Greenberg Dysplasia

Mendelian MONDO:0008974 Pathograph 12 Show in embeddings browser Sterol Biosynthesis Disorder Chondrodysplasia Punctata Laminopathy

Greenberg dysplasia - also called HEM skeletal dysplasia, for hydrops, ectopic calcification, and the moth-eaten appearance of the long bones and pelvis - is an autosomal recessive, prenatally lethal chondrodystrophy caused by biallelic loss-of-function variants in LBR. Its interest is that the causal protein does two unrelated jobs. LBR is an inner nuclear membrane protein whose nucleoplasmic domain tethers heterochromatin to the nuclear periphery and shapes the interphase nucleus, while its transmembrane domains carry the 3-beta-hydroxysterol delta-14-reductase activity of the cholesterol biosynthetic pathway. Which of those two functions the lethal skeletal phenotype comes from was genuinely open for a decade, and the question was settled by an experiment rather than by argument: two Greenberg-causing missense variants were shown to fail to rescue a C14-sterol-reductase-deficient yeast strain, while the carrier parents had no Pelger anomaly - so the alleles abolished the enzyme without measurably disturbing nuclear structure. The metabolic function is therefore the one that is essential for human intrauterine development, and Greenberg dysplasia belongs with the sterol-biosynthesis malformation syndromes rather than with the laminopathies, despite LBR sitting in the nuclear envelope. The same gene supports an unusually clean allelic series that maps onto the two functions: heterozygous variants impairing the structural role give the benign Pelger-Huet anomaly of hypolobulated granulocyte nuclei, biallelic variants leaving residual reductase activity give a mild, spontaneously regressing spondylometaphyseal dysplasia, and biallelic variants abolishing it give this disorder. That the healthy mother of the index Greenberg fetus had hypolobulated nuclei in 60% of her granulocytes is what first showed classic Pelger-Huet anomaly to be the heterozygous state of the same enzyme deficiency.

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1
Mappings
1
Inheritance
5
Pathophys.
7
Phenotypes
2
Gaps
12
Pathograph
1
Genes
1
Medical Actions
3
Differentials
7
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE ENDOCRINOLOGY METABOLISM
ICIMD (Inherited Metabolic Disorders)
sterol metabolism
ISDS Skeletal Nosology
chondrodysplasia punctata
🔗

Mappings

MONDO
MONDO:0008974 Greenberg dysplasia
skos:exactMatch MONDO
The dismech entry and the MONDO class denote the same entity: the biallelic LBR-related prenatally lethal HEM skeletal dysplasia. The other LBR phenotypes (Pelger-Huet anomaly, the anadysplasia-like spondylometaphyseal dysplasia, the reported non-lethal skeletal dysplasia) are discussed here as an allelic series but are not part of this class.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic variants are required. A heterozygous carrier is not merely unaffected but may carry a detectable trait of their own - the classic Pelger-Huet anomaly - which is how the relationship between the two phenotypes was first recognized.
autosomal recessive inheritance
Show evidence (1 reference)
PMID:12618959 SUPPORT Human Clinical
"The fact that the healthy mother of the fetus showed hypolobulated nuclei in 60% of her granulocytes confirms that classic Pelger-Huët anomaly represents the heterozygous state of 3beta-hydroxysterol delta(14)-reductase deficiency."
Establishes both the recessive inheritance and the identity of the heterozygous state with Pelger-Huet anomaly.
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Discussions and Knowledge Gaps

2
By what route does loss of sterol C14-reductase activity produce ectopic calcification and moth-eaten long bones, rather than some other consequence of cholesterol deficiency?
KNOWLEDGE GAP OPEN sterol_to_skeleton_route_greenberg
Attached to
pathophysiology#Accumulation of Cholesta-8,14-dien-3-beta-ol pathophysiology#Abnormal Chondro-Osseous Calcification
The upstream half of this disorder is unusually well established - the accumulating sterol was measured, the enzyme inferred, the gene found, patient cells complemented, and the enzymatic arm separated experimentally from the structural one. The downstream half is not. Lbr expression in the embryonic mouse skeleton and skin matches the sites of histological change, which localizes the lesion but does not explain it, and the same gap exists for the other post-squalene disorders in this nosology group. The tractable comparison is within the allelic series itself: Greenberg dysplasia, the anadysplasia-like spondylometaphyseal dysplasia, and the reported non-lethal biallelic phenotype differ in residual reductase activity, so they form a natural dose-response series against which any proposed downstream mechanism could be tested.
Show evidence (1 reference)
PMID:21327084 SUPPORT Model Organism
"We studied Lbr in mouse embryos and demonstrate expression in skin and the developing skeletal system consistent with sites of histological changes in Greenberg dysplasia."
Expression mapping localizes the lesion to the affected tissues without identifying the mechanism within them.
Given that the enzymatic arm is established as the cause of lethality, does the structural arm contribute anything to the Greenberg phenotype in patients carrying truncating rather than missense alleles?
KNOWLEDGE GAP OPEN lbr_dual_function_residual_role
Attached to
pathophysiology#LBR Structural Function at the Inner Nuclear Membrane
The uncoupling experiment used two missense alleles and showed that abolishing the reductase activity alone is sufficient for the lethal phenotype. That is not the same as showing the structural function never contributes. The index Greenberg allele is truncating, and truncated LBR variants have separately been shown to be highly unstable and rapidly degraded by a nuclear-membrane protein quality control pathway - so a patient with two truncating alleles loses the protein entirely, both functions at once, while a patient with two missense alleles may keep the structural one. Whether those two genotype classes differ phenotypically has not been tested, and the question bears on whether this entry's mechanism is complete as modelled.
Show evidence (1 reference)
PMID:27830109 SUPPORT In Vitro
"Moreover, two disease-associated LBR truncation mutants were found to be highly unstable at the protein level and are rapidly turned over by a novel nuclear membrane-based protein quality control pathway."
Establishes that truncating alleles remove the protein rather than only its enzymatic activity, which is the basis for expecting the two genotype classes to differ.
⚙

Pathophysiology

5
LBR Sterol C14-Reductase Deficiency
Biallelic LBR variants abolish the 3-beta-hydroxysterol delta-14-reductase activity carried by the protein's transmembrane domains, blocking the C14 reduction step of post-squalene cholesterol synthesis. The gene was reached through the biochemistry rather than the other way round: an accumulating sterol was identified first, that pointed to a C14 reductase, and only two candidate genes were then sequenced.
Genetic context LBR hgnc:6518 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns LBR (hgnc:6518). hgnc:6518 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic (homozygous or compound heterozygous) germline loss-of-function variants, including truncating alleles and missense alleles at residues conserved among sterol reductases. The Greenberg phenotype requires essentially complete loss of the reductase activity; alleles leaving residual activity give the milder biallelic phenotype instead.
cholesterol biosynthesis GO:0006695 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cholesterol biosynthesis, annotated with cholesterol biosynthetic process (GO:0006695). GO:0006695 is a biological process from the Gene Ontology. ↓ DECREASED
3-beta-hydroxysterol delta-14-reductase activity GO:0050613 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves 3-beta-hydroxysterol delta-14-reductase activity, annotated with Delta14-sterol reductase activity (GO:0050613), qualified as loss of function. GO:0050613 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Cellular Cholesterol Deficiency The block also starves the cell of the pathway end product. This is the second arm of the dual lesion that the post-squalene cholesterol-synthesis disorders share, and it is the arm that reaches limb patterning rather than mineralization.
Accumulation of Cholesta-8,14-dien-3-beta-ol Substrate immediately above the C14 reduction step accumulates, and its elevation in cultured fibroblasts is the biochemical marker that identified the enzyme.
Show evidence (2 references)
PMID:12618959 SUPPORT In Vitro
"Functional complementation of the HEM cells by transfection with control LBR cDNA confirmed that LBR encoded the defective sterol delta(14)-reductase."
Complementation of patient cells with wild-type LBR establishes that the enzymatic deficiency is caused by the LBR lesion, rather than merely co-occurring with it.
PMID:21327084 SUPPORT In Vitro
"In contrast to wildtype LBR, both mutations failed to rescue C14 sterol reductase deficient yeast, indicating an enzymatic defect."
A yeast complementation assay demonstrates the enzymatic defect for the specific Greenberg-causing missense alleles.
Cellular Cholesterol Deficiency
Loss of the pathway end product, separately from any toxicity of the sterol that accumulates above the block. Cholesterol is required for the maturation and signalling of hedgehog proteins, which is the route by which a lipid-synthesis enzymopathy reaches embryonic patterning rather than mineralization. This node is why postaxial polydactyly belongs in this entry at all: it is a limb patterning defect, not a consequence of disordered calcification, and it recurs across the distal cholesterol-pathway disorders that have nothing else in common with Greenberg dysplasia. The same node and the same argument appear in the CDPX2 entry.
smoothened signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Postaxial Polydactyly Impaired hedgehog signalling is the standing explanation for the postaxial polydactyly seen across the distal cholesterol-biosynthesis disorders. The specific steps have not been demonstrated in Greenberg dysplasia, so the edge is recorded as having unknown intermediates rather than as a worked-out mechanism.
Show evidence (1 reference)
PMID:20929975 SUPPORT Other
"Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development."
States the hedgehog dependence on cholesterol that connects this enzyme class to malformation rather than to mineralization phenotypes.
Accumulation of Cholesta-8,14-dien-3-beta-ol
The sterol intermediate immediately upstream of the block accumulates while cholesterol synthesis falls - the same dual lesion seen across the post-squalene cholesterol-synthesis disorders. It is the diagnostic analyte for the disorder in cultured fibroblasts.
Downstream
Abnormal Chondro-Osseous Calcification The route from the sterol lesion to disordered mineralization of cartilage and bone is not resolved, but the tissue distribution matches: Lbr is expressed in the developing skeletal system and skin in the mouse embryo, the sites of the histological changes seen in the disorder.
Show evidence (1 reference)
PMID:30561119 SUPPORT Human Clinical
"Pathogenic variants associated with GRBGD or PHASK result in a deficiency of sterol reductase activity and in elevated levels of sterol intermediates [Tsai and others 2016]."
Confirms that both biallelic LBR phenotypes share the reductase deficiency with accumulation of upstream sterol intermediates.
LBR Structural Function at the Inner Nuclear Membrane
The second, separable function of the same protein: the nucleoplasmic domain binds lamin B and chromatin and tethers heterochromatin to the nuclear periphery, maintaining interphase nuclear shape. This node is modelled not because it drives Greenberg dysplasia but because establishing that it does not is what defines the disorder's mechanism. Alleles that impair it heterozygously give Pelger-Huet anomaly; the Greenberg alleles studied for this question left it measurably intact.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
heterochromatin organization GO:0070828 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves heterochromatin organization (GO:0070828). GO:0070828 is a biological process from the Gene Ontology. nuclear envelope organization GO:0006998 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves nuclear envelope organization (GO:0006998). GO:0006998 is a biological process from the Gene Ontology.
Downstream
Abnormal Chondro-Osseous Calcification A structural-function route to the skeletal phenotype is the hypothesis that the uncoupling experiment argued against, and it is retained here as a refuted alternative rather than an asserted mechanism.
Show evidence (2 references)
PMID:21327084 SUPPORT In Vitro
"The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural function interacting with chromatin and lamins, and an enzymatic function as a sterol reductase."
States the protein's two functions, which the disorder's mechanism turns on.
PMID:21327084 REFUTE Human Clinical
"We found no Pelger anomaly in the carrier parent excluding marked effects on nuclear structure."
Recorded as REFUTE because it is evidence against the structural arm being the cause of the Greenberg phenotype: the carrier parent of these Greenberg alleles had no nuclear-morphology phenotype at all.
Abnormal Chondro-Osseous Calcification
Disordered mineralization of cartilage and bone gives the disorder its radiographic signature: ectopic calcifications together with a "moth-eaten" appearance of the long bones and pelvis, on a background of markedly shortened limbs.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ⚠ ABNORMAL endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Ectopic Calcification Calcific deposits outside the normal ossification sequence, the "EC" of HEM.
Epiphyseal Stippling Punctate epiphyseal calcification with stippling of the spine and of the tarsal and carpal bones.
Abnormal Long Bone Morphology The moth-eaten appearance of the long bones and pelvis, the "M" of HEM.
Micromelia Markedly shortened limbs.
Short Ribs and Narrow Thorax A small thorax with transverse rib defects, the thoracic expression of the same disordered chondro-osseous development.
Hydrops Fetalis Fetal hydrops accompanies the skeletal lesion in this disorder; the route from disordered chondro-osseous development to fluid accumulation is not established, and is recorded here as an observed association within the syndrome rather than an explained one.
Show evidence (1 reference)
PMID:12618959 SUPPORT Human Clinical
"characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification"
Names abnormal chondro-osseous calcification as a defining feature.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Greenberg Dysplasia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Limbs 2
Postaxial Polydactyly HP:0100259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial polydactyly (HP:0100259). HP:0100259 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32304187 SUPPORT Human Clinical
"bilateral post-axial polydactyly of the feet and a small chest with protuberant abdomen"
Documents postaxial polydactyly of the feet in the reported fetus, alongside the narrow chest.
PMID:32304187 SUPPORT Human Clinical
"Two fetuses were subsequently reported with post-axial polydactyly of the hands"
Establishes that the polydactyly recurs across reported cases rather than being a one-off finding, and that it affects the hands as well as the feet.
Micromelia HP:0002983 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micromelia (HP:0002983). HP:0002983 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12618959 SUPPORT Human Clinical
"characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification"
Names short limbs as a defining feature.
Metabolism 1
Hydrops Fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12618959 SUPPORT Human Clinical
"characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification"
Names fetal hydrops as a defining feature.
Musculoskeletal 1
Short Ribs and Narrow Thorax Narrow chest HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow chest (HP:0000774). HP:0000774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"marked platyspondyly and stippled spine, small thorax, transverse rib defects"
The postmortem skeletal survey documents the small thorax and the rib defects in a molecularly confirmed case.
Other 3
Ectopic Calcification HP:0010766 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ectopic calcification (HP:0010766). HP:0010766 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"It is also referred to as HEM skeletal dysplasia due to the characteristic clinical features of hydrops, ectopic calcification, and the moth-eaten appearance of long bones and the pelvis (Chitayat et al., 1993)."
Names ectopic calcification as one of the three characteristic features.
Abnormal Long Bone Morphology HP:0011314 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal long bone morphology (HP:0011314). HP:0011314 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"the moth-eaten appearance of long bones and the pelvis (Chitayat et al., 1993)"
Names the moth-eaten long-bone appearance.
Epiphyseal Stippling HP:0010655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epiphyseal stippling (HP:0010655). HP:0010655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"rhizo-mesomelic shortening and deformity of all four limbs, punctate epiphyses, stippled tarsal and carpal bones, and widespread ectopic ossification"
The postmortem skeletal survey documents punctate epiphyses and stippling of the tarsal and carpal bones in a molecularly confirmed case.
🧬

