Achondrogenesis type 1A: clinical, histologic, molecular, and prenatal ultrasound diagnosis

Abstract

Background: Achondrogenesis type IA (ACG1A) is a rare, lethal autosomal recessive chondrodysplasia affecting endochondral bone ossification and differentiation, causing intrauterine growth restriction, narrow thorax, and short limbs. Mutations in TRIP11, which encodes Golgi microtubule-binding protein 210 in the Golgi apparatus, alter protein transport in tissues.

Case presentation: A 28-week gestation male fetus was diagnosed with ACG1A by clinical, radiological, histologic, and molecular findings.

Results: Whole exome sequencing was performed on fetal DNA and parental blood. Two fetal heterozygous novel variants of TRIP11, c.2304_2307delTCAA (p.Asn768Lysfs*7) and c.2128_2129delAT (p.lle710Cysfs*19), were inherited from the mother and father, respectively. Both variants created a reading frameshift leading to a premature stop codon and loss of protein function.

Conclusion: To our knowledge, this is the first Latin American report with clinical, radiographic, and molecular diagnosis of ACG1A. Clinical and molecular diagnosis in utero is essential for genotype-phenotype correlation and is useful for providing better genetic counseling.

Keywords: GMAP-210; TRIP11; achondrogenesis type IA; endochondral bone.

Figure 1

Patient phenotype and postmortem X-rays. Notes: (A–C) Posterior, lateral, and frontal views. Patient phenotype shows flat face, short nose, protruding tongue and eyes, low-set ears, narrow bell-shaped thorax, and severe micromelia. (D, E) Postmortem X-ray. Lateral and frontal views showing deficient mineralization of the calvaria and vertebral bodies, unossified sacrum, hypoplastic thorax, and markedly short and beaded ribs with flared and spurred ends.

Figure 2

Fetal cartilage section stained with hematoxylin–eosin. Notes: (A) Costochondral junction region magnified 4× reveals hypercellularity in the myxoid matrix. The fibrillary matrix tends to form rings around chondrocytes, simulating vacuolated cells. (B) Costochondral junction region magnified 10× reveals hypercellularity in the myxoid matrix. (C) Femoral region magnified 40× reveals hypercellularity in the myxoid matrix. (D) Femoral region magnified 40× reveals vacuolated chondrocytes.

Figure 3

Exon 11 Sanger sequencing of TRIP11 gene showing the deletion of AT (red arrow) at position 2128–2129 (c.2128_2129delAT) and deletion of TCA at position 2304–2307 (c.2304_2307) which has an effect on the protein and generates a premature stop codon at amino acids 710 and 768, respectively.