Are You Confident of the Diagnosis?

Conradi-Hünermann syndrome is a rare genetic disease, which presents with skeletal, ocular and cutaneous anomalies with asymmetric involvement of the body. It is caused by mutations in the gene encoding delta (8)-delta (7) sterol isomerase emopamil-binding protein (EBP) and is inherited in an X-linked dominant pattern with variable expressivity, possibly due to different patterns of X chromosome inactivation.

What you should be alert for in the history

Past medical history is very important for diagnosis if the patient presents later than neonatal period, since some of the clinical features resolve spontaneously as patients grow older. The alerting history includes congenital ichthyosiform erythroderma, systematized follicular atrophoderma, facial anomalies, limb shortening, joint dysfunction, hexadactyly and cataracts.

Since this disease is inherited in X-linked dominant fashion, it is usually transmitted from mother to daughter, and male hemizygote status is not compatible with life. The mother and/or maternal grandmother may have a personal history or current manifestations of skeletal, ocular or skin anomalies. History of spontaneous miscarriage is also consistent with the disease.

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Characteristic findings on physical examination

Characteristic cutaneous findings are lesions displayed in a linear, whorled or blotchy pattern following lines of Blaschko.

Congenital ichthyosiform erythroderma is a characteristic finding in newborn patients, who display generalized erythema and thick adherent scales arranged in a linear or whorled pattern. These lesions clear up spontaneously within several weeks or months, replaced by follicular atrophoderma with hypopigmentation or hyperpigmentation.

Patterned atrophoderma occurs in the areas of scaling and is thought to be caused by inflammation and hyperkeratosis in the newborn.

Ichthyosis usually appears in older children or adults, although occurrence in newborns has also been reported. It usually spares palms and soles and tends to be more conspicuous in areas of atrophoderma.

Hair anomalies include cicatricial alopecia and coarse lusterless hair. The alopecia is simply a local manifestation of systematized atrophoderma, and the coarse hair grows predominantly around the alopecic areas.

Hypopigmented and hyperpigmented whorls follow lines Blaschko, but may not be congruent with the pattern of atrophoderma. This is a relatively uncommon finding.

Nail anomalies are also less common. Both flattening of the nail plates (platonychia) and splitting into layers (onychoschizia) have been described in affected patients.

The most prominent skeletal findings include short stature, facial lesions, limb shortening, and vertebral column anomalies. These lesions present predominantly in an asymmetric pattern.

Limb anomalies include shortening of limb bones, joint dysfunction and hexadactyly. The majority of patients present with shortening of tubular bones, mostly femoral and humeral bones, although metacarpals and metatarsals can also be affected. Joint dysfunction often presents with severe dysplasia of the hip joints, less commonly flexion contraction of the hip, knee, elbow and finger joints. Lateral and dorsal dislocation of patellar bones has also been reported. Hexadactyly is not uncommon in patients with CDPX2. In addition, talipes and equinus or valgus of the foot may be associated with the disease.

Short stature can be a marked feature in some patients. Height usually ranges between 130s to low 150s centimeters.

Facial anomalies often present as flattened bridge of nose, frontal bossing and hypoplasia of one side of head.

Vertebral column anomalies may be caused by an asymmetric shortening of legs and frequently present as moderate to severe scoliosis. Clefting, wedging or absence of vertebral bodies and shortening of the neck may be observed.

The predominant ocular lesion is unilateral or bilateral cataracts, which could be congenital or develop early in life. Other anomalies, such as epicanthus and nystagmus, have also been observed.

Expected results of diagnostic studies

Cutaneous histopathologic features include laminated orthohyperkeratosis with a thin granular layer and prominent dilatation of pilosebaceous units. Dystrophic calcification within keratotic follicular plugs have been observed in the majority of newborn cases, but not in older patients, consistent with the fact that ichthyosiform skin lesions are transient, resolving by early infancy.

Biochemical studies: Since this disease is caused by mutations of protein responsible for cholesterol synthesis, decrease of levels of cholesterol and a remarkable increase of levels of the cholesterol precursors, cholest-8(9)-en-3beta-ol and 8-dehydrocholesterol, in plasma, soft tissues or cartilages have been considered diagnostic of CDPX2.

Genetic test: Many different mutations in the EBP gene have been reported to be associated with CDPX2. Patients with truncated mutations present with more severe symptoms than patients with missense mutations. Molecular characterization of the EBP gene is confirmatory of the diagnosis.

Imaging studies: As indicated by the synonym “chondrodysplasia punctata,” abnormal punctate calcification of epiphyseal cartilage and some other cartilaginous structures are found in the majority of newborn patients. Similar to congenital ichthyosiform erythema, epiphyseal stippling clears spontaneously in early infancy.

Diagnosis confirmation

Differential diagnoses for CDPX2 include other forms of chondrodysplasia punctata, especially CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome.

CHILD syndrome is characterized by unilateral congenital lesions including congenital hemidysplasia, ichthyosiform erythroderma, and limb defects. It is also inherited in an X-linked dominant pattern and is caused by a mutation of the NADHL (NAD(P)H steroid dehydrogenase-like protein) gene, which is also involved in cholesterol synthesis. Of note, dystrophic calcification observed in keratotic follicular plugs in newborn CDPX2 patients has never been observed in CHILD syndrome.

In addition to the X-linked dominant forms (CDPX2 and CHILD syndrome), chondrodysplasia punctata (CDP) also presents in various other forms including autosomal recessive, autosomal dominant, X-linked recessive and non-genetic forms, eg, exposure to drugs and teratogens. Autosomal recessive CDP is caused by abnormal peroxisomal functions and is characterized by marked symmetrical proximal limb shortening, contractures, cataracts and mild ichthyosis. This form of CDP carries a poor prognosis, with most patients dying before the second year of life due to respiratory complications.

Autosomal dominant CDP is characterized by short stature and abnormal facies without skin or eye lesions, and carries a very good prognosis. The X-linked recessive form presents as mental retardation, short stature and mild ichthyosis; there are also no eye lesions.

As described above, each of these symptoms presents with a unique constellation of clinical symptoms. When the symptoms are subtle or atypical, diagnostic confirmation of CDPX2 can be made by biochemical or genetic test described in the section on diagnostic studies.

Who is at Risk for Developing this Disease?

Since CDPX2 is an X-linked dominant disease, daughters of a female patient have a 50% possibility of inheriting this condition. Some cases reported in the literature do not have any family history, and these may actually represent de novo mutations or variable expressivity and incomplete penetrance. In the case of de novo mutation, germline mosaicism may be present, and the risk for subsequent pregnancies is dependent on the degree of mosaicism, usually much lower than the familial form.

What is the Cause of the Disease?

CDPX2 is caused by mutations in the gene encoding delta8-delta7-sterol isomerase emopamil-binding protein (EBP) at Xp11.23-p11.22. EBP protein catalyzes an intermediate step in cholesterol synthetic pathway, and loss of function mutations lead to accumulation of the cholesterol precursors, cholest-8(9)-en-3beta-ol and 8-dehydrocholesterol, and decreased levels of cholesterol in the involved tissues. The variable expressivity and incomplete penetrance of this syndrome is attributed to different patterns of X-inactivation.


The molecular mechanism by which mutation of EBP gene causes this characteristic syndrome remains unknown. Some of the findings that appear later in life, eg, systematized atrophoderma and alopecia, are considered consequences of congenital ichthyosiform erythroderma.

Systemic Implications and Complications

Although osseous anomalies constitute the most defining features of Apert syndrome, systemic involvement is common and important to recognize, in order to manage patients properly.

Central nervous system lesions are manifested as structural anomalies, as mentioned above, and mental retardation. MRI is usually performed to diagnose anatomic lesions in the brain. Psychometric evaluation is essential in managing these patients, so that proper early child interventions can be initiated to enhance the functional capabilities of patients.

Since cardiovascular anomalies are present in 10% of patients, a full cardiac evaluation including electrocardiography (EKG) and echocardiography should be performed during the initial evaluation. Cardiothoracic surgeries to correct inborn errors may be indicated, and regular follow-up by a cardiologist is warranted should any anomalies be present.

Respiratory anomalies, although less common, pose a significant risk for early morbidity and mortality. If sleep apnea is suspected, the patient should undergo polysomography to make a definitive diagnosis. When the diagnosis is made and the symptoms are severe, the patient may be initiated on mechanical ventilation until corrective surgery is performed. If long-term mechanical ventilation is required, tracheostomy should be considered.

Genitourinary lesions commonly present as hydronephrosis, cryptorchidism and clitoromegaly. Hydronephrosis can be diagnosed by renal ultrasound. Urology or gynecology referral should be made if any of these symptoms are found.

Gastrointestinal lesions, eg, esophageal atresia, pyloric stenosis, biliary atresia, imperforate or malposed anus, are most likely to present with corresponding symptoms. Work-ups to rule these out may not be necessary if the patient is symptom-free.

Severe pustular facial and trunk acne extending to arms and forearms requiring systemic treatment commonly develops in Apert patients. Most patients do not respond to conventional therapy including topical agents and systemic antibiotics, but they usually do respond to isotretinoin, although prolonged course and repeated treatment may be necessary. Since isotretinoin is associated with severe systemic side effects, eg, teratogenicity, hepatic dysfunction, dyslipidemia, visual changes, pseudotumor cerebri, etc, the risk/benefit ratio should be carefully weighed before initiating treatment. All patients should be followed up closely by dermatologists.

Treatment Options

There is no cure for CDPX2. The treatment is mostly symptomatic management.