Genetic Associations

1
LBR
Gene: LBR hgnc:6518 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LBR (hgnc:6518). hgnc:6518 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:12618959 SUPPORT Human Clinical
"Sequence analysis of two candidate genes encoding putative human sterol delta(14)-reductases (TM7SF2 and LBR) identified a homozygous 1599-1605TCTTCTA-->CTAGAAG substitution in exon 13 of the LBR gene encoding the lamin B receptor, which results in a truncated protein."
Identifies the gene and the index truncating allele, and records that the other candidate C14 reductase, TM7SF2, was excluded.
PMID:30561119 SUPPORT Human Clinical
"The diverse phenotypes are correlated to the functional domain affected, the heterozygous or homozygous state of the variants, and their different impact on the residual protein function."
States the three axes of the genotype-phenotype correlation for this gene.
💊

Medical Actions

1
Prenatal diagnosis and genetic counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
No disease-modifying treatment exists and the course is perinatally lethal, so care is prenatal diagnosis, discussion of the lethal prognosis, and recurrence-risk counselling for the 25% autosomal recessive risk.
Show evidence (1 reference)
PMID:30561119 SUPPORT Human Clinical
"identified by whole exome sequencing and causing Greenberg dysplasia in two fetuses from a consanguineous Moroccan family"
Recurrence in two fetuses of one consanguineous family is the situation counselling addresses; the report also shows exome sequencing as the route to the diagnosis.
🔬

Biochemical Markers

1
Cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts
Show evidence (1 reference)
PMID:12618959 SUPPORT Human Clinical
"We found elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin fibroblasts of an 18-wk-old fetus with HEM"
States the analyte and the sample type.
🔬

Diagnosis

1
Molecular confirmation of biallelic LBR variants
Diagnosis is made on the prenatal clinical and radiographic picture and confirmed by biallelic LBR variants, with fibroblast sterol profiling as the biochemical corroboration. Examining the parents' granulocytes for hypolobulated nuclei is a cheap and informative adjunct, since a carrier may show Pelger-Huet anomaly.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR."
Documents molecular confirmation as the diagnostic route.
📈

Progression

2
Prenatal - hydrops and short limbs on fetal imaging
The disorder presents in utero. Fetal hydrops with markedly short limbs is what brings it to attention, and the moth-eaten long bones and ectopic calcifications are seen on fetal or post-mortem radiographs.
Show evidence (1 reference)
PMID:12618959 SUPPORT Human Clinical
"Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification."
States the presenting prenatal features.
Perinatal lethality
The course is lethal in the perinatal period. There is no postnatal natural history to describe, and management is prenatal diagnosis, counselling, and recurrence-risk assessment.
Show evidence (1 reference)
PMID:30561119 SUPPORT Human Clinical
"Greenberg skeletal dysplasia is an autosomal recessive, perinatal lethal disorder associated with biallelic variants affecting the lamin B receptor (LBR) gene."
States the perinatal lethality.
📊

Prevalence

1
Worldwide
Unknown Ultra Rare
No numeric estimate is available. The literature describes the disorder as very rare and the case series consists of individually reported fetuses.
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"Greenberg dysplasia (OMIM #215140) is a very rare, prenatally lethal, autosomal recessive bone dysplasia (Greenberg et al., 1988)."
Characterizes the disorder as very rare and prenatally lethal.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Greenberg Dysplasia:

