Adult height and long-term outcomes after rhIGF-1 therapy in two patients with PAPP-A2 deficiency

Martín‐Rivada, Álvaro; Barrios, Vicente; Díaz-Guerra, Guillermo Martínez; Pozo, Juan Ignacio; Martos‐Moreno, Gabriel Ángel; Argente, Jesús

doi:10.1016/j.ghir.2021.101419

Cited by 4 publications

(9 citation statements)

References 15 publications

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“…Specifically, rmIgf1 treatment changed mineral compositional properties and increased collagen maturity in the bone of Pappa2 KO females. These rmIgf1 effects on female bone composition were accompanied by increased mRNA levels of Igfbp3 and Igfbp5 , suggesting a feedback response to Igf1 bioavailability and signaling, as previously described by using in vitro assays [ 24 ] and in human trials with a long-term treatment of rhIGF1 [ 57 ]. This treatment also produced increases in the mRNA levels of Col1a1 and osteopontin , suggesting changes in bone matrix resorption and formation [ 70 ].…”

Section: Papp-a2 Mouse Models: What Are We Learning?supporting

confidence: 70%

“…Treatment of PAPP-A2 deficient patients with recombinant human IGF1 (rhIGF1) improves growth [ 56 , 57 ], but not GH treatment as it was shown to be ineffective in one patient [ 49 ]. This is probably because GH would simultaneously increase the three components of the trimolecular complex, IGFs, IGFBPs and ALS, which would not only result in an increase in the free fraction of IGFs but would contribute to further increase the levels of sequestered IGFs.…”

Section: Mutations In the Human Papp-a2 Genementioning

confidence: 99%

“…In the Spanish siblings, treatment with rhIGF1, subcutaneously twice daily, was initiated when they were still prepubertal. An increase in growth velocity was evident in both the short- and the long-term, reaching their midparental target height, with an increase in BMD and modifications in body composition [ 56 , 57 ]. Laboratory analyses revealed a decrease in spontaneous GH secretion and an increase in free IGF1 values following rhIGF1 administration.…”

Section: Mutations In the Human Papp-a2 Genementioning

confidence: 99%

“…Treatment with rhIGF1 was employed to increase growth velocity and height and to palliate bone loss in prepubertal patients with PAPP-A2 deficiency [ 49 , 53 , 56 , 87 ]. Moreover, growth velocity continued to increase and bone mineral density was normalized after 6 years of rhIGF1 treatment [ 57 ]. Studies have also reported beneficial effects of rhIgf1 on bone formation in aged mice [ 88 ] and ovariectomized rats [ 89 ].…”

Section: Papp-a2 Mouse Models: What Are We Learning?mentioning

confidence: 99%

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Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Barrios

Chowen

Martín‐Rivada

et al. 2021

Cells

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The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.

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Section: Papp-a2 Mouse Models: What Are We Learning?supporting

confidence: 70%

Section: Mutations In the Human Papp-a2 Genementioning

confidence: 99%

Section: Mutations In the Human Papp-a2 Genementioning

confidence: 99%

Section: Papp-a2 Mouse Models: What Are We Learning?mentioning

confidence: 99%

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Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Barrios

Chowen

Martín‐Rivada

et al. 2021

Cells

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“…The affected sister had completed growth and therefore was not initiated on therapy. Recently, Martin-Rivada et al [11] reported 6-year treatment results from the two affected siblings with PAPP-A2 deficiency in the second family from the initial report of PAPP-A2 deficiency. They observed significant increases in height velocity (HV), height standard deviation score (HtSDS), BMD, and lean body mass [11].…”

Section: Introductionmentioning

confidence: 99%

Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency

Muthuvel¹,

Dauber²,

Alexandrou³

et al. 2023

Horm Res Paediatr

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Introduction: The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF) binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe five-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. Methods: Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 mcg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). Results: Treatment with rhIGF-1 was started in 10.4y (P3) and 14.5y (P2) old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; HV increased (3.0 cm/y at baseline; 5.0-7.6 cm/y thereafter) as did height SDS (+0.6). P3’s pubertal onset was at 12.4y. BMD height-adjusted-Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-hr glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-hr glucose: 152 mg/dL) developed during puberty. Conclusion: Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPPA-2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.

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Pappalysins and Stanniocalcins and Their Relationship With the Peripheral IGF Axis in Newborns and During Development

Martín‐Rivada

Guerra-Cantera

Campillo-Calatayud

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Background Pappalysins (PAPP-A, PAPP-A2) modulate body growth by increasing IGF-I bioavailability through cleavage of IGFBPs and are inhibited by stanniocalcins (STC1, STC2). Normative data of these novel factors, as well as of free IGF-I and uncleaved fractions of IGFBPs are not well established. Objective To determine serum concentrations of PAPP-A, PAPP-A2, STC1 and STC2, in relationship with other GH-IGF axis parameters during development. Patients and methods Full-term newborns (150; gestational age: 39.30 ± 1.10 weeks), 40 preterm newborns (30.87 ± 3.35 weeks) and 1071 healthy individuals (1-30 years old) were included in the study and divided according to their Tanner stages (males and females): I:163 males, 154 females; II:100 males, 75 females; III:83 males, 96 females; IV: 77 males, 86 females; and V:109 males,128 females. Results Serum concentrations of PAPP-A, PAPP-A2, STC1, STC2, IGFBP-2, total IGFBP-4 and total IGFBP-5 were elevated at birth and declined throughout childhood. In postnatal life, PAPP-A2 concentrations decreased progressively in concomitance with the free/total IGF-I ratio; however, stanniocalcin concentrations remained stable. PAPP-A2 concentrations positively correlated with the free/total IGF-I ratio (r=+0.28 p<0.001) and negatively with the intact/total IGFBP-3 ratio (r=-0.23, p<0.001). PAPP-A concentrations inversely correlated with intact/total IGFBP-4 ratio (r=-0.21, p<0.001), with PAPP-A concentrations being lower in females at all ages. Association studies indicate the importance of stanniocalcins and pappalysins in the control of this axis in an age specific manner. Conclusion This study provides reference values of pappalysins and stanniocalcins, which modulate IGF-I activity by changing the concentrations of cleaved and uncleaved IGFBPs.

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Adult height and long-term outcomes after rhIGF-1 therapy in two patients with PAPP-A2 deficiency

Cited by 4 publications

References 15 publications

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency

Pappalysins and Stanniocalcins and Their Relationship With the Peripheral IGF Axis in Newborns and During Development

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