, KLF4, and c-MYC reprogramming factors. The iPSCs demonstrated normal morphology and karyotype, expressed pluripotency markers, and the ability to differentiate into the three germ layers. This iPSC line is valuable for investigating the mechanisms underlying CMT2EE.

Enhancing Diagnostic Accuracy Through Neuroimaging Revisions in Pediatric Pseudotumor Cerebri Syndrome: A Cross-Sectional Study.

BACKGROUND: This cross-sectional study aimed to report all neuroimaging findings suggestive of raised intracranial pressure in children with pseudotumor cerebri syndrome (PTCS), before and after re-review by two neuroradiologists. METHODS: We included 48 children aged <18 years diagnosed with PTCS between 2016 and 2021. Clinical and radiological data were obtained from their medical files. Two neuroradiologists independently re-reviewed all neuroimages, and the average of their assessments was compared with the initial neuroimaging reports; an additional review was done to analyze inter- and intraclass correlation. RESULTS: The initial neuroimaging reports showed under-reporting of findings, with only 26 of 48 (54.1%) patients identified with abnormal reports. After revision, the proportion of the reported findings increased to 44 of 48 (91.6%). Distention of the perioptic space was the most commonly reported finding after revision (36.5 of 48; 76%). Flattening of the posterior globe and empty sella were initially under-reported but improved after revision. Moreover, several findings suggestive of increased intracranial pressure not mandated by Friedman criteria were identified, such as narrowing of the Meckel cave, posterior displacement of the pituitary stalk, and narrowing of the cavernous sinus. Analysis of associations between neuroimaging findings and demographic and clinical characteristics yielded no statistically significant results. The inter- and intraclass correlation results demonstrated a significant agreement between raters and within each rater's assessment (P < 0.05). CONCLUSIONS: This study highlights the impact of image revision in enhancing PTCS diagnosis. Intra- and interclass correlations underscore the reliability of the review process, emphasizing the importance of meticulous image analysis in clinical practice.

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.

Global developmental delay and intellectual disability in the era of genomics: Diagnosis and challenges in resource limited areas.

AIMS: To report the diagnostic yield of clinical singleton whole exome sequencing (WES) performed among a group of Jordanian children presenting with global developmental delay /intellectual disability (GDD/ID), discuss the underlying identified genetic disorders and the challenges encountered. PATIENTS AND METHODS: This retrospective medical record review study included 154 children who were diagnosed with GDD/ID at our clinic at Jordan University Hospital between 2016 and 2021, and whose diagnostic work up included WES. RESULTS: Consanguinity among parents was reported in 94/154 (61.0%) patients and history of other affected siblings in 35/154 (22.7%) patients. Pathogenic and likely pathogenic variants (solved cases) were reported in 69/154 (44.8%) patients, a variant of uncertain significance was reported in 54/154 (35.0%) and a negative result was reported in 31/154 (20.1%) cases. In the solved cases, autosomal recessive diseases were the most common (33/69; 47.8%). Metabolic disorders were identified in 20/69 (28.9%) patients, followed by developmental and epileptic encephalopathies (9/69; 13.0%) and MECP2 related disorders (7/69; 10.1%). Other single gene disorders were identified in 33/69; 47.8%) patients. CONCLUSION: This study had several limitations, as it was hospital-based and only including patients who were able to afford the test. Nevertheless, it yielded several important findings. In resource-limited countries, WES may be a reasonable approach. We discussed the challenges that clinicians meet in the context of shortage of resources.

Autism services in low-resource areas.

OBJECTIVES: To explore access to intervention services for children with autism spectrum disorder (ASD) in Jordan. METHODS: We used prospective cross sectional design and survey methodology to collect information from the parents of a convenient sample of children with ASD aged 2.5-17 years and who attended pediatric neurology clinics in 3 different university affiliated hospitals in 3 geographic areas in Jordan from February to December 2018. RESULTS: We interviewed parents of 274 children with ASD. One hundred ninety-six (71.5%) received rehabilitation services. The average age at first session was 3.9 years. The most common services received were behavioral therapy (182; 66.4%). The average weekly hours were highest for speech and behavioral therapy; 6.25 and 6.64 respectively. Private centers for developmental disabilities were the most commonly used followed by private centers for ASD. The most common barriers were costs (138; 58%) and transportation (88; 37.5%). Most parents (198; 72.3%) prefer to receive rehabilitation in a specialized center for autism, and most did not want to receive training to train their child themselves. CONCLUSION: Most children with ASD in Jordan have limited access to recommended autism services. The development of future interventions must consider the needs of those living in limited resource regions.

