General Medical Information

XX Gonadal Dysgenesis and Multiple Malformation Syndromes

Joe Leigh Simpson

Mutant genes that act on multiple organ systems are called pleiotropic. The pleiotropic gene causing XX gonadal dysgenesis and neurosensory deafness (Perrault syndrome) has already received comment. Other syndromes include XX gonadal dysgenesis and cerebellar ataxia; XX gonadal dysgenesis, microcephaly, and arachnodactyly; XX gonadal dysgenesis and epibulbar dermoid; and XX gonadal dysgenesis, short stature, and metabolic acidosis. These four disorders presumably are distinct and autosomal recessive in nature, based on presence of multiple affected siblings.

An autosomal dominant syndrome of relevance is the blepharophimosis-ptosis syndrome, recognized as associated with ovarian failure. Sib-pair analysis using polymorphic DNA variants localized the gene for blepharophimosis-ptosis to chromosome 3 (3q21-24), a region that contains no obvious candidate gene. Surprisingly, Fraser reported that ovaries in one blepharophimosis-ptosis case were unresponsive to gonadatropins.

In each of the multiple malformation syndromes associated with ovarian failure, underlying biologic questions must be posed. Does the seemingly pleiotropic gene cause both the somatic anomalies and the ovarian failure? Do the somatic and nonsomatic phenotypes involve only closely linked genes, i.e., contiguous gene syndrome? Could an unrecognized parental chromosomal rearrangement exist? In turn, do any of these genes play pivotal roles in normal ovarian differentiation and maintenance? Or, is perturbation of ovarian development merely secondary, perhaps occurring through generalized disturbance of connective tissue?

Other Causes of 46,XX Ovarian Failure

A more complete discussion of this topic is provided elsewhere. Of note, however, are the several disorders that need to be considered in differential diagnosis: 17a-hydroxylase deficiency, aromatase defects, and galactosemia.