RESUMEN

OBJECTIVES: Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), often experience a higher prevalence of gastrointestinal (GI) symptoms but have complex medical and behavioral comorbidities that make diagnosis and treatment difficult. A multi-stakeholder conference was convened to (a) determine patient and family experiences related to GI symptoms in NDDs, (b) review the clinicians' and researchers' perspectives, and (c) determine actionable steps for future research. METHODS: The Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID; www.candidgi.com) virtually over 2 days in 2022 and consisted of four key activities: (1) an electronic family survey to assess underlying NDDs and GI symptoms, (2) a session focused on family perspectives, (3) review current clinical care and research, and (4) discussion to identify key next steps. Survey results were obtained electronically via the REDCap platform, and descriptive statistics were generated. The sessions were recorded, and themes were identified. RESULTS: The pre-conference survey ran for ~2 months and 739 families provided responses, with 634 completing all items. 83% had a child with an NDD under age 18, and most patients were White (85%) and non-Hispanic (87%). Constipation (80%), gastrointestinal reflux disease (51%), and bloating (49%) were the most frequently reported symptoms. Families gave unstructured feedback that the measures used in the surveys were often difficult to answer for patients with NDDs or who were nonspeaking. Family and clinical/scientific sessions identified several common themes, including (1) the need for less invasive diagnostic modalities, (2) the need to validate or adapt existing diagnostic measures (e.g., the Rome IV criteria) and outcome assessments, and (3) the need for enhanced attention to parent and caregiver input in treatment plans. CONCLUSIONS: Those providing care to children with NDDs, especially those with communication and cognitive challenges, should be aware of the differing needs in this community and consider family perspectives in managing, treating, and measuring GI issues. Future research should focus on adapting or creating diagnostic and research measures for those with NDDs, developing new diagnostic methods to account for diversity in neurodevelopment and communication, and improving methods for family and caregiver engagement in the care of GI disorders.

RESUMEN

INTRODUCTION: Although gastrointestinal (GI) comorbidities are experienced by over 90% of individuals with Rett syndrome (RTT), a neurodevelopmental disorder associated with mutations in the MECP2 gene, many neurologists and pediatricians do not rank the management of these comorbidities among the most important treatment goals for RTT. Trofinetide, the first approved pharmacologic treatment for RTT, confers improvements in RTT symptoms but is associated with adverse GI events, primarily diarrhea and vomiting. Treatment strategies for GI comorbidities and drug-associated symptoms in RTT represent an unmet clinical need. AREAS COVERED: This perspective covers GI comorbidities experienced by those with RTT, either with or without trofinetide treatment. PubMed literature searches were undertaken on treatment recommendations for the following conditions: constipation, diarrhea, vomiting, aspiration, dysphagia, gastroesophageal reflux, nausea, gastroparesis, gastritis, and abdominal bloating. EXPERT OPINION: The authors recommend a proactive approach to management of symptomatic GI comorbidities and drug-associated symptoms in RTT to enhance drug tolerance and improve the quality of life of affected individuals. Management strategies for common GI comorbidities associated with RTT are reviewed based on authors' clinical experience and augmented by recommendations from the literature.

Asunto(s)

Enfermedades Gastrointestinales , Síndrome de Rett , Humanos , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/complicaciones , Enfermedades Gastrointestinales/inducido químicamente , Comorbilidad , Calidad de Vida , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/efectos adversos

RESUMEN

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials. METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale. RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis (CFA). The final MDS-specific GHS included 38 items and 7 factors that underwent further reliability and validity assessments. The power of the study was at least 0.982. The Cronbach's alphas of the instruments were General Health: 0.799, Eating-Chewing-Swallowing: 0.809, Reflux: 0.794, Motility: 0.762, Mood: 0.906, Medication: 0.595, Parenting: 0.942 and all items together: 0.928. The correlation coefficient between total and individual item scores ranged from 0.215 to 0.730. Because of the ordinal nature of the variables, the diagonal weighted least squares estimation (DWLS) method was used to execute the CFA and Structural Equation Modeling. The GHS had excellent model fit with the acceptable range of fit indices values. CONCLUSIONS: We developed a parent-reported, reliable, and valid MDS-specific GHS. This scale can be utilized in clinical settings or as an outcome measure in translational and clinical research.

