Greenberg Dysplasia
A number sign (#) is used with this entry because of evidence that Greenberg dysplasia (GRBGD) is caused by homozygous or compound heterozygous mutation in the LBR gene (600024), which encodes the lamin B receptor, on chromosome 1q42.
Homozygous mutation in the LBR gene can also cause Pelger-Huet anomaly with mild skeletal anomalies (618019). Heterozygous mutation in the LBR gene can cause Pelger-Huet anomaly (169400).
DescriptionGreenberg dysplasia, also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is a rare autosomal recessive osteochondrodysplasia characterized by gross fetal hydrops, severe shortening of all long bones with a moth-eaten radiographic appearance, platyspondyly, disorganization of chondroosseous calcification, and ectopic ossification centers. It is lethal in utero. Patient fibroblasts show increased levels of cholesta-8,14-dien-3-beta-ol, suggesting a defect of sterol metabolism (summary by Konstantinidou et al., 2008).
Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in postsqualene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis (607330), and HEM skeletal dysplasia.
Clinical FeaturesGreenberg et al. (1988) described 2 sibs, the offspring of consanguineous parents, who presented with an apparently 'new' severe form of short-limb dwarfism. The chondroosseus radiologic and histologic features were distinctive. The first sib presented at 30 weeks of gestation with severe hydrops following fetal death; the second was detected by ultrasonography at 20 weeks. Radiologic abnormalities included an unusual 'moth-eaten' appearance of the markedly short long bones, bizarre ectopic ossification centers, and marked platyspondyly with unusual ossification centers. Extensive extramedullary erythropoiesis was found in both fetuses. Chondroosseous histology was characterized by marked disorganization with interspersed masses of cartilage, bone, and mesenchymal tissue. The first fetus was male, the second female. The parents were third cousins of Greek extraction.
Spranger and Maroteaux (1990) reported a third case of the association of hydrops fetalis with ectopic calcifications and 'moth-eaten' skeletal dysplasia.
Chitayat et al. (1993) reported a fourth case in an offspring of consanguineous parents of East Indian origin. They referred to the disorder as Greenberg hydrops-ectopic calcification-moth-eaten skeletal dysplasia, or HEM dysplasia. The radiologic changes included platyspondyly with multiple extra ossification centers, extraneous calcification in the ribs, sternum, pelvis, and epiphyses, and moth-eaten long bones. The histopathologic changes included chondrocytes with dilated rough endoplasmic reticulum and inclusion bodies with homogeneous material of intermediate electron density.
Horn et al. (2000) described several nonskeletal malformations in a case of Greenberg dysplasia: omphalocele, intestinal malformation, abnormal fingernails, and hypolobated lungs.
Trajkovski et al. (2002) reported the prenatal ultrasound diagnosis of a case of Greenberg dysplasia in the male fetus of a nonconsanguineous Macedonian couple. Polyhydramnios, hydrops fetalis, severely short limbs, and cystic hygroma were noted on ultrasound. After the pregnancy was terminated, radiologic examination showed typical features of Greenberg dysplasia. The fetus had a large head with depressed nasal bridge, midface hypoplasia, and prominent orbital arches. Light microscopic examination of ribs and long bones showed severe disorganization, absent cartilage column formation, and abrupt transition from cartilage to normal bone.
Offiah et al. (2003) reported a fetus, born of unrelated Caucasian parents, with HEM skeletal dysplasia. Prenatal ultrasound at 14 weeks' gestation showed severe micromelia, and the pregnancy was terminated. Postmortem examination showed a small thorax, hepatomegaly, severely shortened limbs, and postaxial hexadactyly of the upper limbs. Dysmorphic features included a large forehead, mild mandibular recession, a flattened nose, and mild hypertelorism. Histologic examination of the bones showed disorganization of the growth plate with no chondrocyte column formation, but random, abrupt transition between cartilage and bone. Radiographs showed a moth-eaten appearance of extremely shortened long bones and significant platyspondyly. There was evidence of ectopic calcification. Biochemical analysis of muscle tissue showed increased 8,14-cholestadien-2-beta-ol.
