X-linked dominant chondrodysplasia punctata type 2 (CDPX2, Conradi-Hunermann-Happle syndrome) is caused by heterozygous loss-of-function variants in EBP, which encodes the 3-beta-hydroxysteroid-delta8,delta7-isomerase (emopamil-binding protein) that isomerizes the double bond one step below lanosterol in post-squalene cholesterol biosynthesis. As in the other distal-cholesterol-pathway disorders the lesion is dual: cells lose the pathway end product and simultaneously accumulate the immediately upstream intermediates, 8(9)-cholestenol and 8-dehydrocholesterol, whose elevation in plasma, skin scale, or cultured cells is the biochemical signature of the disease. What makes CDPX2 mechanistically distinctive within its ISDS nosology group is not the enzymology but the fact that the phenotype is a *mosaic* readout of it. EBP is X-linked, so a heterozygous female is a functional mosaic of enzyme-competent and enzyme-deficient clones, and the disease is written onto the body in that clonal geometry - blaschkolinear ichthyotic scaling in the newborn that later resolves into linear follicular atrophoderma and scarring alopecia along the same lines, asymmetric rather than symmetric rhizomelic shortening, sectorial rather than whole-lens cataract, and side-to-side differences in epiphyseal stippling. The same mosaicism explains the disorder's unusual epidemiology at both extremes: at least 95% of live-born affected individuals are female because hemizygous males are usually lost in early gestation, while the affected males who do survive do so by being mosaic themselves (post-zygotic variants or a 47,XXY karyotype) or by carrying a hypomorphic allele that leaves residual isomerase activity. Because clone proportions vary between individuals and between body regions, the severity range is correspondingly enormous - from fetal demise with multiple malformations to obligate carrier mothers whose only finding is a strand of atrophic scalp skin, recognized only after a severely affected daughter is born.
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Conditions with similar clinical presentations that must be differentiated from X-linked Chondrodysplasia Punctata 2:
name: X-linked Chondrodysplasia Punctata 2
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
X-linked dominant chondrodysplasia punctata type 2 (CDPX2, Conradi-Hunermann-Happle
syndrome) is caused by heterozygous loss-of-function variants in EBP, which encodes
the 3-beta-hydroxysteroid-delta8,delta7-isomerase (emopamil-binding protein) that
isomerizes the double bond one step below lanosterol in post-squalene cholesterol
biosynthesis. As in the other distal-cholesterol-pathway disorders the lesion is
dual: cells lose the pathway end product and simultaneously accumulate the
immediately upstream intermediates, 8(9)-cholestenol and 8-dehydrocholesterol, whose
elevation in plasma, skin scale, or cultured cells is the biochemical signature of
the disease. What makes CDPX2 mechanistically distinctive within its ISDS nosology
group is not the enzymology but the fact that the phenotype is a *mosaic* readout of
it. EBP is X-linked, so a heterozygous female is a functional mosaic of
enzyme-competent and enzyme-deficient clones, and the disease is written onto the
body in that clonal geometry - blaschkolinear ichthyotic scaling in the newborn that
later resolves into linear follicular atrophoderma and scarring alopecia along the
same lines, asymmetric rather than symmetric rhizomelic shortening, sectorial rather
than whole-lens cataract, and side-to-side differences in epiphyseal stippling. The
same mosaicism explains the disorder's unusual epidemiology at both extremes: at
least 95% of live-born affected individuals are female because hemizygous males are
usually lost in early gestation, while the affected males who do survive do so by
being mosaic themselves (post-zygotic variants or a 47,XXY karyotype) or by carrying
a hypomorphic allele that leaves residual isomerase activity. Because clone
proportions vary between individuals and between body regions, the severity range is
correspondingly enormous - from fetal demise with multiple malformations to obligate
carrier mothers whose only finding is a strand of atrophic scalp skin, recognized
only after a severely affected daughter is born.
synonyms:
- CDPX2
- Conradi-Hunermann-Happle syndrome
- Conradi-Hunermann syndrome
- X-linked dominant chondrodysplasia punctata
- EBP-related X-linked chondrodysplasia punctata
- EBP-CDPX
disease_term:
preferred_term: X-linked chondrodysplasia punctata 2
term:
id: MONDO:0020603
label: X-linked chondrodysplasia punctata 2
parents:
- X-linked Chondrodysplasia Punctata
- Sterol Biosynthesis Disorder
- Hereditary Skin Disorder
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
An X-linked Mendelian disorder whose entire clinical logic - male lethality, the
mosaic distribution of lesions, the severity range between relatives carrying the
same allele - is genetic rather than organ-system based.
- classification_value: DERMATOLOGY
notes: >-
The newborn presentation is cutaneous, and the linear ichthyosis, follicular
atrophoderma, and scarring alopecia are the findings that persist and that most
often bring an adult carrier to attention.
- classification_value: ENDOCRINOLOGY_METABOLISM
notes: >-
Also an inborn error of metabolism: an enzymatic block in post-squalene
cholesterol biosynthesis, confirmed by the plasma or tissue sterol profile.
