Teen-age mothers are much in the news, but what about kindergartenkids as parents? We've all seen headlines in the checkout-countertabloids reporting "Six-Year-Old Fathers Child." Such stories are notnecessarily figments of sensational journalism.

By age six or seven, a little boy afflicted with male-limited precocious puberty (MLPP) is fully equipped physically toinseminate a sexually mature female.

This rare syndrome runs in families, though perhaps 10 percent of thefew known MLPP cases have occurred sporadically. What causesthese three-year-olds suddenly to sprout pubic and under-arm hair,and grow adult-size testes and phalluses, while acquiring deep voices,acne, fertility and libido, are mutations in their luteinizing hormonereceptor.

This is the hormone that kicks in at the onset of adolescence totrigger production of testosterone as the opening act of puberty inboys. Testosterone, of course, is the macho male hormone that setsthe men apart from the boys.

Except those boys who inherit or acquire MLPP, and prematurelysynthesize testosterone, uncontrolled by luteinizing hormone. Whatmakes this untoward endocrine aberration happen is point mutationof genes on the luteinizing hormone receptor. Scientists atGeorgetown University in Washington have just reported identifyingthese mutation-prone sites in the current Proceedings of the NationalAcademy of Sciences, dated March 14.

Their paper is titled: "Genetic heterogeneity of constitutivelyactivating mutations of the human luteinizing hormone receptor infamilial male-limited precocious puberty."

Pediatric endocrinologist Louisa Lauwe, the article's first author, toldBioWorld Today: "We conclude that there are multiple sites withinthe luteinizing hormone receptor gene where mutations can occur thatcause MLPP. These mutations will help us to understand themechanism of signal transduction for other G-protein-coupledreceptors."

Premature Puberty: One Of 5 Comparable Diseases

"These guanine-nucleotide binding proteins," she explained, "couplesignals from the external environment, such as light or smell or ahormone, to an effector. They really act as transducers."

She said that besides MLPP, which was the first gene identified, fourother maladies "are actually due to such constitutively activatingmutations." Two of the four are hyperactive-thyroid disorders, inwhich the gland functions on its own, rather than under hormonalcontrol. A third is a form of hypocalcemia. The fourth, retinitispigmentosa, involves a mutant rhodopsin, the retinal pigment protein.

Lauwe added that this finding "has opened up a lot of peoples'thinking about mechanisms of a lot of other human diseases."

Premature sexual maturity involves more than just growing up toosoon. "If these MLPP boys are not treated with proper medication,"Lauwe pointed out, "they'll finish their pubertal development by thetime they're seven or eight. We've actually had cases of six- andseven-year-old boys fathering children."

She said, "They actually stop growing at that point, and end up short_ around five feet tall."

Two types of treatment are available for MLPP. One is a drug calledketoconazole, which prevents testosterone production; the other,spironolactone, an anti-androgen, plus testolactone, which inhibitsaromatase, an enzyme that converts testosterone to estrogen.

There is no routine prenatal diagnosis test for MLPP. "All we can doright now, Lauwe explained is, in families that have an affectedmember, find a mutation in that individual, then look for it in thefetus. You would have to have an affected family history," she said,"to know that that particular kindred carries the abnormal gene."

Females as well as males may be carriers of the mutation, but onlymales can actually manifest the autosomal, dominant syndrome.

In their study, Lauwe and her co-authors examined the genomic DNAof 38 unrelated MLPP families from the U.S., Canada, Scotland andHong Kong. They mapped amino-acid-shuffling mutations in thesixth transmembrane helix of the human luteinizing hormone receptorgene (which resides on chromosome 2), and localized a 117-basestretch of the gene's exon 11 as "a hot spot for heterogeneous pointmutations that constitutively activate the human luteinizing hormonereceptor, and cause male-limited precocious puberty."

More Understanding, Better Therapy

"Really, this group has made the pivotal discovery," said pediatricendocrinologist Ora Pescovitz. "Probably its greatest significance isin understanding how the luteinizing hormone receptor works, andhow it might act in constitutive situations, where it's turned onwithout stimulation from its normal stimuli, namely the gonadotropin.

"Obviously," she told BioWorld Today, "it has critical implicationsfor the treatment of this small group of children."

Pescovitz, who directs pediatric endocrinology at Indiana Universityin Indianapolis, added, "It would be wonderful if one could devise aform of therapy based on this discovery. Current clinical treatmentfor MLPP is really not too effective." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.