Growth failure and outcome in Rett syndrome Specific growth references

Article (PDF Available)inNeurology 79(16):1653-61 · October 2012with79 Reads
DOI: 10.1212/WNL.0b013e31826e9a70 · Source: PubMed
Abstract
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. 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. 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). 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.

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DOI 10.1212/WNL.0b013e31826e9a70
; Published online before print October 3, 2012; 2012;79;1653Neurology
Daniel Charles Tarquinio, Kathleen J. Motil, Wei Hou, et al.
references
Growth failure and outcome in Rett syndrome : Specific growth
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Growth failure and outcome in
Rett syndrome
Specific growth references
Daniel Charles Tarquinio,
DO
Kathleen J. Motil, MD,
PhD
Wei Hou, PhD
Hye-Seung Lee, PhD
Daniel G. Glaze, MD
Steven A. Skinner, MD
Jeff L. Neul, MD, PhD
Fran Annese, LMSW
Lauren McNair, MS,
CGC
Judy O. Barrish, BSN,
RN
Suzanne P. Geerts, MS,
RD
Jane B. Lane, BSN, RN
Alan K. Percy, MD
ABSTRACT
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 par-
ticipants was recruited, and cross-sectional and longitudinal growth data and comprehensive
clinical information were collected. A reliability study confirmed interobserver consistency. Refer-
ence 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 mor-
bidity typically associated with RTT, and late truncation mutations.
Neurology
®
2012;79:1653–1661
GLOSSARY
ANOVA analysis of variance; BMI body mass index; CSS Clinical Severity Score; EDF equivalent degrees of free-
dom; FDR false discovery rate; FOC fronto-occipital head circumference; MBA Motor Behavioral Assessment; non-
RTT participants possessing MECP2 mutation but without Rett syndrome; RNHS Rett Natural History Study; RTT Rett
syndrome.
Growth failure is a prominent feature in Rett syndrome (RTT); however, no RTT-specific
growth charts exist. Many comorbid disorders have an impact on growth in RTT, such as
oropharyngeal and gastrointestinal dysfunction, scoliosis, seizures, and osteopenia. The pattern
of growth in female patients with RTT trends well below the lowest centile on standard growth
references,
1
which fail to differentiate a normal RTT growth pattern from one caused by
malnutrition or illness.
Disease-specific standards screen for disease
2–13
and measure the effect of therapeutic inter-
ventions designed to improve nutrition and neurologic function.
14,15
With more than 200
mutation sites identified in the methyl-CpG-binding protein 2 gene (MECP2), the clinical
From the Miami Children’s Hospital (D.C.T.), Miami, FL; Baylor College of Medicine (K.J.M., D.G.G., J.L.N., J.O.B.), Houston, TX; University of
Florida (W.H.), Gainesville, FL; University of South Florida (H.-S.L.), Tampa, FL; Greenwood Genetic Center (S.A.S., F.A., L.M.), Greenwood, SC;
and University of Alabama at Birmingham (S.G., J.L., A.K.P.).
Study funding: Supported by NIH U54 grants RR019478 (National Center for Research Resources) and HD061222 (National Institute of Child
Health and Human Development [NICHD]), Intellectual and Developmental Disabilities Research Center grant HD38985 (NICHD), and funds
from the International Rett Syndrome Foundation and Civitan International Research Center.
Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.
Supplemental data at
www.neurology.org
Supplemental Data
Correspondence & reprint
requests to Dr. Tarquinio:
danieltarq@aol.com
Copyright © 2012 by AAN Enterprises, Inc. 1653
severity in RTT varies widely.
16
Associations
exist among specific mutations and functional
outcomes such as ambulation, hand use, and
language.
17
No study has generated accurate
RTT growth references or adequately examined
the associations between the degree of growth
failure and genotype or clinical severity.
The aim of this study was to develop RTT-
specific growth references for clinical and re-
search use. The secondary objectives were to
1) compare the patterns of growth between
patients with RTT and the normative popula-
tion and 2) examine the effects of secular
changes, disease severity, and MECP2 muta-
tion on growth.
METHODS Participants and data collection. Partici-
pants with classic RTT and atypical RTT and MECP2-positive
participants without clinical RTT (non-RTT) were recruited
from 2006 to 2011 through the multicenter RTT Natural His-
tory Study (RNHS) at 1 of 7 sites and evaluated every 612
months as described previously.
