Congenital disorders of glycosylation: other causes of ichthyosis

We read with interest the comprehensive review by Schmuth et al¹ on inherited ichthyoses/generalized Mendelian disorders of cornification. We would like to point out that some congenital disorders of glycosylation (CDG) present ichthyosis. Associations have been described for MPDU1-CDG (formerly CDG-If), DOLK-CDG (CDG-Im), SRD5A3-CDG (CDG-Iq) and PIGL-CDG (CHIME syndrome, Zunich neuroectodermal syndrome). MPDU1-CDG is a defect in the N-glycan assembly in the endoplasmic reticulum (ER). The four reported patients showed skin involvement (ichthyosis and/or erythroderma). Other features included psychomotor retardation, seizures, hypotonia, gastrointestinal problems, visual impairment, dwarfism and transient growth hormone deficiency. The MPDU1 protein is considered to be a chaperone favoring the efficient utilization of dolicholphosphoglucose and dolicholphosphomannose in glycosylation. A reduced level of the glycosylphosphatidylinositol (GPI)-anchor CD59 has been found in these patients suggesting that they have also a deficiency in GPI-anchor biosynthesis (see PIGL-CDG).^{2, 3} DOLK-CDG is a defect in dolichol kinase, the last step of the dolichol phosphate biosynthesis. It shows a clinical spectrum with at one end a non-syndromic dilated cardiomyopathy (reported in nine patients),⁴ and at the other end a severe syndrome (reported in four patients) with ichthyosis, as well as dilated cardiomyopathy, epilepsy, microcephaly, visual impairment, hypoglycemia and death within the first 6 months.⁵ SRD5A3-CDG is a defect in polyprenol reductase, involved in the biosynthesis of dolichol. This cerebro-cerebello-oculo-cutaneous syndrome has been described in some 15 patients. Its skin component consists of ichthyosis, erythroderma and/or dry skin.^{6, 7} PIGL-CDG or CHIME syndrome is characterized by colobomas, congenital heart defects, early-onset migratory ichthyosiform dermatosis, mental retardation and ear anomalies, besides other clinical manifestations. This is a defect in an ER-localized enzyme that catalyzes the second step of GPI-anchor biosynthesis, the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol that occurs on the cytoplasmic side of the ER. It has been reported in eight patients.⁸

The two dolichol phosphate synthesis disorders and MPDU1-CDG can be picked up by serum transferrin isoelectrofocusing. Therefore, we strongly recommend to perform this test in any patient with syndromic ichthyosis or with a syndromic ichthyosis-like skin disorder.