Asunto(s)

Discapacidad Intelectual Ligada al Cromosoma X , Padres , Humanos , Reproducibilidad de los Resultados , Psicometría/métodos , Encuestas y Cuestionarios

RESUMEN

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, and pathogenic Methyl-CpG-binding Protein 2 (MECP2) variants are identified in >95% of individuals with typical RTT. Most of RTT-causing variants in MECP2 are de novo and usually on the paternally inherited X chromosome. While paternal age has been reported to be associated with increased risk of genetic disorders, it is unknown whether parental age contributes to the risk of the development of RTT. Clinical data including parental age, RTT diagnostic status, and clinical severity are collected from 1226 participants with RTT and confirmed MECP2 variants. Statistical analyses are performed using Student t-test, single factor analysis of variance (ANOVA), and multi-factor regression. No significant difference is observed in parental ages of RTT probands compared to that of the general population. A small increase in parental ages is observed in participants with missense variants compared to those with nonsense variants. When we evaluate the association between clinical severity and parental ages by multiple regression analysis, there is no clear association between clinical severity and parental ages. Advanced parental ages do not appear to be a risk factor for RTT, and do not contribute to the clinical severity in individuals with RTT.

Asunto(s)

Síndrome de Rett , Humanos , Síndrome de Rett/diagnóstico , Síndrome de Rett/epidemiología , Síndrome de Rett/genética , Mutación , Proteína 2 de Unión a Metil-CpG/genética , Cromosomas Humanos X , Padres

RESUMEN

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare neurogenetic syndrome caused by duplications of MECP2 at the Xq28 region. Although constipation and gastrointestinal reflux are reported in MDS, a comprehensive characterization of gastrointestinal health has not been fully explored. METHODS: We conducted a parent survey to explore the characteristics of gastrointestinal health in individuals with MDS using a secure online registry and compared differences in gastrointestinal symptoms between individuals with MDS and those with Rett syndrome (RTT). KEY RESULTS: One hundred six surveys were analyzed. Symptoms commonly associated with constipation occurred in 72% to 89% of MDS individuals. Eleven percent of MDS individuals underwent surgery for complications associated with constipation. We observed a bimodal distribution for gastroesophageal reflux disease (GERD) and gastrostomy feeding, with higher prevalence in 0-3 and >12-year-old MDS individuals. Constipation and GERD were significantly more common, and gas bloating was significantly less common in MDS than in RTT. Biliary tract disease requiring surgery was an unrecognized problem in 5% of MDS individuals. We determined that gastrointestinal problems in MDS individuals contribute to caretaker burden. CONCLUSION AND INFERENCES: Our study is the first in-depth investigation that characterizes gastrointestinal health in MDS and enumerates differences in gastrointestinal symptoms between MDS and RTT. Strategies to reduce gastrointestinal symptoms will alleviate caregiver burden in MDS. Further studies are needed to examine the mechanisms that cause gastrointestinal problems in MDS.

Asunto(s)

Reflujo Gastroesofágico , Enfermedades Gastrointestinales , Discapacidad Intelectual Ligada al Cromosoma X , Síndrome de Rett , Humanos , Niño , Discapacidad Intelectual Ligada al Cromosoma X/complicaciones , Proteína 2 de Unión a Metil-CpG , Estreñimiento/complicaciones , Enfermedades Gastrointestinales/epidemiología , Reflujo Gastroesofágico/complicaciones

RESUMEN

OBJECTIVE: To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. STUDY DESIGN: We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. RESULTS: Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. CONCLUSIONS: The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

Asunto(s)

Síndrome de Rett , Antropometría , Femenino , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG , Caminata/fisiología

RESUMEN

Obesity prevention interventions generally have either not worked or had effects inadequate to mitigate the problem. They have been predicated on the simple energy balance model, which has been severely questioned by biological scientists. Numerous other etiological mechanisms have been proposed, including the intestinal microbiome, which has been related to childhood obesity in numerous ways. Public health research is needed in regard to diet and the microbiome, which hopefully will lead to effective child obesity prevention.