Konstantinidou et al. (2008) reported a fetus, the product of consanguineous Greek parents, with HEM skeletal dysplasia. Prenatal ultrasound at 11 weeks' gestation showed an abnormal fetus with hydrops, micromelia, narrow thorax, and hepatomegaly. Radiographic examination showed a moth-eaten appearance of long bones. Light microscopy showed complete ossification of the femoral diaphysis and abnormal heterotopic ossification centers in the vertebrae and the long bones. The physeal growth zone was virtually absent, with abrupt transition from cartilage to mineralized, hypocellular bone. There was a history of 2 previously affected fetuses detected by prenatal ultrasound. Postmortem examination of 1 of these fetuses showed hydrops fetalis, severe rhizomelic and mesomelic shortening of all long bones, macrocephaly, low-set ears, hypertelorism, depressed nasal bridge, narrow thorax, and postaxial polydactyly of the feet. Radiographic examination showed a moth-eaten appearance of long bones. Light microscopy showed disorganization of the cartilage column and ectopic calcification.
Molecular GeneticsWaterham et al. (2003) conducted chemical and molecular investigations in cells from a fetus with HEM skeletal dysplasia, the product of healthy consanguineous Turkish parents, who presented with intrauterine growth retardation at 17 weeks' gestation on fetal ultrasound performed on the 24-year-old mother. The fetus showed severe hydrops and short-limb skeletal dysplasia. Amniotic fluid examination showed a 46,XY karyotype. Intrauterine death occurred at 18 weeks and delivery was induced. Postmortem examination showed severe hydrops, extremely short edematous limbs, and postaxial polydactyly on both hands. Radiographic examination showed severe platyspondyly, short irregular ribs, a 'moth-eaten' aspect of scapular and pelvic bones, and very short tubular bones with angulated diaphyses. Waterham et al. (2003) found elevated levels of cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts, compatible with a deficiency of the cholesterol biosynthetic enzyme 3-beta-hydroxysterol delta(14)-reductase. Sequence analysis of 2 candidate genes encoding putative human sterol delta(14)-reductases, TM7SF2 (603414) and LBR, identified homozygosity for a 7-bp substitution in exon 13 of the LBR gene (600024.0003), which resulted in a truncated protein. Functional complementation of the HEM cells by transfection with control LBR cDNA confirmed that LBR encoded the defective sterol delta(14)-reductase. The healthy mother showed hypolobulated nuclei in 60% of her granulocytes. Waterham et al. (2003) suggested that classic Pelger-Huet anomaly (PHA; 169400), which is also caused by mutation in the LBR gene, represents a heterozygous state of 3-beta-hydroxysterol delta(14)-reductase deficiency.
In a fetus, the product of consanguineous Greek parents, with HEM skeletal dysplasia, Konstantinidou et al. (2008) identified a homozygous missense mutation in the LBR gene (N547D; 600024.0008).
In 3 unrelated fetuses with HEM skeletal dysplasia, Clayton et al. (2010) identified homozygous or compound heterozygous mutations in the LBR gene (600024.0008-600024.0011). One of the patients had been reported by Offiah et al. (2003). A parent who was heterozygous for a missense mutation in the sterol reductase domain had no abnormalities of peripheral blood cells, whereas this missense mutation was shown to result in a loss of sterol reductase activity. Cellular studies showed localization of LBR outside of the nuclear membrane, where it colocalized with markers of the endoplasmic reticulum. Nonnuclear LBR was also expressed in lymphoblastoid cells, differentiated osteoclasts, and osteosarcoma cells, as well as in various tissues of developing mouse embryos. These findings suggested to Clayton et al. (2010) that HEM skeletal dysplasia results from defects in the sterol reductase activity of LBR, not from the structural function of LBR as part of the nuclear membrane. The uncoupling of the metabolic and structural functions of LBR explained how mutations in the same gene can cause distinct disorders. The findings also indicated that sterol reductase function is essential for intrauterine development in humans.
Animal ModelWassif et al. (2007) studied mice with deficits of Lbr and/or Tm7sf2, another sterol delta(14)-reductase, and demonstrated that these proteins provide substantial enzymatic redundancy with respect to cholesterol synthesis; they concluded, therefore, that HEM dysplasia is a laminopathy rather than an inborn error of cholesterol synthesis.