These authors contributed equally.
Wrinkled Skin and Fat Pads in Patients with ALG8-CDG: Revisiting Skin Manifestations in Congenital Disorders of Glycosylation
Article first published online: 26 NOV 2013
© 2013 Wiley Periodicals, Inc.
Volume 31, Issue 1, pages e1–e5, January/February 2014
How to Cite
Kouwenberg, D., Gardeitchik, T., Mohamed, M., Lefeber, D. J. and Morava, E. (2014), Wrinkled Skin and Fat Pads in Patients with ALG8-CDG: Revisiting Skin Manifestations in Congenital Disorders of Glycosylation. Pediatric Dermatology, 31: e1–e5. doi: 10.1111/pde.12233
- Issue published online: 7 JAN 2014
- Article first published online: 26 NOV 2013
Glycosylation is the posttranslational coupling of sugar chains to proteins or lipids. Proper glycosylation is essential for normal protein structure, function, and trafficking. Mutations in the glycosylation pathway lead to a phenotypically heterogeneous group of metabolic disorders, the congenital disorders of glycosylation (CDG). Some of these conditions, including PMM2-CDG, frequently present with recognizable skin abnormalities such as abnormal fat distribution, skin wrinkling, or peau d'orange, whereas others, such as COG7-CDG and ATP6V0A2-CDG, have been described in association with cutis laxa: wrinkled, inelastic, and sagging skin. Ichthyosis is also common in several types of CDG. ALG8-CDG is a severe disorder characterized by dysmorphic features, failure to thrive, protein-losing enteropathy, neurologic and ophthalmologic problems, and developmental delay. We reviewed the clinical features in all nine previously reported patients diagnosed with ALG8-CDG with a special focus on their skin signs. Three of the nine patients had abnormal fat distribution and skin wrinkling. As the spectrum of CDG presenting with skin signs expands further, we suggest screening for CDG in all patients presenting with any type of central nervous involvement and wrinkled skin, cutis laxa, severe ichthyosis, or abnormal fat distribution.
The congenital disorders of glycosylation (CDG) are a group of inherited metabolic disorders. Glycosylation occurs through a complex pathway of enzymatic reactions within the endoplasmic reticulum (ER) and Golgi apparatus . Each individual CDG corresponds to deficiency of a specific enzyme in this pathway. CDG syndromes have an autosomal recessive pattern of inheritance and show great heterogeneity in symptomatology and disease severity . Because glycans are essential for the normal function of glycoproteins, and more than half of all human proteins are glycosylated, these disorders are often characterized by multisystem involvement . CDG can be subdivided in two subtypes. Defective synthesis of N-linked glycans in the ER causes type I CDG, whereas the synthesis or processing of glycans in the Golgi apparatus is abnormal in type II CDG.
Skin involvement is common in CDG, and in some types it is virtually pathognomonic. Congenital skin wrinkling as a form of cutis laxa (CL) has been described as a cardinal sign in two CDG syndromes: COG7-CDG  and ATP6V0A2-CDG  (Fig. 1). Dry skin and ichthyosis are frequently observed in patients with MPDU1-CDG [6, 7], DK1-CDG , and SRD5A3-CDG  (Fig. 2).
Herein we describe a patient with CDG type Ih (ALG8-CDG; Mendelian Inheritance in Man 608104) presenting with wrinkled skin and review all patients reported with ALG8-CDG. We also review the different skin manifestations of CDG. An overview of skin abnormalities in CDG is provided in Table 1. Metabolic pathways in CDG types with skin involvement are illustrated in Fig. 3.
|CDG syndrome||Alternative name||Wrinkly skin and cutis laxa||Inverted nipples and abnormal fat distribution||Peau d'Orange||Thick skin and lichenification||Dry skin and ichthyosis||Focal hyperpigmentation||Hypertrichosis||Trichorrhexis and pili torti||Hair loss||Nail abnormalities|
The boy, the first child of healthy unrelated parents (Caucasian mother and African father), was born at 35 weeks gestation after an uncomplicated pregnancy. His birthweight was 2,920 g and he had a ventricular septum defect, patent ductus arteriosus, lung hypoplasia, dysmorphic features, a large wide-open fontanel, hypertelorism, low-set abnormally positioned ears, a long philtrum, a short neck, camptodactyly of the third and fourth fingers of both hands, club feet, short humeri and femora, and a micropenis. Laboratory analyses revealed thrombocytopenia, anemia, electrolyte disturbances, hypoalbuminemia, and primary hypothyroidism. Neurologic signs included hypotonia and bilateral peripheral hearing impairment. Brain imaging showed hypoplasia of the corpus callosum. He had failure to thrive and, from the age of 8 weeks on, developed severe generalized edema and died at the age of 3 months. In supplementary Table S1, the clinical and autopsy findings in our patient are compared with the phenotype in the other ALG8-deficient patients described in the literature. In supplementary Table S2, data from laboratory and genetic studies are summarized. Despite severe generalized edema, our patient had wrinkled, inelastic, lax skin on the dorsum of the hands and on the feet distally from the wrists and ankles, especially on the dorsal side of the feet (Fig. 1D). A nuchal skin fold and abnormal fat distribution were also observed.
