Introduction

Definition of achondrogenesis

Achondrogenesis is a group of disorders that affects the development of bone and cartilage, causing extreme short stature in unborn babies. Achondrogenesis also affects the lungs, causing lung underdevelopment. Lung underdevelopment is the main reason for this condition being lethal. The majority of these babies born prematurely, do not make it to life (stillborns), or survive only a few days after birth.¹

Classification of achondrogenesis

There are three subtypes of achondrogenesis that differ clinically, radiologically, histologically, and genetically: Type IA; Type IB; Type II.

• Type IA (also known as Houston-Harris subtype)
• Type IB (also known as Parenti-Fraccaro subtype)
• Type II (also known as Langer-Saldino achondrogenesis)

Prevalence of achondrogenesis 

Achondrogenesis is present equally in males and females. Researchers aren’t sure how frequently Achondrogenesis type IA and type IB occur, but they are extremely rare. Achondrogenesis type II is estimated to occur in about one out of 40,000 to 60,000 births.¹ 

Pattern of inheritance of achondrogenesis

The type of inheritance is different between type I and type II. The inheritance of type IA and type IB  is autosomal recessive, meaning that the baby needs to inherit a mutation from both parents to develop the condition. The inheritance of type II is autosomal dominant, meaning that the baby needs only one mutation to develop the condition. However, in many cases, type II results from new mutations happening at the time of conception with the absence of similar conditions in the family.¹

Genetic mutations associated with achondrogenesis

Achondrogenesis is a genetic disorder caused by genetic mutations (changes in genes); type IA is associated with an inherited mutation in the SLC26A2 gene; type IB is associated with an inherited mutation in the COL2A1 gene; type II is mostly associated with newly formed (de novo) mutation in type II collagen.^2,3

Diagnosis of achondrogenesis 

The diagnosis of achondrogenesis can be made during pregnancy, firstly suggested by signs on ultrasound, then confirmed by other tests (e.g. Amniocentesis and Chorionic villus sampling). Amniocentesis involves inserting a needle through the belly to get a sample of the amniotic fluid. Chorionic villus sample involves either inserting a needle through the belly or inserting a tube through the vagina to get a sample. Both tests can detect the genetic abnormality if present.¹ 

The diagnosis of achondrogenesis after the baby is born can be made by performing a physical examination of the newborn baby, x-ray radiograph, and genetic testing.¹ 

Importance of radiological assessment

For prenatal (during pregnancy) diagnosis

Ultrasonography is an essential component in diagnosing achondrogenesis. Given that the condition is lethal, a definitive prenatal diagnosis of achondrogenesis may be an indication of pregnancy termination. 

For postnatal (after delivery) diagnosis

After the baby is born, an x-ray of the whole body of the newborn is performed, also known as a babygram. 

For differentiation from other skeletal dysplasias

Cases of achondrogenesis can be differentiated from other similar conditions of skeletal dysplasia by the presence of severe degree of limb shortening on ultrasonography. The demineralization is only a differential diagnosis in osteogenesis imperfecta and hypophosphatasia, which do not present with the same degree of limb shortening.⁵

Radiological features

Prenatal ultrasound findings

Diagnosis by sonography is possible after 13 weeks of gestation. An abnormality is suggested by the presence of nuchal oedema, although this finding is not specific to achondrogenesis and can be a sign of other conditions. Other specific signs include:²

• Severe micromelia (shortened limbs)
• Calvarial bone (skull) absence (in type IA and type I2)
• Lung hypoplasia or lung aplasia (underdevelopment or absence of the lung, respectively) 
• Narrow thorax
• Rib fractures (in type IA)
• Micrognathia (small jaw bone)
• Flat face
• Macrocephaly (large head)
• Frontal bossing (protrusion of the front of the skull)

Postnatal x-ray characteristics

Defective or absent ossification in body skeleton detected on babygram. This can affect any part of the newborn skeleton. On a case report, there was almost complete ossification of all bony skeleton with only the clavicle being visible.⁴

Achondrogenesis type I is considered to be more severe than type II, associated with inadequate ossification of multiple bones, including the skull, the vertebral column, and the pelvis, associated with multiple rib fractures, and extreme shortening of the extremities. On the other hand, achondrogenesis type II is associated with various degree of calcification of the pelvis, the skull, and the vertebral column, and not associated with rib fractures. 

Estimation of the degree of demineralization is important to differentiate the two types. Demineralization of the skull and hip bone suggests type I; on the other hand, normal mineralization of the skull suggests type II. 

Detection of demineralization is first done on ultrasound, and then confirmed on x-ray. In cases of absent demineralization on ultrasound, x-ray can be used to assume demineralization. 

However, according to studies, the recognition of demineralization by ultrasound is sometimes inaccurate, reporting negative results when there is demineralization, this leads to a tendency of over-reporting type II compared to type I.⁵

In a case report,⁵ there was a reported demineralization of the skull and iliac wings of the hip bone associated with multiple rib fractures observed in both ultrasonographic and radiological images. These findings support the diagnosis of type I achondrogenesis. In addition, there was positive consanguinity of the parents, which also confirms the diagnosis of type I, since it is autosomal recessively inherited.

Differential diagnosis

Thanatophoric dysplasia

Thanatophoric dysplasia is another skeletal disorder that is also characterized by extremely short limbs and may also include narrow thorax, short ribs, large head, and underdeveloped lungs. There are two types of thanatophoric dysplasia; type I is associated with curved thigh bones and flattened spine bones (platyspondyly); type II is associated with straight thigh bones and a skull abnormality called a cloverleaf skull (trilobar skull configuration when viewed from the front or behind).⁶

Osteogenesis imperfecta

Osteogenesis imperfecta (called brittle bone disease) is another skeletal disorder that causes the bones to break easily, with no or minimal injury. There are several types of osteogenesis imperfecta based on the nature of the underlying gene defect and the disease severity. Osteogenesis imperfecta also manifests as a short stature with bowing of long bones associated with easy bruising of the skin and discolouration of the sclera of the eyes that can look blue, purple, or gray.⁷

Hypophosphatasia

Hypophosphatasia is a genetic metabolic disorder that causes abnormal development of bones and teeth. The symptoms of hypophosphatasia vary from mild to severe. They manifest mainly as short stature, weak bones, respiratory problems associated with poor feeding, and hypercalcemia.⁸

Clinical implications and prognosis

Unfortunately, there is no treatment for achondrogenesis and affected babies will mostly pass away either during pregnancy or within a few days of delivery.¹

Prenatal counselling and decision making

Achondrogenesis is a lethal condition that may indicate pregnancy termination. Making the diagnosis during pregnancy is essential to guide counselling with the parents about the risk of this condition on their baby. Counseling also includes discussing the risk of recurrence of achondrogenesis in future pregnancy, the percentage of risk of recurrence is different between type I and type II; for type I, there is a 25% risk of the condition in each pregnancy; for type II, the risk is 0% if it is an acquired mutation. 

Postnatal care considerations

Some hospitals have special programs to provide support for babies with achondrogenesis to relieve their pain and other symptoms.¹

Summary

Achondrogenesis is a term that encompasses a group of skeletal disorders that affect the development of bone and cartilage of unborn babies. Achondrogenesis is a lethal condition given that it adversely affects lung development. There are three subtypes of achondrogenesis that differ in the underlying gene abnormality, the clinical symptoms, and the radiological appearance. Achondrogenesis can be diagnosed during pregnancy by ultrasonography, the most characteristic feature is severe short limbs (micromelia). Currently, there is no cure for this condition.