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". EBP is the
sterol-delta8-isomerase of the distal cholesterol pathway, placing CDPX2 with
CHILD syndrome, Smith-Lemli-Opitz syndrome, and the other post-squalene defects
rather than with the peroxisomal members of its skeletal nosology group.
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 23-0020 "CDP, X-linked dominant, EBP-related (Conradi-Hunermann type; CDPX2)"
(MIM 302960). Carried forward from the 2019 revision (Mortier et al.,
PMID:31633310), where the group was numbered 21. Exactly one group is assigned:
the nosology lists each entity once, and CDPX2's sterol-pathway biology - shared
with CHILD syndrome and Greenberg dysplasia, which sit in the same group, but
also with Smith-Lemli-Opitz syndrome, which is not a nosology entity at all - is
handled by the table's cross-references, not by dual membership.
mappings:
mondo_mappings:
- term:
id: MONDO:0020603
label: X-linked chondrodysplasia punctata 2
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
The dismech entry and the MONDO class denote the same entity: EBP-related
X-linked dominant chondrodysplasia punctata. The entry additionally discusses
the hypomorphic-allele male phenotype, which some authors argue is a distinct
X-linked recessive entity; that is recorded as a discussion rather than folded
into the mapping.
references:
- reference: PMID:21634086
title: "EBP-Related X-Linked Chondrodysplasia Punctata."
tags:
- GeneReviews
- reference: PMID:10391219
title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
- reference: PMID:10391218
title: "Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com."
- reference: PMID:24700572
title: "A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2."
- reference: PMID:20929975
title: "Malformation syndromes caused by disorders of cholesterol synthesis."
prevalence:
- population: Live-born affected individuals, sex distribution
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
No population prevalence estimate is cited here. What the literature does quantify
is the sex ratio among live births, which is itself a consequence of the mechanism
(early gestational lethality in hemizygous males).
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At least 95% of live-born individuals with EBP-CDPX are female."
explanation: >-
Quantifies the sex distribution among live births that follows from male
hemizygous lethality.
- population: Affected females, proportion with a de novo variant
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
A recurrence-risk rather than an occurrence figure, recorded here because it is the
number that drives counselling: most affected females are simplex cases, but a
substantial minority have a mildly affected or mosaic parent.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "About 60% of affected females have the disorder as the result of a de novo pathogenic variant."
explanation: >-
Establishes that roughly 40% inherit the variant, which is why parental
evaluation is part of the diagnostic workup.
progression:
- phase: Neonatal period - scaling skin and stippled skeleton
notes: >-
The disorder is most recognizable at birth, when both of its diagnostic findings
are present simultaneously: patterned ichthyotic scaling and radiographic
epiphyseal stippling. Both are transient, which is why a diagnosis missed in the
newborn period becomes markedly harder later.
evidence:
- reference: PMID:33147667
reference_title: "Conradi-Hünermann-Happle syndrome: report of a novel heterozygous mutation on the emopamil-binding protein gene, c.333delC."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Herein, we report a full-term newborn that presented at birth with scattered
blaschkolinear bands of adherent scales and scalp erosions in a spiral
distribution.
explanation: >-
Documents the newborn cutaneous presentation and its blaschkolinear geometry.
- phase: Infancy and childhood - scaling resolves into follicular atrophoderma
notes: >-
The ichthyotic scaling of the newborn gives way to linear and whorled atrophic
patches centred on hair follicles, with coarse hair and scarring alopecia in the
same distribution. The skin findings change character but keep the same clonal
geometry, because the underlying mosaic is fixed.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
linear or blotchy scaling ichthyosis in the newborn; later appearance of linear
or whorled atrophic patches involving hair follicles (follicular atrophoderma);
coarse hair with scarring alopecia; and cataracts.
explanation: >-
States the sequence from newborn scaling to follicular atrophoderma and scarring
alopecia.
- phase: Childhood to adulthood - orthopedic course
notes: >-
Epiphyseal stippling resolves as the epiphyses ossify, but the asymmetric limb
shortening it accompanied does not, and scoliosis becomes the dominant orthopedic
problem. Surveillance is therefore orthopedic and ophthalmologic rather than
dermatologic in later life.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Orthopedic evaluations to monitor kyphoscoliosis, joint problems, linear growth,
and any leg length discrepancy per orthopedist
explanation: >-
The recommended surveillance identifies kyphoscoliosis and leg-length discrepancy
as the persisting skeletal problems.
- phase: Whole-lifespan severity range
notes: >-
CDPX2 has no single natural history. The same gene, and sometimes the same variant
within one family, produces outcomes from fetal demise to an adult with no
recognizable abnormality, because the phenotype is a function of the mosaic
proportion rather than of the allele alone.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The findings in EBP-related X-linked chondrodysplasia punctata (EBP-CDPX) range
from fetal demise with multiple malformations and severe growth deficiency to
much milder manifestations, including females with no recognizable physical
abnormalities.
explanation: >-
States the full severity range directly.
pathophysiology:
- name: EBP Sterol-Delta8-Isomerase Deficiency
biological_scale: MOLECULAR
description: >-
Loss-of-function variants in EBP abolish or reduce
3-beta-hydroxysteroid-delta8,delta7-isomerase activity, the step that moves the
sterol double bond from position 8 to position 7 in the conversion of lanosterol to
cholesterol. The enzymatic assignment was made in the reverse of the usual
direction: the sterol profile of patients was characterized first and pointed at
the isomerase, and the candidate gene was then found mutated in every proband
tested.
