Introduction: Very short stature is a common presenting complain that gives rise to numerous investigations. FBN1 heterozygous mutations cause acromelic dysplasia syndromes. The phenotypic spectrum of these growth disorders is broad, ranging from short stature with short extremities, stiff joints, skin thickening with tracheal stenosis and cardiac valvulopathy to nearly isolated short stature. Here, we report on a girl with disproportionate short stature, a history of small birth length, aortic bicuspidy and learning difficulties that harbours a previously described FBN1 mutation.
Case Report: A 3.5y-old girl presented for short stature. Her parents were healthy, non-consanguineous, of Caucasian origin. Their height was 175,6 cm (father) and 166,8 cm (mother). She was born at 37 weeks of gestational age by caesarean section after a twin pregnancy obtained by IVF with 1900g and 44,5 cm. Her physical examination at 3.5 years revealed short stature (Height -3.1 SDS, ref Cole 1995), with relative macrocephaly (head circumference 0SDS), lumbar hyperlordosis. Parents repeatedly reported behavioural and learning difficulties. She also presented bicuspid aortic valve asymptomatic Arnold Chiari 1 associated with minor syringomyelia. Growth hormone was administered at 4.9y when her height was at -3.5 SDS with a bone age equal to chronological age. It was given for 18 months at a dose of 25 mcg/kg/d (height gain after 1 year: +0.4 SD) then stopped for 1 year (loss of 0,4 SD) and then restarted at a dose of 50 mcg/kg/d for 36 months (gain of 0,5 SD after 2 years). She started puberty at 10.3 years of age and 122 cm (-3SDS) and a bone age of 10 years (G and P). She had her menarche at 12.7 years of age and 132.1cm. Her final height is 133.5 cm (-5,1 SDS) with an arm span of 133cm, head circumference of 58 cm (+2.5 SDS), sittingHeight/Height = 0.56. Her diagnostic work-up included: repeated growth hormone stimulation tests, skeletal survey, caryotype with FISH for SHOX, microarray, PTPN11 and FGFR3 sequencing, 3M syndrome suspicion (bone dysplasia clinic advice). At 13,5 years of age, targeted exome sequencing showed a c.5183C>T (p.Ala1728Val) heterozygous mutation in the FBN1 gene.
Conclusion: We highlight the very poor pubertal growth and very short adult height of this patient with acromicric dysplasia due to a FBN1 mutation. In addition, we illustrate the diagnostic challenge for which targeted exome sequencing was of great help. Finally, Growth hormone therapy response was very poor.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology