Genetic disorders with ocular manifestations

Summary

There are several genetic disorders with ocular manifestations that are important to learn about for the Duke-Elder exam. Here, we summarise the key learning points about these conditions.

Stickler syndrome

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Stickler syndrome is a group of hereditary connective tissue disorders involving defective collagen (types II, IX and XI) production. As well as affecting the eye, Stickler syndrome has auditory, maxillofacial and musculoskeletal manifestations.

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Five types of Stickler syndrome exist, with types 1-4 being inherited in an autosomal dominant fashion (although many cases can be sporadic). Type 5 is autosomal recessive.

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Systemic features

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• In children: micrognathia (small mandible) and macroglossia (large tongue), which leads to a cleft palate (known as Pierre-Robin sequence)

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• Osteoarthritis of the hip, knee and spine

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• Hearing loss (sensorineural and/or conductive)

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Ocular features

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• Vitreous abnormalities – vitreous syneresis (liquefaction of the vitreous) in a membranous/beaded configuration). This can lead to a giant retinal tear

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• Radial perivascular retinal lattice degeneration

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• Retinal detachment – this is often how Stickler syndrome presents. Stickler syndrome is the most common cause of inherited retinal detachment, and the most common cause of rhegmatogenous retinal detachment in childhood

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• Congenital megalophthalmos, which can lead to myopia

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• Open angle glaucoma

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• Cataract

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Marfan’s syndrome

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Marfan’s syndrome is a connective tissue disorder that is inherited in an autosomal dominant fashion. It is caused by a mutation in the FBN1 gene on chromosome 15 that encodes fibrillin-1 glycoprotein, an essential component of elastin. The prevalence of Marfan’s syndrome is approximately 1 in 3000, and it affects males and females equally.

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Systemic features

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Since elastin is a major component of connective tissue, lots of organ systems are affected. The main clinical features are summarised below.

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Cardiac:

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• Dilatation of the aortic sinuses (found in 90%), which can lead to the following…

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• Aortic aneurysms and dissection

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• Aortic root dilatation —> aortic regurgitation

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• Mitral valve prolapse (found in 75%) ± regurgitation

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Musculoskeletal:

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• Tall stature

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• Arachnodactyly (long, slender fingers)

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• High-arched palate

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• Pectus excavatum (where the sternum grows inwards —> inward depression in the chest)

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• Scoliosis

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• Pes planus (flat feet)

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• Joint hypermobility

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Lungs:

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• Repeated pneumothoraces

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The key complications to be aware of are ruptured aortic aneurysms, spontaneous pneumothoraces and hernias, including diaphragmatic hernias.

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Ocular features

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The connective tissue defect in Marfan’s syndrome can affect the cornea, lens and growth of the eye.

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Most people with Marfan’s syndrome are affected by:

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• Myopia

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• Astigmatism

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• Abnormal curvature of the eye

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Other ocular manifestations include:

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• Ectopia lentis (subluxation of the lens i.e. a shift in the normal position of the lens in the eye) – caused by weakness in the zonules that hold the lens in place. This occurs in 60% of patients

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• Corneal thinning

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• Flattened corneal curvature

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• Cataract

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• Glaucoma

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• Strabismus

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• Retinal detachment

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Ectopia lentis can also occur in other conditions, namely homocystinuria, and more rarely Ehlers-Danlos syndrome, Weill-Marchesani syndrome, sulphite oxidase deficiency and hyperlysinaemia.

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Down’s syndrome

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Down’s syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of a complete or partial third copy of chromosome 21. It occurs in approximately 1 in 1000 births.

