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Advances in differential diagnosis and management of growth hormone deficiency in children

Abstract

Growth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000–10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care.

Key points

  • Growth hormone (GH) affects growth, body composition, metabolic profile, bone mineral density and quality of life; a secretory defect leads to impaired growth and function, known as GH deficiency (GHD).

  • GHD can occur in isolation (isolated GHD, IGHD) or in conjunction with other pituitary hormone deficits (multiple pituitary hormone deficiency, MPHD); GHD might be congenital or acquired.

  • GHD is familial in 3–30% of affected patients: in IGHD, the most commonly mutated genes are GH1 or GHRHR, whereas MPHD can be caused by mutations in several pituitary-specific transcription factors.

  • Congenital hypothalamic–pituitary abnormalities confirmed via imaging, such as anterior pituitary hypoplasia, pituitary stalk anomalies and ectopic posterior pituitary, are common in both children with moderate to severe IGHD and those with MPHD.

  • Recombinant human GH (rhGH), 0.16–0.24 mg/kg per week, is used to treat children with GHD; rhGH is best when initiated upon diagnosis and adjusted by serum concentrations of IGF1, height velocity and bone age.

  • Transitional care is the shift from paediatric care to adult treatment that provides full-body maturation, metabolic control and improved quality of life for those at risk of persistent GHD.

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Fig. 1: Normal MRI study in a healthy 9-year-old boy.
Fig. 2: Pathological MRI in children with hypopituitarism.
Fig. 3: MRI findings in congenital hypopituitarism based on genotype.

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Acknowledgements

We are thankful to Prof. Andrea Rossi and Prof. Giovanni Morana for their contributions to the neuroimaging. C.H. acknowledges the support of a generous gift from the Ward Family.

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C.H., H.-W.G., A. I. and G.P. researched data for the article. R.S., M.D. and S.L. contributed substantially to discussion of the content. C.H., H.-W.G., A.I., G.P. and M.M. wrote the article. R.S., M.D., S.L. and M.L. reviewed and/or edited the manuscript before submission.

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Correspondence to Roberto Salvatori.

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Competing interests

R.S. has served on advisory boards for Novo Nordisk and Ipsen. M.D. has served on advisory boards for Novo Nordisk, Pfizer and Ipsen and has received consulting/lecture fees from Sandoz, Pfizer and Novo Nordisk. M.M. has served on advisory boards for Ascendis, Biomarin, Merck, Novo Nordisk, Pfizer and Merk and has received lecture fees at several meetings. S.L. has received lecture fees and served on advisory board for Merck Serono, Ipsen and Sandoz. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks G. Binder, R. Brauner and C. Deal for their contribution to the peer review of this work.

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OMIM #615961: https://www.omim.org/entry/615961

PSIS: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=95496

Supplementary information

Glossary

Ectopic posterior pituitary

A disruption of normal embryogenesis of the posterior pituitary resulting in an incomplete downward extension of the diencephalon (infundibulum).

Holoprosencephaly

A syndrome caused by failure of separation of the cerebral hemispheres and ventricles and associated with a wide range of midline facial defects, ranging from cyclopia to midfacial hypoplasia, cleft lip and/or palate and a single incisor.

T2-DRIVE

A T2-weighted driven equilibrium (DRIVE) imaging obtained via turbo fast spin-echo sequences at sub-millimetre thickness, which provide excellent contrast between the cerebrospinal fluid and the adjacent parenchymal structures.

Slipped capital femoral epiphysis

A disorder seen in adolescents in which the growth plate is damaged and the femoral head moves (‘slips’) with respect to the rest of the femur: the head of the femur stays in the cup of the hip joint while the rest of the femur is shifted.

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Hage, C., Gan, HW., Ibba, A. et al. Advances in differential diagnosis and management of growth hormone deficiency in children. Nat Rev Endocrinol 17, 608–624 (2021). https://doi.org/10.1038/s41574-021-00539-5

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