Spanish scientists identify defect that causes delayed physical development in children with functioning growth hormone

Researchers have long thought that children with delays in their physical development had a growth hormone deficiency. A recent study by Spain's research council (CSIC), however, has identified a new cause.

According to the study, poor nerve connectivity between the brain and liver during the early stages of life can also cause such delays.

Based on animal models and one patient with a specific genetic mutation, the study has determined that an early defect in the nervous system prevents the liver from properly receiving the signals necessary to produce IGF-1, a hormone essential for postnatal growth.

Member of the IBFG institute of functional biology and genomics and the IBSAL biomedical research institute Ángeles Almeida explained the process. "It is not enough for the growth hormone to function correctly; the liver also needs to be well connected to the nervous system," she said.

The study, published in the high-impact scientific journal Communications Biology, is part of a line of research on neurodevelopmental disorders that the group has been pursuing for more than 15 years.

In previous studies, Almeida had demonstrated in animal models that the loss of a protein called Cdh1 altered the development of the cerebral cortex and caused problems such as microcephaly and impaired neuron formation.

Years later, a team from Hospital Universitario Quirónsalud in Madrid contacted them after identifying a child with a pathological mutation in Cdh1, who presented with psychomotor disability, refractory epilepsy and microcephaly. The team then confirmed that this mutation was responsible for the patient's neurological abnormalities.

Subsequently, other European hospitals identified new cases consistent with mutations in Cdh1, all associated with neurodevelopmental disorders and growth retardation. Ángeles Almedia noted that the coincidence of the cases had led the team to investigate what was happening.

To achieve this, they used genetically modified mice that exhibited neurological abnormalities during embryonic development. The impaired neural connection between the brain and the liver reduced the activation of a molecular pathway essential for producing IGF-1.

They noticed that the classic growth hormone axis (hypothalamus, pituitary gland and GH) functioned correctly, but the liver was unable to respond adequately due to the neural dysfunction. As a result, IGF-1 levels decreased and growth delays occurred.

One of the most encouraging results is that the team were able to reverse much of the growth delay in mice simply by administering IGF-1 during the first few days of life. "This opens the door to potential future clinical applications in certain patients with neurodevelopmental disorders," Almeida stated.

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