National Organization for Rare Disorders, Inc.

Conradi Hunermann Syndrome

Important
It is possible that the main title of the report Conradi Hunermann Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Chondrodystrophia Calcificans Congenita
  • Conradi Disease
  • Dysplasia Epiphysialis Punctata
  • Chondrodysplasia Punctata, X-linked Dominant Type

Disorder Subdivisions

  • None

Related Disorders List

Information on the following diseases can be found in the Related Disorders section of this report:

  • Chondrodysplasia Punctata, X-linked Recessive Type
  • Chondrodysplasia Punctata, Rhizomelic Type (Autosomal Recessive Type)
  • Fetal Warfarin Syndrome (Coumarin Embryopathy)
  • CHILD Syndrome
  • Associated Disorders (General

General Discussion

Conradi-Hunermann syndrome is a form of chondrodysplasia punctata, a group of rare, genetic disorders of skeletal development (skeletal dysplasias) characterized by unusual, "dotlike" (punctate) opacities representing abnormal accumulations of calcium salts (calcifications) within the growing ends of long bones (i.e., "stippled" epiphyses) and other regions. Conradi-Hunermann syndrome is commonly associated with mild to moderate growth deficiency; disproportionate shortening of long bones, particularly those of the upper arms (humeri) and the thigh bones (femora); short stature; and/or curvature of the spine. Many affected individuals also have a prominent forehead; unusually flattened midfacial regions (midfacial hypoplasia), with a low nasal bridge; loss of transparency of the lenses of the eyes (cataracts); sparse, coarse scalp hair; and/or abnormal thickening, dryness, and scaling of the skin. In rare cases, mild to moderate mental retardation may also be present. Evidence suggests that Conradi-Hunermann syndrome is usually inherited as an X-linked dominant trait that predominantly occurs in females. However, rare cases have also been reported in which males are affected.
.

Symptoms

Associated symptoms and findings may vary greatly in range and severity from case to case. However, in many affected infants, Conradi-Hunermann syndrome is characterized by failure to grow and gain weight at the expected rate (failure to thrive). In some instances, affected infants may also be prone to recurrent infections.

Conradi-Hunermann syndrome is a form of chondrodysplasia punctata that is considered intermediate in severity. During infancy, the disorder is typically associated with abnormal, dotlike (punctate) calcifications scattered throughout various regions of the cartilaginous skeleton. (When the skeleton begins to develop, it initially predominantly consists of cartilage, which is gradually replaced by bone [in a process known as ossification].)

In infants with Conradi-Hunermann syndrome, punctate calcifications may be present throughout the spinal column; the pelvis; the front ends of the ribs (costal cartilages); the breastbone (sternum); the shoulder blades (scapulae); the collarbones (clavicles); and the epiphyses, which are the growing ends of long bones of the limbs. Such characteristic, so-called "stippling" of the epiphyses typically resolves during infancy or early childhood.

Individuals with the disorder typically have associated musculoskeletal abnormalities. Such features commonly include asymmetric shortening of long bones of the limbs, particularly those of the upper arms (humeri) and the thigh bones (femora), causing variable, disproportionate limb length. Affected individuals also frequently have short stature; abnormal sideways and, in some cases, front-to-back curvature of the spine (scoliosis or kyphoscoliosis); and/or fixed bending of multiple joints (flexion contractures), such as of the knees, hips, elbows, and/or fingers. In some cases, additional musculoskeletal abnormalities have also been reported, including deformities in which the feet are abnormally twisted out of shape or position ("clubfeet" [talipes]).

Many individuals with Conradi-Hunermann syndrome also have distinctive abnormalities of the skull and facial (craniofacial) region. These may include an unusually prominent forehead (frontal bossing); a flattened midface (midfacial hypoplasia), with a low nasal bridge; and/or downslanting eyelid folds (palpebral fissures). In addition, in some cases, one side of the face may appear relatively dissimilar to the other (facial asymmetry).

Conradi-Hunermann syndrome is also commonly characterized by loss of transparency of the lens of one or both eyes at birth (congenital unilateral or bilateral cataracts). Additional reported eye (ocular) defects have included reduction in the size of the eyes (microphthalmia) or unusually small corneas, which are the dome-shaped transparent regions forming the front of the eyeballs.

In the newborn period, many affected infants also have redness (erythema) and unusual thickening, dryness, and scaling of the skin (ichthyosiform erythroderma) distributed in a linear, blotchy pattern over the body. Although the eruption usually resolves during infancy, older children may subsequently develop inflammation and wasting (atrophy) of follicles (follicular atrophoderma), causing pores to appear unusually large and patchy areas of hair loss (alopecia) on the scalp. The sparse scalp hair may also be unusually coarse.

In some instances, additional abnormalities have also been reported in association with Conradi-Hunermann syndrome. Such features have included abnormal calcifications and potential narrowing (stenosis) of the windpipe (trachea) and/or the larynx, which connects the throat and the trachea; an unusually short neck; abnormalities of the nails; various structural malformations of the heart (congenital heart defects); and/or other physical findings.

In most individuals with Conradi-Hunermann syndrome, intelligence appears to be normal. However, in rare cases, mild to moderate mental retardation may be present.
.

Causes

Evidence suggests that Conradi-Hunermann syndrome is typically inherited as an X-linked dominant trait that appears to primarily occur in females. However, a few rare cases have been described in which males are affected.

In the past, some researchers have suggested that the syndrome has autosomal dominant inheritance. However, many experts now conclude that all reported cases of Conradi-Hunermann syndrome, including those initially thought to have autosomal dominant inheritance, actually represent the X-linked dominant condition. (Additional forms of chondrodysplasia punctata have also been described that are inherited as an X-linked recessive or an autosomal recessive trait. For further information, please see the "Related Disorders" section of this report below.)

X-linked disorders are conditions that result from changes (mutations) of a gene on the X chromosome. Females have two X chromosomes, while males have one X chromosome from the mother and one Y chromosome from the father. In females, certain disease traits on the X chromosome may in some cases be "masked" by the normal gene on the other X chromosome. However, since males have only one X chromosome, if they inherit a gene for a disease present on the X, it is usually more likely to be fully expressed. Men with a disease gene for an X-linked disorder transmit the gene to their daughters but not to their sons. Women with a copy of the disease gene have a 50 percent risk of transmitting the gene to their daughters and their sons.

According to researchers, in males who inherit a disease gene for certain X-linked dominant disorders (hemizygotes), it is suspected that full expression of the disorder may often be associated with loss of life before birth (male lethality); as a result, the disorder may appear to predominantly affect females. However, some investigators suggest that, in extremely rare cases, mutated genes for particular X-linked dominant disorders, possibly including Conradi-Hunermann syndrome, may be transmitted both by females and by carrier males who are completely unaffected for unknown reasons, with sparing of males (rather than male lethality) resulting in the apparent selective involvement of females.

Some cases of Conradi-Hunermann syndrome have also been reported in which there is no apparent family history, with the disorder appearing to occur spontaneously for unknown reasons (sporadically). These have included rare instances in which more than one child of apparently unaffected parents have the disorder. Some researchers suggest that such cases may be due to gonadal mosaicism. In gonadal mosaicism, some of a parent's reproductive cells (germ cells) may carry the gene mutation while others contain a normal cell line ("mosaicism"). As a result, one or more of the parent's children may inherit the gene mutation, potentially leading to manifestation of the disorder, while the parent may have no apparent symptoms (asymptomatic carrier). Gonadal mosaicism may be suspected when apparently unaffected parents have more than one child with the same genetic abnormality.

Further research is necessary to determine the underlying genetic mechanisms responsible for transmission and expression of the disease gene for Conradi-Hunermann syndrome.

Evidence indicates that Conradi-Hunermann syndrome may result from various mutations of a gene mapped to the short arm (p) of chromosome X (Xp11.23-p11.22).* The gene, known as the emopamil binding protein (EBP) gene, is thought to play a role in cholesterol biosynthesis. Biosynthesis refers to the building up or conversion of complex chemical compounds from simple substances in the body.

*Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.
.

Affected Populations

Conradi-Hunermann syndrome is named for the investigators who initially described the disease entity in 1914 (Conradi E) and 1931 (Hunermann C). As noted above, Conradi-Hunermann syndrome is predominantly seen in females; however, rare cases have also been reported in which males are affected.
.

