Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Art & Psychiatry
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Conference Oration
Conference Summary
Continuing Medical Education
Cosmetic Dermatology
Current Best Evidence
Current Issue
Current View
Derma Quest
Dermato Surgery
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
Editor Speaks
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
In Memorium
Inaugural Address
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Medicolegal Window
Miscellaneous Letter
Net Case
Net case report
Net Image
Net Letter
Net Quiz
Net Study
New Preparations
News & Views
Observation Letter
Observation Letters
Original Article
Original Contributions
Pattern of Skin Diseases
Pediatric Dermatology
Pediatric Rounds
Presedential Address
Presidential Address
Presidents Remarks
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Review Article
Review Articles
Revision Corner
Self Assessment Programme
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Special Article
Specialty Interface
Study Letter
Study Letters
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Systematic Review and Meta-Analysis
Systematic Reviews and Meta-analyses
Systematic Reviews and Meta-analysis
Therapeutic Guideline-IADVL
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapy Letter
Therapy Letters
View Point
What’s new in Dermatology
View/Download PDF

Translate this page into:

Net Letter
87 (
); 892-892

A case of Conradi-Hünermann-Happle syndrome with typical clinical manifestations confirmed by genetic mutation analysis

Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea
Department of Pediatrics, Chung-Ang University College of Medicine, Seoul, Korea
Corresponding author: Dr. Kui Young Park, Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea. Dr. Su Yeong Kim, Department of Pediatrics, Chung-Ang University College of Medicine, Seoul, Korea.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Hong JK, Han HS, Seo SJ, Kim SY, Park KY. A case of Conradi-Hünermann-Happle syndrome with typical clinical manifestations confirmed by genetic mutation analysis. Indian J Dermatol Venereol Leprol, doi: 10.25259/IJDVL_876_20


Conradi-Hünermann-Happle syndrome, also known as X-linked dominant chondrodysplasia punctata (CDPX2), is a group of disorders affecting cholesterol metabolism due to mutations in the emopamil-binding protein gene encoding emopamil-binding protein, the 3-beta-hydroxysteroid-delta(8)- and delta(7)-isomerase. Patients with ConradiHünermann-Happle syndrome present with skeletal dysplasia as well as cutaneous and ocular abnormalities. The annual incidence of Conradi-Hünermann-Happle is approximately one in 400,000 births and over 95% of patients are female.

A one-day-old full-term female neonate was brought to our department with diffuse scaly patches covering almost the whole of her body. Her mother had a medical history of ichthyosis, cataracts and shortening of her left upper arm. The patient has one sister who has relatively mild clinical abnormalities including short stature and ichthyosis. On clinical examination, feather-like yellowish hyperkeratotic scales were found covering almost the entire body along the Blaschko lines [Figures 1a and 1b]. In addition, asymmetric rhizomelic shortening of the upper limbs and polydactyly with pathological short stature (<1 percentile) were also noted [Figures 1c and 1d]. Ophthalmic consultations revealed mild cortical opacities in both eyes, suggestive of early-stage cataract.

Figure 1a:: Distinctive cutaneous manifestations with orthopedic abnormalities. Yellow-to-white hyperkeratotic scales on the back distributed along Blaschko lines
Figure 1b:: Feather-like yellowish scales were found along the Blaschko lines
Figure 1c:: Asymmetric rhizomelic shortening of the upper extremities (right only)
Figure 1d:: Polydactyly of the left hand

A radiographic survey revealed punctate stippled calcification involving the multiple vertebrae, sternum, femoral epiphysis, left radius and ulna, along with scoliosis [Figures 2a-2c]. After obtaining informed consent, genomic mutation analysis was performed and it was found that the patient was heterozygous for a mutation of one guanine residue at nucleotide position 388 to thymine (c.388G>T) in the emopamil-binding protein gene with a missense mutation (p.Gly130*). This mutation is a “likely pathogenic” variant of the emopamil-binding protein gene, which causes Conradi-Hünermann-Happle syndrome.

Figure 2a:: Radiologic characteristics of the patient. Punctate stippled calcification in the vertebral bodies of multiple thoracolumbar vertebrae and sternum with scoliosis.
Figure 2b:: Punctate stippled calcifications also found in both the epiphysis of the femur (red arrows)
Figure 2c:: In the radius and the ulna, multiple prominent punctate stippled calcifications were observed (red arrows)

For the treatment of ichthyosis, the parents were asked to apply moisturizers and urea cream twice a day, which cured most of the lesions, leaving linear hypopigmented lesions after about a month. Regular examinations were performed for her orthopedic and ophthalmic problems.