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
gene:
preferred_term: EBP
term:
id: hgnc:3133
label: EBP
description: >-
Heterozygous germline (or, in the surviving affected male, post-zygotic mosaic)
loss-of-function variants. Missense alleles were shown to be functionally
deficient by complementation in an isomerase-deficient yeast strain. Zygosity is
recorded as heterozygous because that is the state in the affected female who
constitutes at least 95% of live births; a hemizygous male with a null allele is
generally not viable.
molecular_functions:
- preferred_term: sterol delta8-delta7 isomerase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0000247
label: C-8 sterol isomerase activity
biological_processes:
- preferred_term: cholesterol biosynthesis
modifier: DECREASED
term:
id: GO:0006695
label: cholesterol biosynthetic process
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using SSCP analysis and sequencing of genomic DNA, we found EBP mutations in all probands."
explanation: >-
Establishes EBP variants as the cause in the biochemically defined patient
cohort.
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We confirmed the functional significance of two missense alleles by expressing
them in a sterol-delta8-isomerase-deficient yeast strain.
explanation: >-
A complementation assay in an isomerase-deficient yeast strain establishes that
the patient missense alleles are functionally deficient, not merely associated.
downstream:
- target: Accumulation of 8(9)-Cholestenol and 8-Dehydrocholesterol
description: >-
Blocking the isomerase backs up flux immediately above the block, so the two
substrate sterols accumulate in plasma and tissue.
causal_link_type: DIRECT
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This pattern of accumulated cholesterol intermediates suggested a deficiency of
3beta-hydroxysteroid-delta8,delta7-isomerase (sterol-delta8-isomerase), which
catalyses an intermediate step in the conversion of lanosterol to cholesterol.
explanation: >-
Explicitly links the accumulated intermediates to the position of the enzymatic
block.
- target: Cellular Cholesterol Deficiency
description: >-
The same block starves the cell of the pathway end product. Both arms of the
lesion operate together, which is the general pattern of the post-squalene
cholesterol-synthesis disorders.
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 that applies to this class of disorders, of which CDPX2
is one of the reviewed members.
- name: Accumulation of 8(9)-Cholestenol and 8-Dehydrocholesterol
biological_scale: MOLECULAR
description: >-
The two sterols immediately upstream of the isomerase accumulate. Their elevation
is both the diagnostic marker of the disease and, in the shared model for this
disorder class, a potentially bioactive or toxic insult in its own right rather
than an inert by-product. Because the accumulation occurs only in
mutant-expressing clones, it is a cell-autonomous signal that tracks the mosaic.
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue samples
from seven female probands with CDPX2 (ref. 4).
explanation: >-
Documents the accumulated sterols in patient tissue.
downstream:
- target: Abnormal Cartilage Calcification and Endochondral Ossification
description: >-
Sterol-pathway disruption in growth-plate and epiphyseal cartilage produces the
punctate calcification that names the disorder family.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and
suggest a role for sterols in bone development.
explanation: >-
The authors themselves frame the connection between the enzyme defect and bone
development as a suggestion, which is why this edge is annotated as having
unknown intermediates.
- target: Epidermal Barrier and Follicular Dysfunction
description: >-
Keratinocytes depend on the distal cholesterol pathway for barrier lipid
synthesis, and the mutant-expressing clones show the ichthyotic and follicular
phenotype.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cellular Cholesterol Deficiency
biological_scale: CELLULAR
description: >-
Beyond its structural membrane role, cholesterol is required for the covalent
modification and signalling competence of hedgehog proteins, so a block in its
synthesis has a developmental-patterning consequence that is separate from any
toxicity of the accumulating intermediates. This is the shared explanatory route
from a lipid-synthesis enzymopathy to a malformation syndrome across the
post-squalene disorders.
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 of cholesterol that connects this enzyme class to
malformation phenotypes.
downstream:
- target: Abnormal Cartilage Calcification and Endochondral Ossification
description: >-
Hedgehog signalling governs growth-plate chondrocyte proliferation and
differentiation, so its impairment is a plausible route from the enzyme block to
the skeletal phenotype.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: X-Inactivation Mosaicism
biological_scale: ORGANISM
description: >-
EBP is on Xp11.22-p11.23, so random X inactivation makes a heterozygous female a
functional mosaic of enzyme-competent and enzyme-deficient clones. This node is
what converts a uniform enzymopathy into the disorder's signature patterned,
asymmetric phenotype, and it is also what accounts for the severity range and for
the survival of the rare affected male. It is the mechanistic feature that most
sharply distinguishes CDPX2 from the autosomal recessive members of the same
skeletal nosology group, where every cell carries the same deficiency.
biological_processes:
- preferred_term: random X inactivation
term:
id: GO:0060816
label: random inactivation of X chromosome
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Females who inherit an EBP pathogenic variant will be heterozygotes and have a
highly variable clinical phenotype.
explanation: >-
Records the variability among heterozygotes that the mosaic model explains.
- reference: PMID:24700572
reference_title: "A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These males exhibit a phenotype similar to CDPX2 due to either somatic mosaicism
or a 47, XXY karyotype in association with a null EBP allele.
explanation: >-
Affected males with a null allele survive only when they are themselves mosaic,
which is direct evidence that mosaicism rather than allele identity governs
viability.
downstream:
- target: Blaschkolinear Cutaneous Phenotype
description: >-
Clones of mutant-expressing keratinocytes follow the embryonic migration paths of
the epidermis, so their dysfunction is written on the skin as Blaschko lines.
causal_link_type: DIRECT
evidence:
- reference: PMID:33147667
reference_title: "Conradi-Hünermann-Happle syndrome: report of a novel heterozygous mutation on the emopamil-binding protein gene, c.333delC."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Herein, we report a full-term newborn that presented at birth with scattered
blaschkolinear bands of adherent scales and scalp erosions in a spiral
distribution.
explanation: >-
The blaschkolinear and spiral distribution of the lesions is the visible
expression of the clonal mosaic.
- target: Asymmetric Skeletal Involvement
description: >-
Because the mosaic is not bilaterally symmetric, limb shortening and epiphyseal
stippling differ between the two sides - a pattern that separates CDPX2 from the
symmetric rhizomelic CDPs.
causal_link_type: DIRECT
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial
cataracts, patchy alopecia, ichthyosis and atrophoderma.
explanation: >-
The asymmetry of the limb shortening, the sectorial rather than total cataract,
and the patchiness of the alopecia are all mosaic readouts listed together.
- target: Male Hemizygous Lethality
description: >-
A non-mosaic hemizygous male has no enzyme-competent clones anywhere, and is
usually lost in early gestation.
causal_link_type: DIRECT
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
EBP-CDPX is inherited in an X-linked manner with typical (but not absolute)
early gestational male lethality.
explanation: >-
States the male lethality and, in the parenthesis, that it is not absolute -
the escape routes being mosaicism and hypomorphic alleles.
- name: Abnormal Cartilage Calcification and Endochondral Ossification
biological_scale: TISSUE
description: >-
Growth-plate and epiphyseal cartilage calcifies abnormally, producing punctate foci
of calcification in the epiphyses of long bones, the vertebrae, the trachea, and
the costal ends. The stippling is transient - it disappears as the epiphyses
ossify - but the disordered endochondral growth it accompanies leaves permanent
shortening and spinal deformity.
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
- preferred_term: growth plate cartilage chondrocyte
term:
id: CL:1000217
label: growth plate cartilage chondrocyte
biological_processes:
- preferred_term: endochondral ossification
modifier: ABNORMAL
term:
id: GO:0001958
label: endochondral ossification
- preferred_term: cartilage development
modifier: ABNORMAL
term:
id: GO:0051216
label: cartilage development
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
chondrodysplasia punctata (stippling of the epiphyses of the long bones,
vertebrae, trachea, and distal ends of the ribs)
explanation: >-
Enumerates the sites of punctate calcification, which is wider than the epiphyses
alone.
downstream:
- target: Epiphyseal Stippling
causal_link_type: DIRECT
description: Punctate calcification in cartilage is the defining radiographic finding.
- target: Coronal Cleft Vertebrae
causal_link_type: DIRECT
description: Vertebral cartilage involvement produces coronal clefting of the vertebral bodies.
- target: Scoliosis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Asymmetric vertebral growth following disordered endochondral ossification.
description: >-
Spinal deformity develops out of the disordered and asymmetric vertebral growth
and is the orthopedic problem that persists after the stippling resolves.
- target: Short Stature
causal_link_type: DIRECT
description: Disordered endochondral growth limits linear growth.
- name: Asymmetric Skeletal Involvement
biological_scale: ORGANISM
description: >-
Rhizomelic (proximal) limb shortening in CDPX2 is characteristically unequal
between the two sides, giving leg-length discrepancy as well as short stature. The
asymmetry is not incidental - it is the skeletal expression of the same clonal
mosaic that patterns the skin.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "often asymmetric rhizomelic shortening of limbs"
explanation: >-
States that the rhizomelic shortening is characteristically asymmetric.
downstream:
- target: Rhizomelic Limb Shortening
causal_link_type: DIRECT
description: Proximal limb segments are disproportionately short.
- target: Asymmetric Growth
causal_link_type: DIRECT
description: The unequal involvement of the two sides produces measurable asymmetry and leg-length discrepancy.
