By David N. Leff

Being born without thumbnails may seem like a small price to pay for the gift of a baby.

Yet this digital blemish can be the tip of a chilling genetic iceberg, known (but not widely) as nail-patella syndrome.

This unusual inherited disorder is a horrific laundry list of physical defects, affecting fingers, knees, feet and hips, as well as kidneys and eyes.

Reports in medical journals a century ago refer vaguely to descriptions of patients with these symptoms as far back as 1820. Today, though still rare, nail-patella syndrome (NPS) is found all over the world in all ethnic groups.

Last year, the authoritative American Journal of Human Genetics (Vol. 60, p. 133) stated tersely, "The incidence is estimated at 1/50,000 live births." But it didn't indicate any source for that estimate.

Despite its rarity, observed molecular geneticist Douglas Vollrath, "nail-patella syndrome has a long and rich history in human genetics. It's very variable in its expressivity and phenotype [individual features], but in general NPS doesn't compromise the life span of someone or their ability to have children."

That's true in general, but in particular the syndrome can be life-threatening in one of its manifestations, kidney dysfunction, and sight-threatening in another, glaucoma.

Vollrath, whose laboratory at Stanford University focuses on the molecular genetics of inherited blindness, recited the litany of NPS manifestations:

* "Thumbnails are always affected in some degree, ranging from completely absent to fissures. Severity decreases along the fingers from thumb to pinkie.

* "Kneecaps — patellae — can range from totally missing to small size and such knees look squarish.

* "Elbow joints, homologous to the knee, have restricted range of motion, which in severe cases requires surgery to correct.

* "Then there are iliac horns, a feature that's usually picked up only by X-ray. These are internal bony growths from the back of the pelvis, just above the gluteal muscles [buttocks]. They are seen only in NPS patients — about 80 percent of whom are afflicted with these growths."

Vollrath continued, "Those are the classic skeletal features that most people would say define NPS. But there are many variable features, including club foot and hip dislocation."

Then in the non-skeletal, other-organ systems, he noted, "kidney abnormalities can range from just protein in the urine — which happens in normal people under certain circumstances — to conditions that compromise the ability of the kidney to function and threaten the person's life."

NPS-Glaucoma Link Seen Only Nine Months Ago

All of the above NPS stigmata have been recognized down through the years. Glaucoma was something else.

"Last October," Vollrath recalled, "a group of ophthalmologists and statisticians at the University of Michigan, in Ann Arbor, were the first to demonstrate that glaucoma was in some way associated with NPS." Their paper, reported in the American Journal of Human Genetics (Vol. 61, A58) bore the title "Glaucoma and nail patella syndrome (NPS) cosegregate. One gene or two?"

Its senior author, ophthalmologist Julia Richards, is also senior author of a paper in Human Molecular Genetics for July 1998, which answers that question: It's one gene, not two. Her article is titled "Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome." (The human genome's LMX1B gene resides on the long arm of chromosome 9. It's involved in vertebrate limb development.)

Vollrath, that paper's first author, told BioWorld Today how the two centers collaborated to identify the NPS gene, by analyzing the DNA of 31 people with the disease. Sixteen of them also had glaucoma.

"The people in Michigan," he recounted, "recruited all of the individuals who actually donated their blood, used in the DNA study. My contribution was to realize that this gene was a good candidate for NPS and my lab showed that there were mutations in that gene.

"We studied extended families with 120 members. The two university collaborators showed it was NPS; then ours focussed on the eye aspect."

That aspect, linking blinding open-angle glaucoma to nail-patella syndrome, closed a wide gap between pediatric orthopedists and ophthalmologists.

Eye Doctors Miss Skeletons In NPS Patients' Closet

"Children with NPS," Vollrath suggested, "get the severe skeletal defects recognized, and have them fixed very early. Then when they get glaucoma as adults they just don't connect it to the syndrome. And the practitioners who are treating them later in life are ophthalmologists, who may not even be told about the orthopedic problems their patients had corrected in childhood."

Vollrath made the point that "glaucoma is a significant health problem among Americans, so that as you approach the 60s and 70s of life, the numbers quoted are definitely higher than one percent of individuals in that age range. So the question is, will the identification of this gene help us in any way to understand that common open-angle form of glaucoma?

"That's an ongoing question that we're studying right now," he went on, "asking whether mutations in this NPS gene account for a fraction of the late-onset form of inherited glaucoma that's such a significant public health problem. And we don't know the answer to that yet."

Meanwhile, the Stanford geneticist proposes an immediate payoff of the four mutations he and his co-authors discovered in the NPS gene.

"If that gene is involved in some fraction of late-onset glaucoma, which is a common disease, we think that early genetic testing will be of interest. Although there is no complete cure for the eye disease — which many people don't even know they have until it's far advanced — there are treatments that can significantly slow its progression. So the ability to use this mutated gene sequence to identify someone who has glaucoma running in the family would be useful from a health standpoint. One could then monitor subjects with an NPS mutation and institute therapy early.

"So we think," Vollrath concluded, "that genetic testing of this gene may be pretty important." *