Achondrogenesis, Type Ia

A number sign (#) is used with this entry because of evidence that achondrogenesis type IA (ACG1A) is caused by homozygous or compound heterozygous mutation in the TRIP11 gene (604505) on chromosome 14q32.

Description

The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues.

Classification of Achondrogenesis

Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder.

Genetic Heterogeneity of Achondrogenesis

Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).

Clinical Features

Houston et al. (1972) described a family from Saskatchewan, Canada, in which 4 of 10 sibs were diagnosed with achondrogenesis. Two were stillborn and 2 died shortly after birth. No osseous tissue or hemopoietic bone marrow was found in the cartilaginous sternum or vertebral bodies.

Wiedemann et al. (1974) pointed out the importance of distinguishing achondrogenesis from hypophosphatasia (241500).

Smith et al. (1981) reported 3 affected sibs, with in utero diagnosis of the third.

Borochowitz et al. (1988) studied the clinical, radiologic, and morphologic features of 17 cases previously diagnosed with achondrogenesis type I. On radiographic analysis, 2 distinct groups of patients were defined based on the presence or absence of rib fractures and ossification of the vertebral pedicles, ischium, and fibula. Microscopic studies of the chondroosseous morphology showed 2 distinct patterns that correlated directly with the radiographic grouping: one group had round, vacuolated chondrocytes with inclusion bodies, and the other had collagenous rings around the chondrocytes.

Vanegas et al. (2018) reported a male infant, born of nonconsanguineous Colombian parents, who was diagnosed with ACG1A at 28 weeks' gestation and died shortly after birth. Postmortem findings included turricephaly, cerebral gyrus flattening, a hypoplastic nasal bridge, short neck and trunk, short and bowed extremities, clubfoot, and hypoplastic lungs. Radiography showed deficient mineralization of the calvaria and vertebral bodies, unossified sacrum, hypoplastic thorax, and markedly short and beaded ribs with flared and spurred ends. Examination of the sternum and femur tissue demonstrated hypercellularity of bone and myxoid cartilage matrix; cytoplasmic inclusions were described as 'vacuolated chondrocytes.'

Molecular Genetics

Smits et al. (2010) noted similarities between the skeletal and cellular phenotypes of Trip11 (604505)-null mice and patients with ACG1A, including absence of vertebral-body and skull ossification on radiography, lack of organized columnar zones of proliferating chondrocytes on histologic analysis, reduced expression of COL10A1 (120110) on immunohistochemical analysis, and expanded endoplasmic reticulum cisternae in chondrocytes on electron microscopy. Smits et al. (2010) analyzed the TRIP11 gene in 10 unrelated patients with ACG1A and identified homozygous or compound heterozygous loss-of-function mutations in all 10 patients (see, e.g., 604505.0001-604505.0004).

In a male infant, born of nonconsanguineous Colombian parents, with ACG1A, Vanegas et al. (2018) identified compound heterozygous frameshift mutations in the TRIP11 gene (604505.0010 and 604505.0013). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype.

History

Several distinct disorders have been called achondrogenesis, 2 of which are the severe disorder of the limbs described by Grebe (1952), which is now called Grebe dysplasia (200700), and a lethal neonatal chondrodysplasia which had been found to be made up of at least 2 distinct disorders. In the past OMIM referred to Grebe dysplasia as type II achondrogenesis and to the lethal neonatal chondrodysplasias as types IA and IB (200610). Spranger et al. (1974) referred to the lethal neonatal chondrodysplasias as types 'I' and 'II (200600)' a nomenclature which has become widely accepted and is therefore used here.