- name: Blaschkolinear Cutaneous Phenotype
biological_scale: TISSUE
description: >-
Mutant-expressing keratinocyte clones produce ichthyotic scaling at birth that
resolves over infancy into linear and whorled atrophic patches centred on hair
follicles, with coarse hair and scarring alopecia in the same distribution. The
lesion changes over time while its geometry does not.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: keratinocyte differentiation
modifier: ABNORMAL
term:
id: GO:0030216
label: keratinocyte differentiation
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
linear or blotchy scaling ichthyosis in the newborn; later appearance of linear
or whorled atrophic patches involving hair follicles (follicular atrophoderma);
coarse hair with scarring alopecia; and cataracts.
explanation: >-
Describes the evolution of the cutaneous phenotype and its follicular
involvement.
downstream:
- target: Ichthyosis
causal_link_type: DIRECT
description: The newborn presentation is linear or blotchy ichthyotic scaling.
- target: Scarring Alopecia
causal_link_type: DIRECT
description: Follicular destruction within affected clones produces patchy scarring alopecia.
- target: Coarse Hair
causal_link_type: DIRECT
description: Hair shafts arising from affected follicles are coarse and lustreless.
- name: Epidermal Barrier and Follicular Dysfunction
biological_scale: CELLULAR
description: >-
The cutaneous phenotype is cell-autonomous to keratinocyte clones expressing the
mutant allele, which are the clones that both lack cholesterol and accumulate the
upstream sterols. The epidermis is a tissue in which the distal cholesterol pathway
is not redundant, since barrier lipids must be synthesized locally.
biological_processes:
- preferred_term: epidermis development
modifier: ABNORMAL
term:
id: GO:0008544
label: epidermis development
downstream:
- target: Blaschkolinear Cutaneous Phenotype
causal_link_type: DIRECT
description: Clone-restricted keratinocyte dysfunction appears as the patterned cutaneous phenotype.
- name: Male Hemizygous Lethality
biological_scale: ORGANISM
description: >-
A male carrying a null EBP allele on his single X has no enzyme-competent tissue
and is typically lost in early gestation. The rule is not absolute, and the two
documented escape routes are informative about the mechanism: post-zygotic
mosaicism (or a supernumerary X) restores a competent clone population, while a
hypomorphic allele leaves residual isomerase activity in every cell.
evidence:
- reference: PMID:24700572
reference_title: "A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in the Emopamil-binding protein (EBP) gene cause X-linked dominant
chondrodysplasia punctata 2 (CDPX2), a disorder in which at least 95% of liveborn
individuals are female and male intrauterine lethality is assumed.
explanation: >-
States the male lethality and the resulting sex ratio among live births.
- reference: PMID:24700572
reference_title: "A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Alternatively, affected males may exhibit a distinct phenotype if they are
hemizygous for a hypomorphic allele of EBP.
explanation: >-
Identifies residual enzyme activity as the second route by which a hemizygous
male survives, and notes that the resulting phenotype is not CDPX2.
phenotypes:
- name: Epiphyseal Stippling
category: Skeletal
description: >-
Punctate foci of calcification in epiphyseal cartilage, and also in the vertebrae,
trachea, and distal ribs. Present at birth and resolving through infancy.
phenotype_term:
preferred_term: Epiphyseal stippling
term:
id: HP:0010655
label: Epiphyseal stippling
temporality: TRANSIENT
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
chondrodysplasia punctata (stippling of the epiphyses of the long bones,
vertebrae, trachea, and distal ends of the ribs)
explanation: Names epiphyseal stippling as a characteristic feature and gives its distribution.
- name: Rhizomelic Limb Shortening
category: Skeletal
description: >-
Shortening of the proximal limb segments, characteristically unequal between the
two sides.
phenotype_term:
preferred_term: Rhizomelia
term:
id: HP:0008905
label: Rhizomelia
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "often asymmetric rhizomelic shortening of limbs"
explanation: Names rhizomelic shortening as a characteristic feature.
- name: Asymmetric Growth
category: Skeletal
description: >-
Unequal involvement of the two sides of the body, producing leg-length discrepancy
and asymmetric limb shortening - the skeletal signature of the underlying mosaic.
phenotype_term:
preferred_term: Asymmetric growth
term:
id: HP:0100555
label: Asymmetric growth
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial
cataracts, patchy alopecia, ichthyosis and atrophoderma.
explanation: Reports asymmetric rhizomesomelia as a feature of the disorder.
- name: Scoliosis
category: Skeletal
description: >-
Lateral spinal curvature, frequently with a kyphotic component, developing out of
asymmetric vertebral growth and persisting as the main orthopedic problem.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy
scaling ichthyosis in the newborn
explanation: Lists scoliosis among the characteristic features.
- name: Coronal Cleft Vertebrae
category: Skeletal
description: Coronal clefting of the vertebral bodies, a cartilage-maturation finding shared across the CDP family.
phenotype_term:
preferred_term: Coronal cleft vertebrae
term:
id: HP:0003417
label: Coronal cleft vertebrae
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
chondrodysplasia punctata (stippling of the epiphyses of the long bones,
vertebrae, trachea, and distal ends of the ribs)
explanation: >-
Vertebral involvement is documented; the specific coronal-cleft morphology is a
standard CDP finding but is not itself named in this source, so the support is
recorded as partial.