X-linked chondrodysplasia punctata 2 (Conradi-Hunermann-Happle syndrome) MONDO:0020603
Overlapping Features Another sterol-biosynthesis disorder in the same skeletal nosology group whose severe end overlaps the Greenberg picture radiographically. The distinction is inheritance and the specific sterol profile.
Distinguishing Features
  • CDPX2 is X-linked dominant with a mosaic, asymmetric phenotype; Greenberg dysplasia is autosomal recessive and uniform
  • CDPX2 accumulates 8(9)-cholestenol and 8-dehydrocholesterol; Greenberg dysplasia accumulates cholesta-8,14-dien-3-beta-ol
  • CDPX2 has a broad severity range including near-normal adults; Greenberg dysplasia is perinatally lethal
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X-linked dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome"
Names CDPX2 and CHILD syndrome as the sterol-pathway look-alikes.
Dappled diaphyseal dysplasia and Astley-Kendall dysplasia
Overlapping Features Two entities of previously unknown genetic cause whose clinical and radiographic phenotypes closely resemble Greenberg dysplasia. On that comparison they have been proposed to be allelic with it - which, if confirmed, would make them LBR disorders rather than differentials. dismech records the proposal without adopting it.
Distinguishing Features
  • Reported without an established molecular cause, so the distinction rests on radiographic pattern rather than genotype
  • Proposed to be allelic with Greenberg dysplasia rather than genuinely separate entities
Show evidence (1 reference)
PMID:32304187 SUPPORT Human Clinical
"Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic disorders."
States the proposal, at the strength the authors state it.
Pelger-Huet anomaly and the milder biallelic LBR skeletal phenotypes
Overlapping Features Not a diagnostic confusion so much as the rest of the allelic series. Heterozygous structural-domain variants give the benign granulocyte anomaly; biallelic variants with residual reductase activity give a mild, spontaneously regressing spondylometaphyseal dysplasia; and a homozygous missense variant has been reported in two adult sisters with a non-lethal skeletal dysplasia and no Pelger-Huet anomaly at all.
Distinguishing Features
  • Pelger-Huet anomaly is heterozygous, benign, and confined to granulocyte nuclear morphology
  • The anadysplasia-like spondylometaphyseal dysplasia is biallelic but mild and spontaneously regressing
  • Greenberg dysplasia requires biallelic variants that abolish rather than reduce sterol reductase activity
Show evidence (1 reference)
PMID:32827848 SUPPORT Human Clinical
"We identified a homozygous LBR missense mutation (NM_002296.4: c.1366C > G, p.(Leu456Val)) in two adult sisters with a Lamin B receptor-related disorder associated with a skeletal dysplasia milder than Greenberg Dysplasia."
Documents a biallelic non-lethal LBR skeletal phenotype, widening the allelic series beyond the two classical poles.
{ }

