Chondrodysplasia punctata refers to punctate calcifications, due to abnormal calcium deposition in the areas of enchondral bone formation, described in a variety of chondrodysplasias.
GENETICS/BASIC DEFECTS
1. Genetic heterogeneity of chondrodysplasia punctata a. Rhizomelic chondrodysplasia punctata type I (RCDP1)
i. Autosomal recessive disorder
ii. Caused by mutations in PEX7, mapped at 6q22-q24, which encodes the cytosolic peroxi- somal targeting signal type 2 (PTS2)-receptor protein peroxin 7
iii. Genotype–phenotype correlations
a) Classic RCDP1: all patients with homozy- gous for the L292X mutation
b) Phenotype determined by the other allele if the patients are compound heterozygotes for L292X and another mutation
c) A milder phenotype associated with several PEX7 alleles
b. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) i. Autosomal recessive disorder
ii. Caused by mutations in the gene that encodes peroxisomal dihydroxyacetone phosphate acyl- transferase (DHAPAT)
c. Rhizomelic chondrodysplasia punctata type 3 (RCDP3) i. Autosomal recessive disorder
ii. Caused by mutations in the gene (mapped at 2q31) that encodes peroxisomal alkyl-dihdroxyacetone phosphate synthase (ADHAPS)
d. Relatively mild autosomal dominant Conradi- Hünermann syndrome
i. Chondrodysplasia punctata, tibia-metacarpal type ii. Chondrodysplasia punctata, humero-metacarpal
type
e. X-linked dominant type only in females (Conradi- Hünermann-Happle syndrome) (CDPX2)
i. Lethal in males
ii. Caused by mutations of the 3 β-hydroxysteroid- Δ
8- Δ
7-isomerase (also called emopamil-binding protein, EBP)
iii. The gene encoding EBP mapped to Xp11.22- p11.23
iv. EBP: catalyzes an intermediate step in the con- version of lanosterol to cholesterol
v. Presence of gonadal and somatic mosaicism in CDPX2
f. X-linked recessive type with a deletion of the short arm of the X chromosome (CDPX1)
i. Caused by defects in arysulfatase E, a vitamin K-dependent enzyme
ii. The locus of the disease identified through the characterization of patients with chromosomal abnormalities involving the Xp22.3 region iii. The gene of CDPX1, named ARSE, encoding a
new sulfatase (arylsulfatase E), showing a high sequence homology to steroid sulfatase
iv. Point mutations of the ARSE gene detected in the DNA of karyotypically normal patients with chondrodysplasia punctata
2. Causes of stippled cartilaginous calcifications a. Peroxisomal disorders
i. Zellweger syndrome a) A peroxisomal disorder
b) An autosomal recessive inheritance
c) Associated stippled calcifications of the epi- physes, particularly common in the patella d) Severe hypotonia
e) Characteristic facies with a high forehead, hypertelorism, epicanthal folds, Brushfield spots, and shallow supraorbital ridges f) Club foot deformity
g) The affected infants usually die early in infancy
h) Involvement of other organ systems, espe- cially the brain (migrational disorders) and kidneys (cortical cystic disease of the kid- neys)
ii. Rhizomelic chondrodysplasia punctata b. Genetic disorders
i. Conradi-Hunermann chondrodysplasia punctata ii. X-linked dominant chondrodysplasia punctata iii. Smith-Lemli-Opitz syndrome
iv. Greenberg dysplasia (cholesterol biosynthesis disorder)
a) An autosomal recessive disorder
b) Appears to be caused by an error of sterol metabolism at the level of 3 β-hydroxysteroid- Δ14 reductase
c) Nonimmune hydrops fetalis d) Mid-face hypoplasia e) Micrognathia
f) Rhizo-mesomelic dwarfism with relatively long and broad hands and feet
g) Narrow thorax h) Protuberant abdomen
i) Radiographic findings of grossly irregular and deficient ossification of the short tubular bones, fragmented ossification at the ends of the long tubular bones, small pelvic bones with irregular “moth-eaten” contours, platyspondyly with multiple ossification centers of the ver-
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tebral bodies, and deficient ossification of the calvaria
v. CHILD syndrome
a) Congenital hemidysplasia b) Ichthyosiform erythroderma
c) Limb defects (unilateral hypomelia with ipsilateral epiphyseal stippling)
vi. Dappled diaphyseal dysplasia (lethal short- limbed dysplasia, type Carty)
a) An autosomal recessive disorder b) All cases were stillborn or died in utero c) Fetal hydrops
d) Polyhydramnios
e) Short limbs with relatively long hands and feet
f) Small thorax
g) Protuberant abdomen