18
Diagnosis of classic and atypi-
cal RTT was based on consensus criteria
19,20
and was confirmed
by an RNHS neurologist or geneticist (D.G.G., J.L.N., A.K.P.,
S.A.S.). All participants had MECP2 testing; participants with
clinical RTT were included despite absence of a mutation. Eval-
uation included fronto-occipital head circumference (FOC),
weight, height, or length using standardized techniques, (appen-
dix e-1 on the Neurology
®
Web site at www.neurology.org) and 2
quantitative scales of developmental abilities and disease severity,
the Motor Behavioral Assessment (MBA) and Clinical Severity
Score (CSS) (appendix e-2). Interoperator and intraoperator re-
liability was excellent (within 3 mm or 0.3 kg). To analyze secu-
lar trends, supplemental retrospective data were collected for
participants seen by A.K.P. before the RNHS.
All female participants with classic and atypical RTT were
included. Male participants (n 20) were excluded, and non-
RTT female participants (n 31) were excluded from growth
chart construction because of the paucity of subjects but were
retained for comparison of adult measurements. No participants
were excluded based on premature birth or secondary medical
conditions; however, data on comorbidities were collected. Cor-
rected age was used for premature participants until 2 years of
age. A recruitment goal of 750 participants ensured at least 30
observations at standard visit intervals up to 18 years. Although
the age range of the charts extends to 18 years, data on individu-
als up to 25 years were included to attenuate the flaring “right-
edge effect” of data truncation on statistical smoothing.
Standard protocol approvals, registrations, and patient
consents.
Institutional review board approval was obtained at
each institution-based site; informed assent was obtained from
participants’ families. The RNHS is registered as clinical trial
NCT00296764.
Statistical analysis. Data quality assurance. Data were
screened using exploratory data analysis (individual scatterplots,
boxplots, histograms, and quantile-quantile plots) to identify er-
roneous measurements and frequency at target ages. Erroneous
measurements were investigated through source documentation,
and unresolved errors were discarded. Measurements on scatter-
plots were discarded if they differed from interpolated values by
more than 2 kg for weight, 1 cm for FOC, or 2.5 cm for height;
1% were discarded.
Chart modeling. Charts for the 2nd, 9th, 25th, 50th, 75th,
91st, and 98th percentiles in classic and atypical RTT were cre-
ated using combined cross-sectional and longitudinal data.
Curves were modeled using LMS,
21
a semiparametric technique
that normalizes data using a power transformation (L) and sum-
marizes distribution based on median (M) and coefficient of
variation (S). After transformation, the mean and median are
equivalent. Values of L, M, and S are constrained to change
smoothly with age through penalized maximum likelihood. The
equivalent degrees of freedom (EDF) of curves for L, M, and S
were manipulated based on goodness-of-fit testing,
22
and EDF
values were adjusted to achieve empirical validity and biological
plausibility.
Chart comparisons. Charts were compared with normative
references using multiple t tests weekly for the first 3 months and
monthly thereafter. Adjustment was made using the false discov-
ery rate (FDR), the expected percentage of false predictions in a
set of predictions.
23
Because crossing 2 percentile lines (1.3 SDs)
is commonly considered abnormal growth velocity, the percent-
age of participants who did so was calculated. British normative
growth references were used because National Center for Health
Statistics charts do not include data for age older than 3 years for
FOC or younger than age 2 for body mass index (BMI).
24
Charts were compared for RTT subgroups, including mild
and severe groups based on bimodal distribution of CSS and
MBA score. To study the effect of modern nutrition, secular
changes were compared in those born before vs after the median
year of birth (1997).
Genotype-phenotype and disease severity comparisons.
Common mutation type clustering reduced 148 MECP2 muta-
tions based on molecular similarities (common) into 8 common
point, pre-C-terminal truncating, C-terminal truncating, large
deletion, and other missense mutations (table 1). Measurements
were compared among each category using analysis of variance
(ANOVA) adjusted for multiple comparisons using the Tukey-
Kramer test. Growth velocity (from baseline to 6 years), time to
growth nadir, and measurements at key age ranges (0 –2, 2–7,
7–12, 12–17, and 17 years) were compared among different
genotypes.
The associations of the severity of common RTT character-
istics in childhood with adult measurements (18 years old)
were examined using linear regression. Characteristics included
scoliosis severity (scoliosis), periodic breathing (hyperventila-
tion), repetitive hand movements (stereotypies), seizure severity
(seizure), abi