Source YAML

click to show 
name: Greenberg Dysplasia
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Greenberg dysplasia - also called HEM skeletal dysplasia, for hydrops, ectopic
  calcification, and the moth-eaten appearance of the long bones and pelvis - is an
  autosomal recessive, prenatally lethal chondrodystrophy caused by biallelic
  loss-of-function variants in LBR. Its interest is that the causal protein does two
  unrelated jobs. LBR is an inner nuclear membrane protein whose nucleoplasmic domain
  tethers heterochromatin to the nuclear periphery and shapes the interphase nucleus,
  while its transmembrane domains carry the 3-beta-hydroxysterol delta-14-reductase
  activity of the cholesterol biosynthetic pathway. Which of those two functions the
  lethal skeletal phenotype comes from was genuinely open for a decade, and the question
  was settled by an experiment rather than by argument: two Greenberg-causing missense
  variants were shown to fail to rescue a C14-sterol-reductase-deficient yeast strain,
  while the carrier parents had no Pelger anomaly - so the alleles abolished the enzyme
  without measurably disturbing nuclear structure. The metabolic function is therefore
  the one that is essential for human intrauterine development, and Greenberg dysplasia
  belongs with the sterol-biosynthesis malformation syndromes rather than with the
  laminopathies, despite LBR sitting in the nuclear envelope. The same gene supports an
  unusually clean allelic series that maps onto the two functions: heterozygous variants
  impairing the structural role give the benign Pelger-Huet anomaly of hypolobulated
  granulocyte nuclei, biallelic variants leaving residual reductase activity give a mild,
  spontaneously regressing spondylometaphyseal dysplasia, and biallelic variants
  abolishing it give this disorder. That the healthy mother of the index Greenberg fetus
  had hypolobulated nuclei in 60% of her granulocytes is what first showed classic
  Pelger-Huet anomaly to be the heterozygous state of the same enzyme deficiency.
synonyms:
- HEM skeletal dysplasia
- Hydrops-ectopic calcification-moth-eaten skeletal dysplasia
- Greenberg skeletal dysplasia
- GRBGD
- Skeletal dysplasia, Greenberg type
disease_term:
  preferred_term: Greenberg dysplasia
  term:
    id: MONDO:0008974
    label: Greenberg dysplasia
parents:
- Sterol Biosynthesis Disorder
- Chondrodysplasia Punctata
- Laminopathy
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      An autosomal recessive Mendelian lethal skeletal dysplasia; the clinical encounter
      is prenatal diagnosis and genetic counselling rather than organ-system management.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Also an inborn error of metabolism: a demonstrated block in post-squalene
      cholesterol biosynthesis, with the diagnostic accumulation of
      cholesta-8,14-dien-3-beta-ol.
  icimd_category:
  - classification_value: sterol_metabolism
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders of sterol metabolism"
      under category "Disorders of lipid metabolism". The assignment follows the
      experimental separation of LBR's two functions: the Greenberg-causing alleles
      abolish sterol C14-reductase activity, so this is a cholesterol-synthesis
      enzymopathy rather than a structural nuclear-envelope disease, even though the
      protein is a nuclear envelope protein and the same gene also causes a laminopathy.
  isds_skeletal_category:
  - classification_value: chondrodysplasia_punctata
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 23 "Chondrodysplasia punctata (CDP) group", row
      NOS 23-0050 "Greenberg dysplasia, LBR-related" (MIM 215140). Carried forward from
      the 2019 revision (Mortier et al., PMID:31633310), where the group was numbered 21.
      Exactly one group is assigned. Two caveats worth recording. First, the other
      LBR-related skeletal phenotype - the mild, regressing biallelic
      anadysplasia-like spondylometaphyseal dysplasia - is a separate concept and is not
      covered by this row. Second, dappled diaphyseal dysplasia and Astley-Kendall
      dysplasia have been argued on clinical and radiographic grounds to be allelic with
      Greenberg dysplasia; neither appears as a 2023 group-23 row, and dismech does not
      annotate them here, since a proposed allelic relationship is not a nosology
      placement.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008974
      label: Greenberg dysplasia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The dismech entry and the MONDO class denote the same entity: the biallelic
      LBR-related prenatally lethal HEM skeletal dysplasia. The other LBR phenotypes
      (Pelger-Huet anomaly, the anadysplasia-like spondylometaphyseal dysplasia, the
      reported non-lethal skeletal dysplasia) are discussed here as an allelic series but
      are not part of this class.
references:
- reference: PMID:12618959
  title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
- reference: PMID:21327084
  title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
- reference: PMID:27830109
  title: "Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism."
- reference: PMID:30561119
  title: "A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes."
- reference: PMID:32304187
  title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
- reference: PMID:32827848
  title: "A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly."
- reference: PMID:20929975
  title: "Malformation syndromes caused by disorders of cholesterol synthesis."
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    No numeric estimate is available. The literature describes the disorder as very rare
    and the case series consists of individually reported fetuses.
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Greenberg dysplasia (OMIM #215140) is a very rare, prenatally lethal, autosomal
      recessive bone dysplasia (Greenberg et al., 1988).
    explanation: Characterizes the disorder as very rare and prenatally lethal.
progression:
- phase: Prenatal - hydrops and short limbs on fetal imaging
  notes: >-
    The disorder presents in utero. Fetal hydrops with markedly short limbs is what
    brings it to attention, and the moth-eaten long bones and ectopic calcifications are
    seen on fetal or post-mortem radiographs.
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia is
      an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal
      hydrops, short limbs, and abnormal chondro-osseous calcification.
    explanation: States the presenting prenatal features.
- phase: Perinatal lethality
  notes: >-
    The course is lethal in the perinatal period. There is no postnatal natural history
    to describe, and management is prenatal diagnosis, counselling, and recurrence-risk
    assessment.
  evidence:
  - reference: PMID:30561119
    reference_title: "A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Greenberg skeletal dysplasia is an autosomal recessive, perinatal lethal disorder
      associated with biallelic variants affecting the lamin B receptor (LBR) gene.
    explanation: States the perinatal lethality.
pathophysiology:
- name: LBR Sterol C14-Reductase Deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic LBR variants abolish the 3-beta-hydroxysterol delta-14-reductase activity
    carried by the protein's transmembrane domains, blocking the C14 reduction step of
    post-squalene cholesterol synthesis. The gene was reached through the biochemistry
    rather than the other way round: an accumulating sterol was identified first, that
    pointed to a C14 reductase, and only two candidate genes were then sequenced.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    gene:
      preferred_term: LBR
      term:
        id: hgnc:6518
        label: LBR
    description: >-
      Biallelic (homozygous or compound heterozygous) germline loss-of-function variants,
      including truncating alleles and missense alleles at residues conserved among sterol
      reductases. The Greenberg phenotype requires essentially complete loss of the
      reductase activity; alleles leaving residual activity give the milder biallelic
      phenotype instead.
  molecular_functions:
  - preferred_term: 3-beta-hydroxysterol delta-14-reductase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0050613
      label: Delta14-sterol reductase activity
  biological_processes:
  - preferred_term: cholesterol biosynthesis
    modifier: DECREASED
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional complementation of the HEM cells by transfection with control LBR cDNA
      confirmed that LBR encoded the defective sterol delta(14)-reductase.
    explanation: >-
      Complementation of patient cells with wild-type LBR establishes that the enzymatic
      deficiency is caused by the LBR lesion, rather than merely co-occurring with it.
  - reference: PMID:21327084
    reference_title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to wildtype LBR, both mutations failed to rescue C14 sterol reductase
      deficient yeast, indicating an enzymatic defect.
    explanation: >-
      A yeast complementation assay demonstrates the enzymatic defect for the specific
      Greenberg-causing missense alleles.
  downstream:
  - target: Cellular Cholesterol Deficiency
    description: >-
      The block also starves the cell of the pathway end product. This is the second arm of
      the dual lesion that the post-squalene cholesterol-synthesis disorders share, and it is
      the arm that reaches limb patterning rather than mineralization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20929975
      reference_title: "Malformation syndromes caused by disorders of cholesterol synthesis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Generally, inborn errors of cholesterol synthesis lead to both a deficiency of
        cholesterol and increased levels of potentially bioactive or toxic precursor sterols.
      explanation: >-
        States the dual lesion for this disorder class. The same review covers HEM dysplasia
        by name, so Greenberg dysplasia is one of the entities it is describing.
  - target: Accumulation of Cholesta-8,14-dien-3-beta-ol
    description: >-
      Substrate immediately above the C14 reduction step accumulates, and its elevation in
      cultured fibroblasts is the biochemical marker that identified the enzyme.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12618959
      reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin
        fibroblasts of an 18-wk-old fetus with HEM, compatible with a deficiency of the
        cholesterol biosynthetic enzyme 3beta-hydroxysterol delta(14)-reductase.
      explanation: >-
        Documents the accumulating sterol in patient cells and its inference to the
        enzymatic block.
- name: Cellular Cholesterol Deficiency
  biological_scale: CELLULAR
  description: >-
    Loss of the pathway end product, separately from any toxicity of the sterol that
    accumulates above the block. Cholesterol is required for the maturation and signalling of
    hedgehog proteins, which is the route by which a lipid-synthesis enzymopathy reaches
    embryonic patterning rather than mineralization. This node is why postaxial polydactyly
    belongs in this entry at all: it is a limb patterning defect, not a consequence of
    disordered calcification, and it recurs across the distal cholesterol-pathway disorders
    that have nothing else in common with Greenberg dysplasia. The same node and the same
    argument appear in the CDPX2 entry.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  evidence:
