Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment

Abstract

Aim We aimed to describe the clinical characteristics of patients with congenital combined pituitary hormone deficiency (CPHD) and evaluate the first-year growth responses of individuals with CPHD and isolated growth hormone deficiency (IGHD) in order to establish the influence of other hormone deficiencies on growth response.

Patients and Methods This retrospective study was conducted in four tertiary care centers in Turkey. The records of patients diagnosed with CPHD (n=39) and severe IGHD (n=50) were collected. Cases with acquired lesions or chronic diseases were not included in the study. Data are presented as median (interquartile range).

Results Among 39 patients (13 females; 33%) with a diagnosis of CPHD, the majority of patients (64%) presented initially with combined deficits at baseline examination, whereas isolated deficiencies (36%) were less prevalent. Among all patients with GH deficiency, TSH, ACTH, FSH/LH, and ADH deficiencies were present in 94%, 74%, 44%, and 9% of patients, respectively. Patients with CPHD were diagnosed at a younger age (4.9 (8.4) vs. 11.6 (4.1), p<0.001, respectively) and had lower peak GH concentrations (0.4 (1.8) vs. 3.7 (2.9), p<0.001, respectively) than patients with IGHD. Patients with IGHD and CPHD had similar first-year growth responses (Δheight SD score of 0.55 (0.63) vs. 0.76 (0.71), respectively, p=0.45).

Conclusions We established the nature and timing of numerous hormonal deficits emerging over time. We also identified that the existence of CPHD did not hinder growth response.

Zusammenfassung

Ziel Ziel dieser Studie war es, die klinischen Merkmale von Patienten mit angeborenem kombiniertem Hypophysenhormonmangel (CPHD) zu identifizieren, die Wachstumsreaktionen von Patienten mit CPHD und isoliertem Wachstumshormonmangel (IGHD) im ersten Jahr zu bewerten und um die Auswirkungen anderer Hormonmängel auf die Wachstumsreaktion zu bestimmen.

Patienten und Methoden Diese retrospektive Studie wurde in vier tertiären Versorgungszentren in der Türkei durchgeführt. Die Aufzeichnungen von Patienten mit diagnostizierter CPHD (n=39) und IGHD (n=50) wurden gesammelt. Fälle mit erworbenen Läsionen oder chronischen Erkrankungen wurden nicht in die Studie aufgenommen. Die Daten werden als Median (Interquartilsbereich) angegeben.

Ergebnisse Unter den 39 Patienten (13 Mädchen; 33%), bei denen CPHD diagnostiziert wurde, zeigte die Mehrheit der Patienten (64%) zu Studienbeginn kombinierte Defizite, während isolierte Defizite (36%) seltener auftraten. Bei allen Patienten mit GH-Mangel lagen TSH, ACTH, FSH/LH und ADH-Mängel bei 94%, 74%, 44%, 9% der Patienten vor. Patienten mit CPHD wurden in einem jüngeren Alter diagnostiziert (4.9 (8.4) vs. 11.6 (4.1), p<0.001) und hatten niedrigere GH-Spitzenkonzentrationen (0.4 (1.8) vs. 3.7 (2.9), p<0.001) als Patienten mit IGHD. Patienten mit IGHD und CPHD zeigten im ersten Jahr ähnliche Wachstumsreaktionen ohne Geschwindigkeit (Δheight SD score von 0.55 (0.63) vs. 0.76 (0.71), p=0.45).

Schlussfolgerungen Wir haben die Art und den Zeitpunkt zahlreicher hormoneller Defizite bestimmt, die sich im Laufe der Zeit entwickeln. Wir haben auch festgestellt, dass das Vorhandensein von CPHD die Wachstumsgeschwindigkeit nicht behindert.

Key words

growth hormone - combined pituitary hormone deficiency - multiple pituitary hormone deficiency - PROP1 - CHD7

Schlüsselwörter

kombinierter Hypophysenhormonmangel - multipler Hypophysenhormonmangel - Wachstumshormon - PROP1 - CHD7

