Cerebro-facio-thoracic dysplasia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Cerebro-facio-thoracic dysplasia is a rare condition characterized by abnormal development (dysplasia) of the brain (cerebro) and structures in the face (facio) and torso (thoracic). The problems with development lead to the key features of cerebro-facio-thoracic dysplasia, which include severe intellectual disability, distinctive facial features, and abnormalities of the ribs and spinal bones (vertebrae).

In addition to intellectual disability, individuals with cerebro-facio-thoracic dysplasia have delayed development of speech and movement (motor) skills, and in some, these skills never develop. Nearly one-quarter of affected individuals never learn to speak and almost half are unable to walk. Weak muscle tone (hypotonia) and difficulty feeding occur in some affected infants. People with cerebro-facio-thoracic dysplasia can have neurodevelopmental problems, such as anxiety, autism spectrum disorder, or self-injuring behavior; however, many people with the condition are described as friendly and good-natured.

Distinctive facial features common in cerebro-facio-thoracic dysplasia include a wide, short skull (brachycephaly); highly arched eyebrows or eyebrows that grow together in the middle (synophrys); widely spaced eyes (hypertelorism); a wide nasal bridge; low-set ears; an upper lip with pronounced curves (Cupid's bow upper lip); and small teeth (microdontia). Some affected individuals have overgrowth of the gums (gingival hyperplasia), an opening in the roof of the mouth (cleft palate), or a split in the upper lip (cleft lip).

Problems with bone development in the torso (thorax) commonly leads to bone abnormalities such as two or more ribs that are joined together (fused) or ribs that are abnormally shaped with two prongs at one end (bifid ribs). Many people with cerebro-facio-thoracic dysplasia have abnormal side-to-side curvature of the spine (scoliosis) due to malformation of the vertebrae; some vertebrae may also be fused. Additionally, the shoulder blades can be affected in people with this condition.

A wide variety of other features can occur in cerebro-facio-thoracic dysplasia, such as abnormalities involving the eyes, skin, or hair. Heart defects, digestive problems, or genitourinary problems (such as abnormal kidneys or reproductive organs) can also occur. Affected individuals may also have bone or joint abnormalities in other parts of the body.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Cerebro-facio-thoracic dysplasia is caused by mutations in a gene called TMCO1. This gene provides instructions for making a protein that forms specialized structures called channels through which positively charged calcium atoms (calcium ions) flow. The protein is found in the membrane of a cell structure called the endoplasmic reticulum, which acts as a storage center for calcium ions. When there is too much calcium in the endoplasmic reticulum, four TMCO1 proteins come together to form a channel that releases the excess calcium into the surrounding fluid inside the cell (cytoplasm). Calcium acts as a signal for many cellular functions including control of cell growth and division and gene activity. The proper balance of calcium ions in cells and cell compartments is important for the development and function of various tissues and organs.

TMCO1 gene mutations result in a shortage of TMCO1 proteins. Without this protein, TMCO1 channels cannot form, and excess calcium builds up in the endoplasmic reticulum. The imbalance of calcium ions disrupts development of the brain and structures in the head, face, and torso, resulting in the features of cerebro-facio-thoracic dysplasia.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Cerebro-facio-thoracic dysplasia is a rare disorder. Its prevalence is unknown.

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.

Bifid ribs · Very frequent (99-80%)

A bifid rib refers to cleavage of the sternal end of a rib, usually unilateral. Bifid ribs are usually asymptomatic, and are often discovered incidentally by chest x-ray.

Brachycephaly · Very frequent (99-80%)

An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.

Broad philtrum · Very frequent (99-80%)

Distance between the philtral ridges, measured just above the vermilion border, more than 2 standard deviations above the mean, or alternatively, an apparently increased distance between the ridges of the philtrum.

Hemivertebrae · Very frequent (99-80%)

Absence of one half of the vertebral body.

Hypertelorism · Very frequent (99-80%)

Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).

Hypoplasia of the corpus callosum · Very frequent (99-80%)

Underdevelopment of the corpus callosum.

Intellectual disability · Very frequent (99-80%)

The term intellectual disability or intellectual developmental disorder is used to describe significantly sub-average intellectual and adaptive functioning based on clinical assessment and as measured by individually administered, appropriately normed, standardized and validated tests of intellectual functioning and adaptive behavior, with onset during the developmental period from infancy through adolescence.

Midface retrusion · Very frequent (99-80%)

Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.

Other findings in the same source

From: Orphanet

Additional reported features include Narrow chest (Very frequent (99-80%)); Posteriorly rotated ears (Very frequent (99-80%)); Rib fusion (Very frequent (99-80%)); Short neck (Very frequent (99-80%)); Thick eyebrow (Very frequent (99-80%)); Wide mouth (Very frequent (99-80%)); Wide nose (Very frequent (99-80%)); Abnormal hair pattern (Frequent (79-30%)); Cerebellar vermis hypoplasia (Frequent (79-30%)); Cerebral cortical atrophy (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Cerebro-facio-thoracic dysplasia is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

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.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Cerebro-facio-thoracic dysplasia. 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.