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diagnostics Review Skeletal and Bone Mineral Density Features, Genetic Profile in Congenital Disorders of Glycosylation: Review Patryk Lipi ´nski 1,* , Karolina M. St˛epie´n 2 , Elzbieta˙ Ciara 3 , Anna Tylki-Szyma´nska 1 and Aleksandra Jezela-Stanek 4 1 Department of Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; [email protected] 2 Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK; [email protected] 3 Department of Medical Genetics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; [email protected] 4 Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland; [email protected] * Correspondence: [email protected] Abstract: Congenital disorders of glycosylation (CDGs) are a heterogeneous group of disorders with impaired glycosylation of proteins and lipids. These conditions have multisystemic clinical manifestations, resulting in gradually progressive complications including skeletal involvement and reduced bone mineral density. Contrary to PMM2-CDG, all remaining CDG, including ALG12- CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, PGM3-CDG, CSGALNACT1-CDG, SLC35D1-CDG and TMEM-165, are characterized by well-defined skeletal dysplasia. In some of them, prenatal-onset severe skeletal dysplasia is observed associated with early death. Osteoporosis or osteopenia are Citation: Lipi´nski,P.; St˛epie´n,K.M.; frequently observed in all CDG types and are more pronounced in adults. Hormonal dysfunction, Ciara, E.; Tylki-Szyma´nska,A.; limited mobility and inadequate diet are common risk factors for reduced bone mineral density. Jezela-Stanek, A. Skeletal and Bone Skeletal involvement in CDGs is underestimated and, thus, should always be carefully investigated Mineral Density Features, Genetic and managed to prevent fractures and chronic pain. With the advent of new therapeutic develop- Profile in Congenital Disorders of ments for CDGs, the severity of skeletal complications may be reduced. This review focuses on Glycosylation: Review. Diagnostics possible mechanisms of skeletal manifestations, risk factors for osteoporosis, and bone markers in 2021, 11, 1438. https://doi.org/ 10.3390/diagnostics11081438 reported paediatric and adult CDG patients. Academic Editor: Evangelos Terpos Keywords: congenital disorder of glycosylation; growth; skeletal dysplasia; cartilage; joint; bone markers; osteoporosis Received: 13 July 2021 Accepted: 4 August 2021 Published: 9 August 2021 1. Introduction Publisher’s Note: MDPI stays neutral Congenital Disorders of Glycosylation (CDGs) are a clinically heterogenous group of with regard to jurisdictional claims in over 150 diseases caused by defects in different steps of glycan metabolism pathways [1,2]. published maps and institutional affil- These genetic disorders are characterized by an impaired synthesis and attachment of iations. glycans to glycoproteins and glycolipids, and impaired synthesis of glycosylphosphatidyli- nositol (GPI) (Figure1)[ 1]. These disorders are categorized into (a) protein N-glycosylation defects; (b) protein O-glycosylation defects; (c) glycolipid and GPI anchor synthesis defects and (d) multiple glycosylation pathways and other pathways defects [2]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Diagnostics 2021, 11, 1438. https://doi.org/10.3390/diagnostics11081438 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, x FOR PEER REVIEW 2 of 24 Diagnostics 2021, 11, 1438 2 of 22 Figure 1. GPI structure, consisting of the conserved core glycan, phosphatidylinositol and glycan Figureside chains 1. GPI ([ structure,3], own modification). consisting of the conserved core glycan, phosphatidylinositol and glycan side chains ([3], own modification). Among the different glycosylation defects, impaired protein N-glycosylation is the mostAmong common. the Glycandifferent processing glycosylation (remodeling) defects, impaired takes place protein in the endoplasmicN-glycosylation reticulum is the most(ER) common. and Golgi Glycan apparatus processing [2]. O-glycosylation (remodeling) occurs takes place in the in Golgi the endoplasmic apparatus and reticulum no lipid- (ER)linked and intermediates Golgi apparatus are involved. [2]. O-glycosylation In contrast tooccursN-glycosylation, in the Golgi theapparatus process and involves no lipid- only linkedthe sequential intermediates addition are ofinvolved. monosaccharides In contrast without to N-glycosylation, remodeling [ 2the,4]. process Abnormalities involves in onlythe synthesisthe sequential of O -linkedadditionN of-acetylglucosamine, monosaccharides without galactose remodeling (Gal), mannose [2,4]. Abnormalities (Man), glucose in(Glc) the andsynthesis fucose of (Fuc) O-linked glycans N-acetylglucosamine, have also been described galactose [5]. (Gal), GPI ismannose a phosphoglyceride (Man), glu- cose(Figure (Glc)1) and that fucose acts as (Fuc) a membrane glycans have anchor also of been proteins described to the [5]. outer GPI leaflet is a phosphoglycer- of the cellular idemembrane. (Figure 1) GPI-anchor that acts as biosynthesisa membrane defectsanchor (GPI-BD)of proteins are to categorized the outer leaflet by an of inappropriate the cellular membrane.GPI-anchors GPI-anchor biosynthesis biosynthesis or modification defects (protein(GPI-BD) attachment, are categorized structural by an inappropriate remodeling at GPI-anchorsboth glycan biosynthesis and parts of or GPI). modification Most of the(protein CDGs attachment, have autosomal structural recessive remodeling pattern at of bothinheritance, glycan and but parts autosomal of GPI). dominant Most of the and CDGs X-linked have forms autosomal have alsorecessive been pattern described. of in- To heritance,date, about but 80 autosomal