Asunto(s)

Dieta Saludable/métodos , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Microbioma Gastrointestinal/fisiología , Obesidad Infantil/prevención & control , Niño , Femenino , Homeostasis/fisiología , Humanos , Masculino

RESUMEN

BACKGROUND: Gastrointestinal problems affect the health and quality of life of individuals with Rett syndrome (RTT) and pose a medical hardship for their caregivers. We hypothesized that the variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome and metabolome in RTT, predisposing these individuals to gastrointestinal dysfunction. OBJECTIVES: We characterized the gut bacterial microbiome and metabolome in girls and young women with RTT (n = 44) and unaffected controls (n = 21), and examined the relation between the composition of the microbiome and variations in the RTT phenotype. METHODS: Demographics and clinical information, including growth and anthropometric measurements, pubertal status, symptoms, clinical severity score, bowel movement, medication use, and dietary intakes were collected from the participants. Fecal samples were collected for analysis of the gut microbiome using Illumina MiSeq-based next-generation sequencing of the 16S rRNA gene followed by bioinformatics analysis of microbial composition, diversity, and community structure. Selected end-products of microbial protein metabolism were characterized by liquid chromatography-mass spectrometry. RESULTS: The gut bacterial microbiome differed within the RTT cohort based on pubertal status (p<0.02) and clinical severity scores (p<0.02) of the individuals and the type of diet (p<0.01) consumed. Although the composition of the gut microbiome did not differ between RTT and unaffected individuals, concentrations of protein end-products of the gut bacterial metabolome, including γ-aminobutyric acid (GABA) (p<0.001), tyrosine (p<0.02), and glutamate (p<0.06), were lower in the RTT cohort. Differences in the microbiome within RTT groups, based on symptomatic anxiety, hyperventilation, abdominal distention, or changes in stool frequency and consistency, were not detected. CONCLUSIONS: Although variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome, we presently cannot infer causality between gut bacterial dysbiosis and gastrointestinal dysfunction. Nevertheless, alterations in the gut metabolome may provide clues to the pathophysiology of gastrointestinal problems in RTT.

Asunto(s)

Microbioma Gastrointestinal , Metaboloma , Síndrome de Rett/microbiología , Adolescente , Adulto , Niño , Preescolar , Heces/química , Heces/microbiología , Femenino , Cromatografía de Gases y Espectrometría de Masas , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/microbiología , Microbioma Gastrointestinal/genética , Humanos , Fenotipo , ARN Ribosómico 16S/genética , Síndrome de Rett/complicaciones , Síndrome de Rett/metabolismo , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad , Adulto Joven

RESUMEN

OBJECTIVES: We report the development and validation of a tool to assess gastrointestinal health in Rett syndrome (RTT). We hypothesized that the Gastrointestinal Health Questionnaire (GHQ) is a valid clinical outcomes measure of gastrointestinal health in RTT. PATIENTS AND METHODS: We used parent interviews, surveys, and literature review to generate a questionnaire related to gastrointestinal health and function, mood and behaviors, and parental concerns for individuals with RTT. Parents of affected and unaffected individuals provided responses to the GHQ, assessed the relevance and importance of statements, and completed 5 surveys related to gastrointestinal health, child-related mood and behaviors, and parent concerns. We used multivariate item analysis, 2-sample t tests, and correlations to assess the validity of the GHQ. RESULTS: We documented acceptable internal consistency of statements related to gastrointestinal health and function (Cronbach-α = 0.91), RTT-related mood and behaviors (Cronbach-α = 0.89), and parent concerns (Cronbach-α = 0.95) in the GHQ. We documented favorable external validity based on differences in response scores between parents of affected and unaffected individuals (P < 0.001) and correlations in parental response scores between the GHQ and 5 validated questionnaires addressing similar issues (P < 0.001). CONCLUSION: The GHQ is a valid tool for the assessment of gastrointestinal health in RTT and offers the opportunity to field test the safety and efficacy of novel drug therapies in clinical trials for individuals affected with this disorder.