  - reference: PMID:20929975
    reference_title: "Malformation syndromes caused by disorders of cholesterol synthesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cholesterol is also essential for the proper maturation and signaling of hedgehog
      proteins, and thus cholesterol is critical for embryonic development.
    explanation: >-
      States the hedgehog dependence on cholesterol that connects this enzyme class to
      malformation rather than to mineralization phenotypes.
  downstream:
  - target: Postaxial Polydactyly
    description: >-
      Impaired hedgehog signalling is the standing explanation for the postaxial polydactyly
      seen across the distal cholesterol-biosynthesis disorders. The specific steps have not
      been demonstrated in Greenberg dysplasia, so the edge is recorded as having unknown
      intermediates rather than as a worked-out mechanism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32304187
      reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other disorders caused by variants more distally in the cholesterol biosynthesis
        pathway can also present with rhizomelia and post-axial polydactyly, including
        Smith-Lemli-Opitz syndrome and desmosterolosis
      explanation: >-
        Attributes the combination of rhizomelia and postaxial polydactyly to the cholesterol
        biosynthesis pathway across several disorders, which is the basis for routing
        polydactyly through the cholesterol-deficiency arm rather than the calcification arm.
- name: Accumulation of Cholesta-8,14-dien-3-beta-ol
  biological_scale: MOLECULAR
  description: >-
    The sterol intermediate immediately upstream of the block accumulates while
    cholesterol synthesis falls - the same dual lesion seen across the post-squalene
    cholesterol-synthesis disorders. It is the diagnostic analyte for the disorder in
    cultured fibroblasts.
  evidence:
  - reference: PMID:30561119
    reference_title: "A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants associated with GRBGD or PHASK result in a deficiency of sterol
      reductase activity and in elevated levels of sterol intermediates [Tsai and others
      2016].
    explanation: >-
      Confirms that both biallelic LBR phenotypes share the reductase deficiency with
      accumulation of upstream sterol intermediates.
  downstream:
  - target: Abnormal Chondro-Osseous Calcification
    description: >-
      The route from the sterol lesion to disordered mineralization of cartilage and bone
      is not resolved, but the tissue distribution matches: Lbr is expressed in the
      developing skeletal system and skin in the mouse embryo, the sites of the
      histological changes seen in the disorder.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21327084
      reference_title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We studied Lbr in mouse embryos and demonstrate expression in skin and the
        developing skeletal system consistent with sites of histological changes in
        Greenberg dysplasia.
      explanation: >-
        Expression at the affected sites is consistent with a cell-autonomous skeletal
        lesion but does not identify the intervening steps.
- name: LBR Structural Function at the Inner Nuclear Membrane
  biological_scale: CELLULAR
  description: >-
    The second, separable function of the same protein: the nucleoplasmic domain binds
    lamin B and chromatin and tethers heterochromatin to the nuclear periphery,
    maintaining interphase nuclear shape. This node is modelled not because it drives
    Greenberg dysplasia but because establishing that it does not is what defines the
    disorder's mechanism. Alleles that impair it heterozygously give Pelger-Huet anomaly;
    the Greenberg alleles studied for this question left it measurably intact.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: heterochromatin organization
    term:
      id: GO:0070828
      label: heterochromatin organization
  - preferred_term: nuclear envelope organization
    term:
      id: GO:0006998
      label: nuclear envelope organization
  evidence:
  - reference: PMID:21327084
    reference_title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural
      function interacting with chromatin and lamins, and an enzymatic function as a
      sterol reductase.
    explanation: States the protein's two functions, which the disorder's mechanism turns on.
  - reference: PMID:21327084
    reference_title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found no Pelger anomaly in the carrier parent excluding marked effects on nuclear
      structure.
    explanation: >-
      Recorded as REFUTE because it is evidence against the structural arm being the cause
      of the Greenberg phenotype: the carrier parent of these Greenberg alleles had no
      nuclear-morphology phenotype at all.
  downstream:
  - target: Abnormal Chondro-Osseous Calcification
    description: >-
      A structural-function route to the skeletal phenotype is the hypothesis that the
      uncoupling experiment argued against, and it is retained here as a refuted
      alternative rather than an asserted mechanism.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:21327084
      reference_title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: >-
        We conclude that LBR missense mutations can abolish sterol reductase activity,
        causing lethal Greenberg dysplasia but not Pelger anomaly.
      explanation: >-
        The conclusion assigns the lethal phenotype to the enzymatic and not the structural
        arm, so this edge is recorded as hypothesized and refuted rather than supported.
- name: Abnormal Chondro-Osseous Calcification
  biological_scale: TISSUE
  description: >-
    Disordered mineralization of cartilage and bone gives the disorder its radiographic
    signature: ectopic calcifications together with a "moth-eaten" appearance of the long
    bones and pelvis, on a background of markedly shortened limbs.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: bone mineralization
    modifier: ABNORMAL
    term:
      id: GO:0030282
      label: bone mineralization
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification"
    explanation: Names abnormal chondro-osseous calcification as a defining feature.
  downstream:
  - target: Ectopic Calcification
    causal_link_type: DIRECT
    description: Calcific deposits outside the normal ossification sequence, the "EC" of HEM.
  - target: Epiphyseal Stippling
    causal_link_type: DIRECT
    description: >-
      Punctate epiphyseal calcification with stippling of the spine and of the tarsal and
      carpal bones.
  - target: Abnormal Long Bone Morphology
    causal_link_type: DIRECT
    description: The moth-eaten appearance of the long bones and pelvis, the "M" of HEM.
  - target: Micromelia
    causal_link_type: DIRECT
    description: Markedly shortened limbs.
  - target: Short Ribs and Narrow Thorax
    causal_link_type: DIRECT
    description: >-
      A small thorax with transverse rib defects, the thoracic expression of the same
      disordered chondro-osseous development.
  - target: Hydrops Fetalis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Fetal hydrops accompanies the skeletal lesion in this disorder; the route from
      disordered chondro-osseous development to fluid accumulation is not established, and
      is recorded here as an observed association within the syndrome rather than an
      explained one.
phenotypes:
- name: Hydrops Fetalis
  category: Prenatal
  description: Generalized fetal fluid accumulation, the "H" of the HEM acronym.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification"
    explanation: Names fetal hydrops as a defining feature.
- name: Ectopic Calcification
  category: Skeletal
  description: Calcific deposits outside normal ossification centres, the "EC" of the HEM acronym.
  phenotype_term:
    preferred_term: Ectopic calcification
    term:
      id: HP:0010766
      label: Ectopic calcification
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is also referred to as HEM skeletal dysplasia due to the characteristic clinical
      features of hydrops, ectopic calcification, and the moth-eaten appearance of long
      bones and the pelvis (Chitayat et al., 1993).
    explanation: Names ectopic calcification as one of the three characteristic features.
- name: Abnormal Long Bone Morphology
  category: Skeletal
  description: >-
    The "moth-eaten" radiographic appearance of the long bones and pelvis, the "M" of the
    HEM acronym.
  phenotype_term:
    preferred_term: Abnormal long bone morphology
    term:
      id: HP:0011314
      label: Abnormal long bone morphology
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the moth-eaten appearance of long bones and the pelvis (Chitayat et al., 1993)
    explanation: Names the moth-eaten long-bone appearance.
- name: Epiphyseal Stippling
  category: Skeletal
  description: >-
    Punctate epiphyses with stippling of the spine and of the tarsal and carpal bones. This
    is the finding that anchors the disorder in the chondrodysplasia punctata group, and it
    sits alongside - not instead of - the widespread ectopic ossification that gives the
    moth-eaten appearance.
  phenotype_term:
    preferred_term: Epiphyseal stippling
    term:
      id: HP:0010655
      label: Epiphyseal stippling
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rhizo-mesomelic shortening and deformity of all four limbs, punctate epiphyses,
      stippled tarsal and carpal bones, and widespread ectopic ossification
    explanation: >-
      The postmortem skeletal survey documents punctate epiphyses and stippling of the tarsal
      and carpal bones in a molecularly confirmed case.
- name: Short Ribs and Narrow Thorax
  category: Skeletal
  description: >-
    A small thorax with transverse rib defects giving a "cut-glass" radiographic appearance.
    The narrow chest is part of why the disorder is not survivable.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      marked platyspondyly and stippled spine, small thorax, transverse rib defects
    explanation: >-
      The postmortem skeletal survey documents the small thorax and the rib defects in a
      molecularly confirmed case.
- name: Postaxial Polydactyly
  category: Skeletal
  description: >-
    Postaxial polydactyly, reported in the hands and the feet across several cases. It is
    shared with the other post-squalene cholesterol-synthesis disorders that present with
    rhizomelia - Smith-Lemli-Opitz syndrome and desmosterolosis - which is one of the
    overlaps that made the sterol pathway a plausible place to look for the cause.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral post-axial polydactyly of the feet and a small chest with protuberant abdomen
    explanation: >-
      Documents postaxial polydactyly of the feet in the reported fetus, alongside the narrow
      chest.
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two fetuses were subsequently reported with post-axial polydactyly of the hands
    explanation: >-
      Establishes that the polydactyly recurs across reported cases rather than being a
      one-off finding, and that it affects the hands as well as the feet.
- name: Micromelia
  category: Skeletal
  description: Markedly shortened limbs, present from mid-gestation.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by fetal hydrops, short limbs, and abnormal chondro-osseous calcification"
    explanation: Names short limbs as a defining feature.
genetic:
- name: LBR
  relationship_type: CAUSATIVE