Aseptic Meningitis and Its Viral Etiologies, Clinical Characteristics and Management Practices in Children: A Retrospective Hospital-Based Study From Jordan.

Purpose In this study, we aimed to describe the clinical characteristics, laboratory findings, aetiologies, and role of PCR in the decision on the management plan and duration of hospital stay in Jordanian children diagnosed with aseptic meningitis. Methods This retrospective observational cohort study included children diagnosed with meningitis who were admitted to the paediatric ward at Jordan University Hospital (JUH) during the period from January 2016 to August 2020. Patients were identified through the ICD9 discharge code of meningitis. Patients diagnosed with aseptic meningitis (defined as a patient with signs and symptoms of meningitis with a cerebrospinal fluid (CSF) white cell count of >5 cells/mm3, and a negative CSF Gram stain) were included, while patients who had low CSF glucose (<50% of serum) positive cerebrospinal fluid Gram stain and/or culture for bacterial meningitis were excluded. Files were reviewed to collect data on the clinical picture, viruses identified by the CSF viral polymerase chain reaction (PCR) panel, duration of medication, and hospital stay in patients with identified virus versus those with negative viral PCR. Results One hundred and thirty-one patients were included: 87 males (66.4%) and 44 females (33.5%). Fever was the most common presenting symptom, followed by headache, vomiting, and excessive sleep in 48.0%, 42.7%, and 35.8% of the patients, respectively. Prior oral antibiotic use was reported in 48/125 (38.4%) patients. White blood cell count (WBC) ranged from 4.800 to 22.000. cells/mL, 45 patients (34.3%) had counts above 15.000 cells/mL. C-reactive protein level was high in 61/103 (59.2%) patients. CSF WBC count was <100 in 62 (47.3%) patients while neutrophils predominance of >70% was present in 27 (20.6%) patients. Viral panel PCR was done for 100/131 (76.3%) patients and was positive in 66/100 (66%) patients; with enterovirus being the most common identified viruses (60/100; 60%). The average duration of hospital stay was 5.9 and 5.5 days for those with negative and positive PCR respectively. Ten (7.6%) patients had seizures upon presentation. None of the patients had any neurological sequel related to his meningitis. Conclusion Enteroviruses are the most common identified cause of paediatric aseptic meningitis in Jordan. Although PCR revealed an identified virus in around half of the patients, nevertheless, there was no adjustment in the management plan regarding duration of empirical antibiotic use and hospital stay. Increasing knowledge and awareness among clinicians on viral meningitis' lab characteristics might have great impact on duration of hospital stay and thus would be reflected on the patient and the healthcare system as well.

Facemask wearing does not impact neuro-electrical brain activity.

Given the massive use of facemasks (FMs) during the covid-19 pandemic, concerns have been raised regarding the effect of FMs wearing on overall health. This study aimed at evaluating the effect of surgical FM on brain neuro-electrical activity. Electroencephalography (EEG) background frequency (BGF) and background amplitude (BGA) was performed on 30 volunteers before (baseline), during and after wearing a FM for 60 min. Measurements were done during normal ventilation, hyperventilation and post-hyperventilation (PHVR). Blood gas levels were assessed at baseline and after FM use. EEG analysis concerning baseline (without FM) (BGA), was 47.69 ± 18.60 µV, wearing FM, BGA was 48.45 ± 17.79 µV, post FM use BGA was 48.08 ± 18.30 µV. There were no statistically significant differences between baseline BGA and BGA under FM and post FM. BGF, Baseline data were 10.27 ± 0.79, FM use 10.30 ± 0.76 and post FM use was 10.33 ± 0.76. There were no statistically significant differences between baseline BGF and BGF under FM and post FM. Venous blood gases, and peripheral oxygen saturation were not significantly affected by FM use. Short-term use of FM in young healthy individuals has no significant alteration impact on brain's neuro-electrical activity.

Congenital muscle dystrophies: Role of singleton whole exome sequencing in countries with limited resources.

