X-linked dominant chondrodysplasia punctata (ORPHA:35173)
A rare genodermatosis disease with great phenotypic variation and characterized most commonly by ichthyosis following the lines of Blaschko, chondrodysplasia punctata (CDP), asymmetric shortening of the limbs, cataracts and short stature.
Epidemiology
Annual incidence of X-linked dominant chondrodysplasia punctata (CDPX2) has been estimated to be at least 1/400,000 births with 95% of patients being female.
Clinical description
Congenital ichthyosiform erythroderma is the typical neonatal manifestation. Erythema is usually generalized while hyperkeratotic scales generally follow Blaschko's lines and tend to fade during a period of weeks to months. In older children, ichthyosis following Blaschko's lines is the most frequent clinical finding (95% of cases) and it improves with age. Hyperkeratosis, especially involving hair follicles, and late atrophy appear at sites of previous scaling, typically in a follicular pattern (atrophoderma vermiculata). Follicular atrophoderma is particularly common on the trunk, forearms and dorsal aspect of the hands. Patchy areas of cicatricial alopecia are common. Asymmetric shortening of the limbs, usually affecting the humerus and femur, together with CDP, are the most common skeletal abnormalities. Facial dysmorphism (low nasal bridge, frontal bossing, hypertelorism, high arched palate) is common. Joint contractures affecting the hips, hands and feet are frequent. Talus valgus and other deformities may be seen. The vertebral column exhibits moderate to severe scoliosis and short stature is common. Most patients (60%) suffer from cataracts (mainly unilateral), which may be congenital or appear early in life. Microphthalmia, microcornea and epicanthus have been reported. Intelligence is normal.
Etiology
CDPX2 is due to mutations in the EBP gene (Xp11.23-p11.22) encoding the emopamil binding protein (EBP), which acts as a delta8-delta7-sterol isomerase that catalyzes the conversion of 8(9)-cholestenol to lathosterol in the distal cholesterol biosynthesis pathway. A deficiency in EBP leads to the accumulation of 8-dehydrocholesterol (8DHC) and 8(9)-cholestenol in the skin, plasma and other body tissues.
Diagnostic methods
Diagnosis of CDPX2 relies on clinical, biochemical and genetic tests. CDP, usually consisting of epiphyseal stippling, is the fundamental radiological finding. Biochemical analyses show increased levels of 8(9) cholestenol and 8-dehydrocholesterol. Molecular testing for EBP mutations confirms diagnosis.
Differential diagnosis
Differential diagnoses include CDPX1; RCDP; chondrodysplasia punctata, tibia-metacarpal type; CHILD syndrome; systemic lupus erythematosus; MEND syndrome, and vitamin K deficiencies.
Antenatal diagnosis
Prenatal diagnosis and preimplantation genetic diagnosis may be an option for families with a known disease-causing mutation.
Genetic counseling
CDPX2 is inherited in an X-linked dominant manner and genetic counseling is possible. Somatic mosaicism in the father or de novo mutations can explain the occurrence of offspring with CDPX2 when no mutations are found in the mother. Germline mosaicism and anticipation has also been reported in families with CDPX2. In most cases it is lethal in males.
Management and treatment
Management is multidisciplinary. Treatment of skin lesions includes the use of emollients and keratolytics (i.e. ammonium lactate 12%, petrolatum ointment). Topical administration of lovastatin and cholesterol may be beneficial for ichthyosis. Orthopedic management and surgery may be necessary in those with bone deformities. Cataracts should be extracted and vision correction devices provided. Physical, occupational and speech therapies may be necessary. Regular follow-up with dermatologists and ophthalmologists and orthopedic evaluations are recommended. Hearing aids may be needed.
Prognosis
There is usually no effect on life-expectancy (rarely scoliosis can compromise cardiac and pulmonary function) but quality of life may be severely affected.

                            Last update: 
                            September 2019


                            - Expert reviewer(s): 
                            Pr Rogelio GONZÁLEZ SARMIENTO