- name: Short Stature
category: Growth
description: Growth deficiency, present prenatally in the severe end of the spectrum.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Characteristic features include growth deficiency; distinctive craniofacial appearance"
explanation: Names growth deficiency as a characteristic feature.
- name: Ichthyosis
category: Dermatologic
description: >-
Linear or blotchy adherent scaling present in the newborn period, distributed along
Blaschko lines, and resolving over the first months.
phenotype_term:
preferred_term: Ichthyosis
term:
id: HP:0008064
label: Ichthyosis
temporality: TRANSIENT
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "linear or blotchy scaling ichthyosis in the newborn"
explanation: States the newborn ichthyotic scaling and its linear geometry.
- name: Scarring Alopecia
category: Dermatologic
description: >-
Patchy cicatricial alopecia following follicular destruction within
mutant-expressing clones, in the same linear distribution as the earlier scaling.
phenotype_term:
preferred_term: Scarring alopecia of scalp
term:
id: HP:0004552
label: Scarring alopecia of scalp
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "coarse hair with scarring alopecia; and cataracts"
explanation: Names scarring alopecia as a characteristic feature.
- name: Coarse Hair
category: Dermatologic
description: Coarse, lustreless hair arising from affected follicles.
phenotype_term:
preferred_term: Coarse hair
term:
id: HP:0002208
label: Coarse hair
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "coarse hair with scarring alopecia; and cataracts"
explanation: Names coarse hair as a characteristic feature.
- name: Cataract
category: Ophthalmologic
description: >-
Lens opacity, characteristically sectorial rather than whole-lens - itself a mosaic
readout, since only lens fibre clones expressing the mutant allele are affected.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial
cataracts, patchy alopecia, ichthyosis and atrophoderma.
explanation: Reports sectorial cataracts, the segmental pattern being the mosaic readout.
- name: Hearing Impairment
category: Otologic
description: Hearing loss occurs and is an explicit target of surveillance and standard intervention.
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "standard interventions for hearing loss and hydronephrosis; family support"
explanation: Hearing loss is listed among the manifestations requiring standard intervention.
- name: Hydronephrosis
category: Renal
description: Hydronephrosis occurs in a subset and is monitored when present.
phenotype_term:
preferred_term: Hydronephrosis
term:
id: HP:0000126
label: Hydronephrosis
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "monitor hydronephrosis if present per nephrologist"
explanation: Hydronephrosis is named as a manifestation requiring surveillance.
genetic:
- name: EBP
relationship_type: CAUSATIVE
presence: Present
gene_term:
preferred_term: EBP
term:
id: hgnc:3133
label: EBP
notes: >-
EBP encodes 3-beta-hydroxysteroid-delta8,delta7-isomerase (emopamil-binding
protein), mapped to Xp11.22-p11.23. Pathogenic variants span missense, nonsense,
frameshift, and splice classes; the missense alleles have been shown to be
functionally deficient by complementation in an isomerase-deficient yeast strain
rather than inferred from prediction alone.
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A candidate gene encoding a sterol-delta8-isomerase (EBP) has been identified and
mapped to Xp11.22-p11.23 (refs 5,6).
explanation: Identifies the gene and its cytogenetic location.
- reference: PMID:10391218
reference_title: "Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identified alterations in human EBP in seven unrelated CDPX2
patients.
explanation: >-
An independent group identified EBP variants in seven unrelated CDPX2 patients
alongside the orthologous mouse mutation, corroborating the gene assignment.
inheritance:
- name: X-linked dominant inheritance with male lethality
inheritance_term:
preferred_term: X-linked dominant inheritance
term:
id: HP:0001423
label: X-linked dominant inheritance
description: >-
Inherited in an X-linked manner with early gestational lethality in hemizygous
males. About 60% of affected females carry a de novo variant; the remainder inherit
it from a mildly affected mother or from a somatically/gonadally mosaic father. A
female who inherits a variant is a heterozygote whose severity cannot be predicted
from the genotype.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
EBP-CDPX is inherited in an X-linked manner with typical (but not absolute) early
gestational male lethality.
explanation: States the inheritance pattern and the male-lethality qualifier.
biochemical:
- name: Plasma and tissue 8(9)-cholestenol and 8-dehydrocholesterol
notes: >-
Elevation of the two sterols immediately upstream of the isomerase block, measurable
in plasma, in scale from skin lesions, or in cultured lymphoblasts or fibroblasts.
Sampling lesional skin scale is diagnostically useful precisely because the disorder
is mosaic: a mildly affected individual may have an unremarkable plasma profile
while affected clones remain biochemically abnormal.