AIM: Identify the genetic determinants of congenital muscle dystrophy (CMD) in Jordanian children. METHODS: This prospective study included patients suspected to have CMD. Singleton whole-exome sequencing (WES) was performed as the first-tier diagnostic test. RESULTS: 44 patients were included: 27 boys and 17 girls. Consanguinity was reported in 32/44 (72.7%) patients, and a positive family history in 16/44 (36.3%) patients. WES uncovered pathogenic/ likely pathogenic variants in 19/44 (43.1%) patients, variants of uncertain significance (VUS) and negative results were identified in 15/44 (34.0%) and 10/44 (22.7%) patients respectively. Variants related to CMD were identified in 23/44 (52.2%) patients; pathogenic /likely pathogenic variants were identified in 12/23 (52.1%) and VUS in 11/23 (47.8%). The most common genes were related to basal membrane/extracellular proteins followed by genes related to alpha­dystroglycanopathies. We have identified a rare association of one family with one sibling affected by CMD and the other sibling with Duchenne muscle dystrophy. A history suggestive of perinatal insult was found in 6/23 (26.0%) patients necessitating a high index of suspicion as CMD may present as cerebral palsy mimickers.Several strong candidate VUSs were identified and need future second tier testing for confirmation. WES identified genes related to other neuromuscular and non neuromuscular disorders in 21/44 (47.7%) patients;7/21 were pathogenic/likely pathogenic and 14/21 (66.6%) were VUS. CONCLUSIONS: In countries with limited resources singleton WES could be considered the first tier diagnostic test to limit costs.

Pseudotumor cerebri syndrome in children: Clinical characteristic and re-classification.

AIM: To describe the clinical characteristics of children with pseudotumor cerebri syndrome (PTCS) who were diagnosed according to the modified Dandy criteria and to reclassify them according to the newly proposed diagnostic criteria by Freidman. METHODOLOGY: This retrospective study included the period from January 2016-to July 2021. RESULTS: 50 patients were included; 34 males and 16 females with a male to female ratio of 2.1:1. The average age at onset of symptoms was 8 years. Obesity was noticed in 6 (12%) patients; 34 (68%) had symptoms upon presentation. The most common presenting symptom was headache (28 patients; 56%), papilledema was present in 33 (66%) patients. Most patients (37; 74%) had an initial cerebrospinal fluid (CSF) pressure ≥280 mmH2O. At last follow-up, papilledema resolved in 11/32 (34.3%) patients, and headache resolved in 17/23 (74%) patients. 22/50 (44%) patients fulfilled the definite criteria proposed by Freidman, 11/50 (22%) fulfilled the probable, 10/50 (20%) were categorized as possible, and 7 (14%) patients were categorized as unmet. CONCLUSION: PTCS is a chronic condition. Managing patients who do not have papilledema or who do not meet the newly proposed higher CSF pressure is challenging. Although, applying the newly proposed criteria captured most of our patients, however, around one quarter were managed based on clinical experience. This study indicates a strong need for future guidelines tailored specifically for children, taking into consideration that the cut-off point of CSF pressure might not be similar for all populations.

Generation of a human induced pluripotent stem cell (iPSC) line (JUCTCi019-A) from a patient with Charcot-Marie-Tooth disease type 2A2 (CMT2A2) due to a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in MFN2 gene.

Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder characterized by the progressive damage of the peripheral nerves. We generated a human induced pluripotent stem cell (iPSC) line JUCTCi019-A using dermal fibroblasts-derived from a 50-year-old CMT2A2 patient carrying a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in the MFN2 gene. Fibroblasts were reprogrammed by Sendai viruses encoding for the reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. Characterization showed normal iPSC morphology and karyotype, expression of pluripotency markers and differentiation into three-germ layers. This iPSC line represents an ideal source for disease modelling and drug development of CMT2A2 disease.

Post SARS-CoV-2 Guillain-Barré syndrome in a child: case report and review of the literature.

Guillain-Barré syndrome has been defined as a post-infectious immune-mediated polyneuropathy. COVID-19 usually presents with respiratory symptoms but can less commonly present with extra-respiratory manifestations such as neurological symptoms. Few cases were published in the literature regarding post-COVID-19 infection Guillain-Barré in the pediatric age group. In this paper, we present a 13-year-old male with possible Guillain-Barré syndrome occurring 2 weeks after a presumed COVID-19 infection. We conducted a systematic review and searched for published pediatric cases until March 2022. We included 35 patients in 25 publications.

Genetic evaluation of children with autism spectrum disorders in developing and low-resource areas.