Related Disorders

Symptoms of the following disorders may be similar to those of Conradi-Hunermann syndrome. Comparisons may be useful for a differential diagnosis:

Chondrodysplasia punctata, X-linked recessive type, is a form of chondrodysplasia punctata characterized by abnormal, symmetric, dotlike (punctate) calcifications within the growing ends of certain long bones (i.e., stippled epiphyses) and other regions; short stature; and underdevelopment (hypoplasia) of the bones at the ends of the fingers (distal phalanges). Additional characteristic findings may include sparse, unruly hair; ichthyosis, primarily over the neck, on the chest, under the arms, and on the backs of the legs; and underdevelopment of the nose (nasal hypoplasia). Some with the disorder may also have additional features, including a relatively small head (microcephaly), bilateral cataracts, and/or mental retardation. According to reports in the medical literature, because the disorder is inherited as an X-linked recessive trait, it is typically fully expressed in males only; however, some females who carry a single copy of the disease gene (heterozygous females) may have certain, typically milder features, such as short arms, broad wrists, and relatively short stature as compared to noncarriers. Evidence suggests that the disorder is due to deletions or chromosomal rearrangements (translocations) involving the end of the short arm (p) of chromosome X (Xp22.3). A gene mapped to this chromosomal region regulates production of an enzyme known as arylsulfatase E (ARSE). (Enzymes are proteins that increase the rate of certain chemical reactions in the body.) Mutations of this gene have been identified in several individuals with the disorder, suggesting that altered ARSE activity plays a causative role.

Chondrodysplasia punctata, rhizomelic type, is considered a severe form of chondrodysplasia punctata. It is typically characterized by marked punctate calcifications within the growing ends of certain long bones (stippled epiphyses) and other regions. Associated musculoskeletal abnormalities may include severe, disproportionate shortening of the long bones of the upper arms (humeri) and the thigh bones (femora); short stature; curvature of the spine and/or other irregularities of certain bones of the spinal column (vertebrae); and/or fixed bending or extension of multiple joints (contractures). Affected individuals also typically have malformations of the craniofacial region, such as a prominent forehead; a small head (microcephaly); and a flattened midface (midfacial hypoplasia), with underdevelopment of the nose (nasal hypoplasia), a low nasal bridge, and small nostrils. In addition, the disorder may also be characterized by upwardly slanting eyelid folds (palpebral fissures), bilateral cataracts, ichthyosis, developmental delays, severe mental retardation, and/or excessive muscle tone with increased resistance to passive stretching (spasticity). Chondrodysplasia punctata, rhizomelic type, is inherited as an autosomal recessive trait and therefore may be fully expressed in males and females. The disorder has been shown to result from impaired functioning of various peroxisomal enzymes. Peroxisomes are tiny, specialized structures (organelles) within cells that play an essential role in various, ongoing chemical and physical processes in the body (metabolism).

Fetal warfarin syndrome, which may also be referred to as coumarin embryopathy, is a characteristic pattern of birth defects in a newborn resulting from exposure to certain anticlotting drugs (i.e., coumarin anticoagulants [vitamin K antagonists]), such as warfarin, during pregnancy. Evidence suggests that the greatest period of risk occurs from approximately six to nine weeks following conception. The most consistent feature is midfacial hypoplasia, with an unusually small, flattened nose; a deep groove between the "wings" of the nose (alae) and the tip; and abnormally small nostrils. Additional characteristic features may include stippled epiphyses, disproportionate short stature, mental retardation, eye abnormalities, hearing loss, sudden episodes of uncontrolled electrical activity in the brain (seizures), and/or other abnormalities. Experts indicate that Conradi-Hunermann syndrome and other forms of chondrodysplasia punctata must be differentiated from the fetal effects of warfarin or other coumarin anticoagulants.

