Prevalence and changes in genetic and clinical abnormalities in growth hormone-treated girls with Turner syndrome: a study from the Belgian- Luxembourgish growth hormone registry (BELGROW)

Background: Since the initial clinical description of Turner
Syndrome (TS), there have been notable changes in the genotypic
and phenotypic presentation of the disease. Our aim is to provide
an overview of the current genetic and clinical characteristics of a
large Belgian cohort of girls with TS, and the evolution over the
last 3 decades.
Methods: We therefore analyzed the genetic and clinical data of
growth hormone(GH)-treated girls with TS, included in BELGROW
(national GH registry of the BELux Society for Pediatric
Endocrinology and Diabetology) between 1985 and 2022. Age at
diagnosis, karyotype, and phenotype were retrieved from 719 girls
with TS. Changes between two time periods (1991-2002 [Group 1,
n=250] vs 2003-2017 [Group 2, n=272]) were studied.
Results: No significant trend in the number of patients with TS
starting GH was observed (mean number 19/year). The majority
of patients were diagnosed with 45,X monosomy (44%) whereas
26.5% carried structural anomalies of the X chromosome (isochromosome
being the most frequent), 13% had 45,X/46,XX mosaicism,
4% were mosaic for a “triple X” cell line, 6.4% had 45,X/46,XY
mosaicism or complex Y chromosome anomalies and 5.6% other
genotypes. The percentage of 45,X decreased from 46% in Group
1 to 38% in Group 2 (p < 0.05). Median age (p25-75) at diagnosis
in the overall cohort was 6.4 years (0.2-11.1), 7.7% were diagnosed
prenatally, 24% before the age of 1 year, 49% during childhood and
19% after 12 years. The percentage of prenatal diagnosis increased
significantly (15% in Group 2 vs 3% in Group 1, p-value < 0.001).
Monosomy for X was diagnosed significantly earlier than all other
genotypes combined (median age [p25-75] 2.2 years [0.0-9.9] vs 8
years [3-11.9], p-value < 0.001). 45,X/46,XX and 45,X/46,X,i(X)
mosaics were diagnosed at a later age (9.45 years, p-value < 0.01
and 9.0 years respectively, p-value < 0.001), compared to other
genotypes. The most frequently affected body systems were the
skeletal (73%), neurosensory (60%) and cardiac system (29%).
Cardiac (p-value < 0.01) and skeletal (p-value < 0.05) malformations
were more frequent in 45,X patients in comparison with
other genotypes.
Conclusion: The proportion of different genotypes and the
timing of diagnosis changed significantly since 1991, while the
number of TS girls initiating GH therapy in Belgium and
Luxembourg remained stable. The most frequently associated
malformations are skeletal and cardiac anomalies, especially in
patients carrying 45,X genotype. The genotype-phenotype correlation
should be further clarified, ideally within the framework of
international registries.