Expanding spectrum of congenital disorder of glycosylation Ig (CDG‐Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality

Abstract

In this report, we describe a brother and sister who presented at birth with short-limb skeletal dysplasia, polyhydramnios, prematurity, and generalized edema. Dysmorphic features included broad nose, thick ears, thin lips, micrognathia, inverted nipples, ulnar deviation at the wrists, spatulate fingers, fifth finger camptodactyly, nail hypoplasia, and talipes equinovarus. Other features included short stature, microcephaly, psychomotor retardation, B-cell lymphopenic hypogammaglobulinemia, sensorineural deafness, retinal detachment and blindness, intestinal malrotation with poor gastrointestinal motility, persistent hyponatremia, intermittent hypoglycemia, and thrombocytopenia. Cardiac anomalies included PDA, VSD, hypertrophic cardiomyopathy, and arrhythmias. The brother had a small penis with hypospadias, hypoplastic scrotum, and non-palpable testes. Skeletal findings included absent ossification of cervical vertebral bodies, pubic bones, knee epiphyses, and tali. Both sibs died before age 2 years, one of overwhelming sepsis and the other of cardiorespiratory failure associated with her cardiomyopathy. Metabolic studies showed a type 1 pattern of abnormal serum transferrin glycosylation. Fibroblasts synthesized truncated LLOs, primarily Man(7)GlcNAc(2), suggestive of CDG-Ig. Both sibs were compound heterozygotes for a novel 301 G > A (G101R) mutation and a previously described 437 G > A (R146Q) mutation in ALG12. Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurodevelopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy.

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

“…7 In accordance with the notion that the CDGs are recessive disorders and that the capacity of the LLO biosynthetic machinery can cope with haploinsufficiency, we found no signs of underglycosylation in the parental serum (data not shown).…”

“…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.…”

Regulated and aberrant glycosylation modulate cardiac electrical signaling

“…The primary target organ for Chagas disease and for some CDGs is the heart, leading to an increased susceptibility to conduction anomalies, cardiac arrhythmias, and heart failure (16)(17)(18)(19). Thus, these diseases lead to aberrant cardiac glycosylation and to symptomatic changes in cardiac excitability.…”

Diagnostic dilemma's: The congenital disorders of glycosylation are clinical chameleons

“…8 Less common manifestations include a 'dysostosis multiplex like phenotype', 9 and even a primary skeletal dysplasia has been reported in CDG-Ia, 10 CDG-Id, 11 and CDG-Ig. 12 Dysmorphic features are a common reason to prompt referral to a clinical genetics clinic, thus highlighting the importance of the clinical geneticist in diagnosing the CDG. The 'CDG facies' constitutes a prominent forehead, triangular face, large floppy ears, strabismus, and thin upper lip.…”