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Chondrodysplasia punctata 2 X-linked dominant(CDPX2)

MedGen UID:
79381
Concept ID:
C0282102
Disease or Syndrome
Synonyms: CDPX2; Chondrodysplasia Punctata 2, X-Linked; Chondrodysplasia punctata, X-linked dominant; Conrad Hunermann Happle syndrome; CONRADI-HUNERMANN-HAPPLE SYNDROME; Happle syndrome; Hunermann-Conradi Syndrome
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Sources: HPO, OMIM, 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.
X-linked dominant inheritance (HPO, OMIM, Orphanet)
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)
 
Gene (location): EBP (Xp11.23)
OMIM®: 302960
Orphanet: ORPHA35173

Definition

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 adults with no recognizable physical abnormalities. At least 95% of liveborn individuals with CDPX2 are female with the following findings: Growth deficiency/short stature. Distinctive craniofacial appearance. Skeletal changes: stippling (chondrodysplasia punctate) on x-rays of the epiphyses of the long bones and vertebrae, the trachea and distal ends of the ribs seen in children prior to completion of normal epiphyseal ossification; rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric; scoliosis. Ectodermal changes: linear or blotchy scaling ichthyosis in the newborn that usually resolves in the first months of life leaving linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; occasional flattened or split nails; normal teeth. Ocular changes: cataracts; microphthalmia and/or microcornea. Intellect is usually normal. Rarely affected males have been identified with a phenotype that includes: hypotonia; moderate to profound developmental delay; seizures; cerebellar (primarily vermis) hypoplasia and/or Dandy-Walker variant; and agenesis of the corpus callosum. [from GeneReviews]

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 GHR
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://ghr.nlm.nih.gov/condition/x-linked-chondrodysplasia-punctata-2

Clinical features

Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
Dandy-Walker syndrome
MedGen UID:
4150
Concept ID:
C0010964
Disease or Syndrome
Dandy-Walker malformation is defined by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus. DWM is a heterogeneous disorder. The low empiric recurrence risk of approximately 1 to 2% for nonsyndromic DWM suggests that mendelian inheritance is unlikely (summary by Murray et al., 1985).
Erythroderma
MedGen UID:
3767
Concept ID:
C0011606
Disease or Syndrome
Edema
MedGen UID:
4451
Concept ID:
C0013604
Sign or Symptom
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma is a group of eye disorders in which the optic nerves connecting the eyes and the brain are progressively damaged. This damage can lead to reduction in side (peripheral) vision and eventual blindness. Other signs and symptoms may include bulging eyes, excessive tearing, and abnormal sensitivity to light (photophobia). The term "early-onset glaucoma" may be used when the disorder appears before the age of 40.In most people with glaucoma, the damage to the optic nerves is caused by increased pressure within the eyes (intraocular pressure). Intraocular pressure depends on a balance between fluid entering and leaving the eyes.Usually glaucoma develops in older adults, in whom the risk of developing the disorder may be affected by a variety of medical conditions including high blood pressure (hypertension) and diabetes mellitus, as well as family history. The risk of early-onset glaucoma depends mainly on heredity.Structural abnormalities that impede fluid drainage in the eye may be present at birth and usually become apparent during the first year of life. Such abnormalities may be part of a genetic disorder that affects many body systems, called a syndrome. If glaucoma appears before the age of 5 without other associated abnormalities, it is called primary congenital glaucoma.Other individuals experience early onset of primary open-angle glaucoma, the most common adult form of glaucoma. If primary open-angle glaucoma develops during childhood or early adulthood, it is called juvenile open-angle glaucoma.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
Hydronephrosis
MedGen UID:
42531
Concept ID:
C0020295
Disease or Syndrome
Microphthalmos
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.People 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.People 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.Between 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.
Intellectual disability, moderate
MedGen UID:
7680
Concept ID:
C0026351
Mental or Behavioral Dysfunction
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Tracheal stenosis
MedGen UID:
21227
Concept ID:
C0040583
Disease or Syndrome
Congenital ichthyosiform erythroderma
MedGen UID:
86936
Concept ID:
C0079583
Disease or Syndrome
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Concave nasal ridge
MedGen UID:
78105
Concept ID:
C0264169
Finding
Tracheal calcification
MedGen UID:
75539
Concept ID:
C0264324
Disease or Syndrome
Hemivertebrae
MedGen UID:
82720
Concept ID:
C0265677
Congenital Abnormality
Hemiatrophy
MedGen UID:
451036
Concept ID:
C0333662
Pathologic Function
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Scoliosis
MedGen UID:
195976
Concept ID:
C0700208
Finding
The presence of an abnormal lateral curvature of the spine.
Abnormality of the pinna
MedGen UID:
167800
Concept ID:
C0857379
Finding
An abnormality of the pinna, which is also referred to as the auricle or external ear.
Patellar dislocation
MedGen UID:
253896
Concept ID:
C1135812
Injury or Poisoning
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Bilateral talipes equinovarus
MedGen UID:
332956
Concept ID:
C1837835
Finding
Elevated 8-dehydrocholesterol
MedGen UID:
333461
Concept ID:
C1840013
Finding
Elevated 8(9)-cholestenol
MedGen UID:
327010
Concept ID:
C1840014
Finding
Sparse eyelashes
MedGen UID:
375151
Concept ID:
C1843300
Finding
Stippled calcification in carpal bones
MedGen UID:
337100
Concept ID:
C1844846
Finding
Tarsal stippling
MedGen UID:
337101
Concept ID:
C1844848
Finding
Flat face
MedGen UID:
342829
Concept ID:
C1853241
Finding
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Epiphyseal stippling
MedGen UID:
349104
Concept ID:
C1859126
Finding
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
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.
Abnormality of pelvic girdle bone morphology
MedGen UID:
866545
Concept ID:
C4020847
Anatomical Abnormality
Abnormality of the thorax
MedGen UID:
867424
Concept ID:
C4021797
Anatomical Abnormality
Punctate vertebral calcifications
MedGen UID:
870240
Concept ID:
C4024678
Anatomical Abnormality
Sparse and thin eyebrow
MedGen UID:
924309
Concept ID:
C4282407
Finding
Decreased density/number and/or decreased diameter of eyebrow hairs.

