Frontometaphyseal dysplasia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Frontometaphyseal dysplasia is a disorder involving abnormalities in skeletal development and other health problems. It is a member of a group of related conditions called otopalatodigital spectrum disorders, which also includes otopalatodigital syndrome type 1, otopalatodigital syndrome type 2, Melnick-Needles syndrome, and terminal osseous dysplasia. In general, these disorders involve hearing loss caused by malformations in the tiny bones in the ears (ossicles), problems in the development of the roof of the mouth (palate), and bony abnormalities involving various areas of the skeleton.

Frontometaphyseal dysplasia is distinguished from the other otopalatodigital spectrum disorders by the presence of joint deformities called contractures that restrict the movement of certain joints. People with frontometaphyseal dysplasia may also have bowed limbs, an abnormal curvature of the spine (scoliosis), and abnormalities of the fingers and hands.

Characteristic facial features may include prominent brow ridges; wide-set and downward-slanting eyes; a very small lower jaw and chin (micrognathia); and small, missing, or misaligned teeth. Some affected individuals have hearing loss.

In addition to skeletal abnormalities, individuals with frontometaphyseal dysplasia may have obstruction of the ducts between the kidneys and bladder (ureters), heart defects, or constrictions in the passages leading from the windpipe to the lungs (the bronchi) that can cause problems with breathing.

There are three types of frontometaphyseal dysplasia, known as type 1, type 2, and type 3. The three types differ in their genetic cause and the way they are inherited.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the FLNA gene cause frontometaphyseal dysplasia type 1. Variants in the MAP3K7 gene cause frontometaphyseal dysplasia type 2, and TAB2 gene variants cause type 3.

The FLNA gene provides instructions for producing the protein filamin A, which helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Filamin A binds to another protein called actin, and helps the actin form the branching network of filaments that make up the cytoskeleton. Filamin A also links actin to many other proteins to perform various functions within the cell.

Variants in the FLNA gene have been identified in people with frontometaphyseal dysplasia. These mutations are described as "gain-of-function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Researchers think that the mutations may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of frontometaphyseal dysplasia.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

When frontometaphyseal dysplasia is caused by variants in the FLNA gene, it is inherited in an X-linked dominant pattern. The FLNA gene is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a variant in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a variant in the only copy of the gene in each cell causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. Males with frontometaphyseal dysplasia type 1 generally have more severe signs and symptoms of the disorder than do females, who may show only the characteristic facial features.

When frontometaphyseal dysplasia is caused by variants in the MAP3K7 or TAB2 gene, it is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Frontometaphyseal dysplasia is a rare disorder; over a hundred cases have been reported worldwide.

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 facial shape · Very frequent (99-80%)

An abnormal morphology (form) of the face or its components.

Broad thumb · Very frequent (99-80%)

Increased thumb width without increased dorso-ventral dimension.

Downslanted palpebral fissures · Very frequent (99-80%)

The palpebral fissure inclination is more than two standard deviations below the mean.

Hearing impairment · Very frequent (99-80%)

A decreased magnitude of the sensory perception of sound.

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).

Joint contracture of the hand · Very frequent (99-80%)

Contractures of one ore more joints of the hands meaning chronic loss of joint motion due to structural changes in non-bony tissue.

Long fingers · Very frequent (99-80%)

The middle finger is more than 2 SD above the mean for newborns 27 to 41 weeks EGA or above the 97th centile for children from birth to 16 years of age AND the five digits retain their normal length proportions relative to each other (i.e., it is not the case that the middle finger is the only lengthened digit), or, Fingers that appear disproportionately long compared to the palm of the hand.

Micrognathia · Very frequent (99-80%)

Developmental hypoplasia of the mandible.

Other findings in the same source

From: Orphanet

Additional reported features include Prominent supraorbital ridges (Very frequent (99-80%)); Scoliosis (Very frequent (99-80%)); Short phalanx of finger (Very frequent (99-80%)); Skeletal dysplasia (Very frequent (99-80%)); Wide nasal bridge (Very frequent (99-80%)); Abnormal heart morphology (Frequent (79-30%)); Camptodactyly of finger (Frequent (79-30%)); Coarse facial features (Frequent (79-30%)); Conductive hearing impairment (Frequent (79-30%)); Dislocated radial head (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 Frontometaphyseal dysplasia 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 Frontometaphyseal 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.