Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis

Ertl, Diana-Alexandra; Mantovani, Giovanna; Nanclares, Guiomar Pérez de; Elli, Francesca Marta; Pereda, Arrate; Pagnano, Angela; Sanchís, Amparo; Cueto‐González, Anna M.; Berrade, Sara; León, María Clemente; Rothenbühler, Anya; Audrain, Christelle; Berkenou, Jugurtha; Knight, Nina; Dolman, K; Gleiß, Andreas; Argente, Jesús; Linglart, Agnès

doi:10.1007/s40618-023-02026-2

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…Our own experience regarding this therapy in other PTH/PTHrP resistance disorders, such as iPPSD4 (acrodysostosis type 1), where patients are not GH deficient, suggests a benefit in terms of adult height. 39 …”

Section: Discussionmentioning

confidence: 99%

Recombinant growth hormone improves growth and adult height in patients with maternal inactivating GNAS mutations

Ertl

Nanclares

Jüppner

et al. 2023

European Journal of Endocrinology

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Background Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating PTH/PTHrP signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height. Objectives Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls. Methods We included 190 patients; 26 received rhGH. Height, weight, body mass index (BMI) at various time-points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models. Results Adult height was available for 11/26 of rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 SDS after one year (CI +0.5 to +0.8, p<0.001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, p<0.001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared to untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, p<0.001). BMI SDS did not vary significantly upon rhGH therapy. Conclusion rhGH treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.

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Section: Discussionmentioning

confidence: 99%

Recombinant growth hormone improves growth and adult height in patients with maternal inactivating GNAS mutations

Ertl

Nanclares

Jüppner

et al. 2023

European Journal of Endocrinology

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“…Patients with mutations in PRKAR1A usually present with hormone resistance 11 , 33-35 (although this is not unique to those with PRKAR1A mutations 35 ), short stature 31 and small size for gestational age at birth. 36 …”

Section: Pde4d Mutations As a Cause Of Acrodysostosismentioning

confidence: 99%

“… 84 and d denotes mutations first described by Ertl et al . 36 UCR1 and 2, upstream conserved regions.…”

Section: Pde4d Mutations As a Cause Of Acrodysostosismentioning

confidence: 99%

Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?

Gardner,

Bai,

Baillie

et al. 2024

Brain Communications

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Members of the phosphodiesterase 4 (PDE4) enzyme family regulate the availability of the secondary messenger cyclic adenosine monophosphate (cAMP) and, by doing so, control cellular processes in health and disease. In particular, PDE4D has been associated with Alzheimer’s disease and the intellectual disability seen in fragile X syndrome. Furthermore, single point mutations in critical PDE4D regions cause acrodysostosis type 2(ACRDYS2, also referred to as inactivating PTH/PTHrP signalling disorder 5 or iPPSD5), where intellectual disability is seen in ∼90% of patients alongside the skeletal dysmorphologies that are characteristic of acrodysostosis type 1 (ACRDYS1/iPPSD4) and ACRDYS2. Two contrasting mechanisms have been proposed to explain how mutations in PDE4D cause iPPSD5. The first mechanism, the ‘over-activation hypothesis’, suggests that cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signalling is reduced by the overactivity of mutant PDE4D, whilst the second, the ‘over-compensation hypothesis’ suggests that mutations reduce PDE4D activity. That reduction in activity is proposed to cause an increase in cellular cAMP, triggering the overexpression of other PDE isoforms. The resulting over-compensation then reduces cellular cAMP and the levels of cAMP/PKA signalling. However, neither of these proposed mechanisms accounts for the fine control of PDE activation and localization, which are likely to play a role in the development of iPPSD5. This review will draw together our understanding of the role of PDE4D in iPPSD5 and present a novel perspective on possible mechanisms of disease.

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Pseudohypoparathyroidism

Germain-Lee,

Levine

2024

Pediatric Endocrinology

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Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis

Cited by 4 publications

References 39 publications

Recombinant growth hormone improves growth and adult height in patients with maternal inactivating GNAS mutations

Recombinant growth hormone improves growth and adult height in patients with maternal inactivating GNAS mutations

Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?

Pseudohypoparathyroidism

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