ESPEYB17 4. Growth and Growth Factors Important for clinical practice (5 abstracts)
4.1. Diagnosis, genetics, and therapy of short stature in children: A growth hormone research society international perspective
Collett-Solberg PF , Ambler G , Backeljauw PF , Bidlingmaier M , Biller BMK , Boguszewski MCS , Cheung PT , Choong CSY , Cohen LE , Cohen P , Dauber A , Deal CL , Gong C , Hasegawa Y , Hoffman AR , Hofman PL , Horikawa R , Jorge AAL , Juul A , Kamenický P , Khadilkar V , Kopchick JJ , Kriström B , Lopes MdLA , Luo X , Miller BS , Misra M , Netchine I , Radovick S , Ranke MB , Rogol AD , Rosenfeld RG , Saenger P , Wit JM & Woelfle J
Disciplina de Endocrinologia, Departamento de Medicina Interna, Faculdade de Ciencias Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil paulosolberg@yahoo.com
To read the full abstract: Horm Res Paediatr. 2019;92:1–14
In March 2019, 46 international experts from 14 countries across 5 continents attended a 3-day workshop organized by the Growth Hormone Research Society (GRS) and produced this perspective on the diagnosis, management and therapy in children with short stature. In this context, this expert panel tackled almost all aspects related to the management of children with short stature, providing recommendations for clinical practice.
Clinical evaluation: The panel underlined the importance of family and personal history, physical examination and the correct choice of growth charts. WHO growth charts can be utilized for children up to 2 years of age, whereas national growth charts are more appropriate for older children. A thorough work-up should be considered in a child with height below – 2 SDS, height deviating from their family background, or a significant decrease in height SDS over time (by at least 0.3 SDS/year).
Laboratory tests: should be guided by clinical evaluation rather than routinely applied in all short children. Use of sitting height, arm span and sitting/height ratio measurements may provide clues for genetic short stature (SHOX deficiency, FGFR3 mutations, etc). Bone age was confirmed to be helpful for driving to the right diagnosis although it needs to be critically considered within the clinical, laboratory and radiological context. IGF-I values play a key role in the evaluation of a child with growth failure, but IGF-I levels are physiologically low in children aged <3 years when there is an overlap in values between normal and GHD children. An IGF-I level >0 SDS at any age makes the diagnosis of GHD unlikely. Measurement of IGF binding protein (BP)-3 may be helpful in the work-up of GHD in very young children. GH provocative tests were confirmed to be the gold standard in GHD diagnosis and the values of insulin tolerance test (ITT), glucagon, arginine, clonidine, L-dopa and GH-releasing peptide-2 were considered similar. The majority of delegates suggested 7 ng/ml as the threshold to distinguish between normal and subnormal peak GH responses to stimulation. In neonates in first week of life, a random GH value <7 ng/ml should be considered diagnostic for GHD. Provocative tests were considered unnecessary for children with Turner syndrome, Noonan syndrome, Prader-Willi syndrome, SHOX deficiency, renal insufficiency, Silver-Russell syndrome and short children born small for gestational age (SGA). There was no consensus on the use of sex steroid priming prior to performing GH stimulation tests, except for adolescents with clinically ascertained delayed puberty.
Radiology: Pituitary Magnetic Resonance Imaging (MRI) should be performed in all patients diagnosed with GHD but is not a test for the diagnosis of GHD. If a midline defect, hypoglycemia or microphallus in newborns has been detected, GH provocative tests are not necessary as a routine. The presence of empty sella, ectopic posterior pituitary and/or absence of anterior pituitary, as such as pituitary stalk hypoplasia, are suggestive of GHD.
Genetics: Karyotype should be performed in all girls with short stature to exclude Turner syndrome. Genetic and epigenetic testing are not required for all children with short stature, but only in those with a phenotype suggestive of a genetic cause, or in severe GHD, severe short stature (<3 SDS), or signs of skeletal dysplasia. SNP array, whole genome sequencing and methylation analysis should be performed on the basis of phenotype.
GH therapy: The panel suggested that GH doses should be titrated on the basis of diagnosis (severe or partial GHD), auxological parameters (severe short stature), or genetic diagnosis (Turner syndrome, Prader Willi Syndrome, etc.). The suggested doses ranged from 25 to 43 μg/kg per day, and the panel recommend to titrate the initial dose by severity of GHD with lower doses in more severe deficiency. In non-GHD patients, the dose may be higher according to the approved indication. IGF-I levels during treatment may provide further information for dose adjustment and should be kept in the normal range, with the exception of specific conditions such as IGF-I resistance where a level above 2 SD could be accepted at least transiently. An inadequate response to GH therapy in patients with GHD is defined by one or more of the following criteria: increase of height velocity by <2 cm/year, height velocity <0 SDS, or increase in height by <0.3 SDS during the first 6–12 months of therapy. Long acting GH therapy was discussed as well as oral Ghrelin analogue in severe forms of GHD, and C-Natriuretric peptide analogues in achondroplasia.
The paper is extremely comprehensive and deals with all aspects relating to children with short stature. Although comprehensive, it is not exhaustive. The document is largely confirmatory and reasserts well established notions. In addition, the indications are based on expert views instead of a systematic review of the literature, meta-analysis and grading of the evidence. Therefore, these recommendations should be considered as suggestions rather than guidelines, which will require an evidence-based approach.
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ESPE Yearbook of Paediatric Endocrinology
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