New genomic sequencing techniques have contributed to increasing the understanding of the causes of short stature in children, so that more and more idiopathic cases can be identified. The key is knowing when and how to conduct genetic studies. This is the purpose of the first international clinical guideline on genetic testing in children with short stature, developed by a broad group of experts in pediatric endocrinology and genetics and published in the European Journal of Endocrinology.
This guideline introduces a practical algorithm that helps pediatricians decide which genetic test to use according to the case and is based on a systematic review and GRADE methodology. "In recent years, we have discovered many genes that regulate growth and today we are able to make a more precise diagnosis," says Jesús Argente, a full academician of Pediatrics at the Royal National Academy of Medicine of Spain (RANME) and one of the authors of the document. "This has led us to create this first international guideline with 8 scientific associations, trying to reorganize our knowledge and provide specific recommendations on when to request this type of studies."
Short stature can be proportionate or disproportionate, meaning with a normal or abnormal body proportion, and is a highly heritable trait: around 80% depends on genetic factors. It is also important to note that "the inheritance of growth in humans is polygenic, and therefore, many genes are involved in the normal development and growth of the child," highlights Argente, who is the Head of the Pediatric and Endocrinology Service at the University Children's Hospital Niño Jesús in Madrid.
"Previously, we studied isolated genes, then we started analyzing gene panels, and currently we tend to perform what we call exomes, that is, studying multiple genes included in the study of short stature." This has allowed us to "find anomalies in specific genes where there is no relationship between the patient's phenotype and the altered gene, and therefore, genetic studies are substantially helping us to reach a precise diagnosis."
The academic emphasizes the substantial increase in the use of genetic tests in recent years. They currently constitute "a key complementary study for patients with short stature" for two fundamental reasons: because this way specific diagnoses can be reached in idiopathic short statures and because they enable "providing appropriate genetic counseling for the family, especially for young people who plan to have more offspring."
The guideline proposes a structured approach. First, conduct a complete clinical evaluation: medical and family history (including a three-generation family tree), detailed physical examination, laboratory and radiological tests. If after this assessment no obvious cause is identified (such as celiac disease or hypothyroidism), genetic testing is considered.
Main genetic causes of short stature
The main genetic causes of short stature can be summarized in three situations. Firstly, when there is a growth hormone deficiency, in which case it involves "genes mainly related to the hypothalamus and pituitary gland." It can also be due to a phenomenon of resistance to the action of growth hormone, which occurs when the child produces growth hormone but the problem lies in the receptor gene where the molecule binds. Thirdly, there are syndromic entities. "We are increasingly better understanding the causes of these syndromes associated with short stature," emphasizes Argente.
"We talk about height from the age of two, when the child can stand, and we talk about length below the age of two, when we measure the patient lying down. Therefore, it is defined as pathological when their length or height is below -2 SD (standard deviation) from the mean of their population and sex," explains the academic, who adds that the characteristics vary depending on the diagnosis: "If it is a growth hormone deficiency, it presents a peculiar phenotype: harmonious growth, doll-like face, trunk-abdominal adiposity. If it is a disproportionate growth, dysplastic alterations can be observed. If it is a syndromic entity, it presents alterations specific to each syndrome."
Treatment based on the diagnosis
Knowledge of the genetic cause helps guide treatment "to a substantial extent," asserts the expert. When it is due to a growth hormone deficiency, treatment with biosynthetic growth hormone can be used. However, when there is resistance to the action of this hormone, "it is already accepted by the European Medicines Agency (EMA) and the Spanish Agency of Medicines and Medical Devices (Aemps) that we can treat it with recombinant IGF-1."
When short stature is part of a syndromic entity, the use of growth hormone is approved for patients with Prader-Willi syndrome, Turner syndrome, children who are small for gestational age, and patients with chronic kidney disease. However, this therapy is not approved when dealing with "other types of syndromes in which clinical trials have not been conducted, and we do not have evidence of whether treatment with growth hormone will improve the height prognosis or not."