Term Hierarchy

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

Recent clinical studies

Etiology

Viart V, Willems M, Ishmukhametova A, Dufernez F, Anahory T, Hamamah S, Schmitt S, Claustres M, Girardet A
Prenat Diagn 2017 Feb;37(2):201-205. Epub 2017 Jan 5 doi: 10.1002/pd.4982. PMID: 27943351
Lefebvre M, Dufernez F, Bruel AL, Gonzales M, Aral B, Saint-Onge J, Gigot N, Desir J, Daelemans C, Jossic F, Schmitt S, Mangione R, Pelluard F, Vincent-Delorme C, Labaune JM, Bigi N, D'Olne D, Delezoide AL, Toutain A, Blesson S, Cormier-Daire V, Thevenon J, El Chehadeh S, Masurel-Paulet A, Joyé N, Vibert-Guigue C, Rigonnot L, Rousseau T, Vabres P, Hervé P, Lamazière A, Rivière JB, Faivre L, Laurent N, Thauvin-Robinet C
Prenat Diagn 2015 Jul;35(7):675-84. Epub 2015 Mar 30 doi: 10.1002/pd.4591. PMID: 25754886
Lykissas MG, Sturm PF, McClung A, Sucato DJ, Riordan M, Hammerberg KW
J Pediatr Orthop 2013 Oct-Nov;33(7):685-93. doi: 10.1097/BPO.0b013e31829e86a9. PMID: 23836071
Pazzaglia UE, Zarattini G, Donzelli C, Benetti A, Bondioni MP, Groli C
Fetal Pediatr Pathol 2008;27(2):71-81. doi: 10.1080/15513810802077487. PMID: 18568995
Martanová H, Krepelová A, Baxová A, Hansíková H, Cánský Z, Kvapil M, Gregor V, Magner M, Zeman J
Prague Med Rep 2007;108(3):263-9. PMID: 18399064

