Knobloch syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Knobloch syndrome is a rare condition characterized by severe vision problems and a skull defect.

A characteristic feature of Knobloch syndrome is extreme nearsightedness (high myopia). In addition, several other eye abnormalities are common in people with this condition. Most affected individuals have vitreoretinal degeneration, which is breakdown (degeneration) of two structures in the eye called the vitreous and the retina. The vitreous is the gelatin-like substance that fills the eye, and the retina is the light-sensitive tissue at the back of the eye. Vitreoretinal degeneration often leads to separation of the retina from the back of the eye (retinal detachment). Affected individuals may also have abnormalities in the central area of the retina, called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Due to abnormalities in the vitreous, retina, and macula, people with Knobloch syndrome often develop blindness in one or both eyes.

Another characteristic feature of Knobloch syndrome is a skull defect called an occipital encephalocele, which is a sac-like protrusion of the brain (encephalocele) through a defect in the bone at the base of the skull (occipital bone). Some affected individuals have been diagnosed with a different skull defect in the occipital region, and it is unclear whether the defect is always a true encephalocele. In other conditions, encephaloceles may be associated with intellectual disability; however, most people with Knobloch syndrome have normal intelligence.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the COL18A1 gene can cause Knobloch syndrome. The COL18A1 gene provides instructions for making a protein that forms collagen XVIII, which is found in the basement membranes of tissues throughout the body. Basement membranes are thin, sheet-like structures that separate and support cells in these tissues. Collagen XVIII is found in the basement membranes of several parts of the eye, including the vitreous and retina, among other tissues. Little is known about the function of this protein, but it appears to be involved in normal development of the eye.

Several mutations in the COL18A1 gene have been identified in people with Knobloch syndrome. Most COL18A1 gene mutations lead to an abnormally short version of the genetic blueprint used to make the collagen XVIII protein. Although the process is unclear, the COL18A1 gene mutations result in the loss of collagen XVIII protein, which likely causes the signs and symptoms of Knobloch syndrome.

When the condition is caused by COL18A1 gene mutations, it is sometimes referred to as Knobloch syndrome type I. Research indicates that mutations in at least two other genes that have not been identified may cause Knobloch syndrome types II and III. Although they are caused by alterations in different genes, the three types of the condition have similar signs and symptoms.

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

Knobloch syndrome is a rare condition. However, the exact prevalence of the condition 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.

Macular degeneration · Very frequent (99-80%)

A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.

Myopia · Very frequent (99-80%)

An abnormality of refraction characterized by the ability to see objects nearby clearly, while objects in the distance appear blurry.

Occipital encephalocele · Very frequent (99-80%)

A type of encephalocele (that is, a a protrusion of part of the cranial contents including brain tissue through a congenital opening in the cranium, typically covered with skin or mucous membrane) in the occipital region of the skull. Occipital encephalocele presents as a midline swelling over the occipital bone. It is usually covered with normal full-thickness scalp.

Retinal detachment · Very frequent (99-80%)

Separation of the inner layers of the retina (neural retina) from the pigment epithelium.

Skull defect · Very frequent (99-80%)

A localized defect in the bone of the skull resulting from abnormal embryological development. The defect is covered by normal skin. In some cases, skull x-rays have shown underlying lytic bone lesions which have closed before the age of one year.

Abnormal vitreous humor morphology · Frequent (79-30%)

Any structural anomaly of the vitreous body.

Hydrocephalus · Frequent (79-30%)

Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.

Nystagmus · Frequent (79-30%)

Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Other findings in the same source

From: Orphanet

Additional reported features include Progressive visual loss (Frequent (79-30%)); Visual loss (Frequent (79-30%)); Vitreoretinopathy (Frequent (79-30%)); Abnormality of the hair (Occasional (29-5%)); Bifid ureter (Occasional (29-5%)); Cataract (Occasional (29-5%)); Depressed nasal bridge (Occasional (29-5%)); Dextrocardia (Occasional (29-5%)); Ectopia lentis (Occasional (29-5%)); Epicanthus (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Knobloch syndrome 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 Knobloch syndrome. 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.