Asunto(s)

Síndrome de Rett , Niño , Tracto Gastrointestinal , Estado de Salud , Humanos , Padres , Reproducibilidad de los Resultados , Síndrome de Rett/diagnóstico , Encuestas y Cuestionarios

Asunto(s)

Obesidad Infantil , Investigación Conductal , Niño , Promoción de la Salud , Humanos , Salud Pública

Asunto(s)

Investigación Conductal/métodos , Promoción de la Salud/métodos , Obesidad Infantil/prevención & control , Niño , Ritmo Circadiano , Microbioma Gastrointestinal , Humanos

RESUMEN

Focal dermal hypoplasia (FDH) is a rare genetic disorder caused by mutations in the PORCN gene located on the X chromosome. Short stature was previously noted to be a common finding in FDH, however the etiology of this is unclear. The present study sought to elucidate specific causes for short stature by assessing growth charts, determining bone ages and auxologic measurements, examining laboratory data for the common causes of growth failure, assessing dietary intake, and performing a growth hormone stimulation test. Sixteen patients with FDH between the ages of 3 and 18 years of age consented to the study. While 11 out of 16 patients had short stature based on height less than 2 standard deviations below mid-parental target height percentile and bone age not suggestive of likely catch-up growth, only four had a BMI less than the 5th percentile for age. Laboratory studies did not support a gastrointestinal, allergy or autoimmune cause of growth failure. Three patients had results suggestive of possible growth hormone deficiency. Although short stature is a common feature in FDH, our data suggests that severe undernutrition is not common in this group and that there may be underlying treatable causes for this short stature in some patients.

Asunto(s)

Insuficiencia de Crecimiento/etiología , Insuficiencia de Crecimiento/patología , Hipoplasia Dérmica Focal/complicaciones , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/patología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Fenotipo

RESUMEN

OBJECTIVE: We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and women with Rett syndrome (RTT). METHODS: Sixty-two individuals with RTT and biliary tract disease were identified from the membership of Rett Syndrome Organization and patient files of the principal investigator. Medical records of 46 individuals were reviewed for presenting features, diagnostic tests, and treatment outcomes of biliary tract disease. We designed a questionnaire that probed the frequency of risk factors and treatment outcomes of biliary tract disease in RTT. The questionnaire was completed by 271 parents whose daughters met the clinical criteria for RTT and/or had MECP2 mutations and participated in the Natural History of Rett Syndrome Study. RESULTS: Presenting symptoms identified by record review included abdominal pain (94%), irritability (88%), weight loss (64%), and vomiting (52%). Biliary dyskinesia, cholecystitis, and cholelithiasis were identified in 90%, 77%, and 70%, respectively, by cholescintigraphy, surgical pathology, and abdominal ultrasound. The prevalence of biliary tract disease was 4.4% (n = 12) in the RTT cohort. Risk factors included older age (P < 0.001) and a positive family history (P < 0.01). Diagnoses included cholecystitis (n = 5), biliary dyskinesia (n = 6), and cholelithiasis (n = 7). Ten individuals underwent surgery; 7 had resolution of symptoms after surgical intervention. CONCLUSIONS: Biliary tract disease is not unique to RTT, but may be under-recognized because of the cognitive impairment of affected individuals. Early diagnostic evaluation and intervention may improve the health and quality of life of individuals affected with RTT and biliary tract disease.

