Achondrogenesis

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Achondrogenesis is a group of severe disorders that affect cartilage and bone development. These conditions are characterized by skeletal abnormalities that cause serious health problems. As a result, most infants with achondrogenesis die before birth or soon after, often due to respiratory failure.

Researchers have described three main types of achondrogenesis: type 1A, type 1B, and type 2. While these types differ in their genetic causes and inheritance patterns, they often have overlapping signs and symptoms. Genetic testing and medical imaging are often needed to tell them apart.

All forms of achondrogenesis feature short arms and legs, a narrow chest, and underdeveloped lungs. Infants with achondrogenesis type 1A, which is also called TRIP11-related achondrogenesis, typically have ribs that fracture easily. Bone formation (ossification) is also severely reduced in the skull and spine.

Infants with achondrogenesis type 1B, which is also called SLC26A2-related achondrogenesis, often have short fingers and toes and feet that may turn inward and upward (clubfeet). Infants with achondrogenesis type 1B may also have a sac (pouch) formed from the inner lining of the abdominal cavity that pushes through a hole in the abdominal wall around the belly-button (umbilical hernia) or near the groin (inguinal hernia).

The ossification of the spine and pelvis may be severely reduced in infants with achondrogenesis type 2, which is also called COL2A1-related achondrogenesis. The distinctive facial features seen in infants with achondrogenesis type 2 include a prominent forehead, a small chin, and, in some cases, an opening in the roof of the mouth (cleft palate).

Achondrogenesis type 2 and a similar skeletal disorder called hypochondrogenesis were once thought to be distinct conditions. However, because these conditions have overlapping features and a shared genetic cause, they are now considered to be part of the same disease spectrum.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in different genes cause the three main types of achondrogenesis.

Variants in the TRIP11 gene cause achondrogenesis type 1A. This gene provides instructions for making a protein called thyroid receptor-interacting protein 11 (TRIP-11). TRIP-11 helps maintain the Golgi apparatus, a cell structure in which proteins are modified. Most of the variants in the TRIP11 gene that cause achondrogenesis type 1A prevent the production of functional TRIP-11 proteins. Researchers suspect that cells called chondrocytes may be sensitive to these changes. Chondrocytes give rise to cartilage, a tough, flexible tissue that makes up much of the skeleton during early development. Without enough functional TRIP-11, the Golgi apparatus cannot work properly, which likely contributes to the characteristic features of achondrogenesis type 1A.

Achondrogenesis type 1B is caused by variants in the SLC26A2 gene. This gene provides instructions for making a protein that transports charged molecules (ions), particularly sulfate ions, across cell membranes. This protein is essential for the normal development of cartilage and for converting cartilage into bone. Variants in the SLC26A2 gene disrupt the structure of developing cartilage, which prevents bones from forming properly. These changes cause the skeletal problems that are characteristic of achondrogenesis type 1B.

Achondrogenesis type 2 and hypochondrogenesis are caused by variants in the COL2A1 gene. This gene provides instructions for making a protein that forms type II collagen, which is found in the clear gel that fills the eyeball (the vitreous) and in cartilage. Type II collagen is essential for the normal growth and development of bones and other connective tissues. Variants in the COL2A1 gene interfere with the formation of mature type II collagen molecules, which prevents bones and other connective tissues from developing properly in people with achondrogenesis type 2 and hypochondrogenesis.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Achondrogenesis type 1A and type 1B both have an autosomal recessive pattern of inheritance. A variant must be present in both copies of the TRIP11 gene in each cell to cause achondrogenesis type 1A, while a variant must be present in both copies of the SLC26A2 gene in each cell to cause achondrogenesis type 1B. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Achondrogenesis type 2 is considered to be an autosomal dominant disorder because one copy of the altered gene in each cell is sufficient to cause the condition. Most cases of this condition are the result of a new (de novo) variant in the COL2A1 gene that occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals have no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Achondrogenesis occurs in approximately 1 in 40,000 to 60,000 newborns.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal enchondral ossification · Very frequent (99-80%)

An abnormality of the process of endochondral ossification, which is a type of replacement ossification in which bone tissue replaces cartilage.

Abnormality of bone mineral density · Very frequent (99-80%)

This term applies to all changes in bone mineral density which (depending on severity) can be seen on x-rays as a change in density and or structure of the bone. Changes may affect all bones of the organism, just certain bones or only parts of bones and include decreased mineralisation as may be seen in osteoporosis or increased mineralisation and or ossification as in osteopetrosis, exostoses or any kind of atopic calicfications of different origin and distribution. The overall amount of mineralization of the bone-organ can be measured as the amount of matter per cubic centimeter of bones, usually measured by densitometry of the lumbar spine or hip. The measurements are usually reported as g/cm3 or as a Z-score (the number of standard deviations above or below the mean for the patient's age and sex). Note that measurement with this method does not reflect local changes in other bones, and as such might not be correct with regard the hole bone-organ.

Anteverted nares · Very frequent (99-80%)

Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).

Flat face · Very frequent (99-80%)

Absence of concavity or convexity of the face when viewed in profile.

Frontal bossing · Very frequent (99-80%)

Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.

Hydrops fetalis · Very frequent (99-80%)

The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.

Long philtrum · Very frequent (99-80%)

Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.

Macrocephaly · Very frequent (99-80%)

Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.

Other findings in the same source

From: Orphanet

Additional reported features include Micrognathia (Very frequent (99-80%)); Micromelia (Very frequent (99-80%)); Narrow chest (Very frequent (99-80%)); Severe short stature (Very frequent (99-80%)); Short neck (Very frequent (99-80%)); Short nose (Very frequent (99-80%)); Short thorax (Very frequent (99-80%)); Skeletal dysplasia (Very frequent (99-80%)); Thickened nuchal skin fold (Very frequent (99-80%)); Aplasia/Hypoplasia of the lungs (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Achondrogenesis is Orthopaedics, with a orthopaedic specialist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What explains the change in pain, movement or function?
• Which activities need adjustment while the diagnosis is being clarified?
• What are the roles of rehabilitation, observation and surgery in this situation?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Achondrogenesis. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.