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Chondrodysplasia punctata 2 X-linked dominant(CDPX2)

MedGen UID:
79381
Concept ID:
C0282102
Disease or Syndrome
Synonyms: CDPX2; Chondrodysplasia punctata, X-linked dominant; Conrad Hunermann Happle syndrome; CONRADI-HUNERMANN-HAPPLE SYNDROME; Happle syndrome; Hunermann-Conradi Syndrome
SNOMED CT: Chondrodysplasia punctata, Conradi-Hünermann type (398719004); Chondrodysplasia punctata, X-linked dominant type (398958000); Conradi's syndrome (398719004); Conradi disease (398719004); Conradi-Hunermann syndrome (398719004); Chondrodysplasia calcificans congenita (398719004); Chondrodysplasia punctata, Conradi-Hunermann type (398719004); Conradi-Hünermann syndrome (398719004); Conradi Hünermann Happle syndrome (398958000); X-linked chondrodysplasia punctata type 2 (398958000); Chondrodystrophia calcificans congenita (398958000); Happle syndrome (398958000)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): EBP (Xp11.23)
 
Monarch Initiative: MONDO:0020603
OMIM®: 302960
Orphanet: ORPHA35173

Disease characteristics

Excerpted from the GeneReview: Chondrodysplasia Punctata 2, X-Linked
The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of live-born individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; 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. [from GeneReviews]
Authors:
Smitha Kumble  |  Ravi Savarirayan   view full author information

Additional descriptions

From OMIM
Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form. CDPX2 arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortness, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia. Affected males are extremely rare and the clinical features in males almost always result from postzygotic mosaicism for an EBP mutation (summary by Aughton et al., 2003 and Arnold et al., 2012). Genetic Heterogeneity of Chondrodysplasia Punctata See also CDPX1 (302950), caused by mutation in the ARSE gene (300180). See 118650, 602497, and 118651 for possible autosomal dominant forms of CDP. In addition, CDP can be caused by maternal vitamin K deficiency or warfarin teratogenicity (see 118650).  http://www.omim.org/entry/302960
From MedlinePlus Genetics
X-linked chondrodysplasia punctata 2 is a disorder characterized by bone, skin, and eye abnormalities. It occurs almost exclusively in females.

Although the signs and symptoms of this condition vary widely, almost all affected individuals have chondrodysplasia punctata, an abnormality that appears on x-rays as spots (stippling) near the ends of bones and in cartilage. In this form of chondrodysplasia punctata, the stippling typically affects the long bones in the arms and legs, the ribs, the spinal bones (vertebrae), and the cartilage that makes up the windpipe (trachea). The stippling is apparent in infancy but disappears in early childhood. Other skeletal abnormalities seen in people with X-linked chondrodysplasia punctata 2 include shortening of the bones in the upper arms and thighs (rhizomelia) that is often different on the right and left sides, and progressive abnormal curvature of the spine (kyphoscoliosis). As a result of these abnormalities, people with this condition tend to have short stature.

Infants with X-linked chondrodysplasia punctata 2 are born with dry, scaly patches of skin (ichthyosis) in a linear or spiral (whorled) pattern. The scaly patches fade over time, leaving abnormally colored blotches of skin without hair (follicular atrophoderma). Most affected individuals also have sparse, coarse hair on their scalps.

Most people with X-linked chondrodysplasia punctata 2 have clouding of the lens of the eye (cataracts) from birth or early childhood. Other eye abnormalities that have been associated with this disorder include unusually small eyes (microphthalmia) and small corneas (microcornea). The cornea is the clear front surface of the eye. These eye abnormalities can impair vision.

