Regulation Of Childhood Growth

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

We seek to explore the fundamental mechanisms regulating childhood growth and development and to elucidate the pathogenesis of disorders that affect these important processes. Much of our work has focused on the growth plate, a thin layer of cartilage which is responsible for bone growth in children and therefore for height gain. Growth at the growth plate is controlled by multiple interacting regulatory systems, involving endocrine, paracrine, extracellular matrix-related, and intracellular pathways. Previously, our group has studied growth plate regulation by FGFs, BMPs, C-type natriuretic peptide, retinoids, WNTs, PTHrP/IHH, IGFs, estrogens, glucocorticoids, and microRNAs. More recently, we have shown evidence that SOX9, a transcription factor, regulates the transdifferentiation of growth plate chondrocytes into osteoblasts. In other previous work, we investigated the mechanisms that cause bone growth to occur rapidly in early life but then to progressively slow with age and eventually cease. We showed that the developmental program responsible for the decline in growth plate function plays out more slowly in larger bones compared to smaller bones and that this differential aging contributes to the disparities in bone length and therefore to establishing normal mammalian skeletal proportions. For many children with disorders of growth and development, the etiology remains unknown. In some conditions, genetic variants affect growth plate chondrogenesis, which impairs bone elongation and can present clinically as isolated short stature or a skeletal dysplasia. In some other conditions, genetic variants affect hypothalamic-pituitary function, which can cause endocrine abnormalities that include growth hormone deficiency, which impairs body growth, and/or gonadotropin deficiency, which impairs pubertal development. To discover new genetic causes of these disorders, we are using powerful genetic approaches including SNP arrays to detect deletions, duplications, mosaicism, and uniparental disomy, combined with exome sequencing to detect single nucleotide variants and small insertions/deletions in coding regions and splice sites. Using this approach, we have previously explored the roles of ACAN, QRICH1, BRF1, and CYP26A1/C1 in disorders of human growth. Using this approach, we also previously discovered that variants in DLG2 cause delayed puberty and contribute to isolated hypogondotropic hypogonadism by a mechanism that involves decreased NMDA receptor phosphorylation and signaling, and consequently decreased GnRH expression. We recently used similar approaches to study the etiology of congenital hypopituitarism. Children with this disorder present with pituitary hormone deficiencies and can have a small or absent anterior pituitary gland and an ectopic posterior pituitary. Occasionally the condition is familial but more often occurs sporadically. In most patients, the etiology remains unknown. We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with non-familial short stature. Similarly, the number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in non-familial short stature. Second, we assessed the frequency of rare, predicted-pathogenic variants in any protein-coding gene in the genome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the probands condition (congenital hypopituitarism or non-familial short stature) with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive). There were fewer monogenic candidates in probands with congenital hypopituitarism than those with non-familial short stature. Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but is infrequently monogenic with full penetrance, suggesting that the disorder often has a more complex etiology, which we are continuing to investigate.