Diagnosis

Viart V, Willems M, Ishmukhametova A, Dufernez F, Anahory T, Hamamah S, Schmitt S, Claustres M, Girardet A
Prenat Diagn 2017 Feb;37(2):201-205. Epub 2017 Jan 5 doi: 10.1002/pd.4982. PMID: 27943351
Posey JE, Burrage LC, Campeau PM, Lu JT, Eble TN, Kratz L, Schlesinger AE, Gibbs RA, Lee BH, Nagamani SC
Am J Med Genet A 2015 Jun;167(6):1309-14. Epub 2015 Apr 2 doi: 10.1002/ajmg.a.36899. PMID: 25846959Free PMC Article
Lefebvre M, Dufernez F, Bruel AL, Gonzales M, Aral B, Saint-Onge J, Gigot N, Desir J, Daelemans C, Jossic F, Schmitt S, Mangione R, Pelluard F, Vincent-Delorme C, Labaune JM, Bigi N, D'Olne D, Delezoide AL, Toutain A, Blesson S, Cormier-Daire V, Thevenon J, El Chehadeh S, Masurel-Paulet A, Joyé N, Vibert-Guigue C, Rigonnot L, Rousseau T, Vabres P, Hervé P, Lamazière A, Rivière JB, Faivre L, Laurent N, Thauvin-Robinet C
Prenat Diagn 2015 Jul;35(7):675-84. Epub 2015 Mar 30 doi: 10.1002/pd.4591. PMID: 25754886
Kolb-Mäurer A, Grzeschik KH, Haas D, Bröcker EB, Hamm H
Acta Derm Venereol 2008;88(1):47-51. doi: 10.2340/00015555-0337. PMID: 18176751
Rakheja D, Read CP, Hull D, Boriack RL, Timmons CF
Pediatr Dev Pathol 2007 Mar-Apr;10(2):142-8. doi: 10.2350/06-06-0111.1. PMID: 17378690

Therapy

Lefebvre M, Dufernez F, Bruel AL, Gonzales M, Aral B, Saint-Onge J, Gigot N, Desir J, Daelemans C, Jossic F, Schmitt S, Mangione R, Pelluard F, Vincent-Delorme C, Labaune JM, Bigi N, D'Olne D, Delezoide AL, Toutain A, Blesson S, Cormier-Daire V, Thevenon J, El Chehadeh S, Masurel-Paulet A, Joyé N, Vibert-Guigue C, Rigonnot L, Rousseau T, Vabres P, Hervé P, Lamazière A, Rivière JB, Faivre L, Laurent N, Thauvin-Robinet C
Prenat Diagn 2015 Jul;35(7):675-84. Epub 2015 Mar 30 doi: 10.1002/pd.4591. PMID: 25754886
Morice-Picard F, Kostrzewa E, Wolf C, Benlian P, Taïeb A, Lacombe D
Arch Dermatol 2011 Sep;147(9):1073-6. doi: 10.1001/archdermatol.2011.230. PMID: 21931045
Mason DE, Sanders JO, MacKenzie WG, Nakata Y, Winter R
Spine (Phila Pa 1976) 2002 Sep 15;27(18):1995-2002. PMID: 12634559
Sato M, Ishikawa O, Miyachi Y
Dermatology 1996;192(1):23-7. doi: 10.1159/000246308. PMID: 8832947

Prognosis

Lykissas MG, Sturm PF, McClung A, Sucato DJ, Riordan M, Hammerberg KW
J Pediatr Orthop 2013 Oct-Nov;33(7):685-93. doi: 10.1097/BPO.0b013e31829e86a9. PMID: 23836071
Martanová H, Krepelová A, Baxová A, Hansíková H, Cánský Z, Kvapil M, Gregor V, Magner M, Zeman J
Prague Med Rep 2007;108(3):263-9. PMID: 18399064
Rakheja D, Read CP, Hull D, Boriack RL, Timmons CF
Pediatr Dev Pathol 2007 Mar-Apr;10(2):142-8. doi: 10.2350/06-06-0111.1. PMID: 17378690
Umranikar S, Glanc P, Unger S, Keating S, Fong K, Trevors CD, Myles-Reid D, Chitayat D
Prenat Diagn 2006 Dec;26(13):1235-40. doi: 10.1002/pd.1594. PMID: 17086568
Mason DE, Sanders JO, MacKenzie WG, Nakata Y, Winter R
Spine (Phila Pa 1976) 2002 Sep 15;27(18):1995-2002. PMID: 12634559

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
Morice-Picard F, Kostrzewa E, Wolf C, Benlian P, Taïeb A, Lacombe D
Arch Dermatol 2011 Sep;147(9):1073-6. doi: 10.1001/archdermatol.2011.230. PMID: 21931045
Pazzaglia UE, Zarattini G, Donzelli C, Benetti A, Bondioni MP, Groli C
Fetal Pediatr Pathol 2008;27(2):71-81. doi: 10.1080/15513810802077487. PMID: 18568995
Al-Gazali LI, Bakir M, Hamid Z, Varady E, Varghes M, Haas D, Bener A, Padmanabhan R, Abdulrrazzaq YM, Dawadu A
Birth Defects Res A Clin Mol Teratol 2003 Feb;67(2):125-32. doi: 10.1002/bdra.10009. PMID: 12769508
Mason DE, Sanders JO, MacKenzie WG, Nakata Y, Winter R
Spine (Phila Pa 1976) 2002 Sep 15;27(18):1995-2002. PMID: 12634559

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