Dubowitz syndrome is a malformation syndrome. A malformation is defined as
an "intrinsically abnormal process of development generally attributed to genetic
processes." The development of the fetus is abnormal from the very beginning
of the pregnancy, and is not caused by anything done or not done by the parents.
Dr. Opitz has this to say about the mode of inheritance: "At this time the
prevailing opinion is that the Dubowitz syndrome is an autosomal recessive
disorder. This opinion is based on the occurrence of a few cases of affected
siblings. In a few cases a parent has shown a few minor signs suggestive
of the carrier state. However all of these observations, including the
occurrence of apparent Dubowitz syndrome in the niece of our initial "prototype"
Dubowitz syndrome patient, may also be interpreted as evidence for autosomal
dominant inheritance; one of the parents of the familial cases being a mosaic
carrier of the mutation. In any event, until the genetic mystery of the Dubowitz
syndrome is solved molecularly, the most prudent view is to proceed as if the
disorder were a recessive trait."
Autosomal recessive describes a condition that results from the inheritance
of two copies of a defective gene. Since two genes are present at every site
in DNA, the syndrome is not present in individuals (carriers) who have one
normal and one defective gene because the normal gene is dominant over the
defective (recessive) gene. The condition is present in children who receive one
defective gene from each carrier parent, with the result that both
of their genes at that particular location are defective. In each pregnancy
produced by two carrier parents, the probability that the child will have the
condition (two defective genes) is 25%. The likelihood that the child will be a
carrier (one defective and one normal gene) is 50%, and the probability that
the child will neither be a carrier nor have the condition (two normal genes)
is 25%.
Neither the gene location nor the pathogenesis (the physiologic and
biochemical mechanisms by which the condition progresses) is yet known.
Opitz et al. [52] use the word pleiotropic in describing the syndrome:
pleiotropy is defined as "the production of diverse phenotypic effects
produced by a mutation in a single gene." Tsukahara and Optiz (1996)
[11] speculate on possible mechanisms: "The pathogenesis is unknown;
however a metabolic and/or DNA repair defect must be ruled out. The
phenotype suggests mosaic pleiotropy, i.e., intracellular action of the
mutant genotype at various times during pre- and post-natal development."
The frequency of carriers in the general population is unknown; however,
Tsukahara and Opitz [11] express the opinion that the "condition is probably
much more common than suggested by the literature." In a paper presenting
four Hungarian patients, Wilhelm and Mehes (1986) [1] comment, "the fact that
four cases from three families were simultaneously discovered in a town of about
100,000 inhabitants raises the possibility that the Dubowitz syndrome is not so
rare as usually believed."
The fact that only two of all reported cases involve biologically related
(consanguinous) parents also supports the premise that the gene may
not be all that rare. This point is made by Ilyina and Lurie [9] (1990):
"Rarity of parental consanguinity among patients with Dubowitz syndrome
is suggestive of a rather wide occurrence of the gene, although the syndrome
may be under-diagnosed because of mild manifestations and normal intellect."
In a 1997 article describing a 5-year-old American child adopted from Russia
who displayed no indication of developmental delay, Wallerstein et al. (1997)
[3] remark, "Most likely, Dubowitz syndrome has a range of expression with
the more severely affected patients most likely to come to attention.
Perhaps, as Ilyina and Lurie (1990) suggested, Dubowitz syndrome is
under-diagnosed because some patients are mildly affected physically and
have normal intelligence."
Although cases have been reported from all over the world, the majority,
thus far, are from the United States, Germany, and Russia (including Belarus
and other former Soviet republics).
There are numerous instances of two affected children in a single family,
and two families reportedly have three affected children. Three cases involve
twins. In a case involving non-identical twins, only one twin was affected;
however, in two cases involving identical twins, both twins were affected.
Interestingly, in both sets of identical twins (Wilroy et al. 1978 [8] and
Mohrenschlager et al. 1998 [16]), one twin had a greater number of, and
more severe manifestations than the other, and in both cases the more
affected child was the smaller of the two.