  presence: Present
  gene_term:
    preferred_term: LBR
    term:
      id: hgnc:6518
      label: LBR
  notes: >-
    LBR at 1q42.1. The gene supports at least three clinical phenotypes, and which one
    results is a function of the domain affected, the zygosity, and the residual protein
    activity - heterozygous structural-domain variants give Pelger-Huet anomaly, biallelic
    variants with residual reductase activity give the anadysplasia-like
    spondylometaphyseal dysplasia, and biallelic variants abolishing reductase activity
    give Greenberg dysplasia.
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of two candidate genes encoding putative human sterol
      delta(14)-reductases (TM7SF2 and LBR) identified a homozygous
      1599-1605TCTTCTA-->CTAGAAG substitution in exon 13 of the LBR gene encoding the
      lamin B receptor, which results in a truncated protein.
    explanation: >-
      Identifies the gene and the index truncating allele, and records that the other
      candidate C14 reductase, TM7SF2, was excluded.
  - reference: PMID:30561119
    reference_title: "A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diverse phenotypes are correlated to the functional domain affected, the
      heterozygous or homozygous state of the variants, and their different impact on the
      residual protein function.
    explanation: States the three axes of the genotype-phenotype correlation for this gene.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic variants are required. A heterozygous carrier is not merely unaffected but
    may carry a detectable trait of their own - the classic Pelger-Huet anomaly - which is
    how the relationship between the two phenotypes was first recognized.
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fact that the healthy mother of the fetus showed hypolobulated nuclei in 60% of
      her granulocytes confirms that classic Pelger-Huët anomaly represents the
      heterozygous state of 3beta-hydroxysterol delta(14)-reductase deficiency.
    explanation: >-
      Establishes both the recessive inheritance and the identity of the heterozygous state
      with Pelger-Huet anomaly.
biochemical:
- name: Cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts
  notes: >-
    Elevation of the sterol immediately upstream of the C14 reduction step, measured in
    cultured skin fibroblasts. This was the finding that identified the enzyme before the
    gene was known, and it remains the biochemical confirmation of the diagnosis.
  evidence:
  - reference: PMID:12618959
    reference_title: "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin fibroblasts
      of an 18-wk-old fetus with HEM
    explanation: States the analyte and the sample type.
diagnosis:
- name: Molecular confirmation of biallelic LBR variants
  description: >-
    Diagnosis is made on the prenatal clinical and radiographic picture and confirmed by
    biallelic LBR variants, with fibroblast sterol profiling as the biochemical
    corroboration. Examining the parents' granulocytes for hypolobulated nuclei is a
    cheap and informative adjunct, since a carrier may show Pelger-Huet anomaly.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a
      pathogenic variant in LBR.
    explanation: Documents molecular confirmation as the diagnostic route.
treatments:
- name: Prenatal diagnosis and genetic counselling
  description: >-
    No disease-modifying treatment exists and the course is perinatally lethal, so care is
    prenatal diagnosis, discussion of the lethal prognosis, and recurrence-risk counselling
    for the 25% autosomal recessive risk.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30561119
    reference_title: "A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified by whole exome sequencing and causing Greenberg dysplasia in two fetuses
      from a consanguineous Moroccan family
    explanation: >-
      Recurrence in two fetuses of one consanguineous family is the situation counselling
      addresses; the report also shows exome sequencing as the route to the diagnosis.
differential_diagnoses:
- name: X-linked chondrodysplasia punctata 2 (Conradi-Hunermann-Happle syndrome)
  disease_term:
    preferred_term: X-linked chondrodysplasia punctata 2
    term:
      id: MONDO:0020603
      label: X-linked chondrodysplasia punctata 2
  description: >-
    Another sterol-biosynthesis disorder in the same skeletal nosology group whose severe
    end overlaps the Greenberg picture radiographically. The distinction is inheritance and
    the specific sterol profile.
  distinguishing_features:
  - CDPX2 is X-linked dominant with a mosaic, asymmetric phenotype; Greenberg dysplasia is autosomal recessive and uniform
  - CDPX2 accumulates 8(9)-cholestenol and 8-dehydrocholesterol; Greenberg dysplasia accumulates cholesta-8,14-dien-3-beta-ol
  - CDPX2 has a broad severity range including near-normal adults; Greenberg dysplasia is perinatally lethal
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conditions with abnormal sterol metabolism and different genetic basis have clinical
      and radiographic features similar to Greenberg dysplasia, for example X-linked
      dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome
    explanation: Names CDPX2 and CHILD syndrome as the sterol-pathway look-alikes.
- name: Dappled diaphyseal dysplasia and Astley-Kendall dysplasia
  description: >-
    Two entities of previously unknown genetic cause whose clinical and radiographic
    phenotypes closely resemble Greenberg dysplasia. On that comparison they have been
    proposed to be allelic with it - which, if confirmed, would make them LBR disorders
    rather than differentials. dismech records the proposal without adopting it.
  distinguishing_features:
  - Reported without an established molecular cause, so the distinction rests on radiographic pattern rather than genotype
  - Proposed to be allelic with Greenberg dysplasia rather than genuinely separate entities
  evidence:
  - reference: PMID:32304187
    reference_title: "A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled
      diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic
      disorders.
    explanation: States the proposal, at the strength the authors state it.
- name: Pelger-Huet anomaly and the milder biallelic LBR skeletal phenotypes
  description: >-
    Not a diagnostic confusion so much as the rest of the allelic series. Heterozygous
    structural-domain variants give the benign granulocyte anomaly; biallelic variants with
    residual reductase activity give a mild, spontaneously regressing spondylometaphyseal
    dysplasia; and a homozygous missense variant has been reported in two adult sisters
    with a non-lethal skeletal dysplasia and no Pelger-Huet anomaly at all.
  distinguishing_features:
  - Pelger-Huet anomaly is heterozygous, benign, and confined to granulocyte nuclear morphology
  - The anadysplasia-like spondylometaphyseal dysplasia is biallelic but mild and spontaneously regressing
  - Greenberg dysplasia requires biallelic variants that abolish rather than reduce sterol reductase activity
  evidence:
  - reference: PMID:32827848
    reference_title: "A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous LBR missense mutation (NM_002296.4: c.1366C > G,
      p.(Leu456Val)) in two adult sisters with a Lamin B receptor-related disorder
      associated with a skeletal dysplasia milder than Greenberg Dysplasia.
    explanation: >-
      Documents a biallelic non-lethal LBR skeletal phenotype, widening the allelic series
      beyond the two classical poles.
discussions:
- discussion_id: sterol_to_skeleton_route_greenberg
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Accumulation of Cholesta-8,14-dien-3-beta-ol
  - pathophysiology#Abnormal Chondro-Osseous Calcification
  prompt: >-
    By what route does loss of sterol C14-reductase activity produce ectopic calcification
    and moth-eaten long bones, rather than some other consequence of cholesterol
    deficiency?
  rationale: >-
    The upstream half of this disorder is unusually well established - the accumulating
    sterol was measured, the enzyme inferred, the gene found, patient cells complemented,
    and the enzymatic arm separated experimentally from the structural one. The downstream
    half is not. Lbr expression in the embryonic mouse skeleton and skin matches the sites
    of histological change, which localizes the lesion but does not explain it, and the
    same gap exists for the other post-squalene disorders in this nosology group. The
    tractable comparison is within the allelic series itself: Greenberg dysplasia, the
    anadysplasia-like spondylometaphyseal dysplasia, and the reported non-lethal biallelic
    phenotype differ in residual reductase activity, so they form a natural dose-response
    series against which any proposed downstream mechanism could be tested.
  evidence:
  - reference: PMID:21327084
    reference_title: "Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We studied Lbr in mouse embryos and demonstrate expression in skin and the developing
      skeletal system consistent with sites of histological changes in Greenberg dysplasia.
    explanation: >-
      Expression mapping localizes the lesion to the affected tissues without identifying
      the mechanism within them.
- discussion_id: lbr_dual_function_residual_role
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#LBR Structural Function at the Inner Nuclear Membrane
  prompt: >-
    Given that the enzymatic arm is established as the cause of lethality, does the
    structural arm contribute anything to the Greenberg phenotype in patients carrying
    truncating rather than missense alleles?
  rationale: >-
    The uncoupling experiment used two missense alleles and showed that abolishing the
    reductase activity alone is sufficient for the lethal phenotype. That is not the same
    as showing the structural function never contributes. The index Greenberg allele is
    truncating, and truncated LBR variants have separately been shown to be highly unstable
    and rapidly degraded by a nuclear-membrane protein quality control pathway - so a
    patient with two truncating alleles loses the protein entirely, both functions at once,
    while a patient with two missense alleles may keep the structural one. Whether those
    two genotype classes differ phenotypically has not been tested, and the question bears
    on whether this entry's mechanism is complete as modelled.
  evidence:
  - reference: PMID:27830109
    reference_title: "Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, two disease-associated LBR truncation mutants were found to be highly
      unstable at the protein level and are rapidly turned over by a novel nuclear
      membrane-based protein quality control pathway.
    explanation: >-
      Establishes that truncating alleles remove the protein rather than only its enzymatic
      activity, which is the basis for expecting the two genotype classes to differ.
notes: >-
  Curated as its own dismech entry because the ISDS 2023 nosology lists it as its own row
  (NOS 23-0050). The other LBR phenotypes are deliberately not modelled as subtypes here:
  Pelger-Huet anomaly is not a skeletal disorder at all, and the milder biallelic skeletal
  phenotypes are separate concepts that MONDO:0008974 does not cover. They are recorded as
  an allelic series in the differential diagnoses instead, which keeps the genotype-phenotype
  gradient visible without asserting that they are the same disease. A member of the
  Chondrodysplasia_Punctata grouping.