Asunto(s)

Enfermedades de las Vías Biliares/epidemiología , Síndrome de Rett/complicaciones , Adolescente , Enfermedades de las Vías Biliares/genética , Niño , Femenino , Humanos , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Prevalencia , Estudios Prospectivos , Estudios Retrospectivos , Síndrome de Rett/genética , Factores de Riesgo , Encuestas y Cuestionarios , Adulto Joven

RESUMEN

PURPOSE OF REVIEW: The simple energy balance model of obesity is inconsistent with the available findings on obesity etiology, prevention, and treatment. Yet, the most commonly stated causes of pediatric obesity are predicated on this model. A more comprehensive biological model is needed upon which to base behavioral interventions aimed at obesity prevention. In this light, alternative etiologies are little investigated and thereby poorly understood. RECENT FINDINGS: Three candidate alternate etiologies are briefly presented: infectobesity, the gut microbiome, and circadian rhythms. Behavioral child obesity preventive investigators need to collaborate with biological colleagues to more intensively analyze the behavioral aspects of these etiologies and to generate innovative procedures for preventing a multi-etiological problem, e.g., group risk analysis, triaging for likely causes of obesity.

Asunto(s)

Composición Corporal , Diálisis Renal , Niño , Humanos , Estado Nutricional , Análisis Espectral

RESUMEN

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0 years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60-70%). Remission was common, lasting 1 year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.

Asunto(s)

Trastornos Respiratorios/fisiopatología , Síndrome de Rett/fisiopatología , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Niño , Preescolar , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Prevalencia , Calidad de Vida , Trastornos Respiratorios/epidemiología , Trastornos Respiratorios/etiología , Trastornos Respiratorios/genética , Síndrome de Rett/complicaciones , Síndrome de Rett/epidemiología , Síndrome de Rett/genética , Factores de Riesgo , Escoliosis/complicaciones , Escoliosis/epidemiología , Escoliosis/genética , Escoliosis/fisiopatología , Convulsiones/complicaciones , Convulsiones/epidemiología , Convulsiones/genética , Convulsiones/fisiopatología , Adulto Joven

RESUMEN

Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

Asunto(s)

Epilepsia/epidemiología , Síndrome de Rett/epidemiología , Niño , Preescolar , Epilepsia/psicología , Femenino , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Mutación/genética , Prevalencia , Modelos de Riesgos Proporcionales , Calidad de Vida , Estudios Retrospectivos , Síndrome de Rett/complicaciones , Síndrome de Rett/genética , Síndrome de Rett/psicología

RESUMEN

Focal dermal hypoplasia (FDH) is a rare genetic disorder caused by mutations in the PORCN gene located on the X-chromosome. In the present study, we characterized the pattern of growth, body composition, and the nutritional and gastrointestinal aspects of children and adults (n = 19) affected with this disorder using clinical anthropometry and a survey questionnaire. The mean birth length (P < 0.06) and weight (P < 0.001) z-scores of the participants were lower than the reference population. The mean head circumference (P < 0.001), height (length) (P < 0.001), weight (P < 0.01), and BMI (P < 0.05) for age z-scores of the participants were lower than the reference population. The height-for-age and weight-for-age z-scores of the participants did not differ significantly between birth and current measurements. Three-fourths of the group reported having one or more nutritional or gastrointestinal problems including short stature (65%), underweight (77%), oral motor dysfunction (41%), gastroesophageal reflux (24%), gastroparesis (35%), and constipation (35%). These observations provide novel clinical information about growth, body composition, and nutritional and gastrointestinal aspects of children and adults with FDH and underscore the importance of careful observation and early clinical intervention in the care of individuals affected with this disorder.

