Background: Patients born small for gestational age (SGA) with additional syndromic features to short stature are likely to present with genetic causes.
Aim: To perform a clinical and genetic-molecular investigation of a group of syndromic SGA patients without catch-up growth.
Methods: We selected 118 patients born SGA [birth weight and/or length standard deviation score (SDS) ≤−2 for gestational age] without catch-up growth at the age of 2 or above [height SDS ≤−2] and dysmorphic features, developmental delay and/or intellectual disability. These patients were evaluated clinically, laboratory and radiologically by professionals with expertise in dysmorphology. Among these syndromic patients, they were reclassified as known or unknown syndromic short stature, according to the establishment of the clinical diagnosis by routine exams and clinical evaluation. Molecular evaluation was performed according to the clinical diagnosis. Unknown syndromic short stature patients were submitted for molecular karyotyping (aCGH/SNPa) and/or whole exome sequencing (WES).
Results: Fifty-three (44.9%) patients had a clinical diagnosis of a specific genetic syndrome and 78.7% confirmed the initial diagnosis by target genetic tests. These patients were diagnosed as Silver-Russell (n=9), Achondroplasia (n=6), Hypochondroplasia (n=4), Bloom (n=3), Noonan (n=2), Floating-Harbor (n=2), Leri-Weill dyschondrosteosis (n=2), Langer dysplasia (n=2), Cornelia de Lange (n=2) and other syndromes (Seckel, Laron, CHARGE, Osteogeneses imperfecta, Spondyloepimetaphyseal dysplasia; each one, n=1). Ten patients did not confirm the initial diagnoses by target analyses. Sixty-five patients were classified as unknown syndromic short stature based on the clinical data. Forty-three underwent aCGH/SNPa screening and 12 (27.9%) patients had pathogenic CNVs. Twenty-six patients were submitted to WES and 13 (50%) had pathogenic/possibly pathogenic variants in genes already associated with growth disturbance: ANKRD11 (n=3); COL2A1 (n=2); SRCAP (n=2); BRCA1; POC1A; IGF1R; PTPN11; KIF11 and PCNA (each one, n=1). These genes were associated with rare syndromic conditions associated with growth impairment. All identified SNVs are extremely rare or absent in public database, were predicted to be deleterious and segregated with the phenotype.
Conclusion: The rarity, variability and clinical heterogeneity of syndromic short stature makes establishing a clinical diagnosis difficult. Our genetic evaluation protocol established the definitive diagnosis in 52.5% (62/118) of a group of patients with syndromic short stature. Of these patients, 40.3% (25/62) had no initial clinical diagnosis. A clinical diagnostic paradigm with a systematic phenotype evaluation, targeted genetic testing and exome sequencing increases the diagnostic rate of syndromic short stature patients.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology