Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis.

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.

Growth failure and outcome in Rett syndrome: specific growth references.

OBJECTIVES: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes. METHODS: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression. RESULTS: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). CONCLUSIONS: RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations.

Vitamin D deficiency is prevalent in girls and women with Rett syndrome.

OBJECTIVES: The aim of the study was to determine the prevalence of vitamin D deficiency and identify the relation between 25-hydroxyvitamin D (25-(OH)D) levels and the consumption of dietary sources of vitamin D or exposure to anticonvulsants in girls and women with Rett syndrome (RTT). SUBJECTS AND METHODS: Retrospective review of the medical records of 284 girls and women with RTT to determine serum 25-(OH)D and parathyroid hormone levels, nutritional status, dietary sources of vitamin D, exposure to anticonvulsants, degree of mobility, and MECP2 status. RESULTS: Twenty percent of girls and women who were tested (n = 157) had 25-(OH)D levels <50 nmol/L. Multivitamin supplements, vitamin D-fortified milk, and commercial formulas were consumed by 40%, 52%, and 54%, respectively. Anticonvulsants were used by 57%, and 39% ambulated independently. Median 25-(OH)D levels were lower in individuals who did not receive multivitamin supplements (P < 0.05) or commercial formulas (P < 0.001) than in those who did. Median 25-(OH)D levels differed (P < 0.01) among racial and ethnic groups, but the number in some groups was small. Nutritional status, use of anticonvulsants, degree of mobility, and MECP2 status did not influence 25-(OH)D levels. CONCLUSIONS: Vitamin D deficiency is prevalent in girls and women with RTT. The use of multivitamin supplements or commercial formulas is associated with improved vitamin D levels. Attention to vitamin D may enhance bone mineral deposition and reduce the frequency of bone fractures in these individuals.

Profiling scoliosis in Rett syndrome.

To understand scoliosis, related comorbidities, and phenotype-genotype correlations in individuals with Rett syndrome (RTT), the Rare Disease Clinical Research Network database for RTT was probed. Clinical evaluations included a detailed history and physical examination, comprehensive anthropometric measurements, and two quantitative measures of clinical status, Clinical Severity Scale (CSS) and motor-behavioral analysis (MBA). All data were exported to the Data Technology Coordinating Center (DTCC) at the University of South Florida. Scoliosis assessment was based on direct examination and curvature measurements by radiography (Cobb angle). Statistical analyses included univariate and multiple logistic regression models, adjusting for age at enrollment or mutation type. Scoliosis data were available from 554 classic RTT participants, mean age = 10 y (0-57 y). Scoliosis was noted in 292 (53%); mean age = 15 y with scoliosis and 6 y without. Using multiple regression analysis, MBA severity score, later acquisition, loss or absent walking, and constipation were associated with scoliosis. Two common methyl-CpG-binding protein 2 (MECP2) mutations, R294X and R306C, had reduced risk for scoliosis. These findings corroborated previous reports on scoliosis and extended understanding of comorbidities, clinical severity, and relative risk reduction for specific mutations. Clinical trial design should account for scoliosis and related factors judiciously.