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma,
scales from skin lesions, or cultured lymphoblasts or fibroblasts
explanation: States the analytes and the acceptable sample types.
diagnosis:
- name: Sterol profiling plus EBP molecular testing
description: >-
The diagnosis rests on typical clinical findings together with the characteristic
sterol elevation and/or an EBP variant. GeneReviews states the criterion separately
for female probands (mosaic heterozygous variant) and male probands (mosaic
hemizygous variant), which encodes the point that a male reaching diagnosis is
expected to be mosaic.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of EBP-CDPX is established in a female proband with typical
clinical findings; increased concentration of 8(9)-cholestenol and
8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts
or fibroblasts; and/or a mosaic heterozygous pathogenic variant in EBP identified
by molecular genetic testing.
explanation: States the diagnostic criteria for a female proband.
treatments:
- name: Orthopedic management and surveillance
description: >-
Management of kyphoscoliosis, joint problems, linear growth, and leg-length
discrepancy. No disease-modifying therapy exists; unlike CHILD syndrome, where
topical cholesterol plus a statin has been shown to clear the skin, no equivalent
pathogenesis-based intervention has been established for CDPX2.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Orthopedic evaluations to monitor kyphoscoliosis, joint problems, linear growth,
and any leg length discrepancy per orthopedist
explanation: States the recommended orthopedic surveillance.
- name: Emollients and keratolytics for the cutaneous phenotype
description: Topical management of the ichthyotic scaling, with sun protection.
therapeutic_modality: OTHER
treatment_term:
preferred_term: therapeutic procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
target_phenotypes:
- preferred_term: ichthyosis
term:
id: HP:0008064
label: Ichthyosis
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dermatologic management with emollients and keratolytics; sun protection"
explanation: States the recommended dermatologic management.
- name: Cataract extraction
description: Standard surgical management of the lens opacity.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
target_phenotypes:
- preferred_term: cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:21634086
reference_title: "EBP-Related X-Linked Chondrodysplasia Punctata."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
cataract extraction and standard treatment of ocular manifestations per
ophthalmologist
explanation: States the recommended ophthalmologic management.
animal_models:
- name: Tattered (Td) mouse
species: Mouse
genotype: Ebp missense substitution, X-linked semi-dominant (Td), heterozygous females
publication: PMID:10391218
description: >-
A spontaneous X-linked semi-dominant mouse mutation that was independently mapped to
Ebp, giving a naturally occurring orthologue of CDPX2 in which the mosaic logic of
the disease is directly visible: heterozygous females develop hairless hyperkeratotic
patches that read out as coat striping in the adult, and hemizygous males die
prenatally.
modeled_mechanisms:
- target: X-Inactivation Mosaicism
relationship: RECAPITULATES
fidelity: HIGH
description: >-
The striped coat of the heterozygous female is the mouse equivalent of Blaschko
lines - a directly observable map of which clones inactivated which X - and
prenatal death of the hemizygous male reproduces the human male lethality.
limitations: >-
Mouse coat striping follows the mouse pattern of clonal skin development, so the
geometry is not the same as human Blaschko lines even though the underlying
mosaicism is; and the mouse allele is a single missense substitution, so the model
speaks to that allele class rather than to nulls.
readouts:
- name: Hairless hyperkeratotic skin patches producing adult coat striping
target: X-Inactivation Mosaicism
direction: ALTERED
interpretation: >-
A visible clonal map of mutant-expressing versus wild-type-expressing skin in the
heterozygous female.
evidence:
- reference: PMID:10391218
reference_title: "Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Heterozygous females are small and at 4-5 days of age develop patches of
hyperkeratotic skin where no hair grows, resulting in a striping of the coat in
adults.
explanation: Reports the patterned skin phenotype and its progression to coat striping.
evidence:
- reference: PMID:10391218
reference_title: "Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Tattered (Td) is an X-linked, semi-dominant mouse mutation associated with prenatal male lethality."
explanation: >-
The X-linked semi-dominant inheritance with prenatal male lethality is the same
genetic architecture as human CDPX2.
- target: EBP Sterol-Delta8-Isomerase Deficiency
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Td is an Ebp allele, so the model carries the same molecular lesion as the human
disease rather than a phenocopy.
limitations: >-
A single amino-acid substitution rather than a null; residual activity is not
characterized in the cited report.
evidence:
- reference: PMID:10391218
reference_title: "Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We have now identified the defect in Td mice as a single amino acid substitution
in the delta8-delta7 sterol isomerase emopamil binding protein (Ebp; encoded by
Ebp in mouse)
explanation: Establishes that the mouse mutation is in the orthologue of the human disease gene.
differential_diagnoses:
- name: CHILD syndrome
disease_term:
preferred_term: CHILD syndrome
term:
id: MONDO:0010621
label: CHILD syndrome
description: >-
The nearest mechanistic neighbour: also X-linked, also male-lethal, also a mosaic
disorder of the post-squalene cholesterol pathway, and also placed in ISDS group 23.