h) Radiographic findings of fragmented appear- ance of the ribs, small islands of ossification from disruption of the facial bones, axial and appendicular skeleton (multifocal or dappled ossification of long bones), and absent ossifi- cation of the calvaria
vii. Acrodysostosis viii. De Barsy syndrome
a) Cutis laxa b) Corneal clouding c) Mental retardation d) Stippled epiphysis ix. GM1 gangliosidosis
x. Galactosialidosis xi. Fibrochondrogenesis xii. Mucolipidosis II xiii. De Lange syndrome
xiv. X-linked ichthyosis xv. Keutel syndrome
a) Stippled epiphysis (knees, elbows) b) Brachytelephalangism
c) Pulmonary stenosis xvi. Hypothyroidism
xvii. Chromosome translocation xviii. Trisomy 21 and 18
xix. Turner syndrome
xx. Brachytelephalangic chondrodysplasia punctata a) An X-linked recessive disorder
b) Male infants affected with a very small nose, anteverted and grooved nares
c) Benign type of chondrodysplasia punctata d) Also observed in a patient with Xp terminal
deletion with ichthyosis and mental retardation e) Distal phalangeal hypoplasia: the most char-
acteristic radiological sign of this form xxi. Chondrodysplasia punctata, metacarpal type
a) Including tibial-metacarpal type and humeral- metacarpal type
b) An autosomal dominant disorder
c) Named for a specific long bone but with overlap in the long bone involved
d) All have short metacarpals.
e) Affected children with a hypoplastic mid- face, a depressed nasal bridge, small mouth, micrognathia, short neck, and short limbs f) Radiographically, with short metacarpals
associated with short tibias in the tibia- metacarpal type and short humeri in humero- metacarpal type
xxii. Sheffield-type chondrodysplasia punctata a) Heterogeneous group of patients with punc-
tate epiphyses, particularly in the calcaneus and spine
b) A benign course
c) Distal phalangeal hypoplasia
d) Probably not a specific entity but rather a heterogeneous group of disorders that can be included in other entities
xxiii. Pacman dysplasia
a) A single case report with peculiar bone dys- plasia, stippling in many areas, short bowed bones, and periosteal cloaking
b) Osteoclasts with an unusual appearance reminiscent of the Pacman figures in com- puter games on bone histology
c) The entire coccygeal and sacral regions replaced by stippling
d) Dense stippling also observed in the thoracic region
e) Considerable stippling also observed in the epiphyses of the proximal femur, talus, calcaneus, cuboid, and the bones of the hand
f) Wide periosteal cloaking of many bones and poor ossification
g) Bowed femora
h) Superior inferior sagittal clefting in the AP views in the upper spine
c. Vitamin K disorders i. Warfarin embryopathy
a) Associated with maternal use of warfarin sodium
b) Consistent features: saddle nose deformity, hypertelorism, frontal bossing, high-arched palate, short neck, and short stature
c) Other features: rhizomelia, micromelia, flexion contractures, optic atrophy, psy- chomotor retardation, cataracts, congenital heart disease, and renal anomalies
ii. Vitamin K epoxide reductase deficiency d. Acquired in utero
i. Fetal alcohol syndrome ii. Phenacetin intoxication iii. Fetal hydantoin syndrome
iv. Femoral hypoplasia unusual facies syndrome v. Maternal diabetes
vi. Maternal systemic lupus erythematosis vii. Febrile illness
e. Other conditions involving unusual calcification that may be confused with puncta
i. Amelia and other absence deficiency
ii. Cerebrocostomandibular syndrome
iii. Dysplasia epiphysealis hemimelica iv. Calcifying arthritis
v. Metachondromatosis
CLINICAL FEATURES
1. Recessive rhizomelic form a. Classic RCDP1
i. Skeletal abnormalities
a) Severe symmetric shortening of the proxi- mal limb segments (more severe in humeri than femora)
b) Stippled (punctate) epiphyses involving knees, hips, elbows, shoulders, hyoid bone, larynx, sternum, and ribs
ii. Peripheral calcifications iii. Facial dysmorphism
a) Frontal bossing b) A short, saddle nose iv. Ocular features
a) Cataracts: the most common ocular defect developing in virtually all patients: usually present at birth or appear in the first few months of life and are progressive
b) Optic atrophy
c) Posterior embryotoxon d) Strabismus
e) Adhesions between iris and cornea in the ring of Schwabe
v. Severe failure to thrive with profound postnatal growth deficiency
vi. Gross developmental retardation
vii. Contractures and stiff, painful joints, causing irritability in infancy
viii. Other complications a) Seizures