In affected females, X-linked chondrodysplasia punctata 2 is typically associated with normal intelligence and a normal lifespan. However, a much more severe form of the condition has been reported in a small number of males. Affected males have some of the same features as affected females, as well as weak muscle tone (hypotonia), changes in the structure of the brain, moderately to profoundly delayed development, seizures, distinctive facial features, and other birth defects. The health problems associated with X-linked chondrodysplasia punctata 2 are often life-threatening in males.  https://medlineplus.gov/genetics/condition/x-linked-chondrodysplasia-punctata-2

Clinical features

From HPO
Hydronephrosis
MedGen UID:
42531
Concept ID:
C0020295
Disease or Syndrome
Severe distention of the kidney with dilation of the renal pelvis and calices.
Postaxial polydactyly
MedGen UID:
67394
Concept ID:
C0220697
Congenital Abnormality
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012). Genetic Heterogeneity of Postaxial Polydactyly Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22; PAPA8 (618123), caused by mutation in the GLI1 gene (165220) on chromosome 12q13; PAPA9 (618219), caused by mutation in the CIBAR1 gene (617273) on chromosome 8q22; and PAPA10 (618498), caused by mutation in the KIAA0825 gene (617266) on chromosome 5q15.
Bilateral talipes equinovarus
MedGen UID:
332956
Concept ID:
C1837835
Congenital Abnormality
Bilateral clubfoot deformity.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Hemiatrophy
MedGen UID:
451036
Concept ID:
C0333662
Pathologic Function
Undergrowth of the limbs that affects only one side.
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Abnormal pinna morphology
MedGen UID:
167800
Concept ID:
C0857379
Congenital Abnormality
An abnormality of the pinna, which is also referred to as the auricle or external ear.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Intellectual disability, moderate
MedGen UID:
7680
Concept ID:
C0026351
Mental or Behavioral Dysfunction
Moderate mental retardation is defined as an intelligence quotient (IQ) in the range of 35-49.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Tracheal calcification
MedGen UID:
75539
Concept ID:
C0264324
Disease or Syndrome
Calcification (abnormal deposits of calcium) in the tracheal tissues.
Hemivertebrae
MedGen UID:
82720
Concept ID:
C0265677
Congenital Abnormality
Absence of one half of the vertebral body.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Patellar dislocation
MedGen UID:
253896
Concept ID:
C1135812
Injury or Poisoning
The kneecap normally is located within the groove termed trochlea on the distal femur and can slide up and down in it. Patellar dislocation occurs if the patella fully dislocates out of the groove.
Stippled calcification in carpal bones
MedGen UID:
337100
Concept ID:
C1844846
Finding
Point-shaped (punctate) calcifications affecting the carpal bones.
Tarsal stippling
MedGen UID:
337101
Concept ID:
C1844848
Finding
The presence of abnormal punctate (speckled, dot-like) calcifications in one or more tarsal bones.
Calcific stippling
MedGen UID:
340441
Concept ID:
C1849993
Finding
An abnormal punctate (speckled, dot-like) pattern of calcifications in soft tissues within or surrounding bones (as observed on radiographs).
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Epiphyseal stippling
MedGen UID:
349104
Concept ID:
C1859126
Finding
The presence of abnormal punctate (speckled, dot-like) calcifications in one or more epiphyses.
Dandy-Walker malformation
MedGen UID:
419183
Concept ID:
C2931867
Congenital Abnormality
A congenital brain malformation typically characterized by incomplete formation of the cerebellar vermis, dilation of the fourth ventricle, and enlargement of the posterior fossa. In layman's terms, Dandy Walker malformation is a cyst in the cerebellum (typically symmetrical) that is involved with the fourth ventricle. This may interfere with the ability to drain cerebrospinal fluid from the brain, resulting in hydrocephalus. Dandy Walker cysts are formed during early embryonic development, while the brain forms. The cyst in the cerebellum typically has several blood vessels running through it connecting to the brain, thereby prohibiting surgical removal.
Abnormal pelvic girdle bone morphology
MedGen UID:
866545
Concept ID:
C4020847
Anatomical Abnormality
An abnormality of the bony pelvic girdle, which is a ring of bones connecting the vertebral column to the femurs.
Abnormal thorax morphology
MedGen UID:
867424
Concept ID:
C4021797
Anatomical Abnormality
Any abnormality of the thorax (the region of the body formed by the sternum, the thoracic vertebrae and the ribs).
Punctate vertebral calcifications
MedGen UID:
870240
Concept ID:
C4024678
Anatomical Abnormality
The presence of punctiform calcification of the bone of the vertebral bodies.
Tracheal stenosis
MedGen UID:
21227
Concept ID:
C0040583
Disease or Syndrome
Narrowing of the lumen of the trachea.
Erythroderma
MedGen UID:
3767
Concept ID:
C0011606
Disease or Syndrome
An inflammatory exfoliative dermatosis involving nearly all of the surface of the skin. Erythroderma develops suddenly. A patchy erythema may generalize and spread to affect most of the skin. Scaling may appear in 2-6 days and be accompanied by hot, red, dry skin, malaise, and fever.
Edema
MedGen UID:
4451
Concept ID:
C0013604
Pathologic Function
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Elevated 8-dehydrocholesterol
MedGen UID:
333461
Concept ID:
C1840013
Finding
Elevated 8(9)-cholestenol
MedGen UID:
327010
Concept ID:
C1840014
Finding
Concave nasal ridge
MedGen UID:
78105
Concept ID:
C0264169
Finding
Nasal ridge curving posteriorly to an imaginary line that connects the nasal root and tip.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Sparse eyebrow
MedGen UID:
371332
Concept ID:
C1832446
Finding
Decreased density/number of eyebrow hairs.
Flat face
MedGen UID:
342829
Concept ID:
C1853241
Finding
Absence of concavity or convexity of the face when viewed in profile.
Congenital nonbullous ichthyosiform erythroderma
MedGen UID:
38180
Concept ID:
C0079154
Disease or Syndrome
The term collodion baby applies to newborns who appear to have an extra layer of skin (known as a collodion membrane) that has a collodion-like quality. It is a descriptive term, not a specific diagnosis or disorder (as such, it is a syndrome). Affected babies are born in a collodion membrane, a shiny waxy outer layer to the skin. This is shed 10-14 days after birth, revealing the main symptom of the disease, extensive scaling of the skin caused by hyperkeratosis. With increasing age, the scaling tends to be concentrated around joints in areas such as the groin, the armpits, the inside of the elbow and the neck. The scales often tile the skin and may resemble fish scales.
Congenital ichthyosiform erythroderma
MedGen UID:
86936
Concept ID:
C0079583
Disease or Syndrome
An ichthyosiform abnormality of the skin with congenital onset.
Sparse eyelashes
MedGen UID:
375151
Concept ID:
C1843300
Finding
Decreased density/number of eyelashes.
Patchy alopecia
MedGen UID:
350774
Concept ID:
C1862862
Finding
Transient, non-scarring hair loss and preservation of the hair follicle located in in well-defined patches.
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVChondrodysplasia punctata 2 X-linked dominant

