DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied. The DNAm episignature was developed with an Infinium Methylation EPIC BeadChip array analysis using peripheral blood cells. Support vector machine (SVM) modeling and clustering methods were employed to generate a DNAm classifier for PTHS. Validation was extended to an additional cohort of 11 individuals with PTHS. The episignature was assessed in relation to other neurodevelopmental disorders and its specificity was examined. A specific DNAm episignature for PTHS was established. The classifier exhibited high sensitivity for TCF4 haploinsufficiency and missense variants in the basic-helix-loop-helix domain. Notably, seven individuals with TCF4 variants exhibited negative episignatures, suggesting complexities related to mosaicism, genetic factors, and environmental influences. The episignature displayed degrees of overlap with other related disorders and biological pathways. This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negatively underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.

Clinical and genetic characterization of 47 Chinese pediatric patients with Pitt-Hopkins syndrome: a retrospective study.

BACKGROUND: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder that remains underdiagnosed and its clinical presentations and mutation profiles in a diverse population are yet to be evaluated. This retrospective study aims to investigate the clinical and genetic characteristics of Chinese patients with PTHS. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 47 pediatric patients diagnosed with PTHS between 2018 and 2021 were retrospectively analyzed. RESULTS: The Chinese PTHS patients presented with specific facial features and exhibited global developmental delay of wide severity range. The locus heterogeneity of the TCF4 gene in the patients was highlighted, emphasizing the significance of genetic studies for accurate diagnosis, albeit no significant correlations between genotype and phenotype were observed in this cohort. The study also reports the outcomes of patients who underwent therapeutic interventions, such as ketogenic diets and biomedical interventions. CONCLUSIONS: The findings of this retrospective analysis expand the phenotypic and molecular spectra of PTHS patients. The study underscores the need for a long-term prospective follow-up study to assess potential therapeutic interventions.

Hyperventilation testing in the diagnosis of vasospastic angina: A clinical review and meta-analysis.

BACKGROUND: Given the limited access to invasive vasospastic reactivity testing in Western Countries, there is a need to further develop alternative non-invasive diagnostic methods for vasospastic angina (VSA). Hyperventilation testing (HVT) is defined as a class IIa recommendation to diagnose VSA by the Japanese Society of Cardiology. METHODS: In this systematic review and meta-analysis reported according to the PRISMA statement, we review the mechanisms, methods, modalities and diagnostic accuracy of non-invasive HVT for the diagnostic of VSA. RESULTS: A total of 106 articles published between 1980 and 2022 about VSA and HVT were included in the systematic review, among which 16 were included in the meta-analysis for diagnostic accuracy. Twelve electrocardiogram-HVT studies including 804 patients showed a pooled sensitivity of 54% (95% confidence intervals [CI]; 30%-76%) and a pooled specificity of 99% (95% CI; 88%-100%). Four transthoracic echocardiography-HVT studies including 197 patients revealed a pooled sensitivity of 90% (95% CI; 82%-94%) and a pooled specificity of 98% (95% CI; 86%-100%). Six myocardial perfusion imaging-HVT studies including 112 patients yielded a pooled sensitivity of 95% (95% CI; 63%-100%) and a pooled specificity of 78% (95% CI; 19%-98%). Non-invasive HVT resulted in a low rate of adverse events, ventricular arrhythmias being the most frequently reported, and were resolved with the administration of nitroglycerin. CONCLUSIONS: Non-invasive HVT offers a safe alternative with high diagnostic accuracy to diagnose VSA in patients with otherwise undiagnosed causes of chest pain.

A patient with Pitt-Hopkins syndrome with concomitant common variable immunodeficiency.

In patients with 18q deletion syndrome (18q-), immunodeficiency, autoimmunity, and allergies have been described in a subset. Pitt-Hopkins syndrome represents a specific subset of patients with 18q- who have a proximal deletion involving the TCF4 gene or a TCF4 variant. Immunodeficiency has been reported in the overall 18q- population; however, immunodeficiency with Pitt-Hopkins syndrome has not been highlighted. This case report details the immunologic evaluations and the associated infections seen in a young adult with Pitt-Hopkins syndrome to underscore the challenges of managing adults with a complex phenotype who develop frequent infections. This patient with Pitt-Hopkins syndrome ultimately fulfilled the diagnostic criteria for common variable immunodeficiency. Immunoglobulin replacement has led to a somewhat improved infection pattern, although she continues to have aspiration events leading to pneumonia. This case highlights the clinical evolution of Pitt-Hopkins syndrome and serves as a reminder that immunodeficiency can occur in this syndrome.

Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.

Hyperventilation and Seizures: Not a New Sense: A Literature Review.

Hyperventilation and seizures have a long association in the clinical literature and were known to have a relationship long before the electroencephalogram (EEG) was used to record changes in brain activity. As the use of EEG recording progressed, hyperventilation was the first activation method used to assist with diagnosis of epilepsy. Along with slowing of brain activity, hyperventilation can activate epileptiform spiking activity in patients with epilepsy. Currently, hyperventilation is used in standard practice to assist with the diagnosis of epilepsy during EEG recording. Hyperventilation activates epileptiform spiking activity more often than seizures but can trigger clinical seizures in up to 50% of patients with generalized epilepsy. It is more likely to trigger events in children with absence seizures than adults, and it acts as a trigger in patients with focal epilepsy far less often. However, while some clinicians suggest that its diagnostic value is limited, especially in adults with focal epilepsies, others suggest that it is simple, safe, and an important diagnostic tool, even in these patients. This review presents the history of hyperventilation and seizures, its use in the clinical practice, and possible mechanisms involved.

The clinical utility of the Breathing Pattern Assessment Tool (BPAT) to identify dysfunctional breathing (DB) in individuals living with postural orthostatic tachycardia syndrome (POTS).

BACKGROUND: Dysfunctional breathing (DB) resulting in inappropriate breathlessness is common in individuals living with postural orthostatic tachycardia syndrome (POTS). DB in POTS is complex, multifactorial, and not routinely assessed clinically outside of specialist centres. To date DB in POTS has been identified and diagnosed predominately via cardiopulmonary exercise testing (CPEX), hyperventilation provocation testing and/or specialist respiratory physiotherapy assessment. The Breathing Pattern Assessment Tool (BPAT) is a clinically validated diagnostic tool for DB in Asthma. There are, however, no published data regarding the use of the BPAT in POTS. The aim of this study was therefore to assess the potential clinic utility of the BPAT in the diagnosis of DB in individuals with POTS. METHODS: A retrospective observational cohort study of individuals with POTS referred to respiratory physiotherapy for formal assessment of DB. DB was determined by specialist respiratory physiotherapist assessment which included physical assessment of chest wall movement/breathing pattern. The BPAT and Nijgmegen questionnaire were also completed. Receiver operating characteristics (ROC) analysis was used to compare the physiotherapy assessment based diagnosis of DB to the BPAT score. RESULTS: Seventy-seven individuals with POTS [mean (sd) age 32 (11) years, 71 (92 %) female] were assessed by a specialist respiratory physiotherapist, with 65 (84 %) being diagnosed with DB. Using the established BPAT cut off of four or more, receiver operating characteristics (ROC) analysis indicated a sensitivity of 87 % and specificity of 75 % for diagnosing DB in individuals with POTS with an area under the curve (AUC) of 0.901 (95 % CI 0.803-0.999), demonstrating excellent discriminatory ability. CONCLUSION: BPAT has high sensitivity and moderate specificity for identifying DB in individuals living with POTS.

[Hyperventilation syndrome, definition, diagnostic and therapy]. / Le syndrome d'hyperventilation, définition, diagnostic et thérapeutique.

Hyperventilation syndrome (HVS) is a frequent disorder of which the etiology is unclear. Diagnosis is based on the ruling out of organic disease and, more positively, on results of the Nijmegen questionnaire, reproduction of symptoms during the hyperventilation provocation test (HPVT), and detected hypocapnia. Treatment is based on targeted respiratory physiotherapy consisting in voluntary hypoventilation and instructions to the patient on regular respiratory exercise over an appreciable period of time. Additional research is needed to evaluate the validity of current investigative tools leading to the diagnosis of hyperventilation syndrome and to appraise the efficacy of current respiratory physiotherapy methods.

Fatal gastrointestinal complications in Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by mutations of the transcription factor 4 (Tcf4) gene. Individuals with PTHS often suffer from severe abdominal bloating and constipation. In this short communication, we discuss two individuals with PTHS who died unexpectedly due to gastrointestinal complications. We aim to increase awareness among healthcare professionals who care for individuals with PTHS, to ensure adequate screening and management of gastrointestinal symptoms in this population. Moreover, we discuss how fatal gastrointestinal complications may be related to PTHS and provide an overview of the literature.

