Why does X-linked chondrodysplasia punctata 2 (CDPX2) primarily affect females, even though it's an X-linked condition?

CDPX2 is an X-linked dominant condition. Males have only one X chromosome, so a pathogenic EBP variant on that chromosome is often lethal early in development. Females have two X chromosomes, and X-inactivation allows some cells to use the healthy EBP gene copy, leading to a milder, but still significant, presentation. This mosaicism allows affected females to survive, while males with the variant are typically severely affected or do not survive to term.

How is X-linked chondrodysplasia punctata 2 (CDPX2) typically managed, given the issues with cholesterol and toxic byproducts?

Management of CDPX2 is primarily supportive and focuses on addressing the specific symptoms. This can involve orthopedic interventions for bone deformities, dermatological care for skin issues, and ophthalmological treatment for eye problems like cataracts. While the underlying cholesterol synthesis defect is known, there isn't a standard treatment to directly correct the enzyme deficiency or cholesterol levels. Research is ongoing into potential therapeutic strategies, but current care aims to improve quality of life and manage complications.

What are the key signs and symptoms of X-linked chondrodysplasia punctata 2 (CDPX2) that would prompt a diagnosis?

CDPX2 is characterized by a range of abnormalities affecting bone, skin, and eyes. Skeletal features include stippled (punctate) calcifications in cartilage, especially in the spine and long bones, which can lead to short stature, bone deformities, and scoliosis. Skin abnormalities often include linear streaks of redness and scaling (ichthyosis) or hair loss. Eye problems can include cataracts and optic atrophy. These signs are often present at birth or in early infancy.

EBP gene

The EBP gene encodes the enzyme 3β‑hydroxysteroid‑Δ8,Δ7‑isomerase, a key step in cholesterol synthesis, and pathogenic variants cause X‑linked chondrodysplasia punctata 2.

Overview

Normal Function

The EBP gene provides instructions for making an enzyme called 3β‑hydroxysteroid‑Δ8,Δ7‑isomerase. This enzyme is responsible for one of the final steps in the production of cholesterol. Specifically, it converts a molecule called 8(9)-cholestenol to lathosterol. Other enzymes then modify lathosterol to produce cholesterol.

Cholesterol is a waxy, fat‑like substance that is produced in the body and obtained from foods that come from animals (particularly egg yolks, meat, poultry, fish, and dairy products). Although too much cholesterol is a risk factor for heart disease, this molecule is necessary for normal embryonic development and has important functions both before and after birth. It is a structural component of cell membranes and plays a role in the production of certain hormones and acids used in digestion (bile acids).

Health Conditions Related to Genetic Changes

X‑linked chondrodysplasia punctata 2

More than 55 mutations in the EBP gene have been found to cause X‑linked chondrodysplasia punctata 2, a condition that occurs almost exclusively in females and is characterized by bone, skin, and eye abnormalities. Some of the mutations responsible for this condition in females insert or delete a small amount of genetic material from the EBP gene, while others change single protein building blocks (amino acids) in the 3β‑hydroxysteroid‑Δ8,Δ7‑isomerase enzyme. All of these mutations impair the normal function of the enzyme, preventing cells from producing enough cholesterol. A shortage of this enzyme also allows potentially toxic byproducts of cholesterol production to build up in the body. The combination of low cholesterol levels and an accumulation of other substances likely disrupts the growth and development of many body systems. It is not known, however, how this disturbance in cholesterol production leads to the specific features of X‑linked chondrodysplasia punctata 2.

Rarely, a severe form of X‑linked chondrodysplasia punctata 2 has been reported in males. These cases result from changes involving single amino acids in the 3β‑hydroxysteroid‑Δ8,Δ7‑isomerase enzyme. Affected males have some of the same features as affected females, as well as changes in the structure of the brain, moderately to profoundly delayed development, and other birth defects.

Other Names for This Gene

3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
3-beta-hydroxysteroid-delta-8,delta-7-isomerase
CDPX2
CPXD
D8-D7 sterol isomerase
delta(8)-Delta(7) sterol isomerase
EBP_HUMAN
emopamil binding protein (sterol isomerase)
emopamil-binding protein (sterol isomerase)
sterol 8-isomerase

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Tests of EBP

Scientific Articles on PubMed

PubMed

Catalog of Genes and Diseases from OMIM

EMOPAMIL-BINDING PROTEIN; EBP

Gene and Variant Databases

NCBI Gene
ClinVar

References

Ausavarat S, Tanpaiboon P, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. Two novel EBP mutations in Conradi-Hunermann-Happle syndrome. Eur J Dermatol. 2008 Jul‑Aug;18(4):391‑3. doi: 10.1684/ejd.2008.0433. Epub 2008 Jun 23.
Braverman N, Lin P, Moebius FF, Obie C, Moser A, Glossmann H, Wilcox WR, Rimoin DL, Smith M, Kratz L, Kelley RI, Valle D. Mutations in the gene encoding 3 beta‑hydroxysteroid‑delta 8, delta 7‑isomerase cause X‑linked dominant Conradi‑Hunermann syndrome. Nat Genet. 1999 Jul;22(3):291‑4. doi: 10.1038/10357.
Furtado LV, Bayrak‑Toydemir P, Hulinsky B, Damjanovich K, Carey JC, Rope AF. A novel X‑linked multiple congenital anomaly syndrome associated with an EBP mutation. Am J Med Genet A. 2010 Nov;152A(11):2838‑44. doi: 10.1002/ajmg.a.33674.
Herman GE, Kelley RI, Pureza V, Smith D, Kopacz K, Pitt J, Sutphen R, Sheffield LJ, Metzenberg AB. Characterization of mutations in 22 females with X‑linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med. 2002 Nov‑Dec;4(6):434‑8. doi: 10.1097/00125817-200211000-00006.
Ikegawa S, Ohashi H, Ogata T, Honda A, Tsukahara M, Kubo T, Kimizuka M, Shimode M, Hasegawa T, Nishimura G, Nakamura Y. Novel and recurrent EBP mutations in X‑linked dominant chondrodysplasia punctata. Am J Med Genet. 2000 Oct 2;94(4):300‑5. doi: 10.1002/1096-8628(20001002)94:43.0.co;2‑3.
Milunsky JM, Maher TA, Metzenberg AB. Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‑linked dominant Conradi‑Hunermann‑Happle syndrome and a mutation in EBP. Am J Med Genet A. 2003 Jan 30;116A(3):249‑54. doi: 10.1002/ajmg.a.10849.
Steijlen PM, van Geel M, Vreeburg M, Marcus‑Soekarman D, Spaapen LJ, Castelijns FC, Willemsen M, van Steensel MA. Novel EBP gene mutations in Conradi‑Hunermann‑Happle syndrome. Br J Dermatol. 2007 Dec;157(6):1225‑9. doi: 10.1111/j.1365-2133.2007.08254.x. Epub 2007 Oct 18.

Genomic Location

The EBP gene is found on the X chromosome.

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