LAY ABSTRACT: Autism is the most common neurodevelopmental disorder in children worldwide. Genetic factors play an important role in the risk of developing autism. Determining the genetic cause of autism is key to understanding the biological processes that lead to the clinical manifestations of autism, and can inform the management and even prevention of this condition. Establishing genetic causes of autism requires collection of genetic data on a global scale. Limited research on genetic testing for individuals with autism is available from developing countries in low-resource regions. In this study, we explored the types of investigations ordered for Jordanian children with autism by their physicians. A representative sample of parents of children with autism in Jordan was questioned about the studies that their children received. We found that the recommended genetic testing was only performed in a small number of children with autism. In contrast, most children in the sample received non-genetic testing, which is not routinely recommended. We also explored the sociocultural factors that may influence the decision to perform genetic testing in this population. We discuss our findings in light of the data available from other developing and developed countries.

Population Pharmacokinetics Modeling of Lamotrigine in Jordanian Epileptic Patients Using Dried Blood Spot Sampling.

AIMS: To characterize the population pharmacokinetics of lamotrigine in Jordanian epileptic patients and to identify factors affecting therapeutic parameters. PATIENTS AND METHODS: A population pharmacokinetics model for lamotrigine was established based on a prospectively collected data of 52 steady-state concentrations from 38 adult and pediatric patients with epilepsy. Lamotrigine concentrations were determined by a dried blood spot liquid chromatography method. Data were analyzed according to a one-compartment model with first-order absorption and elimination using the nonlinear mixed effect modeling program. The covariates effect of total body weight, gender, age, and co-medication with topiramate, carbamazepine, phenytoin, phenobarbital, and valproic acid on lamotrigine clearance were investigated using a stepwise forward addition followed by a stepwise backward elimination. RESULTS: The final population pharmacokinetics model for lamotrigine clearance was as follows: CL/Fpop=θ1*exp (θ3*age)*exp (θ5*carbamazepine)*exp (θ6*valproic acid) , where θ1 is the relative clearance (L/hr) estimated, and θ3, θ5, and θ6 are the fixed parameters relating to age and co-medication with carbamazepine and valproic acid, respectively.The population mean value of lamotrigine total clearance generated in the final model (with covariates) was 2.12 L/hr. Inter-individual variability and residual unexplained variability expressed as the coefficient of variation was 37.1 and 26.1%, respectively. CONCLUSION: Lamotrigine total clearance in the Jordanian patients is comparable to that reported by others for Caucasian patients. Age and concomitant therapy with carbamazepine and valproic acid significantly affected lamotrigine clearance, and accounted for 48% of its inter-individual variability.

Could vagus nerve stimulation influence bone remodeling?

OBJECTIVES: To investigate the effect of vagus nerve stimulation (VNS) on the bone mineral density (BMD) in epileptic patients. METHODS: A prospective cohort study was conducted on individuals with refractory seizures who underwent VNS surgery between January 2012 and December 2018. BMD was measured preoperatively and between 6 months and one year after surgery. RESULTS: Twenty-one patients (mean age (±SD)=23.6±12.3 years) were recruited for the implantation of a VNS device. The mean absolute increase in lumbar BMD in the 21 patients was 0.04±0.04 g/cm2 resulting in an overall percent increase from baseline of 4.7±6.1%. BMD increased by an amount ≥ the least significant change (LSC) for the lumbar spine in 13 patients (61.9%). The lumbar Z score also increased in these patients from -1.22±1.15 to -0.88±1.22, P=0.006). Pre and Post VNA femoral BMD was measured in only 11 patients and, of those 3 showed a significant increase in BMD, 1 a significant decrease and 7 no change. CONCLUSION: The implantation of a VNS was associated with an increase in lumbar BMD. This study could lead to a new application for VNS in the treatment of osteoporosis.

The clinical characteristics of primary headache and associated factors in children: A retrospective descriptive study.

BACKGROUND: Headache is the most encountered manifestation of pain in childhood. The purpose of this study was to investigate the incidence and clinical characteristics of primary headaches. Further, the factors associated with primary headache were examined. MATERIALS AND METHODS: A retrospective study was conducted among young children and adolescents over 3 years at a tertiary referral teaching hospital in North Jordan. Relevant patient information was obtained by reviewing patients' medical records. RESULTS: This study included 194 children (95 males, 99 females). The incidence rate of primary headache in the current study was 2.815 per 1000 children visited pediatric clinic. The mean age of patients at the time of headache onset was 10 years, and about half of them were males (95/194; 49%). Approximately 30% (56/194) had a family history of headache. Migraine headaches were the most commonly reported types (87/194; 44.8%) and only 17/194; 8.7% suffered from tension type headaches. Approximately, 40% (84/194) of patients reported severe headache and a third of them (67/194; 34.5%) complained of daily headaches. Pain location was reported as bilateral in most patients (153/194; 78.9%). About one fifth (41/194; 21.1%) stated that their headache was precipitated by sleep deprivation. Abnormal serum level of vitamin D and family history of headache were significantly associated with primary headache (p < 0.001). CONCLUSIONS: These findings highlight the importance of early detection and management of headaches among pediatric population. In addition, screening vitamin D status should be encouraged for children presented with primary headaches.