Publication History

Article published online:
04 December 2023

• References

• 1 Fang Q, George AS, Brinkmeier ML. et al. Genetics of combined pituitary hormone deficiency: Roadmap into the genome era. Endocr Rev 2016; 37: 636-675
• 2 Hietamaki J, Karkinen J, Iivonen AP. et al. Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years. EClinicalMedicine 2022; 51: 101556
• 3 Jakobsen LK, Jensen RB, Birkebaek NH. et al. Diagnosis and incidence of congenital combined pituitary hormone deficiency in denmark - a national observational study. J Clin Endocrinol Metab 2023;
• 4 Castinetti F, Reynaud R, Quentien MH. et al. Combined pituitary hormone deficiency: Current and future status. J Endocrinol Invest 2015; 38: 1-12
• 5 Darendeliler F, Lindberg A, Wilton P. Response to growth hormone treatment in isolated growth hormone deficiency versus multiple pituitary hormone deficiency. Horm Res Paediatr 2011; 76: 42-46
• 6 Lim HH, Kim YM, Lee GM. et al. Growth responses during 3 years of growth hormone treatment in children and adolescents with growth hormone deficiency: Comparison between idiopathic, organic and isolated growth hormone deficiency, and multiple pituitary hormone deficiency. J Korean Med Sci 2022; 37: e90
• 7 Maghnie M, Ambrosini L, Cappa M. et al. Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 2006; 91: 2900-2905
• 8 Ranke MB. Short and long-term effects of growth hormone in children and adolescents with gh deficiency. Front Endocrinol (Lausanne) 2021; 12: 720419
• 9 Pozzobon G, Partenope C, Mora S. et al. Growth hormone therapy in children: Predictive factors and short-term and long-term response criteria. Endocrine 2019; 66: 614-621
• 10 Demir K, Konakci E, Ozkaya G. et al. New features for child metrics: Further growth references and blood pressure calculations. J Clin Res Pediatr Endocrinol 2020; 12: 125-129
• 11 Bang P, Bjerknes R, Dahlgren J. et al. A comparison of different definitions of growth response in short prepubertal children treated with growth hormone. Horm Res Paediatr 2011; 75: 335-345
• 12 Ranke MB, Lindberg A, Board KI. Observed and predicted growth responses in prepubertal children with growth disorders: Guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metab 2010; 95: 1229-1237
• 13 Erbas IM, Paketci A, Acar S. et al. A nonsense variant in fgfr1: A rare cause of combined pituitary hormone deficiency. J Pediatr Endocrinol Metab 2020; 33: 1613-1615
• 14 Wang F, Han J, Shang X. et al. Distinct pituitary hormone levels of 184 chinese children and adolescents with multiple pituitary hormone deficiency: A single-centre study. BMC Pediatr 2019; 19: 441
• 15 Diwaker C, Thadani P, Memon SS. et al. Pituitary stalk interruption syndrome: Phenotype, predictors, and pathophysiology of perinatal events. Pituitary 2022; 25: 645-652
• 16 Bosch IAL, Katugampola H, Dattani MT. Congenital hypopituitarism during the neonatal period: Epidemiology, pathogenesis, therapeutic options, and outcome. Front Pediatr 2020; 8: 600962
• 17 El Kholy M, Elsedfy H, Perin L. et al. Normal growth despite combined pituitary hormone deficiency. Horm Res Paediatr 2019; 92: 133-142
• 18 van Iersel L, Brokke KE, Adan RAH. et al. Pathophysiology and individualized treatment of hypothalamic obesity following craniopharyngioma and other suprasellar tumors: A systematic review. Endocr Rev 2019; 40: 193-235
• 19 Cerbone M, Dattani MT. Progression from isolated growth hormone deficiency to combined pituitary hormone deficiency. Growth Horm IGF Res 2017; 37: 19-25
• 20 Cerbone M, Katugampola H, Simpson HL. et al. Approach to the patient: Management of pituitary hormone replacement through transition. J Clin Endocrinol Metab 2022; 107: 2077-2091
• 21 Binder G, Schnabel D, Reinehr T. et al. Evolving pituitary hormone deficits in primarily isolated ghd: A review and experts’ consensus. Mol Cell Pediatr 2020; 7: 16
• 22 Blum WF, Deal C, Zimmermann AG. et al. Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated gh deficiency. Eur J Endocrinol 2014; 170: 13-21
• 23 Otto AP, Franca MM, Correa FA. et al. Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: A long term follow-up of patients from a single center. Pituitary 2015; 18: 561-567
• 24 van Iersel L, van Santen HM, Zandwijken GRJ. et al. Low ft4 concentrations around the start of recombinant human growth hormone treatment: Predictor of congenital structural hypothalamic-pituitary abnormalities?. Horm Res Paediatr 2018; 89: 98-107
• 25 Agha A, Walker D, Perry L. et al. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol (Oxf) 2007; 66: 72-77
• 26 Burns EC, Tanner JM, Preece MA. et al. Final height and pubertal development in 55 children with idiopathic growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr 1981; 137: 155-164
• 27 Rohayem J, Drechsel H, Tittel B. et al. Long-term outcomes, genetics, and pituitary morphology in patients with isolated growth hormone deficiency and multiple pituitary hormone deficiencies: A single-centre experience of four decades of growth hormone replacement. Horm Res Paediatr 2016; 86: 106-116
• 28 Correa FA, Nakaguma M, Madeira JLO. et al. Combined pituitary hormone deficiency caused by prop1 mutations: Update 20 years post-discovery. Arch Endocrinol Metab 2019; 63: 167-174
• 29 Riepe FG, Partsch CJ, Blankenstein O. et al. Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to prop1 mutation. J Clin Endocrinol Metab 2001; 86: 4353-4357
• 30 Goncalves CI, Patriarca FM, Aragues JM. et al. High frequency of chd7 mutations in congenital hypogonadotropic hypogonadism. Sci Rep 2019; 9: 1597