Alternative titles; symbols
SNOMEDCT: 870313002; ORPHA: 355, 85212; DO: 0110960;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Gaucher disease, perinatal lethal | 608013 | Autosomal recessive | 3 | GBA1 | 606463 |
A number sign (#) is used with this entry because perinatal lethal Gaucher disease is caused by homozygous or compound heterozygous mutation in the glucocerebrosidase gene (GBA; 606463) on chromosome 1q22.
Perinatal lethal Gaucher disease is considered to be a distinct form of type II Gaucher disease (230900) (Mignot et al., 2003).
Drukker et al. (1970) reported a Sephardic-Jewish infant with the infantile form of Gaucher disease. Intracranial hemorrhage led to death at age 48 hours. Owada et al. (1977) described 2 Japanese infants with Gaucher disease. Fractions from the liver showed no glucocerebroside activity.
Lui et al. (1988) reported 2 Lebanese sibs with acute infantile cerebral Gaucher disease with prominent collodion skin. Generalized thick skin, hepatosplenomegaly, and hypotonia were noted at birth. The infants showed respiratory distress, convulsions, and thrombocytopenia; 1 had joint contractures. In both, the tight collodion ichthyotic skin began to peel in large sheets. Both died as infants. Postmortem examination of 1 sib showed Gaucher cells in lymph nodes, thymus, liver, spleen, adrenals, and bone marrow. Keratinocytes showed normal maturation with hyperkeratosis and reduced granular layer. No abnormal storage products were identified in the skin. Lui et al. (1988) postulated that the skin abnormalities in these children may have resulted from disturbed composition of lipid in the stratum corneum.
Sidransky et al. (1992) described 2 cases of neonatal Gaucher disease: one, of Greek ancestry, died at age 2 months; the second, of African American ethnicity, died at age 7 days. The second baby required mechanical ventilation throughout life and had stiff, thick, shiny collodion skin. Biopsy demonstrated lamellar exfoliated ichthyosis. In a review of 15 additional patients with neonatal Gaucher disease from 11 unrelated families, they noted that 6 infants in 4 families had Coombs-negative hydrops. They pointed out that the phenotype in these infants is analogous to the Gaucher mouse created by targeted disruption in the mouse glucocerebroside gene.
Fujimoto et al. (1995) described male and female sibs of Mexican extraction who presented with ichthyotic skin at birth and subsequently developed neurologic manifestations of type II Gaucher disease. The authors suggested that Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis, even if the scaling resolves spontaneously.
Sidransky et al. (1996) reported 2 conceptuses from an Afghan family with perinatal lethal Gaucher disease. The first was shown to have severe hydrops fetalis with bilateral hydrothorax and fetal hypokinesia with multiple joint contractures. Fetal blood sampling indicated thrombocytopenia and abnormal liver enzymes. Delivery was induced at 33 weeks' gestation. Other features included joint contractures, hepatosplenomegaly, pulmonary hypoplasia, muscular atrophy, flattened nose with small nares, malformed ears, and tight and shiny skin. The infant died less than an hour after delivery. In the next pregnancy a prenatal diagnosis of Gaucher disease was made by enzyme assay on cultured amniocytes obtained at week 15. Neither hydrops nor joint contractures was found in the fetus aborted at 23 weeks' gestation. The findings were comparable to those in the 'knockout' Gaucher mouse in which absence of enzyme is incompatible with long survival (Sidransky et al., 1992; Tybulewicz et al., 1992).
Stone et al. (1999) reported 2 female sibs and an unrelated male infant with perinatal lethal Gaucher disease. The female sibs were born of a consanguineous couple from Cape Verde. The older sib was hydropic and delivered dead at 31 weeks' gestation. The second infant was hydropic and delivered alive at 30 weeks' gestation but died shortly after birth. The male infant was delivered at 36 weeks' gestation weighing 1900 grams with dysmorphic features including triangular face, small malformed ears, a small thorax, joint contractures, and severe microstomia, hepatosplenomegaly, and collodion-like skin. The infant was immobile except upon painful stimuli and was hypertonic with an absent Moro reflex. GBA enzyme activity was severely decreased in leukocytes from the patient. The patient's father was from Surinam and his mother was Dutch.
