ESPE Abstracts

Background: IGFALS deficiency is a rare cause of GH insensitivity (GHI). We report a German girl with short stature who was born as 2^nd 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.