ANXIETY SYNDROMES IN ADOLESCENTS WITH OPERATIONAL RESPIRATORY CONDITIONS: A PROSPECTIVE STUDY.

Aim - determining the prevalence of anxiety disorders and their effect on disease progression and quality of life in adults with organic illnesses and functional disorders of the respiratory system treated in a pulmonology environment. A total of 135 young adults between the ages of 13 and 17 were analyzed. There were a total of 46 adolescents diagnosed with somatoform respiratory disorders (SRD), 45 adolescents diagnosed with bronchial asthma (BA), and 44 adolescents diagnosed with pneumonia. The Spielberger-Khanin anxiety questionnaire and the Nijmegen hyperventilation syndrome (HVS) scale were used for the research and diagnosis, respectively. The quality of life was measured using the asthma quality of life questionnaire (AQLQ). In comparison to adults with asthma (33.2%) and pneumonia (32.3%), adults with SRD (34.5%). There were mild immediate associations between the Spielberger scale and the Nijmegen HVS questionnaire for both trait and state anxiety, and mild inverse correlations between the Spielberger scale and the AQLQ for both state and trait anxiety. Adolescents with anxiety had a higher prevalence of trauma, pain, and social issues than their non-anxious counterparts who were referred to psychiatry. In adolescents, 5.1% had severe trait anxiety, and 19.3% had severe condition anxiety. Adolescents with SRD were twice as likely to suffer from extreme state and trait anxiety as the general population. It is hypothesized that anxiety problems are at the root of HVS and contribute to adults' dissatisfaction with their quality of life due to lung ailments. Although certain adolescents with anxiety disorders were referred for anxiety, this data nevertheless lends credence to the idea that using standardized and structured instruments regularly might help increase accuracy and detection rates in the clinic, regardless of the reason for referral. Complete evaluations are essential for this patient population due to the intricacy of their symptoms.

The recurrent TCF4 missense variant p.(Arg389Cys) causes a neurodevelopmental disorder overlapping with but not typical for Pitt-Hopkins syndrome.

TCF4 haploinsufficiency by deletions, truncating variants or loss-of-function missense variants within the DNA-binding and protein interacting bHLH domain causes Pitt-Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N-terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non-specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator-recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype-phenotype correlation for TCF4-related NDDs.

Diagnostic tests and subtypes of dysfunctional breathing in children with unexplained exertional dyspnea.

BACKGROUND: Inappropriate hyperventilation during exercise may be a specific subtype of dysfunctional breathing (DB). OBJECTIVE: To assess whether Nijmegen questionnaire and hyperventilation provocation test (HVPT) are able to differentiate inappropriate hyperventilation from other DB subtypes in children with unexplained exertional dyspnea, and normal spirometry and echocardiography. METHODS: The results were compared between a subgroup of 25 children with inappropriate hyperventilation (increased V'E/V'CO2 slope during a cardiopulmonary exercise test (CPET)) and an age and sex matched subgroup of 25 children with DB without hyperventilation (median age, 13.5 years; 36 girls). Anxiety was evaluated using State-Trait Anxiety Inventory for Children questionnaire. RESULTS: All children were normocapnic (at rest and peak exercise) and the children with hyperventilation had lower tidal volume/vital capacity on peak exercise (shallow breathing). The Nijmegen score correlated positively with dyspnea during the CPET and the HVPT (p = 0.001 and 0.010, respectively) and with anxiety score (p = 0.022). The proportion of children with a positive Nijmegen score (≥19) did not differ between hyperventilation (13/25) and no hyperventilation (14/25) groups (p = 0.777). Fractional end-tidal CO2 (FETCO2 ) at 5-min recovery of the HVPT was < 90% baseline in all children (25/25) of both subgroups. Likewise, there was no significant difference between the two subgroups for other indices of HVPT (FETCO2 at 3-min recovery and symptoms during the test). CONCLUSION: The validity of the Nijmegen questionnaire and the HVPT to discriminate specific subtypes of dysfunctional breathing, as well as the relevance of the inappropriate hyperventilation subtype itself may both be questioned.

Ventilation Rates Achieved in Eucapnic Voluntary Hyperpnea Challenge and Exercise-Induced Bronchoconstriction Diagnosis in Young Patients with Asthma.

PURPOSE: Exercise-induced bronchoconstriction (EIB) affects approximately 50% of young asthma patients, impairing their participation in sports and physical activities. Eucapnic voluntary hyperpnea (EVH) is an approved surrogate challenge to exercise for objective EIB diagnosis, but the required minimum target hyperventilation rates remain unexplored in this population. This study aimed to evaluate the association between the achieved ventilation rates (VRs) during a challenge and EIB-compatible response (EIB-cr) in young asthma patients. METHODS: This cross-sectional study included 72 asthma patients aged 10-20 years. Forced expiratory volume in the first second (FEV1) was measured before and 5, 15, and 30 min after the EVH. The target VR was set at 21 times the individual's baseline FEV1. A decrease of > 10% in FEV1 after the challenge was considered an EIB-cr. The challenge was repeated after 48-72 h in those without an EIB-cr. RESULTS: Thirty-six individuals had an EIB-cr at initial evaluation. The median VRs achieved was not different between individuals with and without an EIB-cr (19.8 versus 17.9; p = 0.619). The proportion of individuals with an EIB-cr was nor different comparing those who achieved (12/25) or not (24/47) the calculated target VRs (p = 0.804). At the repeated EVH challenge an EIB-cr was observed in 14/36 individuals with a negative response in the first evaluation, with no differences in achieved VRs between the two tests (p = 0.463). CONCLUSION: Irrespective of the achieved VR, an EIB-compatible response after an EVH challenge must be considered relevant for clinical and therapeutic judgment and negative tests should be repeated.

Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation.

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy. CASE REPORT: The patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy. CONCLUSIONS: To our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.

The feasibility of eucapnic voluntary hyperpnoea for the diagnosis of exercise-induced bronchoconstriction in a community pulmonary practice.

Objective Exercise-induced bronchoconstriction (EIB) is a common condition and is typically treated empirically based on symptoms alone. However, symptoms of EIB are typically nonspecific. Objective testing with eucapnic voluntary hyperpnea (EVH) is a sensitive and specific method to diagnose EIB and may suggest alternative etiologies such as exercise-induced laryngeal obstruction (EILO). To this point, EVH has been primarily utilized in large academic centers and in elite athletes. We intend to discuss the feasibility and clinical application of utilizing EVH to diagnose EIB in a community-based pulmonary practice.Methods Retrospective analysis of 62 patients who completed EVH at The Oregon Clinic Pulmonary Clinic. Patients with inspiratory flow volume loop flattening or clinical symptoms were assessed by otolaryngology for evidence of EILO.Results: 61 of 62 patients were included in the final analysis. 52 of 61 patients (85%) achieved an interpretable test with a maximum voluntary ventilation (MVV) >60%. There was no difference in baseline spirometry or patient characteristics between those who were able to reach an MVV >60% and those who did not. 14 (23%) patients were diagnosed with EIB, 18 (30%) with EILO, and 4 (7%) were diagnosed with both EIB and EILO. Only 1 patient had a non-diagnostic evaluation with MVV <60% and negative for EIB and EILO.ConclusionsEVH is a feasible diagnostic modality to evaluate for EIB in a community pulmonary practice and may suggest alternative conditions such as EILO. Accurate diagnosis is paramount to prescribing proper therapy, decreasing inappropriate medication use, and relieving exercise-induced symptoms.

Blood Gas Analysis Results and Serum Lactate Levels in Patients with Psychogenic Hyperventilation and Urinary Tract Infection with Suspected Sepsis: A Retrospective Comparative Study.

Objective The prognosis differs considerably between patients with psychogenic hyperventilation syndrome (HVS) and those with urinary tract infection (UTI)-associated sepsis; however, the nonspecific symptoms and signs make the diagnosis and management difficult. We herein report the utility of a blood gas analysis for distinguishing HVS from UTI with suspected sepsis. Methods This single-center retrospective cohort study was conducted in a tertiary-care hospital in Japan. Patients ≥18 years old with a quick Sequential Organ Failure Assessment (qSOFA) score ≥2 and HVS or UTIs were included. The results of an arterial blood gas (ABG) or venous blood gas (VBG) analysis of the two groups were compared using the Mann-Whitney U test. We used a receiver-operating characteristic (ROC) curve analysis of the arterial pH and arterial PCO2 to assess the ability of these analyses to distinguish HVS from UTI with suspected sepsis. Results A total of 64 patients with HVS (ABG, n=14; VBG, n=50) and 53 with UTI with suspected sepsis (ABG, n=35; VBG, n=18) were included. Patients with HVS had alkalemia and lower PCO2 levels than patients with UTI with suspected sepsis, but the serum lactate levels were similar between the groups. The ROC analysis determined the pH cut-off value to be 7.509 (sensitivity: 0.91; specificity: 0.86) and the PCO2 cut-off value to be 21.6 mmHg (sensitivity: 1.00; specificity: 0.64). Conclusion Elevated serum lactate levels alone cannot be used to differentiate between patients with HVS and those with UTI with suspected sepsis, but the degree of pH and PCO2 abnormality can help with the differential diagnosis.

Comparative analysis between available challenge tests in the hyperventilation syndrome.

BACKGROUND: The hyperventilation syndrome (HVS) is characterized by somatic/ psychological symptoms due to sustained hypocapnia and respiratory alkalosis without any organic disease. OBJECTIVE: The purpose of this study was to compare ventilatory parameters and symptoms reproducibility during the hyperventilation provocation test (HVPT) and cardiopulmonary exercise test (CPET) as diagnostic tools in patients with HVS, and to identify the most frequent etiologies of the HVS by a systematic assessment. METHODS: After exclusion of organic causes, 59 patients with HVS according to Nijmegen's questionnaire (NQ) score ≥23 with associated hypocapnia (PaCO2/PETCO2<35 mm Hg) were studied. RESULTS: The most frequent comorbidities of HVS were anxiety and asthma (respectively 95% and 73% of patients). All patients described ≥3 symptoms of NQ during the HVPT vs 14% of patients during the CPET (p<0.01). For similar maximal ventilation (61 L/min during HVPT vs 60 L/min during CPET), the median level of PETCO2 decreased from 30 mmHg at baseline to 15 mmHg during hyperventilation and increased from 31 mmHg at baseline to 34 mmHg at peak exercise (all p<0.01). No significant difference for the ventilatory parameters was found between patients with HVS (n = 16) and patients with HVS + asthma (n = 43). CONCLUSIONS: In term of symptoms reproducibility, HVPT is a better diagnostic tool than CPET for HVS. An important proportion of patients with HVS has an atypical asthma previously misdiagnosed. The exercise-induced hyperventilation did not induce abnormal reduction in PETCO2, suggesting that the exercise could be a therapeutic tool in HVS.

Diagnosing and managing childhood absence epilepsy by telemedicine.

The diagnosis of childhood absence epilepsy (CAE) is typically based on history and description of spells, supported by an office-based positive hyperventilation test and confirmed by routine electroencephalography (EEG). In the current coronavirus disease 2019 (COVID-19) pandemic, many pediatric neurologists have switched to telemedicine visits for nonemergent outpatient evaluations. We present a series of children diagnosed as having CAE on the basis of a positive hyperventilation test performed during remote televisits. Several of these children were begun on treatment for CAE prior to obtaining an EEG, with significant seizure reduction. Our series documents the feasibility of CAE diagnosis and management by telemedicine.

CDKL5 mutations may mimic Pitt-Hopkins syndrome phenotype.

Genetic conditions comprise a wide spectrum of different phenotypes, rapidly expanding due to new diagnostic methodologies. Patients' facial features and clinical history represent the key elements leading clinicians to the right diagnosis. CDKL5-early onset epilepsy and Pitt-Hopkins syndrome are two well-known genetic conditions, with a defined phenotype sharing some common characteristics like early-onset epilepsy and hyperventilation episodes. Whilst facial features represent a diagnostic handle in patients with Pitt-Hopkins syndrome, clinical history is crucial in patients carrying a mutation in CDKL5. Here we present the clinical case of a girl evaluated for the first time when she was 24-years old, with a clinical phenotype mimicking Pitt-Hopkins syndrome. Her facial features have become coarser while she was growing up, leading geneticists to raise different clinical hypotheses and to perform several molecular tests before getting the diagnosis of CDKL5-early-epileptic encephalopathy. This finding highlights that although typical facial gestalt has not so far extensively been described in CDKL5 mutated adult patients, peculiar facial features could be present later in life and may let CDKL5-related disorder mimic Pitt Hopkins. Thus, considering atypical Rett syndrome in the differential diagnosis of Pitt Hopkins syndrome could be important to solve complex clinical cases.