A lethal osteochondrodysplasia with mesomelic brachymelia, round pelvis, and congenital hepatic fibrosis: two siblings born to consanguineous parents

Abstract

We report a hitherto unknown, lethal osteochondrodysplasia in two Japanese siblings born to consanguineous parents. The skeletal abnormalities are characterised by mesomelic brachymelia with bowed forearms, a round pelvis with shortened greater sciatic notches, an ossification defect of the pubic bones, and absence of ossification centers in the cervical vertebral bodies. The associated visceral anomalies comprised periportal fibrosis and cystic dysplasia of the intrahepatic bile ducts, pancreatic ductal ectasia, a simple renal cyst, microcephaly with multifocal laminar necrosis and ectopic gray matter, dysplastic tracheobronchial cartilage, abnormal lobulation of the lung, diaphragmatic hernia, and stenotic pulmonary valve. Thrombocytopenia was present but megakaryocytes were slightly increased in the bone marrow. The patients showed various dysmorphic features including aniridia, a long palpebral fissure, prominent nasal bridge, beaked nose, flat philtrum, low-set fleshy ears, micrognathia with submucosal cleft palate, and multiple joint contractures.

A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

“…This splice variant leads to skipping of exon 10, causing a frameshift and prematurely truncated ALG9 protein. The features of our patients were the same as those in a lethal syndrome with skeletal dysplasia first reported by Gillessen-Kaesbach et al and further in detail characterized by Nishimura et al 1,2 This indicates that Gillessen-Kaesbach-Nishimura syndrome belongs to a group of CDG.…”

“…Skeletal dysplasia is not a commonly recognized symptom of CDG syndromes but has been reported in rare patients. 5 Of note, a few patients with ALG3-and ALG12-CDG share some skeletal features with those described by Gillessen-Kaesbach et al and Nishimura et al 1,2,[6][7][8] ALG9 encodes an alpha-1,2-mannosyltransferase that catalyzes two steps in the LLO biosynthesis. The biosynthesis starts on the cytosolic side of the ER where a dolichol pyrophosphate-linked heptasaccharide (GlcNAc 2 Man 5 ) is produced.…”

“…8,10,11 In this report, we describe three patients with skeletal dysplasia, polycystic kidney and several multiple malformations, the phenotypes highly similar to those first reported by Gillessen-Kaesbach and Nishimura and somewhat overlapping with those of the individuals with ALG3-and ALG12-CDG. 1,2,7,12 Our patients are homozygous for a deleterious variant in the splice donor site of exon 10 in ALG9 (NG_009210.1:g.35929T4A also denoted NM_024740.2:c.1173+2T4A). We show that this variant results in skipping of exon 10, leading to a shorter RNA with a frameshift, a premature stop codon and abnormal N-glycosylation pattern in all the affected patients.…”

“…A very rare lethal fetal syndrome with polycystic kidneys, typical facial features and varying malformations, was first reported by Gillessen-Kaesbach et al, while features of skeletal dysplasia in this syndrome were characterized by Nishimura et al 1,2 Despite the varying degree and combination of internal malformations and dysmorphic features, the skeletal features of the patients were strikingly uniform, including short tubular bones, deficient ossification of the cervical vertebral bodies and pubic rami, round pelvis, decreased ossification of the frontoparietal bones, thickening of the occipital bones, ulnar deviation of the hands and short extremities. 1,2 The congenital disorders of glycosylation (CDG) constitute a large group of syndromes with disruption of one or several of the biosynthetic pathways of complex glycans as a common denominator. 3 Most CDG patients have a disruption in the N-linked pathway, in which a lipid-linked precursor oligosaccharide (LLO), preformed in the endoplasmic reticulum (ER), is transferred to asparagine residues in the nascent polypeptide chain.…”

Radiographic and morphologic findings in a previously undescribed type of mesomelic dysplasia resembling atelosteogenesis type II

“…They range in severity from perinatal lethal to mild short stature and demonstrate varying degrees of limb shortness. This variability in shape and involvement of the ulnae, radii, tibiae, or fibulae, as well as additional clinical or radiographic findings such as involvement of the proximal or distal limb segments, vertebral or craniofacial anomalies, or other skeletal malformations have been used to define specific entities [Kaitila et al, 1976;Baxová et al, 1995;Taybi and Lachman, 1996;Castriota-Scanderberg et al, 1997;Nishimura et al, 1998]. …”