Conradi Hünermann Syndrome

Disease Overview

Summary

Conradi-Hünermann syndrome is a rare genetic disorder that affects approximately 1:100,000 to 1:200,000 births. This syndrome typically presents with skeletal abnormalities, short stature, differences in the form of the skull bones (craniofacial), eye or vision differences, and skin, hair, and nail abnormalities. The specific symptoms and severity of the disorder may vary greatly in individuals with Conradi-Hünermann syndrome. Symptoms may manifest anytime between early life to adulthood. Conradi-Hünermann syndrome is classified as a form of chondrodysplasia punctata, a group of disorders characterized by the formation of small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses), the bones of the spine (vertebrae), the windpipe (trachea) and parts of the ribs. Skeletal findings in Conradi-Hünermann syndrome present as asymmetric shortening of long bones, particularly those of the upper arms (humeri), thighs (femora) and of the hands and feet. Individuals with Conradi-Hünermann syndrome may also have abnormalities in the curvature of the spine as well as growth deficiency that can cause short stature. Individuals with Conradi-Hünermann syndrome can have differences in the way the skull bones are formed, and this can be seen as a face or head that is asymmetric, prominent forehead, flattened midfacial regions (midfacial hypoplasia) and a low nasal bridge. Eye findings in Conradi-Hünermann syndrome can include cataracts at birth or early in life, abnormally small eyeballs (microphthalmia), small corneas (microcornea) and loss of transparency of the lenses of the eyes (cataracts). Many individuals with Conradi-Hünermann syndrome also present with sparse, coarse scalp hair, flattened and split nail plates and/or abnormal thickening, dryness, and scaling of the skin. Conradi-Hünermann syndrome is inherited as an X-linked dominant manner; this means that the disorder primarily affects females and can lead to fetal death in males. Treatment is dependent on the individual’s symptoms and no cure exists for Conradi-Hünermann syndrome.

Introduction

Conradi-Hünermann syndrome is named after Dr. Conradi and Dr. Hünermann, who described this condition in medical literature in 1931. In the 1970’s, Dr. Happle contributed additional information about the signs and symptoms, inheritance and causes of this syndrome which is why this condition is also referred to as Conradi-Hünermann-Happle syndrome.

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Synonyms

• CDPXD2
• CDPX2
• X-linked dominant chondrodysplasia punctata 2
• Conradi-Hunermann-Happle syndrome
• Happle syndrome
• chondrodysplasia punctata type 2

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Signs & Symptoms

The symptoms, progression and severity of Conradi-Hünermann syndrome can vary dramatically, even among members of the same family. The disorder can cause serious complications at birth or be so mild that individuals may not be identified until adulthood (usually after having a child with Conradi-Hünermann syndrome). It is important to note that individuals with Conradi-Hünermann syndrome may not have all of the symptoms discussed below. Individuals with Conradi-Hünermann syndrome should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The classic symptoms of Conradi-Hünermann syndrome involve the skeleton, skin and eyes. Intelligence is usually unaffected.

Growth

Infants with Conradi-Hünermann syndrome may fail to grow and gain weight at the rate expected for their age and sex (failure to thrive). Growth deficiencies may ultimately result in a final adult height that is below normal (short stature). Some infants with Conradi-Hünermann syndrome are susceptible to recurrent infections.

Skeletal Findings

Infants with Conradi-Hünermann syndrome have small, hardened spots of calcium on the “growing portion” or heads of the long bones (stippled epiphyses) as well as other areas of the cartilaginous skeleton. Cartilage is a tough, elastic type of connective tissue that provides cushion and structure within the body. When the skeleton begins to develop, it mostly consists of cartilage, which is gradually replaced by bone. The development of these abnormal calcified spots is also known as chondrodysplasia punctata. In infants with Conradi-Hünermann syndrome, punctate calcifications may develop throughout the spinal column, pelvis, front ends of the ribs (costal cartilages), breastbone, shoulder blades, collarbones, and, in rare cases, the voice-box (larynx) and windpipe (trachea). Chondrodysplasia punctata tends to resolve on its own within the first few years of life.

Individuals with Conradi-Hünermann syndrome typically have additional skeletal abnormalities. This commonly includes asymmetric shortening of long bones of the limbs, particularly those of the upper arms (humeri) and the thigh bones (femora). This causes a disproportionate length of the arms and legs with one side typically more impacted than the other. Individuals with Conradi-Hünermann syndrome also frequently have abnormal sideways and front-to-back curvature of the spine (scoliosis or kyphoscoliosis). Abnormal stiffness of the joints or joints that are fixed or locked in a bent position (flexion contractures) may also occur. In some patients, other skeletal abnormalities have also been reported including malformation of the hips (hip dysplasia), defects of the spinal column and deformities in which the feet are abnormally twisted out of shape or position (clubbed feet).

