Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease?

Abstract

In recent years there has been increased recognition of a severe perinatal lethal form of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase. We previously reported a case of severe type 2 Gaucher disease which was seen in a medical center in Rotterdam and now present three new cases from two other families seen at the same center. Mutational analyses of these cases revealed two novel mutations, H311R and V398F, located in exons 8 and 9, respectively. The identification of four cases of lethal type 2 Gaucher disease in a single center seems to be a function of increased awareness of this phenotype, rather than of geographic clustering. The actual incidence of lethal type 2 Gaucher disease may be underestimated, as many cases may have been misclassified as collodion babies or hydrops of unknown cause.

Type 2 Gaucher Disease: An Expanding Phenotype

“…These infants were born at term with collodion skin, hepatosplenomegaly, and apathy. Subsequently, many other cases have been reported, including two other unrelated Australian infants (18,19), a black American infant (20), a Turkish infant (21), a Dutch infant (22), two Afghani fetuses (23), an American fetus (24), and two Mexican siblings (25), all of whom had congenital ichthyosis as a prominent feature at presentation (Fig. 1A).…”

“…A recent survey of cases in the Netherlands revealed that there were a total of 10 cases of type 2 Gaucher disease diagnosed in Holland in the past 27 years. Five of the cases were found to have the perinatal lethal form (22). Likewise, a review of patients diagnosed with type 2 Gaucher disease in Japan included four infants with hydrops fetalis who succumbed at birth (38).…”

“…Although the skin lesions resolved within weeks, several months later both infants developed rapidly progressive neurologic deterioration characteristic of acute neuronopathic Gaucher disease and died before 1 year of age. As a direct consequence of the recognition that Gaucher patients can present perinatally with congenital ichthyosis, an increased number of such cases have been newly diagnosed (22).…”

Homozygous loss of a cysteine residue in the glucocerebrosidase gene results in Gaucher's disease with a hydropic phenotype

“…13 It has been suggested that the true incidence of perinatal lethal Gaucher's disease may be underestimated due to misclassification as hydrops of unknown cause. 4 A recent review of perinatal Gaucher's disease supports this suggestion, finding 56% of cases studied presented with nonimmune hydrops fetalis. 7 This case study is further demonstration of the importance of considering Gaucher's disease in the differential diagnosis of fetal hydrops.…”

“…6,7 The case presented in this study has shown a null phenotype as a result of homozygosity for a missense mutation, an observation that has been previously reported once where homozygosity for the missense mutation H311R also resulted in a hydrops phenotype. 4,6 These cases demonstrate that missense mutations can give rise to null phenotypes.…”