  On the `Laminopathy` parent, which sits oddly beside this entry's argument that the lethal
  phenotype comes from the enzymatic and not the structural arm of LBR. It is kept
  deliberately, and the two claims are compatible rather than contradictory: LBR genuinely is
  an inner nuclear membrane protein, MONDO genuinely classifies this disease beneath
  MONDO:0021106 (laminopathy), and much of the relevant literature - the Pelger-Huet work, the
  protein-quality-control work on truncated LBR - is nuclear-envelope literature that a reader
  should be able to reach from here. What the entry denies is narrower: that the *lethality*
  is caused by loss of the structural function. `parents` is navigational, whereas
  `icimd_category: sterol_metabolism` is the mechanistic claim, and only the latter is
  asserted as mechanism. Dropping the parent would hide a true classification to remove an
  apparent inconsistency.
📚

References & Deep Research

References

7
PMID:12618959
Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene.
No top-level findings curated for this source.
PMID:21327084
Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein.
No top-level findings curated for this source.
PMID:27830109
Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism.
No top-level findings curated for this source.
PMID:30561119
A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes.
No top-level findings curated for this source.
PMID:32304187
A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders.
No top-level findings curated for this source.
PMID:32827848
A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly.
No top-level findings curated for this source.
PMID:20929975
Malformation syndromes caused by disorders of cholesterol synthesis.
No top-level findings curated for this source.