Eye findings

Some individuals with Conradi-Hünermann syndrome have clouding of the lenses of the eye (cataracts). Cataracts may be present at birth (congenital) or may develop during infancy. Cataracts may affect one or both eyes and can cause blurred vision or decreased clarity of vision. Rarely, additional eye (ocular) abnormalities include abnormally small eyes (microphthalmos), abnormally small corneas (microcornea), down-slanting eyelid folds (palpebral fissures), rapid, involuntary eye movements (nystagmus) and degeneration of the main nerve that transmits nerve impulses from the retina to the brain (optic atrophy). In some patients, eye abnormalities can significantly reduce vision.

Facial features

Individuals with Conradi-Hünermann syndrome can have distinctive facial features which include an unusually prominent forehead (frontal bossing), flattened cheekbones (malar hypoplasia), a flattened bridge of the nose, upturned nostrils (anteverted nares) and malformed (dysplastic) ears. Hearing loss has been reported in some patients.

Skin findings

In the newborn period, many infants with Conradi-Hünermann syndrome can 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. In some patients, areas of the skin may be darker or lighter than surrounding areas (hyper- and hypopigmentation). Patchy areas of hair loss and scarring may develop on the scalp (cicatricial alopecia). The sparse scalp hair may also be unusually coarse and lusterless.

Other features reported in individuals with Conradi-Hünermann include 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 such as flattened or split nails; and/or other physical findings.

Typically, individuals with Conradi-Hünermann syndrome have a life expectancy similar to that of the general population unless they have severe spine problems (scoliosis) that affect lung and heart function. The intelligence of individuals with Conradi-Hünermann syndrome is usually not affected.

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Causes

Conradi-Hünermann syndrome is caused by particular changes that disrupt the function of the emopamil-binding protein (EBP) gene. This gene codes for a substance called 3β-hydroxysteroid-∆8,∆7- isomerase or sterol-∆8-isomerase, that works to excite a reaction (enzyme). This enzyme is important in the final steps of the production of cholesterol. Cholesterol is a waxy, fat substance that is present in all the cells of the body. Cholesterol is produced by our cells and obtained by the food we consume. Although too much cholesterol increases our risk for heart disease, cholesterol plays an important role in development before and after birth. The lack of cholesterol has been shown to disrupt certain molecular signaling that impacts the development of the limbs of a fetus. As a result of the dysfunction of sterol-∆8-isomerase, there is an accumulation of substances that precede cholesterol (precursor compounds) called sterols that accumulate and are toxic. How exactly the disruption of cholesterol production results in the signs and symptoms associated with Conradi-Hünermann syndrome are not fully understood.

Changes in the EBP gene that cause Conradi-Hünermann syndrome (pathogenic variants) can occur due to random chance (i.e., de novo) in the affected person or can be inherited in an X-linked dominant manner.

X-linked dominant disorders are conditions caused by a non-working gene on the X chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable features of Conradi-Hünermann syndrome.

Since males only have one X chromosome, if they inherit a disease gene present on the X chromosome, it will always be turned on. Males who inherit the disease-causing gene for EPB typically have more severe symptoms which may not be compatible with life and lead to loss of the pregnancy. However, males have been reported with Conradi-Hünermann syndrome. Typically these males have portions of the cells in their bodies that carry the affected EPB gene while other cells do not (mosaic) or they have an additional X chromosome (XXY chromosomal makeup). Males with a disease gene for an X-linked disorder transmit the gene to their all of 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.

In some people with Conradi-Hünermann syndrome, where there is no apparent family history, the disorder may have occured due to differences in the genetic makeup of a person’s reproductive cells (gonadal mosaicism). This includes rare instances in which more than one child of apparently unaffected parents have the disorder. 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 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. Within families, there is variation in the severity of the clinical picture between affected females, and this is largely secondary to differences in X-inactivation.

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Affected populations

Conradi-Hünermann syndrome is a rare disorder that almost exclusively affects females. The exact incidence of the disorder in the general population is unknown, but one estimate is that 1 in 100,000 to 1 in 200,000 individuals are born with Conradi-Hünermann syndrome. The disorder is often apparent at birth (congenital), but some individuals with mild cases may not be identified until adulthood.

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Disorders with Similar Symptoms

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

Male EBP disorder with neurologic defects (MEND) is a condition caused by a genetic alteration that does not completely disrupt the function of the EBP gene. Unlike Conradi-Hünermann syndrome, which causes the complete disruption of the EBP gene, males with MEND present with moderate-to-severe developmental delay, malformations such as the absence of a part of the brain that connects the hemispheres of the brain (agenesis of the corpus callosum) and abnormalities in the ridges of the cerebral cortex (major gyral). Males with MEND may have a large nasal bridge, ears that are lower than expected and a large front soft spot (anterior fontanelle). MEND in males can also present with other findings such as webbing of the fingers, extra fingers (polydactyly), failure of the testes descend from the abdomen to the scrotum (cryptorchidism) and an abnormality in the position of the opening at the tip of the penis (hypospadias). Males with MEND typically do not have epiphyseal stippling which is a characteristic finding in Conradi-Hünermann syndrome. Females with MEND have no clinical manifestations of the disorder.

Rhizomelic chondrodysplasia punctata (RCDP) spectrum is a group of rare disorders that affect the function and structure of the peroxisomes. Peroxisomes are sac-like structures found inside cells that degrade certain compounds in cells and play a role in the production of fats that are necessary for the body. RCDP is characterized by bilateral and symmetric shortening of the upper long bone of the arms (humerus) and legs (femur), a condition known as rhizomelia. Additional findings include distinctive facial features, the formation of small, hardened spots of calcium (stippling) on the kneecap (patella) and long bones of the arms and legs (chondrodysplasia punctata), cataracts that are present at birth or shortly thereafter, profound growth deficiency after birth, intellectual disability and seizures. RCDP causes life-threatening complications during the first decade of life and in some children during the newborn (neonatal) period. Milder forms of RCDP present with less severe intellectual and developmental deficits and growth deficiency with often no rhizomelia. Many of these disorders are caused by changes in four genes PEX7 (type 1), GNPAT (type 2), AGPS (type 3), PEX5 (type 5). All of the genes that cause RCDP are inherited in an autosomal recessive pattern.

X-linked recessive chondrodysplasia punctata 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, chest, under the arms and on the backs of the legs; and underdevelopment of the nose (nasal hypoplasia). The severity of the disorder can vary greatly from one person to another. Because the disorder is inherited in an X-linked recessive pattern, it is typically fully expressed only in males. X-linked recessive chondrodysplasia punctata is caused by deletions or genetic changes in the ARSL gene which eliminate the function of the gene. The ARSL gene produces a substance whose function is to excite a chemical reaction (enzyme) known as arylsulfatase E (ARSE). The specific function of this enzyme is still unknown. Changes in the ARSL gene have been identified in several individuals with the disorder, suggesting that altered ARSE activity plays a causative role in the development of X-linked recessive chondrodysplasia punctata.

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 right side of the body tends to be affected twice as much as the left side. The term “CHILD” is an acronym that stands for (C)ongenital (H)emidysplasia with (I)chthyosiform erythroderma and (L)imb (D)efects. 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 underdevelopment or incomplete development (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). The majority of cases are due to genetic change in the NSDHL gene on the X chromosome. The gene encodes a steroid dehydrogenase enzyme that also plays a role in cholesterol metabolism. CHILD syndrome is inherited in an X-linked dominant pattern. (For more information on this disorder, choose “CHILD” as your search term in the Rare Disease Database.)

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 anti-clotting 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 common 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, intellectual disability, eye abnormalities, hearing loss, sudden episodes of uncontrolled electrical activity in the brain (seizures) and/or other abnormalities. Conradi-Hünermann syndrome and other forms of chondrodysplasia punctata must be differentiated from the fetal effects of warfarin or other coumarin anticoagulants.

There are additional disorders that involve chondrodysplasia punctata or other skeletal symptoms similar to those found in Conradi-Hünermann syndrome. These disorders include Zellweger spectrum disorders, Smith-Lemli-Optiz syndrome, Keutel syndrome, Antley-Bixler syndrome, desmosterolosis, lathosterolosis, Greenberg dysplasia and chondrodysplasia punctata, tibia-metacarpal type, Astley-Kendall dysplasia, maternal autoimmune disease (systemic lupus, mixed connective tissue disease and scleroderma). There are other disorders that have skin abnormalities similar to those found in Conradi-Hünermann syndrome, including other forms of ichthyosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

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Diagnosis

A diagnosis of Conradi-Hünermann syndrome is based upon identification of characteristic symptoms, a detailed medical history, thorough clinical evaluation and a variety of specialized tests. X-ray (radiographic), eye (ophthalmologic), skin (dermatological), tissue examination (histological exam) and biochemical examinations may be performed to help diagnose Conradi-Hünermann syndrome.
X-ray evaluation looks for characteristic stippling of epiphyses, specked calcium deposits in the bones and other regions of the cartilaginous skeleton (See the “signs and symptoms” section for additional information on stippling of epiphyses). However, there is loss of distinctive epiphyseal stippling over time, potentially making diagnosis difficult.

An important test to confirm a diagnosis of Conradi-Hünermann syndrome is a blood test that looks for elevated levels of substances called sterols. Genetic changes in the EBP gene result in higher levels of sterols (8(9)-cholesterol and 8-dehydrocholesterol) in the blood and certain tissues of the body.
In individuals with skin findings, affected areas of the skin can be analyzed under a microscope (histologic examination) to see if there is thickening and small opening of the outer layer (ostial hyperkeratosis) of the hair follicle with calcium deposits. This finding is common in Conradi-Hünermann syndrome but can also be found in a few other conditions.

A diagnosis of Conradi-Hünermann syndrome can also be confirmed through molecular genetic testing, which may identify the characteristic genetic mutation that causes the disorder. Genetic testing for males may require additional tests to see whether they carry an additional X chromosome (46, XXY males) or if they are mosaic for a genetic change in the EBP gene (See the “causes” section for additional information on mosaic males).

Clinical Testing and Work-Up

Initial evaluation to establish a diagnosis typically requires the help of a multidisciplinary team of specialists. Individuals with suspected Conradi-Hünermann syndrome should have the following evaluations:

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Standard Therapies

Treatment

The treatment of Conradi-Hünermann syndrome is directed toward the specific symptoms that each individual has. 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, scoliosis 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 (when they interfere with vision); implantation of artificial lenses in some patients; and/or certain measures following surgery, such as the use of corrective lenses, to help achieve good vision.

For those individuals with ichthyosis and skin abnormalities, supportive measures may be recommended, such as bathing with bath oil and/or applying appropriate skin ointments and lubricants that soften and soothe the skin (emollients). Sun protection (sunscreen) is also recommended as well avoiding using emollients when exposed to the sun as that can lead to sunburn.

For individuals with hearing loss, standard treatment is provided based on the recommendation of the physicians who specializes in ear conditions (otolaryngologist) and community services can be offered through early intervention services.

Genetic counseling is recommended for affected individuals with and their families to coordinate genetic testing, talk about the risk to family members and discuss family planning. Social workers can help families identify local resources and arrange ongoing support (i.e., palliative care or home nursing).

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

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

Some current clinical trials also are posted on the following page on the NORD website:https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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

For information about clinical trials conducted in Europe, contact:https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
de Almeida H Jr, Has C, Rampon G, Isaacsson H, de Castro LA. MEND syndrome: a case report with scanning electron microscopy findings of the collodion membrane. Acta Derm Venereol. 2017;97(1):110-111.

Bukkems SF, Ijspeert WJ, Vreenurg M, van Rhijn LW, Schrander JJ, van Steensel MA. Het syndroom van Conradi-Hünermann-Happle [Conradi-Hünermann-Happle syndrome]. Ned Tijdschr Geneeskd. 2012;156(10):A4105.

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

Offiah AC, Mansour S, Jeffrey I, et al. Greenberg dysplasia (HEM) and lethal X linked dominant Conradi-Hünermann chondrodysplasia punctata (CDPX2): presentation of two cases with overlapping phenotype. J Med Genet. 2003;40:e129.

Aughton DJ, Kelley RI, Metzenberg A, et al. X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet. 2003;116A:255-260.

Has C, Seedorf U, Kannenberg F, et al. Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-Hünermann-Happle syndrome. J Invest Dermatol. 2002;118:851-858.

Has C, Bruckner-Tuderman L, et al. The Conradi-Hünermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet. 2000;9:1951-1955.

Braverman N, Lin P, Moebius FF, et al. Mutations in the gene encoding 3ß-hydroxysteroid-?8,?7-isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nat Genet. 1999;22:291-294.

INTERNET
Kumble S, Savarirayan R. Chondrodysplasia Punctata 2, X-Linked. 2011 May 31 [Updated 2020 Jan 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK55062/ Accessed June 10, 2021.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:302960; Last Update: 05/03/2017. Available at: https://www.ncbi.nlm.nih.gov/omim/302960 Accessed June 10, 2021.

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