Clinical characteristics (Table 1)

Table 1.

Anthropometric Data at Baseline and After 6 Months and 12 Months of rhIGF-1 Therapy

Subject ID	Age, y	BA (Greulich Pyle)	Height, cm (SDS)	BMI, kg/m2 (SDS)	HC, cm (SDS)	GV/y (SDS)	ΔTH (SDS)-H (SDS)	rhIGF-1 Therapy, μg/kg/dose
Patient 1 (female)
Start	10.54	10.75	132 (−1.25)	14.1 (−1.51)	49 (−2.06)	3.7 (−1.5)	1.94	40–80
6 mo	11.03	11	136.9 (−0.87)	14.4 (−1.44)	49 (−2.06)	9.8 (+4)	1.56	80–120
12 mo	11.54	11.25	139.6 (−0.86)	14.8 (−1.44)	49 (−2.08)	7.6 (+1.6)	1.55	120
Patient 2 (male)
Start	6	4.5	111.5 (−0.74)	13.38 (−1.81)	47.5 (−2.76)	5.8 (−1.6)	1.17	40–80
6 mo	6.5	5.0	115.5 (−0.47)	13.38 (−1.9)	48 (−2.92)	8 (+1.91)	0.90	80–120
12 mo	7	5.5	118.5 (−0.34)	13.64 (−1.69)	48.5 (−2.94)	7 (+1.06)	0.77	120

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Abbreviations: BA, bone age; BMI, body mass index; HC, head circumference; GV, growth velocity; ΔTH-H, Δtarget height − height.

The study included two prepubertal siblings, a 10.5-year-old female (patient 1) and a 6-year-old boy (patient 2), born to nonconsanguineous Spanish parents. Birth weight and length were normal. Postnatally they exhibited a gradual decline in growth velocity causing a progressive deviation from their target height (TH). Other phenotypic features included a small chin, mild microcephaly, and long, thin digits on hands and feet. Skeletal maturation was consistent with chronological age in patient 1 (Δ chronological age–bone age = −0.21) and was delayed in patient 2 (Δ chronological age–bone age = 1.5). Both have a homozygous frameshift mutation in exon 3 of the PAPP-A2 gene (p.D643fs25*) resulting in a premature stop codon and absent PAPP-A2 activity (1). At treatment onset, the height of patient 1 was in the normal range (−1.25 SDS), but was 1.9 SDS below her TH. The height of patient 2 was also normal (−0.74 SDS), but 1.2 SDS below his TH. After 6 months of rhIGF-1 treatment, patient 1 spontaneously entered puberty (Tanner II; chronological and bone age, both 11 years). In an attempt to improve her final height, she received GnRH analog treatment (Triptorelin, 3.75 mg/28 days) during the remaining study period.

Study procedures

Initially, 40–80 μg/kg of rhIGF-1 (Mecasermin, Increlex; Ipsen) was administered sc twice daily for 6 months. The dose was progressively increased to 120 μg/kg twice daily after 9 months of treatment. During the first 3 days of rhIGF-1 administration, glucose levels were measured every 30 minutes, and thereafter at least six times daily (ACC-CHEK; Roche Diagnostics Corp). Patients underwent an anthropometric evaluation and physical examination every 3 months. At 0, 6, and 12 months, hematology and biochemical analyses, thyroid function, and serum insulin, GH, total and bioactive IGF-1 and IGFBP-3 were measured, and radiography of the left hand and wrist was performed. At 0 and 12 months of treatment, abdominal ultrasound (to evaluate spleen and kidney size), echocardiogram, and whole-body dual-energy x-ray absorptiometry for body composition were performed.

Spontaneous GH secretion over 8 hours (7 am to 3 pm), with extractions every 30 minutes, was evaluated at 0 and 6 months of treatment. Serum levels of total and bioactive IGF and IGFBP-3 were measured every 30 minutes during 8 hours after rhIGF-1 administration at 6 months of treatment.

GH secretion and the peripheral GH-IGF axis during treatment

Mean GH secretion was elevated before rhIGF-1 treatment (patient 1, 4.8 ng/mL; patient 2, 5.3 ng/mL), with integrated secretion over 8 hours diminishing markedly after 6 months of treatment (patient 1, 0.80 ng/mL; patient 2, 0.65 ng/mL). Treatment had no significant effect on basal levels of total IGF-1, bioactive IGF-1, or IGFBP-3 at 6 or 12 months (data not shown). Acutely, rhIGF-1 administration increased bioactive IGF-1 60–120 minutes later (Figure 1C), and this was associated with a decrease in the GH secretory peaks occurring at this time. Levels of IGFBP-3 remained constant during the treatment period.

Metabolic measures

Both patients exhibited moderate fasting hyperinsulinemia (15 and 27 μU/mL, respectively; normal range, 4–13 μU/mL), with normal glycemia and glycosylated hemoglobin before treatment. At 1 year of treatment, serum insulin was normalized (patient 1, 11 μU/mL; patient 2, 8 μU/mL). Treatment with rhIGF-1 produced no significant change in bone mineral density but increased the percentage of lean body mass (4.8 and 5%) and decreased the percentage of total body fat mass (4.5%) in both patients.

We thank Dr. Santiago Vila-Dupla for GH measurements.

The authors express their gratitude for the financial support received from the Spanish Ministry of Economy and Competitiveness (Grant CTQ2014–55279-R), and by Fondos de Investigación Sanitaria and Fondos FEDER (Grant PI1302195; to J.A.), Ministerio de Ciencia e Innovación (Grant BFU2014-51836-C2-2-R; to J.A.C.), Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (to J.A.), and Fundación Endocrinología y Nutrición.

Disclosure Summary: The authors declare no conflict of interest.