CHILD syndrome, a rare genetic disorder that is apparent at birth (congenital), is characterized by distinctive skin abnormalities and limb defects affecting one side of the body (hemidysplasia). The term "CHILD" is an acronym that stands for (C)ongenital (H)emidysplasia with (I)chthyosiform erythroderma and (L)imb defects. The disorder is associated with mild growth deficiency before birth; stippled epiphyses; limb malformations on one side of the body (unilateral), which may range from underdevelopment (hypoplasia) of finger bones to absence of a limb; unilateral redness (erythema) and unusual thickening, dryness, and scaling of the skin (ichthyosiform erythroderma); and/or unilateral hair loss (alopecia). CHILD syndrome may also be characterized by hypoplasia of other tissues or organs on the affected side, such as other skeletal regions, the brain, spinal cord, thyroid, adrenal gland, and/or lung. Additional features may include an abnormal opening in the partition that separates the upper or lower chambers of the heart (cardiac septal defects); mental retardation; and/or other abnormalities. CHILD syndrome is thought to be inherited as an X-linked dominant trait that appears to primarily affect females. According to investigators, some cases of the disorder appear to result from different mutations of the same gene (i.e., EBP gene) responsible for Conradi-Hunermann syndrome (see "Causes" above), indicating that the disorders may sometimes be "allelic." (An allele is one of two or more alternative forms of a gene that may occupy a particular chromosomal location.) In addition, other cases have been reported in which CHILD syndrome has appeared to be due to mutations of a different gene on chromosome X (Xq28). The gene, known as the NSDHL gene, is involved in an earlier step of cholesterol metabolism.

A number of other conditions or disorders may also be characterized by epiphyseal stippling during infancy and/or additional symptoms and findings that resemble those associated with Conradi-Hunermann syndrome. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.)
.

Standard Therapies

Diagnosis
According to investigators, it is possible that a diagnosis of Conradi-Hunermann syndrome may be suggested before birth (prenatally) in some cases, based on certain findings detected during ultrasound (e.g., epiphyseal stippling, other calcifications, asymmetric limb shortening). During fetal ultrasonography, reflected sound waves create an image of the developing fetus.

In some instances, Conradi-Hunermann syndrome may be diagnosed or confirmed at birth or during infancy or early childhood, based on a thorough clinical evaluation; identification of characteristic physical findings; patient and family history; and various studies, including x-ray evaluation, which may reveal characteristic stippling of epiphyses and other regions of the cartilaginous skeleton. However, as noted above, there is loss of distinctive epiphyseal stippling over time, potentially making diagnosis difficult. In addition, there have been instances in which individuals with only mild manifestations have not been identified until adulthood.

Treatment
The treatment of Conradi-Hunermann syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); skin specialists (dermatologists); eye specialists; and/or other health care professionals.

Various orthopedic measures, including surgery, may be recommended to help prevent, treat, or correct certain skeletal abnormalities associated with the disorder. Surgery may also be advised for certain craniofacial malformations or other physical abnormalities. The surgical procedures performed will depend on the nature, severity, and combination of anatomical abnormalities, their associated symptoms, and other factors.

Recommended treatment for congenital cataracts may include early surgical removal of the cataracts; implantation of artificial lenses in some cases; and/or certain measures following surgery, such as the use of corrective lenses, to help achieve good vision. For those affected by ichthyosis, supportive measures may be recommended, such as bathing with bath oil and/or applying appropriate emollient skin ointments and lubricants.

Early intervention services may also be important in ensuring that affected children reach their potential. In some cases, special services that may be beneficial include remedial education, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

References

TEXTBOOKS
Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders Company; 2000:2008, 2010.

Beers MH, et al., eds. The Merck Manual. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2225.

Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:308-09, 388-89.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:23-24, 188-93.

Buyse ML. Birth Defects Encyclopedia. Dover, Mass: Blackwell Scientific Publications, Inc; 1990:731-32.

JOURNAL ARTICLES
Tysoe C, Law CJ, Caswell R, Clayton P, Ellard S.
Prenatal testing for a novel EBP missense mutation causing X-linked dominant chondrodysplasia punctata. Prenat Diagn. 2008 Apr 8.

Kolb-Mäurer A, Grzeschik KH, Haas D, Bröcker EB, Hamm H.
Conradi-Hünermann-Happle syndrome (X-linked dominant chondrodysplasia punctata) confirmed by plasma sterol and mutation analysis. Acta Derm Venereol. 2008;88(1):47-51.

Shanske AL, Bernstein L, Herzog R. Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature. Pediatrics. 2007 Aug;120(2):e436-41.

Ikegawa S, et al. Novel and recurrent EBP mutations in X-linked dominant chondrodysplasia punctata. Am J Med Genet. 2000;94:300-05.

Grange DK, et al. CHILD syndrome caused by deficiency of 3-beta-hydroxysteroid-delta-8,delta-7-isomerase. Am J Med Genet. 2000;90:328-35.

Traupe H, et al. The Conradi-Hunermann-Happle syndrome is caused by mutations in the gene that encodes a 8- 7 sterol isomerase and is biochemically related to the CHILD syndrome. Eur J Dermatol. 2000;10:425-28.

Has C, et al. The Conradi-Hunermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet. 2000;9:1951-55.

Herman GE. X-Linked dominant disorders of cholesterol biosynthesis in man and mouse. Biochim Biophys Acta. 2000;1529:357-73.

Braverman N, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hunermann syndrome. Nat Genet. 1999;22:291-94.

Traupe H. Functional X-chromosomal mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko. Am J Med Genet. 1999;85:324-29.

Resources

Human Growth Foundation
997 Glen Cove Avenue
Glen Head, NY 11545
Tel: (516)671-4041
Fax: (516)671-4055
Tel: (800)451-6434
Email: hgf1@hgfound.org
Internet: http://www.hgfound.org/

MAGIC Foundation
6645 W. North Avenue
Oak Park, IL 60302
Tel: (708)383-0808
Fax: (708)383-0899
Tel: (800)362-4423
Email: mary@magicfoundation.org
Internet: http://www.magicfoundation.org

Foundation for Ichthyosis & Related Skin Types
1364 Welsh Road G2
North Wales, PA 19454
Tel: (215)619-0670
Fax: (215)619-0780
Tel: (800)545-3286
Email: info@scalyskin.org
Internet: http://www.scalyskin.org

Arc (a national organization on mental retardation)
1010 Wayne Ave
Suite 650
Silver Spring, MD 20910
Tel: (301)565-3842
Fax: (301)565-3843
Tel: (800)433-5255
TDD: (817)277-0553
Email: info@thearc.org
Internet: http://www.thearc.org/

Little People's Research Fund, Inc.
616 Old Edmondson Avenue
2nd Floor
Catonsville, MD 21228-3305
USA
Tel: (410)747-1100
Fax: (410)747-1374
Tel: (800)232-5773
Email: lprf@lprf.org
Internet: http://www.lprf.org

Little People of America, Inc.
250 El Camino Real
Suite 201
Tustin, CA 92780
Tel: (714)368-3689
Fax: (714)368-3367
Tel: (888)572-2001
Email: info@lpaonline.org
Internet: http://www.lpaonline.org

Restricted Growth Association
RGA Office
PO Box 1024
PETERBOROUGH, Intl PE1 9GX
United Kingdom
Tel: 01733 759458
Internet: http://www.restrictedgrowth.co.uk

NIH/National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse
1 AMS Circle
Bethesda, MD 20892-3675
USA
Tel: (301)495-4484
Fax: (301)718-6366
Tel: (877)226-4267
TDD: (301)565-2966
Email: NIAMSinfo@mail.nih.gov
Internet: http://www.niams.nih.gov/Health_Info

NIH/National Eye Institute
Building 31 Rm 6A32
31 Center Dr MSC 2510
Bethesda, MD 20892-2510
United States
Tel: (301)496-5248
Fax: (301)402-1065
Email: 2020@nei.nih.gov
Internet: http://www.nei.nih.gov/

MUMS National Parent-to-Parent Network
150 Custer Court
Green Bay, WI 54301-1243
USA
Tel: (920)336-5333
Fax: (920)339-0995
Tel: (877)336-5333
Email: mums@netnet.net
Internet: http://www.netnet.net/mums/

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
TDD: (888)205-3223
Email: ordr@od.nih.gov
Internet: http://rarediseases.info.nih.gov/Default.aspx

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.

It is possible that the title of this topic is not the name you selected. Please check the Synonyms listing to find the alternate name(s) and Disorder Subdivision(s) covered by this report

This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

For additional information and assistance about rare disorders, please contact the National Organization for Rare Disorders at P.O. Box 1968, Danbury, CT 06813-1968; phone (203) 744-0100; web site www.rarediseases.org or email orphan@rarediseases.org

Last Updated:  5/22/2008
Copyright  1987, 1990, 1996, 2001 National Organization for Rare Disorders, Inc.


 Go to top of page Go to top of page 


This information does not replace the advice of a doctor. Healthwise disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.

Click here to learn about Healthwise
Click here to learn about Healthwise
Topic Contents
 Synonyms
 Disorder Subdivisions
 Related Disorders List
 General Discussion
 Symptoms
 Causes
 Affected Populations
 Related Disorders
 Standard Therapies
 Investigational Therapies
 References
 Resources