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Uncovering the Genetics of Problem Pituitaries

Uncovering the Genetics of Problem Pituitaries

Romero 2015

Christopher Romero, M.D.

Tumors, head trauma and, less commonly, the radiation or surgery used to treat them can turn a pituitary gland into a dark star. “The loss of pituitary output depends, of course, on where, when and how it’s damaged,” says pediatric endocrinologist Christopher Romero, “but these sources of hypopituitarism, at least, are understood.”

Romero’s concern, however, is on congenital reasons for pituitary pathology. Specifically, he and mentor Sally Radovick focus on mutations that undermine growth hormone availability. “It’s a starting place,” Romero admits, in a field where the nature of illness varies greatly, biology is murky and, until recently, limited technology has cramped research. “Now our approach, at least, is surer.”

Genomic sequencing is lighting pituitary corners. Last year, for example, in sequencing DNA of children diagnosed with growth hormone deficiency, Radovick’s lab spotted mutations within Pit-1 and Prop-1, two developmental genes that help the anterior pituitary mature into specific endocrine tissues.

More recently, the two clinicians began a Johns Hopkins investigation of kids with either suspected isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). Children get the thorough clinical testing that any incoming endocrinology patient has for diagnosis. But there’s an added, extensive clinical going-over to chart the most accurate phenotype possible—something to compare with the gene sequencing to come.

A cheek swab gives enough DNA for sequencing eight candidate genes known to code for pituitary development. Children with the more specific growth hormone deficiency (IGHD) have two additional genes under scrutiny.

“What’s hoped,” says Radovick, “is that we’ll find mutations and match them more consistently to patient symptoms—that would give us certainty in diagnosing. And we’d hope to be able to predict inheritance.” With hypopituitarism, genetic counselors currently have little to go on.

Radovick and Romero expect genomic studies like this to uncover new flawed genes. Also, family studies become possible as more mutations are catalogued—the Hopkins group has some family pedigrees already underway. Then clinicians could sort spontaneous mutations from the congenital.

“For now, though, our ability to sequence the genome outpaces our ability to understand it,” says Romero. “For one thing, human variety stands out in endocrinology; we’ll see five teenagers with an identical transcription-factor mutation but we’d never know it, given the course of their disease.”

For another, the deficiencies are a moving target. “A young boy has clear IGHD and no traditional cause,” he says. “We prescribe growth hormone replacement and all looks fine. But later that child—and many others—develops thyroid problems. His mutation has dug a developmental pothole that we couldn’t see coming.”

Yet another confounder: Some developmental genes lower hormone output by affecting how the pituitary sits in the brain. How to factor that into a prognosis?

“For now,” says Romero, “clinical tests for growth hormone are fairly adequate. Replacement hormones are good. We can keep patients healthy. But time’s lost in figuring out what’s wrong. If we could point to mutations with a useful screen, we could be ready to go when a baby’s born. Otherwise, kids potentially miss a chance to grow.”
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