NSDHL acts one step upstream of EBP. The two are separated clinically by lesion
geometry rather than by pathway.
distinguishing_features:
- CHILD syndrome lesions are strictly lateralized with a sharp body-midline boundary; CDPX2 lesions are bilateral, asymmetric, and follow Blaschko lines
- CDPX2 carries elevated 8(9)-cholestenol and 8-dehydrocholesterol; NSDHL-related CHILD syndrome carries a methylsterol pattern instead
- CHILD syndrome has ipsilateral limb reduction defects; CDPX2 has asymmetric rhizomelic shortening without true reduction defects
- name: Rhizomelic chondrodysplasia punctata type 1
disease_term:
preferred_term: rhizomelic chondrodysplasia punctata type 1
term:
id: MONDO:0008972
label: rhizomelic chondrodysplasia punctata type 1
description: >-
The other major cause of a stippled, rhizomelic newborn skeleton, and the principal
radiographic differential. It is autosomal recessive and peroxisomal rather than
X-linked and sterol-pathway, and every cell is uniformly affected.
distinguishing_features:
- RCDP1 limb shortening is symmetric; CDPX2 shortening is characteristically asymmetric
- RCDP1 has profound developmental impairment and seizures; CDPX2 intellect is usually normal
- RCDP1 is confirmed by erythrocyte plasmalogen deficiency with raised phytanic acid; CDPX2 by the 8(9)-cholestenol / 8-dehydrocholesterol sterol profile
- RCDP1 affects both sexes equally; at least 95% of live-born CDPX2 patients are female
- name: Brachytelephalangic chondrodysplasia punctata (CDPX1) and its phenocopies
disease_term:
preferred_term: X-linked chondrodysplasia punctata 1
term:
id: MONDO:0010555
label: X-linked chondrodysplasia punctata 1
description: >-
The X-linked recessive CDP, affecting males, with nasomaxillary hypoplasia and
distal phalangeal shortening rather than ichthyosis and rhizomelia. Its
vitamin-K-related phenocopies (maternal warfarin exposure, maternal autoimmune
disease) share the same radiographic pattern and must be excluded in a stippled
newborn before either genetic diagnosis is made.
distinguishing_features:
- CDPX1 affects males; CDPX2 live births are overwhelmingly female
- CDPX1 has brachytelephalangy and nasal hypoplasia without ichthyosis, alopecia, or cataract
- CDPX1 has a normal sterol profile
discussions:
- discussion_id: hypomorphic_male_entity
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Male Hemizygous Lethality
- genetic#EBP
prompt: >-
Is the phenotype of a male hemizygous for a hypomorphic EBP allele a mild variant of
CDPX2, or a separate X-linked recessive disorder that happens to share the gene?
rationale: >-
Two distinct routes let a male with an EBP variant survive, and they predict
different phenotypes. A mosaic male, or one with a null allele plus a supernumerary
X, has enzyme-competent clones and presents like a female CDPX2 patient. A male
hemizygous for a hypomorphic allele has no competent clones anywhere but retains
partial activity in all of them, and the reported phenotype - digital abnormalities,
intellectual disability, and short stature, without the ichthyosis and stippling of
CDPX2 - does not look like CDPX2 at all. Whether that is a nosologically separate
entity or the low-activity end of one continuum is unsettled, and it matters for
this entry's boundaries: the ISDS nosology lists only one EBP row, and MONDO carries
only MONDO:0020603, so a decision either way would change what this entry covers.
dismech currently treats it as within scope and flags the question here rather than
creating a second entry on one report.
evidence:
- reference: PMID:24700572
reference_title: "A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The molecular and biochemical evidence convincingly supports the pathogenicity and
association of the p.I75N mutation with this newly described phenotype.
explanation: >-
The authors argue for a distinct male entity on the strength of one family with
biochemical confirmation - enough to raise the question, not to settle it.
- discussion_id: sterol_to_stippling_route
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Accumulation of 8(9)-Cholestenol and 8-Dehydrocholesterol
- pathophysiology#Cellular Cholesterol Deficiency
prompt: >-
Which arm of the dual lesion - cholesterol starvation or accumulation of the
upstream sterols - actually produces the punctate cartilage calcification, and by
what route?
rationale: >-
The enzymology of CDPX2 is settled and the sterol profile is diagnostic, but the
step from either sterol abnormality to abnormal calcification of cartilage is not.
The gene-discovery paper put it no more strongly than that the results "suggest a
role for sterols in bone development", and that remains the state of the argument.
The question is answerable in principle, because CHILD syndrome supplies a
precedent: there, a topical trial separating cholesterol replacement from
suppression of precursor flux showed that neither arm alone accounted for the skin
phenotype. No equivalent dissection has been done for the CDPX2 skeleton, and the
two mechanism edges in this entry are annotated as having unknown intermediates for
that reason.
evidence:
- reference: PMID:10391219
reference_title: "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and
suggest a role for sterols in bone development.
explanation: >-
The authors' own hedged phrasing marks the gap between the established enzyme
defect and the skeletal phenotype.
notes: >-
Curated as a distinct dismech entry rather than folded into a lumped
chondrodysplasia-punctata entry, because the ISDS 2023 nosology lists it as its own
row (NOS 23-0020) with its own gene and inheritance, and because the mosaic logic that
drives its phenotype has no counterpart in the autosomal recessive members of the same
group. The hypomorphic-allele male phenotype is kept inside this entry and flagged as
an open question rather than split off, since a single reported family is not a basis
for a second entry. A member of the Chondrodysplasia_Punctata grouping.