Chondrodysplasia punctata is a rare form of skeletal dysplasia characterized by skeletal abnormalities such as short stature, asymmetrical rhizomelic shortening of the limbs and epiphyseal stippling. Conradi-Hünermann-Happle syndrome, or CDPX2, exhibits distinctive and striking cutaneous changes including striated feather-like hyperkeratotic scales following the Blaschko lines, compared to other subtypes of chondrodysplasia punctata.

This syndrome is caused by mutations in the emopamil-binding protein gene, which encodes emopamil-binding protein that plays a key role in the final step of cholesterol biosynthesis. Enzyme deficiency leads to the accumulation of teratogenic sterol precursor compounds in tissue and serum, leading to various skeletal abnormalities.1 Furthermore, sterol and related metabolites are essential components of the cell membrane. They are also required in the hedgehog signaling pathway, which produces hedgehog protein and plays a key role in skeletal development. Therefore, dysfunction of these pathways leads to various clinical abnormalities of the skin and bony structures. To date, more than 70 emopamil-binding protein mutations have been reported, including mutations in exons and introns. These mutations induce diverse splicing pathogenic emopamil-binding protein, which could result in various phenotypic features in Conradi-Hünermann-Happle syndrome. However, the correlation between genotype and phenotype remains unclear.2,3

There are two types of congenital ichthyosis: nonsyndromic type with symptoms limited only to the skin and syndromic type with underlying genetic defects that affect other organs too. The latter includes Netherton syndrome, Sjögren-Larsson syndrome, Dorfman-Chanarin syndrome and Conradi-Hünermann-Happle syndrome. Therefore, in patients with congenital ichthyosis, other organ abnormalities should be examined to determine the type of syndrome. Furthermore, Conradi-Hünermann-Happle syndrome should be differentiated from congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome. Unlike CHILD syndrome, in Conradi-HünermannHapple syndrome, ichthyosis is bilateral and appears along Blaschko lines with a frequent co-occurrence of ocular lesions.

Interestingly, the affected family members with an abnormal X chromosome in this case showed variable phenotypic features [Figure 3]. Skewed X-inactivation is proposed as a possible mechanism of this phenomenon.4 While skewed X-inactivation can usually account for the phenotypic diversity of X-linked recessive disorders, it has also been reported to cause variable phenotypes in X-linked dominant diseases. There are a few reported cases in which skewed X-inactivation was confirmed by X-inactivation analysis in Conradi-Hünermann-Happle syndrome.4,5 However, the correlation between the severity of Conradi-HünermannHapple syndrome and the presence of skewed X-inactivation has not been established. Considering the intrafamilial variability of phenotypic findings in this case, the presence of skewed X-inactivation cannot be excluded.

Figure 3:: Pedigree chart of the family showing the different phenotypic features

Mutation analysis is a powerful tool to confirm ConradiHünermann-Happle syndrome, but is often time-consuming and usually takes two to three months. Skin involvement is observed in more than 95% of cases of Conradi-Hünermann-Happle syndrome. Therefore, dermatologists should suspect ConradiHünermann-Happle syndrome on encountering patients with distinctive feathery ichthyosis and suggest additional work-up such as orthopedic and ophthalmologic evaluation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


  1. , , , , , , et al. Novel EBP gene mutations in ConradiHünermann-Happle syndrome. Br J Dermatol. 2007;157:1225-9.
    [CrossRef] [Google Scholar]
  2. , , , , , , et al. Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-HünermannHapple syndrome. J Invest Dermatol. 2002;118:851-8.
    [CrossRef] [Google Scholar]
  3. , , , , , , et al. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-Hünermann-Happle syndrome. Eur J Hum Genet. 2018;26:1784-90.
    [CrossRef] [Google Scholar]
  4. , , , , , , et al. Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata. Hum Genet. 2003;112:78-83.
    [CrossRef] [Google Scholar]
  5. , , , , , , et al. Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hünermann-Happle syndrome: New insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature. Br J Dermatol. 2012;166:830-8.
    [CrossRef] [Google Scholar]

Fulltext Views

PDF downloads
View/Download PDF
Download Citations
Show Sections