Stone et al. (2000) reported a male infant born to consanguineous Lebanese parents with perinatal lethal Gaucher disease. Ultrasound scanning demonstrated reduced fetal movement, neck hyperextension, and hepatomegaly. He was born at 34 weeks' gestation and died shortly thereafter. Autopsy findings included thick collodion-like skin, ectropia, joint contractures, hepatosplenomegaly, and facial dysmorphism. Gaucher cells were seen in many tissues. The diagnosis of Gaucher disease was confirmed enzymatically.
Finn et al. (2000) reported a case of type II Gaucher disease in a female Mexican infant who was born at 34 weeks' gestation and died at 2 days of age with arthrogryposis, collodion membrane, minimal neurologic reflexes and few spontaneous movements, hepatosplenomegaly, and other malformations. 'Gaucher cells' were present in the spleen, lymph nodes, bone marrow, brain, spinal cord, and other sites. There was extensive destruction, apoptosis, and loss of neurons in the brain and the spinal cord. Glucocerebroside accumulated in neurons and microglia of the brain. Beta-glucocerebrosidase activity was absent in all tissues tested. The patient was homozygous for a rare null allele, RecNciI.
Mignot et al. (2003) reported a series of perinatal lethal Gaucher disease cases highlighting the specificity of this phenotype. They retrospectively studied 8 cases of proven Gaucher disease with fetal onset. Nonimmune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphism. The similarities between these cases and 33 previously described cases allowed a better delineation of the perinatal lethal Gaucher disease phenotype. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism in 35 to 43% of cases.
The transmission pattern of perinatal lethal Gaucher disease in the patients reported by Sidransky et al. (1996) and Stone et al. (2000) was consistent with autosomal recessive inheritance.
Orvisky et al. (2000) found increased levels of glucosylsphingosine (Glc-sph), a cytotoxic compound, in mice with a severe form of Gaucher disease created with a null Gba allele. Compared with unaffected littermates, affected mice had approximately a 100-fold elevation of Glc-sph in brain, as well as elevated levels in other tissues. This accumulation was detected in utero by embryonic day 13 and increased progressively throughout gestation. Similarly, elevated Glc-sph levels were seen in 2 human fetuses with perinatal lethal Gaucher disease, indicating that therapy initiated after birth may be too late to prevent sequelae of progressive neurologic damage that begins early in gestation. The findings suggested that the accumulation of Glc-sph may be responsible for the rapid demise of Gba-null mice and the devastating clinical course seen in patients with perinatal lethal Gaucher disease.
Sidransky et al. (1996) described homozygosity for a triply mutant recombinant GBA allele (606463.0009) in 2 conceptuses from an Afghan family with lethal perinatal Gaucher disease. Stone et al. (2000) found that a male infant (patient 1) with perinatal lethal Gaucher disease, born to consanguineous Lebanese parents, was homozygous for the triply mutant recombinant allele.
In 2 female sibs with perinatal lethal Gaucher disease, Stone et al. (1999) identified a homozygous mutation in the GBA gene (H311R; 606463.0037).
Stone et al. (2000) reported 6 children who presented at birth with collodion-type skin changes and hepatosplenomegaly and were found to be beta-glucocerebrosidase-deficient. All died shortly after birth or in the first year of life from respiratory insufficiency or progressive neurologic disease. Three of the cases were homozygous for GBA mutations (see 606463.0009 and 606463.0042) and the others were compound heterozygotes.
Stone et al. (2000) performed molecular analyses of a cohort of 31 patients with type 2 Gaucher disease, including 14 patients with either manifestations in utero or diagnosis at birth. Recombinant alleles were particularly prevalent in patients presenting in utero; homozygosity for a recombinant allele was always associated with perinatal lethality.
In a premature infant with the perinatal lethal form of Gaucher disease, Felderhoff-Mueser et al. (2004) identified compound heterozygosity for 2 mutations in the GBA gene (606463.0004 and 606463.0046).