Optimal Therapeutic Approach for this Disease

Optimal management of CDPX2 requires a multidisciplinary team including dermatologists, ophthalmologists and orthopedic surgeons.

For ichthyosis and hyperkeratosis, emollient application (cerave or cetaphil cream for example) is essential to keep the skin hydrated, which promotes desquamation. Medical management includes topical retinoids, alpha-hydroxy acids and keratolytics, eg, salicylic acid. These patients usually require continuous therapy and long-term follow-up. One option would be Amlactin lotion twice a day followed by cetaphil or cerave. Patients with ocular lesions and skeletal defects should be evaluated by ophthalmologists and orthopedic surgeons and should undergo corrective surgeries if necessary.

Patient Management

Patients with ichthyosis usually require continuous therapy and long-term follow-up by dermatologists. Follow-up by orthopedic surgeons and neurosurgeons are also warranted when moderate to severe scoliosis is present.

In addition, genetic counseling plays a very important role in the management. When a newborn is diagnosed with CDPX2, mother and maternal grandmother should be examined carefully to look for clues that indicate they may have the syndrome. If either person does have the syndrome, female siblings carry a 50% risk of having the disease. If neither person has the disease, then the newborn represents a de novo mutation, and the risk for female siblings having the disease is negligible except in the case of gonadal mosaicism.

All patients of reproductive age should also be counseled, ideally before their first pregnancy, since their female offspring have a 50% risk of CDPX2 and male fetuses have a mortality rate at 50%. Routine second trimester ultrasound will identify limb shortening if present. Prenatal genetic testing by gene sequencing has also been reported to be helpful.

Unusual Clinical Scenarios to Consider in Patient Management

For patients with severe scoliosis, corrective surgery should be considered to prevent abnormal pulmonary development and neurologic complications caused by cord compression. If such complications occur, patients should be evaluated and followed up by pulmonologists, neurologists and neurosurgeons.

What is the Evidence?

Happle , R. “X-linked dominant chondrodysplasia punctata: review of literature and report of a case”. Hum Genet . vol. 53. 1979. pp. 65-73. (This is one of the original papers that summarized the clinical presentations of this syndrome with statistics by reviewing the previous case reports.)

Hoang , MP, Carder , KR, Pandya , AG, Bennett , MJ. “Ichthyosis and keratotic follicular plugs containing dystrophic calcification in newborns: distinctive histopathologic features of X-linked dominant chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome)”. Am J Dermatopathol . vol. 26. 2004. pp. 53-8. (This paper demonstrated that dystrophic calcification within keratotic follicular plugs have been observed in the majority of newborn cases, but not in older patients, consistent with the fact that ichthyosiform skin lesions are transient, resolving by early infancy.)

Kelley , RI, Wilcox , WG, Smith , M, Kratz , LE, Moser , A, Rimoin , DS. “Abnormal sterol metabolism in patients with Conradi-Hünermann-Happle syndrome and sporadic lethal chondrodysplasia punctata”. Am J Med Genet . vol. 83. 1999. pp. 213-9. (This is the first paper that showed biochemical evidence of defects in sterol synthesis in patients with this syndrome.)

Has , C, Bruckner-Tuderman , L, Muller , D, Fleoth , M, Folkers , E, Donni , D. “The Conradi-Hünermann-Happle syndrome (CDPX2) and emopanil binding protein: novel mutations, and somatic and gonadal mosaicism”. Hum Mol Genet . vol. 9. 2000. pp. 1951-5. (The paper showed that there are multiple mutations in EBP gene that can contribute to the constellation of CDPX2 and that some mutations could be due to somatic mutations and gonadal mosaicism.

Irving , MD, Chitty , LS, Mansour , S, Hall , CM. “Chondrodysplasia punctata: a clinical diagnostic and radiological review”. Clin Dysmol. vol. 17. 2008. pp. 229-31. (The paper reviewed different forms of chondrodysplasia punctata.)

Jacyk , WK. “What syndrome is this? X-linked dominant chondrodysplasia punctata (Happle syndrome)”. Pediatr Dermatol. . vol. 18. 2001. pp. 442-4. (This is a good summary of Happle syndrome.)

Goodman , P, Dominguez , R. “Cervicothoracic myelopathy in Conradi-Hünermann disease: MRI diagnosis”. Magnetic Resonance Imaging . vol. 8. 1990. pp. 647-50. (This paper discussed the CNS defects in Conradi-Hünermann patients as detected by MRI.)

DiGiovanna , JJ, Robinson-Bostom , L. “Ichthyosis: etiology, diagnosis and management”. Am J Clin Dermatol . vol. 4. 2003. pp. 81-95. (This paper discussed general management of ichthyosis.)

Whittock , NV, Izatt , L, Simpson-Dent , L, Becker , K, Wakelin , SH. “Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata”. Prenat Diagn . vol. 23. 2003. pp. 701-4. (This paper demonstrated the feasibility of in utero molecular diagnosis.)