Overview

Achondrogenesis, which has an incidence of 1 in 40,000 live births, is a series of congenital, lethal skeletal dysplasias characterised by severely shortened limbs and defective skull development.^1,2 Infants with achondrogenesis die prenatally (before birth) or shortly after birth.³

Achondrogenesis can be divided into two subclasses: type I and type II (Langer-Saldino). Type I achondrogenesis can be further divided into type IA (Houston-Harris) and type IB (Parenti-Fraccaro), depending on the affected gene.⁴  

Early and accurate prenatal diagnosis of achondrogenesis would facilitate appropriate arrangements regarding delivery method, perinatal care, postnatal (after birth) management, and future pregnancy planning. 

Understanding achondrogenesis

Achondrogenesis type IA and IB are both caused by autosomal recessive mutations.⁴ This means that if both parents carry the disease-causing gene, each conceived child will have a 25% chance of being affected, a 50% chance of carrying the trait but not showing any symptoms, and a 25% chance of not inheriting the faulty gene. 

Achondrogenesis type II is caused by spontaneous mutations in a gene involved in collagen production. It is less severe than type I and manifests later in pregnancy.⁵ 

Although there is some overlap in the clinical symptoms of types I and II, they can typically be distinguished through a combination of histopathological (microscopic examination of tissues) and radiographic (imaging of internal structures using X-rays) features.⁴ 

General clinical features of achondrogenesis include:^4,6

• Extremely short limbs
• Poorly developed (ossified) skull
• Short ribs, sometimes fractured
• Short neck
• Flat face
• Underdevelopment of the thorax

Prenatal ultrasound diagnosis

Achondrogenesis is commonly detected in routine ultrasound examinations during pregnancy.^3,7,8,9 The achondrogenesis diagnosis can be suspected as early as 12-14 weeks of pregnancy.^2,3,10 A definitive diagnosis could be established within the second trimester of pregnancy (13-27 weeks of pregnancy).⁴

The first reported cases of definitive diagnosis of achondrogenesis identified through ultrasound were in the early 1980s.^10,11,12,13 Ultrasound findings of affected infants showed abnormally short limb length, narrow chest, reduced bone density, and a buildup of amniotic fluid (polyhydramnios) – which is the fluid surrounding the baby in the womb. 

Diagnostic results were communicated to affected families, resulting in the termination of the pregnancies. In selected cases, pregnancies with suspected achondrogenesis were continued.^11,12 These cases were then examined radiographically post-mortem, confirming the achondrogenesis diagnosis. This is important for evaluating the recurrence risk and guiding the family planning decisions.

This was followed by an increase in successful prenatal diagnosis of achondrogenesis using ultrasounds in the subsequent years.^3,8,14,15 Ultrasound is preferred over other diagnostic methods, such as postnatal radiographic tests and amniocentesis, which were commonly used before ultrasound, as it introduces minimal risk to the infant and is more easily accessible.^16,17

Accuracy and reliability of prenatal diagnosis

Overall, prenatal ultrasound has been found to have a diagnostic accuracy of approximately 99% for all cases of skeletal dysplasias. For achondrogenesis specifically, it is estimated to have an 88% detection rate.⁵ 

Other disorders commonly considered in the differential diagnosis of achondrogenesis include: ^5,18

• Thanatophoric dysplasia
• Idiopathic Intrauterine Growth Restriction (IUGR)
• Osteogenesis imperfecta

If a diagnosis cannot be confirmed through ultrasound results, patients may be referred to conduct other tests such as:¹⁷ 

• Magnetic resonance imaging (MRI), where magnetic fields and radio waves are used to generate detailed images 
• Low-dose computed tomography (CT), a radiographic examination where X-rays that give off minimal levels of radiation are used to obtain high-resolution images
• Amniocentesis, where amniotic fluid that surrounds the infant in the womb is extracted for genetic testing
• Cell-free foetal DNA, where maternal blood is used to test the baby’s DNA

Affected families should receive appropriate counselling to understand the implications of diagnostic results and the available interventions once results are obtained. Thorough discussion of the benefits and risks of each recommended test is also crucial for parents to provide informed consent. 

The accuracy and reliability of prenatal diagnosis for achondrogenesis varies depending on the circumstances, such as duration of pregnancy and family history.⁶ Different genetic mutations also give rise to different clinical features, which could result in a misdiagnosis.^3,8 

Therefore, the current standard for achondrogenesis diagnosis includes a multidisciplinary assessment of ultrasound, radiographic and histopathological features.⁹ 

Prenatal genetic test results are typically interpreted in conjunction with clinical findings. 

Treating achondrogenesis

Achondrogenesis is lethal due to respiratory complications from underdeveloped lungs (pulmonary hypoplasia), which results from the lack of skeletal support.² There is no known treatment for achondrogenesis. 

Pregnancies with a definitive achondrogenesis diagnosis are considered fatal anomalies and are usually terminated. This can be performed through medical or surgical means. Affected infants who are delivered receive end-of-life (palliative) care, in which clinicians attempt to minimise the effect of pain and associated symptoms. 

Psychological and emotional support is recommended to affected families to manage the mental stress associated with achondrogenesis. 

Summary

Achondrogenesis is a group of rare, lethal, genetic disorders that result in developmental skeletal abnormalities. Affected infants display severely reduced limb length and are either stillborn or die shortly after birth from respiratory issues. 

Following successful case studies in the late 20th century, achondrogenesis diagnoses are suspected by using ultrasound today. Although the accuracy and reliability of an ultrasound diagnosis is influenced by duration of pregnancy and family history, it has been shown to have a high detection rate for achondrogenesis. 

To confirm the achondrogenesis diagnosis, other tests such as CT scans and genetic tests are performed after adequate counselling about the relevant benefits and risks of the testing methods. 

As there is no known treatment for this disorder, affected infants receive palliative care and affected families receive emotional and psychological support.