Drukker, A., Sacks, M. I., Gatt, S. The infantile form of Gaucher's disease in an infant of Jewish Sephardic origin. Pediatrics 45: 1017-1023, 1970. [PubMed: 5422102]
Felderhoff-Mueser, U., Uhl, J., Penzel, R., van Landeghem, F., Vogel, M., Obladen, M., Kopitz, J. Intrauterine onset of acute neuropathic type 2 Gaucher disease: identification of a novel insertion sequence. Am. J. Med. Genet. 128A: 138-143, 2004. [PubMed: 15214004] [Full Text: https://doi.org/10.1002/ajmg.a.20445]
Finn, L. S., Zhang, M., Chen, S.-H., Scott, C. R. Severe type II Gaucher disease with ichthyosis, arthrogryposis and neuronal apoptosis: molecular and pathological analyses. Am. J. Med. Genet. 91: 222-226, 2000. [PubMed: 10756347]
Fujimoto, A., Tayebi, N., Sidransky, E. Congenital ichthyosis preceding neurologic symptoms in two sibs with type 2 Gaucher disease. Am. J. Med. Genet. 59: 356-358, 1995. [PubMed: 8599361] [Full Text: https://doi.org/10.1002/ajmg.1320590315]
Lui, K., Commens, C., Choong, R., Jaworski, R. Collodion babies with Gaucher's disease. Arch. Dis. Child. 63: 854-856, 1988. [PubMed: 3415310] [Full Text: https://doi.org/10.1136/adc.63.7.854]
Mignot, C., Gelot, A., Bessieres, B., Daffos, F., Voyer, M., Menez, F., Fallet Bianco, C., Odent, S., Le Duff, D., Loget, P., Fargier, P., Costil, J., Josset, P., Roume, J., Vanier, M. T., Maire, I., de Villemeur, T. B. Perinatal-lethal Gaucher disease. Am. J. Med. Genet. 120A: 338-344, 2003. [PubMed: 12838552] [Full Text: https://doi.org/10.1002/ajmg.a.20117]
Orvisky, E., Sidransky, E., McKinney, C. E., LaMarca, M. E., Samimi, R., Krasnewich, D., Martin, B. M., Ginns, E. I. Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediat. Res. 48: 233-237, 2000. [PubMed: 10926300] [Full Text: https://doi.org/10.1203/00006450-200008000-00018]
Owada, M., Sakiyama, T., Kitagawa, T. Neuropathic Gaucher's disease with normal 4-methylumbelliferyl-beta-glucosidase activity in the liver. Pediat. Res. 11: 641-646, 1977. [PubMed: 870871] [Full Text: https://doi.org/10.1203/00006450-197705000-00004]
Sidransky, E., Sherer, D. M., Ginns, E. I. Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene. Pediat. Res. 32: 494-498, 1992. [PubMed: 1437405] [Full Text: https://doi.org/10.1203/00006450-199210000-00023]
Sidransky, E., Tayebi, N., Stubblefield, B. K., Eliason, W., Klineburgess, A., Pizzolato, G.-P., Cox, J. N., Porta, J., Bottani, A., DeLozier-Blanchet, C. D. The clinical, molecular, and pathological characterisation of a family with two cases of lethal perinatal type 2 Gaucher disease. J. Med. Genet. 33: 132-136, 1996. [PubMed: 8929950] [Full Text: https://doi.org/10.1136/jmg.33.2.132]
Stone, D. L., Carey, W. F., Christodoulou, J., Sillence, D., Nelson, P., Callahan, M., Tayebi, N., Sidransky, E. Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch. Dis. Child. Fetal Neonatal Ed. 82: F163-F166, 2000. [PubMed: 10685993] [Full Text: https://doi.org/10.1136/fn.82.2.f163]
Stone, D. L., Tayebi, N., Orvisky, E., Stubblefield, B., Madike, V., Sidransky, E. Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. Hum. Mutat. 15: 181-188, 2000. [PubMed: 10649495] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S]
Stone, D. L., van Diggelen, O. P., de Klerk, J. B. C., Gaillard, J. L. J., Niermeijer, M. F., Willemsen, R., Tayebi, N., Sidransky, E. Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease? Europ. J. Hum. Genet. 7: 505-509, 1999. [PubMed: 10352942] [Full Text: https://doi.org/10.1038/sj.ejhg.5200315]
Tybulewicz, V. L. J., Tremblay, M. L., LaMarca, M. E., Willemsen, R., Stubblefield, B. K., Winfield, S., Zablocka, B., Sidransky, E., Martin, B. M., Huang, S. P., Mintzer, K. A., Westphal, H., Mulligan, R. C., Ginns, E. I. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 357: 407-410, 1992. [PubMed: 1594045] [Full Text: https://doi.org/10.1038/357407a0]