BSPED2022 Oral Communications Oral Communications 1 (2 abstracts)
1Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, United Kingdom; 2Centre for Endocrinology, William Harvey Research Institute, Queen Mary University London, London, United Kingdom
Background: PAPP-A2 is a protease which helps to release IGF-1 from a ternary complex by cleaving the IGF binding proteins (IGFBP-3 and -5). Free IGF-1 subsequently binds to its receptor resulting in cell proliferation and growth. Homozygous loss-of-function PAPPA2 mutations lead to low IGF-1 bioavailability and postnatal short stature (SS). Recombinant human IGF-1 (rhIGF-1) treatment improves height SDS in few patients. We report a patient with SS and high plasma total IGF-1 and IGFBP3 levels secondary to PAPPA2 deficiency.
Case report: A 12.3 years old girl of Jordanian origin presented to the endocrine clinic with SS and generalised delayed dental development. She was born at term with a birth weight of 2.5 Kg. There was no other past medical history of note. Her parents were non-consanguineous. Mid-parental height was 157.2 cm (9th-25th centile). 2 siblings (17 and 15 years old) were of normal stature. Her height was 134.2 cm (-2.3 SDS) with a BMI 20.1 (+0.59 SDS). There were no dysmorphic features. She was pubertal with Breast stage 3. Bone age was advanced by 1 year. Blood biochemistry showed markedly elevated serum IGF-1 level of 183.2 nmol/l (+4.9 SDS) and elevated serum IGFBP3 level of 7.1 mg/l (+1.9 SDS). CGH microarray testing was normal. Initial SS gene panel testing including IGF1R gene was negative. A trial of recombinant human growth hormone did not show a noticeable increment in height velocity (3 cm/year). Further testing on an extended custom short stature gene panel revealed a novel homozygous frame-shift mutation in the PAPPA2 gene c.1223delT, p.L408Rfs*49. As she is now post-menarchal and reaching her final height, rhIGF-1 therapy is not being considered.
Conclusions: Growth failure in PAPP-A2 deficient patients is variable with height SDS ranging from 3.8 to -0.96. Biochemically it causes a decrease in free IGF-1 but elevated total IGF-1 and IGFBP3 levels. Delayed dentition is seen as a consistent feature of this condition. PAPP-A2 deficiency should be considered and the PAPPA2 gene should be studied in all children with SS and persistently elevated serum IGF-1 levels but with negative genetic analysis for the IGF1R gene.