Background: IGFALS deficiency is a rare cause of GH insensitivity (GHI). We report a German girl with short stature who was born as 2nd child at 40 weeks of gestation. Her Caucasian parents were unrelated and healthy (target height 168 cm, SDS 0.2). She was born appropriately sized for gestational age (49 cm, SDS -1.2; 2950 g, SDS-1.2). Height (104.8 cm; SDS -2.94) and height velocity (5.1 cm / year; SDS -1.67) were reduced at the age of 6 years.
Methods/Patient: Serum concentrations of total IGF-I (SDS -2.3; RIA, Mediagnost, FRG), of IGFBP3 (SDS -7.7) and of stimulated GH (max. 7.69 ng/ml) were reduced. cMRT was normal. Height (SDS -3.31), height velocity (SDS -1.68) and serum concentrations of IGF-I (SDS -2.5) and IGF BP 3 (SDS-9.1) remained low during growth hormone therapy (rhGH) for 18 months. Spontaneous GH secretion was elevated (12 hours sampling every 20 minutes: mean GH concentration 7.2 ng/ml, reference >3; 24h area over 0-line 174.79 ng/mlx24 h, reference > 80). ALS serum concentration was low (102 mU/ml; reference 705-1270).
A novel compound heterozygous mutation of the IGFALS gene (chromosome 16; Exon 2) was found: IGFALS p.Pro474Leu/p.Phe602Cys.
Treatment course: Therapy with rhIGF-I was started with 2x40µg/kg/d and gradually escalated to 2x120µg/kg/d s.c. Headaches without papilledema, dizziness and leg pain were reported during follow up. Sequential sampling revealed persistent elevated serum concentrations of IGF-I before (SDS 2.7) an after (SDS 5.61) rhIGF-I injections. Serum glucose and potassium were within the reference ranges throughout. Treatment was stopped after 10 months as no catch up growth occurred (ΔHSDS -0.26; HV SDS -0.94). Serum samples were also screened for anti-rhIGF-I antibodies by electrochemiluminescence assay (ECLA) which revealed low antibody titres before (<1:20) and after treatment (<1:100) but significantly elevated titres during the treatment period (max. 1:2048). Screening for auto-immune diseases remained negative.
Discussion: IGFALS deficiency is a rare cause of GHI. Neither rhGH nor rhIGF-I stimulated growth of our patient. Severe adverse events and lack of efficacy prompted to stop rhIGF treatment. In addition to elevated total IGF-I, neutralizing anti-rhIGF-I antibodies were detected in serum during rhIGF treatment but neither before start of treatment nor after withdrawal. The aetiology of the formation of anti-rhIGF-I antibodies in this patient with IGFALS deficiency during rhIGF-I treatment remains obscure. We speculate that the immunogenic potency of circulating IGF-I exceeds that of local tissue IGF-I.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology