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Conradi-Hünermann-Happle syndrome
CHH is a condition that predominantly affects females, causing distinctive skeletal issues, skin abnormalities, and potential eye involvement. It results from genetic changes that disrupt cholesterol production within the body.
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Overview
Conradi-Hünermann-Happle syndrome (CHH) is a rare inherited condition that can affect many parts of the body. It is mainly characterised by abnormalities in skeletal development, distinctive skin conditions, and eye issues. Most individuals diagnosed with CHH are female, as the condition is linked to the X chromosome [PMID:17729227]. The severity of CHH can vary significantly among affected individuals, even within the same family.
Symptoms & clinical features
The symptoms of Conradi-Hünermann-Happle syndrome often become apparent during infancy or early childhood. Skeletal features commonly include bone abnormalities affecting the spine (scoliosis), short stature, and asymmetrical shortening of the limb bones. A characteristic X-ray finding is known as 'stippled epiphyses' (stippling in the growing ends of long bones), which can resolve over time. Skin manifestations typically involve ichthyosis (dry, scaly skin) and hyperkeratosis (thickening of the outer layer of skin), often appearing in swirling or linear patterns. Hair abnormalities, such as sparse or coarse hair, can also occur. Eye problems may include cataracts, particularly in childhood, and optic atrophy, which can affect vision [PMID:19468971]. In some cases, sensory neural hearing loss has been reported.
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Affected organs
Conradi-Hünermann-Happle syndrome primarily affects the skeletal system, leading to bone changes and growth eccentricities. The skin is also significantly impacted, presenting with characteristic dry patches and thickened areas. The eyes can be affected, potentially causing vision impairment due to cataracts and issues with the optic nerve. Other body systems that may occasionally show involvement include hair, nails, and, in rare instances, the ears.
Risks & severity
The severity of Conradi-Hünermann-Happle syndrome is highly variable; some individuals experience mild symptoms, while others have more significant health challenges. While developmental delay is not typical, a small number of severe cases have been associated with intellectual disability [PMID:19468971]. Life expectancy for most individuals with CHH is generally normal, though severe cases, particularly those with significant skeletal or organ involvement, may lead to early complications. The exact prevalence of CHH is not well established, but it is considered a very rare condition.
Genetic causes
Conradi-Hünermann-Happle syndrome is caused by pathogenic variants in the EBP gene. This gene provides instructions for making an enzyme called 3β-hydroxysteroid-Δ8,Δ7-isomerase. This enzyme plays a crucial role in the body's cholesterol synthesis pathway, specifically converting 8(9)-cholestenol into lathosterol. When the EBP gene has a pathogenic variant, it can lead to a deficiency of this enzyme, disrupting the normal production of cholesterol. Cholesterol is vital for many bodily functions, including cell membrane structure, hormone production, and nervous system development. The disruption in this pathway is thought to underpin the diverse symptoms seen in CHH. Other genes are involved in forms of chondrodysplasia punctata that do not share the same genetic basis as Conradi-Hünermann-Happle syndrome.
- EBP EBP cholestenol delta-isomeraseThe EBP gene encodes an enzyme essential for cholesterol biosynthesis, playing a critical role in normal development and cellular function.
Inheritance pattern
CHH has an X-linked dominant inheritance pattern. This means the gene responsible, EBP, is located on the X chromosome. Because females have two X chromosomes, they are typically more mildly affected than males, as one unaffected X chromosome can often compensate for the X chromosome with the pathogenic variant. Males have only one X chromosome, so if they inherit a pathogenic variant on their single X chromosome, the condition is usually much more severe and often lethal before birth or shortly after. Females have a 50% chance of passing on the pathogenic variant to each of their children, regardless of the child's sex. Affected males cannot pass the condition to their sons but will pass it to all of their daughters.
X-linked dominant: all daughters of an affected father inherit the altered X and are affected. Sons receive the father's Y and are unaffected.
Diagnosis & testing
Diagnosis of Conradi-Hünermann-Happle syndrome typically begins with a clinical evaluation based on the characteristic symptoms, such as skeletal abnormalities, skin changes, and eye findings. Imaging studies, like X-rays, can help identify the characteristic 'stippled epiphyses'. Confirmation of the diagnosis is achieved through genetic testing, which looks for pathogenic variants in the EBP gene. Genetic testing for CHH is available within the NHS Genomic Medicine Service (GMS) pathways, often following a referral from a specialist paediatrician or clinical geneticist. The relevant NHS National Genomic Test Directory R-code for genetic testing for CHH is R408 'Skeletal dysplasia with chondrodysplasia punctata'.
Management & lifestyle
The management of Conradi-Hünermann-Happle syndrome is supportive and aims to address the specific symptoms experienced by each individual. This often involves a multidisciplinary team approach. Skeletal issues may require orthopaedic intervention or physiotherapy. Dermatological treatments can help manage skin dryness and scaling. Regular ophthalmological assessments are crucial to monitor and treat eye problems, such as cataracts, which may require surgical removal. Hearing assessments are also recommended. Individuals with CHH should be followed by a clinical geneticist, and genetic counselling is an important part of managing the condition for affected individuals and their families. This helps them understand the inheritance pattern and implications for future family planning.
UK care pathway
In the UK, individuals suspected of having Conradi-Hünermann-Happle syndrome would typically be referred by their GP or existing specialist to a clinical genetics service. Clinical geneticists and genetic counsellors are specialists in diagnosing and managing rare genetic conditions. They can arrange for genetic testing through the NHS Genomic Medicine Service, often guided by the NHS National Genomic Test Directory R-codes such as R408 for skeletal dysplasias with chondrodysplasia punctata. Genetic counsellors can provide essential information about inheritance, future risks, and support services, helping families navigate the complexities of a genetic diagnosis.
Frequently asked questions
Is Conradi-Hünermann-Happle syndrome always severe?
No, the severity of Conradi-Hünermann-Happle syndrome can vary significantly. Some individuals may have mild symptoms that cause few problems, while others can experience more significant health issues affecting multiple body systems.
Can males have Conradi-Hünermann-Happle syndrome?
While CHH predominantly affects females, males can inherit the pathogenic variant. However, the condition is typically much more severe, often leading to very early complications or being lethal before birth due to the X-linked dominant inheritance pattern.
What kind of doctors treat Conradi-Hünermann-Happle syndrome?
Management often involves a team of specialists, including clinical geneticists, paediatricians, orthopaedic surgeons, dermatologists, ophthalmologists, and physiotherapists, depending on the specific symptoms a person experiences.
Is there a cure for Conradi-Hünermann-Happle syndrome?
There is currently no cure for Conradi-Hünermann-Happle syndrome. Treatment focuses on managing the specific symptoms and providing supportive care to improve quality of life for individuals affected by the condition.
How does CHH affect daily life?
The impact on daily life varies widely depending on the severity of symptoms. Some individuals may lead relatively normal lives with regular medical check-ups, while others might require ongoing support with mobility, vision, or skin care.
References
- Hartman RD, Molho-Pessach V, Schaffer JV. Conradi-Hünermann-Happle syndrome. Dermatology online journal. 2010. PMID: 21163155
- Agud-Dios M, Ortiz Cabrera NV, Noguera-Morel L. Conradi-Hünermann-Happle syndrome with minimal signs. Pediatric dermatology. 2021. PMID: 34749431
- Jira P. Cholesterol metabolism deficiency. Handbook of clinical neurology. 2013. PMID: 23622407
- Del Río-Martínez CJ, de León-Jiménez B, Ramos-Gómez LI. Conradi-Hünermann-Happle syndrome: Clinical and trichoscopic findings. Pediatric dermatology. 2023. PMID: 36263758
- Arnold AW, Bruckner-Tuderman L, Has C. Conradi-Hünermann-Happle syndrome in males vs. MEND syndrome (male EBP disorder with neurological defects). The British journal of dermatology. 2012. PMID: 22229330
- Traupe H, Has C. The Conradi-Hünermann-Happle syndrome is caused by mutations in the gene that encodes a 8- 7 sterol isomerase and is biochemically related to the CHILD syndrome. European journal of dermatology : EJD. 2000. PMID: 10980461
- Yoneda K. Inherited ichthyosis: Syndromic forms. The Journal of dermatology. 2016. PMID: 26945533
- Cañueto J, Girós M, González-Sarmiento R. The role of the abnormalities in the distal pathway of cholesterol biosynthesis in the Conradi-Hünermann-Happle syndrome. Biochimica et biophysica acta. 2014. PMID: 24036494