b) Recurrent respiratory tract infections caused by neurological compromise, aspiration, immobility, and a small chest with restricted expansion
c) Spastic quadriplegia d) Ichthyotic skin changes e) Cleft soft palate
f) Cervical spine stenosis g) Congenital heart disease
h) Ureteropelvic junction obstruction ix. A high mortality
a) About 60% survive the first year b) About 39% survive the second year c) Only a few survive beyond age ten years b. Mild RCDP1
i. Only a few patients reported ii. Consistent features
a) Chondrodysplasia b) Cataracts
iii. Variable expression a) Punctate calcifications b) Rhizomelia
c) Mental and growth deficiency 2. X-linked dominant form (CDPX2)
a. Phenotype
i. Usually a mild form of the disease identified in adult females
ii. May be a stillborn
iii. Occurring almost only in females
iv. Presumably lethal in males, although a few affected males have been reported
b. Lyonization (skewed X-chromosome inactivation) in females resulting in phenotypic variability and asym- metric findings
c. Showing increased disease expression in successive generations (anticipation): another striking clinical feature of CDPX2 that may be associated with skewed methylation
d. Skin lesions
i. The hallmark of the X-linked dominant form ii. Congenital ichthyosiform erythroderma, distrib-
uted in a linear or blotchy pattern
iii. Systematized atrophoderma mainly involving the fair follicles
iv. Circumscribed alopecia v. Sparse eyebrows and lashes vi. Nails: flattened and split into layers e. Epiphyseal calcification in the first year of life
f. Limb shortening i. Rhizomesomelic ii. Usually asymmetric
iii. Severely affected infants with bilateral findings resembling those of RDCP1
g. Other later signs
i. Palmoplantar keratosis ii. Follicular atrophoderma iii. Segmental cataracts
iv. Tooth and bone abnormalities
3. X-linked recessive chondrodysplasia punctata, brachytele- phalangic type (CDPX1)
a. Clinical reports available so far are mainly those of patients who are nullisomic for Xp22.3 in which chondrodysplasia punctata is part of a complex phe- notype due to a “contiguous gene syndrome”
b. Wide spectrum of manifestations, ranging from aborted fetus, neonatal death, midfacial hypoplasia, and brachytelephalangy
c. Facial anomalies with severe nasal hypoplasia d. Short stature
e. Cardinal manifestations i. Epiphyseal stippling
ii. Hypoplasia of the distal phalanges
f. Abnormalities of proximal and middle phalanges after healing of the punctate calcifications: typical diagnostic signs
g. Without limb shortening or cataracts
h. Presence of ichthyosis attributed to the involvement of the STS gene in the patients with Xp deletion i. Mild ichthyosis that improves with age: may be part
of the CDPX phenotype
4. Chondrodysplasia punctata, tibia-metacarpal type
a. Symmetrical rhizomelic shortness of the upper limbs
b. Punctate epiphyseal calcifications noted at birth
c. Abnormal face (flattened mid-face and nose) d. Short hands
e. Normal height f. Normal mentation
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Classic RCDP1
i. Bilateral shortening of the humerus and to a lesser degree the femur
ii. Punctate calcifications in the epiphyseal carti- lage at the knee, hip, elbow, shoulder, hyoid bone, larynx, sternum, and ribs
iii. Radiolucent coronal clefts of the vertebral bod- ies that represent unossified cartilage
iv. Abnormal epiphyses and flared and irregular metaphyses secondary to resolved punctate cal- cification after age one to three years
b. Tibia-metacarpal type
i. Shortened and bowed tibia and radii ii. Overgrowth of the fibulae
iii. Ulnar hypoplasia
iv. Calcific stippling of the proximal bones
v. Punctate calcifications of the trachea, thyroid cartilage, entire spine, and sacrum
vi. Clefting (coronal and/or sagittal) of the vertebral bodies
vii. Symmetrical brachymetacarpy: shortened 2nd, 3rd, and 4th metacarpals
viii. Shortened radial head ix. Patella dislocation 2. Biochemical/molecular studies
a. RCDP1
i. Deficiency of red blood cell plasmalogens ii. Increased plasma concentration of phytanic acid iii. Deficiencies in plasmalogen biosynthesis and phy- tanic acid hydroxylation in cultured skin fibroblasts iv. PEX7 receptor defect in RCDP1 predicted by the
following:
a) Deficiency of plasmalogens in red blood cells b) Increased plasma concentration of phytanic
acid
c) Normal plasma concentration of very long chain fatty acids
v. Molecular genetic analysis: PEX7 gene mutation analysis and sequencing
b. RCDP2