Professional guidelines

PubMed

Schutgens RB, Schrakamp G, Wanders RJ, Heymans HS, Tager JM, van den Bosch H
J Inherit Metab Dis 1989;12 Suppl 1:118-34. doi: 10.1007/BF01799291. PMID: 2509803
Saldino RM
Med Radiogr Photogr 1973;49(3):61-95. PMID: 4775541
Silverman FN
Radiol Clin North Am 1968 Aug;6(2):223-37. PMID: 5667498

Recent clinical studies

Diagnosis

Barboza-Cerda MC, Wong LJ, Martínez-de-Villarreal LE, Zhang VW, Déctor MA
Am J Med Genet A 2014 Jul;164A(7):1642-7. Epub 2014 Apr 3 doi: 10.1002/ajmg.a.36508. PMID: 24700572

Prognosis

Barboza-Cerda MC, Wong LJ, Martínez-de-Villarreal LE, Zhang VW, Déctor MA
Am J Med Genet A 2014 Jul;164A(7):1642-7. Epub 2014 Apr 3 doi: 10.1002/ajmg.a.36508. PMID: 24700572

Clinical prediction guides

Barboza-Cerda MC, Wong LJ, Martínez-de-Villarreal LE, Zhang VW, Déctor MA
Am J Med Genet A 2014 Jul;164A(7):1642-7. Epub 2014 Apr 3 doi: 10.1002/ajmg.a.36508. PMID: 24700572

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