Thanatophoric dysplasia is not exactly a household word. Yet it is thecommonest cause of neonatal death from congenital skeletaldeformities. It occurs in one of about 20,000 live births.

By comparison, achondroplasia, a somewhat similar, but less lethal,form of dwarfism, affects one to 15 births per 100,000. (SeeBioWorld Today, March 10, 1994, p. 1.)

The gene responsible for both achondroplasia and thanatophoricdysplasia encodes fibroblast growth factor receptor 3 (FGFR3),which molecular geneticists at the University of California, Irvine,tracked down last summer to the short arm of human chromosome 4.Now that same team reports that inherited mutants of FGFR3 causeachondroplasia, but sporadic mutations to the same gene bring on thedeadlier thanatophoric dysplasia.

A paper by biological chemist John Wasmuth and his Irvine co-authors in the March issue of Nature Genetics spells outthanatophoric dysplasia's wild-card etiology under the title:"Thanatophoric dysplasia [types I and II] caused by distinctmutations in fibroblast growth factor receptor 3."

A neonate born with either type of thanatophoric dysplasia, I or II,lives, as a rule, for only minutes to a day or two after being born. Itsgrossly deformed skull and skeleton cannot support normal breathing,and the infant dies of respiratory failure. As neonatal medicinedeveloped in recent decades, a few cases of thanatophoric dysplasiahave cheated death for a few days or weeks _ one as long as 212days. Two others "survived with extensive medical intervention forover four years [with] profound developmental delay," beforesuccumbing, Wasmuth notes in his Nature Genetics report.

Mutated Receptor's Prime Victim: Fetal Long Bones

FGFR3 is a cell surface receptor that extends from inside the cell,through its enclosing membrane to the extracellular space. "Itshighest expression levels are in the cartilage growth plates and longbones of developing fetuses," Wasmuth told BioWorld Today."They're the major problem in achondroplasia, and in thanatophoricdysplasia."

The new, uninherited, sporadic thanatophoric dysplasia mutations,besides being bolt-from-the-blue errors of transcription, seem tostrike in two variants, accounting for the affliction's twomorphological types.

In the University of California study, all 16 of 16 individuals withtype II thanatophoric dysplasia, identified by relatively straightfemurs and "cloverleaf" triple-lobed skulls, had a lysine-to-glutamic-acid switch in their FGFR3, at the tyrosine kinase _ i.e., intracellular_ domain of the molecule.

Of another 39 cases, type I thanatophoric dysplasia _ which featurescurved thigh bones _ 22 had arginine-to-cysteine mutations, andone a serine-to-cysteine substitution, both in the extracellular regionof the protein _ beyond its enclosing membrane. But not one of 50control DNAs from normal adults had any of these gene alterations.This showed, the paper said, "that mutations affecting differentfunctional domains of FGFR3 cause different forms of this lethaldisorder."

Achondroplasia (the form of dwarfism affecting so-called "LittlePeople,") also comes in two versions, but for quite different reasonsand outcomes. An autosomal, dominant genetic disorder, its mutantgenes are usually inherited, not sporadic. When the genomicaberration is bequeathed by only one parent, the heterozygoticnewborn _ despite dwarfed stature and characteristic head andfeatures _ can usually grow to maturity, with intact brain function.

Prenatal Diagnosis: Who Needs It?

But when both parents pass on a double dose of the same mutation,the resulting homozygotic neonate's appearance and fate aretragically similar to those of thanatophoric dysplasia; the childsurvives birth only briefly.

When normal couples have achondroplasia in their family history,ultrasound or X-ray examination can often reveal whether a pregnantmother is carrying an achondroplastic infant. Thanatophoricdysplasia, though, strikes with no such prior warning; its spontaneousmutations are unpredictable. For them, Wasmuth proposes that"Elucidation of the causative mutations in most or all cases ofthanatophoric dysplasia II, and in over 50 percent of cases ofthanatophoric dysplasia I, will allow earlier prenatal screening forthese disorders than ultrasound or radiographic studies."

To that prospect, he appends this caveat: "In 45 percent of thethanatophoric dysplasia cases we examined, we found no mutations,indicating that a negative result in any such test would beuninformative."

Wasmuth concluded, "Probably the most logical reason whysomebody might have the prenatal test for thanatophoric dysplasia isif ultrasound or X-ray show that something is clearly wrong with theskeleton. In such cases, at this point, one could identify at least 70percent of the cases by DNA testing.

"That's probably the only reason why somebody would want to havethe prenatal test, or should have it _ to confirm that it is or is notthanatophoric dysplasia," he said.

Such a test, he pointed out, looks for what is "one of the mostcommon mutations around. It's really quite straightforward, so fromthe time the laboratory gets the amniotic fluid cells until you have ananswer _ maybe two days." n

-- David N. Leff Science Editor

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