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Frequency of antiepileptic drugs and response change in pediatric patients receiving 2 or more antiepileptic drugs.

OBJECTIVE: To investigate the frequency of changes in antiepileptic drugs (AEDs) use, as well as concomitant changes in the degree of seizure control in pediatric patients, who are receiving 2 or more AEDs. METHODS: A prospective follow-up study at Jordan University Hospital`s pediatric neurology clinics was conducted on epileptic pediatric patients receiving at least 2 AEDs between December 2013 and April 2014. Patients were followed for 12 months. RESULTS: A total of 82 patients were included, with a mean age of 7.2+/- 4.7 years. The mean number of AEDs received by patients at enrollment was 2.4+/-0.6, and 2.5+/-0.7 after follow-up. Most patients (63.4%) experienced no change in seizure control, and the majority reported at least one adverse drug reaction. Most patients received lower doses than recommended, both at the beginning and end of the study. During the year, only 3 patients (4%) were eligible for dose tapering, which would then be converted to monotherapy. Follow-up appointments average was 4.2+/-2.9 visits/patients in one year. The frequency of medication changes and dose adjustment was very low, about one-third (29.3%) of patients requiring no change in AEDs during any follow-up visits. CONCLUSION: During the one year follow-up study, most patients on polytherapy maintained their level of response to the AEDs, with minimal changes in their regimen despite frequent follow-up visits. Only a small percent could be converted to AEDs monotherapy.

Parental use of conventional and complementary therapy for autism in Jordan.

OBJECTIVE: We investigated parental use of conventional therapies and complementary and alternative medicine (CAM) for children with autism in Jordan. METHOD: This prospective cross-sectional study was conducted from February 2018 through December 2018 at the paediatric neurology clinics of three tertiary referral hospitals in Jordan. The accompanying parent was interviewed to complete a structured questionnaire. RESULTS: 274 parents were interviewed. The most common medications used were those to treat hyperactivity (150; 54.7 %), anticonvulsants (60; 21.9 %), and sleep aids (6; 2.1 %). CAM was used by 129 parents (47.0 %). A casein-free diet was the most commonly used dietary modification (24; 8.7 %), while fish oil (Omega-3) was the most common supplement used (96; 35.0 %). Hyperbaric oxygen, chelation therapy, and antifungal treatment were also occasionally used. Higher parental education levels and access to rehabilitation services correlated with higher CAM use (p < 0.05).

Congenital insensitivity to pain with anhidrosis syndrome: A series from Jordan.

OBJECTIVES: To present the clinical picture, the associated complications and the genetic findings of Jordanian patients diagnosed with Congenital insensitivity to pain with anhidrosis (CIPA). PATIENTS AND METHODS: This is a retrospective study including 7 patients diagnosed with CIPA presenting to Jordan University Hospital neurology clinic between 2001 and 2017. RESULTS: Among five families, seven patients were diagnose with CIPA and followed for a period ranging from one month to 6 years. The initial symptom observed in all patients was high fever in the first few days after birth, decreased sensation to pain and decreased sweating were later noted. Poor weight gain, microcephaly and global developmental delay were present in most cases. All patients had tongue ulcerations. Fingers/toes ulcerations were present in 6/7 (86.0 %), hip joint dislocation in 3/7 (43.0 %), chronic arthritis and joint swelling in 6/7 (86.0 %), corneal ulcers in 4/7 (57.1 %) and kidney amyloidosis in 1/7 (13.0 %) of all patients. Death occurred in 4/7 (57.1 %) patients. Consanguinity was present in all families. Mutation analysis revealed three variants in NTRK1 gene. The frameshift (c.1860_1861insT; p.Pro621fs) mutation was common in our series. One patient carried a novel missense mutation (c.2170 G > A; p.Gly724Ser). The third missense mutation (C2125 G > T; p.Val709Leu) was reported in a previous study in one patient. CONCLUSION: This cohort reveals a severe CIPA phenotype necessitating thorough multidisciplinary care and follow up.