Asunto(s)

Hipoplasia Dérmica Focal/diagnóstico , Fenotipo , Adolescente , Adulto , Composición Corporal , Pesos y Medidas Corporales , Niño , Preescolar , Femenino , Hipoplasia Dérmica Focal/genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estado Nutricional , Adulto Joven

RESUMEN

PURPOSE: Survival in Rett syndrome remains unclear. Although early estimates were grim, more recent data suggest that survival into adulthood is typical. We aimed to define survival in Rett syndrome more clearly and identify risk factors for early death. METHODS: Participants with clinical Rett Syndrome or methyl-CpG-binding protein 2 mutations without clinical RTT were recruited through the Rett Syndrome Natural History study from 2006 to 2015. Clinical details were collected, and survival was determined using the Kaplan-Meier estimator. Risk factors were assessed using Cox proportional hazards models. RESULTS: Among 1189 valid participants, 51 died (range 3.9-66.6 years) during the 9-year follow-up period. Those who died included 36 (3.9%) classic Rett syndrome females, 5 (5.9%) atypical severe Rett syndrome females, 1 (2.4%) non-Rett syndrome female, the single atypical severe male, 6 (30%) non-Rett syndrome males, and 2 (7.1%) methyl-CpG-binding protein 2 duplication syndrome males. All atypical mild Rett syndrome females, methyl-CpG-binding protein 2 duplication syndrome females, and the single classic Rett syndrome male remain alive. Most deaths were due to cardiorespiratory issues. Only one died from severe malnutrition, scoliosis, and extreme frailty. Survival for classic and atypical Rett syndrome was greater than 70% at 45 years. Overall severity and several modifiable risk factors, including ambulation, weight, and seizures, were associated with mortality in classic Rett syndrome. CONCLUSIONS: Survival into the fifth decade is typical in Rett syndrome, and death due to extreme frailty has become rare. Although the leading cause of death remains cardiorespiratory compromise, many risk factors for early death are modifiable. Intense therapeutic interventions could further improve the prognosis for individuals with Rett syndrome.

Asunto(s)

Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/genética , Síndrome de Rett/mortalidad , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Síndrome de Rett/terapia , Factores de Riesgo , Estados Unidos , Adulto Joven

RESUMEN

PURPOSE: Diagnosis of Rett syndrome (RTT) is often delayed. We sought to determine the type of physician who typically makes the RTT diagnosis and to identify risk factors for delayed diagnosis. METHODS: A total of 1085 participants from the multicenter longitudinal RTT natural history study with classic and atypical RTT were recruited between 2006 and 2014. Age of diagnosis, diagnostician, diagnostic criteria, and clinical and developmental data were collected. RESULTS: Among 919 classic and 166 atypical RTT participants, the median diagnosis age was 2.7 years (interquartile range 2.0-4.1) in classic and 3.8 years (interquartile range 2.3-6.9) in atypical RTT. Pediatricians made the diagnosis of classic RTT rarely (5.2%); however, the proportion diagnosed by pediatricians has increased since 2006. Since the first diagnostic criteria, the age of diagnosis decreased among subspecialists but not pediatricians. Odds of a pediatrician making the diagnosis of classic RTT were higher if a child stopped responding to parental interaction, and lower if they possessed gastroesophageal reflux, specific stereotypies, lost babbling, or the ability to follow commands. Delayed acquisition of basic gross motor skills or finger feeding was associated with younger diagnosis; delayed acquisition of higher level fine motor skills, later onset of supportive features, and normal head circumference were associated with late diagnosis. Thirty-three percent with microcephaly before 2.5 years were diagnosed after the median age of 2.7 years. CONCLUSIONS: Age of RTT diagnosis has improved among subspecialists, and pediatricians have made the diagnosis of classic RTT more frequently since 2006. Strategies for educating diagnosticians should incorporate specific risk factors for delayed diagnosis.

Asunto(s)

Síndrome de Rett/diagnóstico , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Niño , Preescolar , Diagnóstico Tardío , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Factores de Riesgo , Índice de Severidad de la Enfermedad , Adulto Joven