Skin involvement is common in CDG, especially abnormal fat distribution and inverted nipples in PMM2-CDG. The combination of skin abnormalities and central nervous system involvement are especially characteristic of several subtypes of CDG. There are many different, more clinically significant anomalies in CDG than skin involvement, but the clinical findings are frequently diverse and in many cases not pathognomonic, so skin wrinkling of the extremities, in addition to abnormal fat distribution, could be a clue to the possibility of CDG.
Abnormal fat distribution (pseudogynecomastia) has also been reported in siblings with ALG8-CDG . Unusual skin folds and wrinkled skin were observed in a recently described ALG8-deficient patient . In several inborn errors of metabolism, CL and wrinkled skin are associated with multisystem pathology , among which are ATP6V0A2-CDG and COG7-CDG. Searching for the pathomechanism, Hucthagowder et al  observed abnormal Golgi morphology with swollen cisternae in ATP6V0A2-deficient skin fibroblasts. In immunostaining studies, they found normal density and morphology of fibrillin-1 microfibrils in the cells of ARCL2 patients, as well as normal activity of the lysyl oxidases, both of which are important prerequisites for elastin production, but elastin deposition proved to be abnormal, with accumulation of its precursor tropoelastin (TE) within cytosolic vesicles. Furthermore, a greater rate of apoptosis was observed in patient cells. The authors suggested a role for ATP6V0A2 in maintaining an acidic pH within Golgi vesicles to facilitate normal protein trafficking. In this model, a mutation in the ATP6V0A2 gene could lead to abnormal Golgi vesicle secretion through aggregation of proteins or impaired secretory carrier formation. The abnormal biosynthesis of elastin and the greater fibroblast apoptosis due to accumulation of TE vesicles could explain the severe cutis laxa observed in ATP6V0A2-deficient patients. The mechanism of impaired Golgi trafficking could possibly be extrapolated to brain- or bone-specific proteins to explain neurodevelopmental and growth defects in these patients [13, 14]. In COG7-CDG, a similar mechanism appears to take place. Wu et al  studied COG7-deficient fibroblasts and found that the integrity of the COG complex, of which COG7 is a subunit, was disrupted. Golgi trafficking was proven to be impaired and could be restored by adding COG7 complementary DNA.
Another possible explanation is skin wrinkling because of abnormal fat distribution. This has been observed in COG7-CDG and ATP6V0A2-CDG and in ALG9-CDG , ALG11-CDG , and ALG12-CDG . The intrauterine development of fat pads could present as hanging skin folds, but fat pads that gradually disappear postnatally might also play a role in the development of skin wrinkling. This type of abnormality with thick, inelastic, uneven skin (peau d'orange) has been mostly described in PMM2-CDG patients  and in two children with DPAGT1-CDG , but has not been reported in other forms of N-linked glycosylation disorders.
By reviewing all reported ALG8-CDG patients, in addition to the striking skin abnormality of abnormal fat distribution in two ALG8-CDG patients , we found another patient with wrinkled skin abnormalities . The skin phenotype in this patient is characterized by nuchal, axillar and gluteal skin folds and darker, wrinkled skin around the knees.
In summary ALG8 patients present with some overlapping, but nonspecific features, even with a very diverse genetic background [10, 11, 20-23]. Feeding problems and failure to thrive are common, and several patients had protein-losing enteropathy, a feature unique for a few types of CDG (MPI-CDG, ALG6-CDG, PMM2-CDG). Almost all patients suffer from hypotonia, and most have ophthalmologic involvement and poor vision, but otherwise the neurologic phenotype is variable. Developmental delay and dysmorphic features were present in all cases, with hypertelorism and low-set ears as the most common signs, along with a wide variation of other dysmorphic features.
ALG8-CDG should be considered in CDG patients with severe dysmorphia, hypotonia, protein-losing enteropathy, and visual loss in association with skin signs such as peau d'orange, abnormal fat distribution, and wrinkled skin, similar to COG7-CDG, ATP6V0A2-CDG, PMM2-CDG, and DPAGT1-CDG. We strongly suggest including CDG in the differential diagnosis of infants with congenital wrinkly skin. CDG is not identified using routine metabolic screening, but an easy screening method is transferrin isoelectric focusing, especially to recognize type I CDG and discriminate it from defects in the later phase of the glycosylation machinery . Abnormalities in apolipoprotein C-III isoelectric focusing can be highly valuable in discriminating between different types of type II CDG .
Skin abnormalities such as abnormal fat distribution, ichthyosis, and wrinkling can offer an extra clue for the diagnosis of CDG in patients with nonspecific multisystem disease. ARCL2A (and the allelic wrinkly skin syndrome) is the most common form of autosomal recessive wrinkled skin in association with neurologic presentation and skeletal anomalies caused by CDG. The identification of more patients with skin signs as part of a CDG phenotype may lead to better understanding of the pathologic mechanisms involved in cutis laxa.
|pde12233-sup-0001-TableS1.docx||Word document||99K||Table S1. Clinical and autopsy findings in previously described ALG8-deficient patients.|
|pde12233-sup-0002-TableS2.docx||Word document||24K||Table S2. Laboratory and genetic data in previously described ALG8-deficient patients.|
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