different entities domina havent and been X-linked described forms in correlationhave also been with described. congenital To disorder date, aboutof glycosylation 80 different orentities CDG-like have diseases. been describe Althoughd in correlation some genotype–phenotype with congenital disorder correlation of glycosylationhas been proposed, or CDG-like there isdiseases. a significant Although phenotypic some genotype–phenotype variability within the correlation same genotype. has been proposed,Glycosylation there is is key a significant for a variety phenotypic of posttranslational variability within biological the processessame genotype. including mainGlycosylation components is of key the for hormone a variety cascades of posttranslational regulating growth biological and metabolismprocesses including [5,6]. As maina result, components CDG patients of the presenthormone with cascades very diverse regulating clinical growth phenotypes, and metabolism with multi-system [5,6]. As a result,involvement CDG patients [4–7]. These present include with very cognitive divers impairment,e clinical phenotypes, neurological with (epilepsy, multi-system hypotonia, in- volvementataxia and [4–7]. polyneuropathy), These include ophthalmological, cognitive impairment, skeletal, neurological cardiac, hepatic, (epilepsy, haematological hypotonia, ataxiaand endocrinological and polyneuropathy), phenotypes ophthalmological, [1,2,7,8]. skeletal, cardiac, hepatic, haematological and endocrinologicalThe mechanisms ph ofenotypes bone disease [1,2,7,8]. in CDGs seem to be multifactorial. Malabsorption andThe liver mechanisms dysfunction of lead bone to adise poorase nutritional in CDGs seem state to which be mu impactsltifactorial. the growth Malabsorption hormone- andinsulin–like liver dysfunction growth lead factor to (GH/IGF)a poor nutrit axisional and state results which in impacts a short the stature growth [9,10 hormone-]. Given insulin–likethat patients growth with factor CDGs (GH/IGF) manifest theiraxis and skeletal results abnormalities in a short stature in childhood, [9,10]. Given one that may patientsspeculate with that CDGs they manifest are attributed their skeletal to the impaired abnormalities glycosylation in childhood, in the one bone may tissue speculate in the thatearly they stages are attributed of life. to the impaired glycosylation in the bone tissue in the early stages of life.So far, there have been no therapies targeting specific organ such as eye, kidney, heart, muscles or skeleton, with only supportive management being available [10]. Diagnostics 2021, 11, 1438 3 of 22 This review describes skeletal manifestations and bone mineral density abnormalities in paediatric and adult CDG patients with the aim to discuss the heterogeneity of clinical manifestations and correlate the genetic data (causative genes) with observed skeletal phenotype to evaluate the potential mechanism of mutational effect on the phenotype. 2. Skeletal Abnormalities 2.1. Skeletal Characteristics of PMM2-CDG PMM2-CDG is the most prevalent disorder of abnormal glycosylation of N-linked oligosaccharides leading to endocrine abnormalities including dysfunction of IGFBP3 and an acid-labile subunit in the IGF pathway which result in short stature [11]. Growth failure is commonly observed in children with PMM2-CDG [7,12–17]. Despite normal serum cal- cium, phosphate and magnesium concentrations, osteopenia/osteoporosis are frequently demonstrated in this condition since childhood (Table1)[ 8–14].
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  • Prenatal Ultrasonography of Craniofacial Abnormalities

    Prenatal Ultrasonography of Craniofacial Abnormalities

    Prenatal ultrasonography of craniofacial abnormalities Annisa Shui Lam Mak, Kwok Yin Leung Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Hong Kong SAR, China REVIEW ARTICLE https://doi.org/10.14366/usg.18031 pISSN: 2288-5919 • eISSN: 2288-5943 Ultrasonography 2019;38:13-24 Craniofacial abnormalities are common. It is important to examine the fetal face and skull during prenatal ultrasound examinations because abnormalities of these structures may indicate the presence of other, more subtle anomalies, syndromes, chromosomal abnormalities, or even rarer conditions, such as infections or metabolic disorders. The prenatal diagnosis of craniofacial abnormalities remains difficult, especially in the first trimester. A systematic approach to the fetal Received: May 29, 2018 skull and face can increase the detection rate. When an abnormality is found, it is important Revised: June 30, 2018 to perform a detailed scan to determine its severity and search for additional abnormalities. Accepted: July 3, 2018 Correspondence to: The use of 3-/4-dimensional ultrasound may be useful in the assessment of cleft palate and Kwok Yin Leung, MBBS, MD, FRCOG, craniosynostosis. Fetal magnetic resonance imaging can facilitate the evaluation of the palate, Cert HKCOG (MFM), Department of micrognathia, cranial sutures, brain, and other fetal structures. Invasive prenatal diagnostic Obstetrics and Gynaecology, Queen Elizabeth Hospital, Gascoigne Road, techniques are indicated to exclude chromosomal abnormalities. Molecular analysis for some Kowloon, Hong Kong SAR, China syndromes is feasible if the family history is suggestive. Tel. +852-3506 6398 Fax. +852-2384 5834 E-mail: [email protected] Keywords: Craniofacial; Prenatal; Ultrasound; Three-dimensional ultrasonography; Fetal structural abnormalities This is an Open Access article distributed under the Introduction terms of the Creative Commons Attribution Non- Commercial License (http://creativecommons.org/ licenses/by-nc/3.0/) which permits unrestricted non- Craniofacial abnormalities are common.