i. Deficiency of the peroxisomal enzyme dihydrox- yacetone phosphate acyltransferase (DHAPRT) in cultured skin fibroblasts
ii. DHAPRT gene mutation analysis by sequencing of coding regions
c. RCDP3
i. Deficiency of the peroxisomal enzyme, akkyl- dihydroxyacetone phosphate synthase (ADHAPS) in cultured skin fibroblasts
ii. ADHAPS gene mutation analysis d. X-linked dominant form (CDPX2)
i. Diagnosis confirmed by measuring the plasma concentration of sterols which show accumula- tion of precursors, 8(9)-cholesterol and 8-dehy- drocholesterol
ii. Identify molecular defect in human EBP in CDPX2 patients
e. X-linked recessive form (CDPX1): ARSE gene muta- tion analysis
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal recessive RCDP1: 25%
ii. Autosomal dominant form: not increased unless one of the parents is affected
iii. X-linked recessive form: 50% of brothers affected when the mother is a carrier
iv. X-linked dominant form
a) 50% of sisters and brothers (lethal) affected when the mother is a carrier
b) Possibility of an apparently normal mother being a carrier to be considered when exam- ining seemingly sporadic cases
b. Patient’s offspring
i. Autosomal recessive RCDP1: do not reproduce ii. Autosomal dominant form: 50%
iii. X-linked recessive form: 50% risk of daughters to be carriers; none of sons will be affected iv. X-linked dominant form: affected mother: 50%
of sons affected (lethal in male); 50% of daugh- ters affected
2. Prenatal diagnosis a. Radiography
i. Stippling of the bones of the extremities and pelvis
ii. Abnormalities of the vertebral bodies b. Ultrasonography
i. Rhizomelic form
a) Severe rhizomelic limb shortening b) Punctuate epiphyseal calcifications
c) Associated sonographic findings: profound hypoplasia of the humeri, metaphyseal flar- ing, a flattened midface, joint contracture, clubfoot deformity, and hydramnios ii. Nonrhizomelic form
a) Asymmetric, variable limb shortening without a clear pattern of rhizomelia or mesomelia b) Calcifications in the long bone epiphyses,
which may be recognizable in the second trimester or may not be recognizable even in the third trimester
c) Other sonographic findings: spinal deformi- ties, frontal bossing, a depressed nasal bridge, ascites, and polyhydramnios iii. X-linked dominant form
a) Growth retardation
b) Skeletal asymmetry
c) Polyhydramnios
c. Assays of plasmalogen biosynthesis in cultured chori- onic villi or amniocytes for pregnancies at 25% risk for RCDP1
d. Enzyme activity of alkyl-dihydroxyacetone phos- phate synthase (ADHAPS) and subcellular localiza- tion of peroxisomal thiolase performed on uncultured chorionic villi
e. Molecular prenatal diagnosis in X-linked dominant chondrodysplasia punctata to identify disease-causing EBP mutation in the fetus
3. Management
a. Mainly supportive
b. G-tube placement for poor feeding and recurrent aspi- ration
c. Cataract extraction to preserve vision
d. Orthopedic procedures to correct contractures to improve function
e. X-linked dominant form i. Emollients for ichthyosis ii. Splinting for clubbed feet iii. Surgery for polydactyly
iv. Ophthalmological care for cataracts
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Fig. 1. Patient 1 (a Japanese newborn boy) with X-linked recessive form of chondrodysplasia punctata. Radiographs show paravertebral and calcaneus punctate calcification.
Fig. 2. FISH (patient 1) with a SHOX (short stature homeobox con- taining gene) probe for Xp22.3 (a pink signal) and Yp11.3 (a pink sig- nal) showing a deleted pink Xp22.3 signal. The pink signal in the X chromosome is an X peri-centromere probe (SXZ1) and the green sig- nal is a Yq12 probe (DXZ1).
Fig 3. The mother of patient 1 is a carrier of del(X)(p22.3p22.3) (SHOX-). Her FISH showed that a red signal (a probe for Xp22.3;
SHOX gene) is deleted in one of her X chromosome.
Fig. 4. A neonate with rhizomelic form of chondrodysplasia punctata, showing short humeri and punctate calcifications in the shoulder and/or elbow joints illustrated by radiograph.
Fig. 5. Radiograph of another neonate with rhizomelic form of chon- drodysplasia punctata, showing similar radiographic features.
Fig. 6. Another neonate with chondrodysplasia punctata showing depressed nasal bridge and under-developed nasal cartilage. The infant has punctate calcifications in the proximal femoral heads.
Fig. 7. Radiographs of a child with an autosomal dominant chon- drodysplasia punctata showing punctate calcifications in the knees.