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Systemic features

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Down’s syndrome is a complex multisystem disorder with numerous possible clinical features. Here are some of the key characteristic features:

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• Short stature

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• Short neck

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• Characteristic facial features – upslanting palpebral fissures (gaps between lower and upper eyelid), prominent epicentral folds (folds of skin covering the medial portion of the eye and eyelid), small low-set ears, flattened nose and face, and a protruding tongue

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• Brachycephaly (a flat occiput of the head)

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• Sinle palmar crase

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• Pronounced ‘sandal gap’ between the great and first toe

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• Congenital heart defects (most commonly atrioventricular septal defects, but also ventricular septal defects, Tetralogy of Fallot and more)

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• Learning disability

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• Deafness

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Patients with Down’s syndrome are also at an increased risk of the following complications later in life:

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• Subfertility

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• Repeated respiratory infections, recurrent otitis media (middle ear infections)

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• Acute lymphoblastic leukaemia (ALL)

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• Hypothyroidism

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• Alzheimer’s disease

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Ocular features

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Some of the common ocular features of Down’s syndrome are summarised in the table below.

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Neurofibromatosis

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Neurofibromatosis is a genetic disorder that involves tumours growing on nerve tissue. These tumours can form anywhere in the central or peripheral nervous system.

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Neurofibromatosis belongs to the group of phakomatoses (neurocutaneous disorders) that tuberous sclerosis, von Hippel-Lindau syndrome, and Sturge-Weber syndrome also belong to.

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There are three types of neurofibromatosis: neurofibromatosis type 1 (NF1), type 2 (NF2) and schwannomatosis. The two important conditions to learn about are NF1 and NF2. Both are inherited in an autosomal dominant fashion, but are caused by different genetic mutations. The table below summarises the key learning points for NF1 and NF2.

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Wilson’s disease

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Also known as hepatolenticular degeneration, Wilson’s disease is a rare autosomal recessive disorder resulting in impaired hepatic copper excretion and increased copper absorption from the small intestine. This results in copper accumulation and deposition in tissues, particularly the liver, brain and cornea.

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It is caused by a mutation of the ATP7B gene on chromosome 13, which results in a defective liver copper transporting ATPase, leading to a failure to incorporate copper into caeruloplasmin and excrete it in bile. Consequently, copper builds up in hepatocytes.

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Wilson’s disease typically presents in late childhood with liver disease, or in young adulthood with neuropsychiatric signs.

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Systemic features

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Some of the important systemic features of be aware of are:

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• Hepatic: acute hepatitis, cirrhosis, hepatosplenomegaly

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• Haematological: haemolytic anaemia (caused by circulating free copper damaging red blood cells)

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• Neurological: speech, behavioural and psychiatric problems (these are often the first manifestations); dementia (when the cerebral cortex is involved), Parkinsonism (when there is basal ganglia degeneration), tremor, dystonia and more.

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Ocular features

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• Kayser-Fleischer rings (most commonly) – a brownish-yellow zone of fine copper dusting in peripheral Descemet’s membrane (caused by a deposition of copper in Descemet’s membrane in the iris). These deposits are best detected on slit-lamp examination and may disappear with penicillamine therapy.

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• Anterior ‘sunflower’ cataract is seen in some patients

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References

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1. Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.

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2. ‘Stickler Syndrome’. NORD (National Organization for Rare Disorders), https://rarediseases.org/rare-diseases/stickler-syndrome/. Accessed 9 Jan. 2023.

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3. Mathan, Joyce John, et al. ‘Down Syndrome and the Eye: Ocular Characteristics and Ocular Assessment’. Survey of Ophthalmology, vol. 67, no. 6, Nov. 2022, pp. 1631–46. ScienceDirect, https://doi.org/10.1016/j.survophthal.2022.03.006.

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4. Marfan Syndrome – American Association for Pediatric Ophthalmology and Strabismus. https://aapos.org/glossary/marfan-syndrome. Accessed 9 Jan. 2023.

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5. Li, Hongyi, et al. ‘Identification and Study of a FBN1 Gene Mutation in a Chinese Family with Ectopia Lentis’. Molecular Vision, vol. 18, Feb. 2012, pp. 504–11. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291523/.

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6. De Maio, Fernando, et al. ‘Orthopaedic Aspects of Marfan Syndrome: The Experience of a Referral Center for Diagnosis of Rare Diseases’. Advances in Orthopedics, vol. 2016, 2016, p. 8275391. PubMed Central, https://doi.org/10.1155/2016/8275391.

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7. Staufenbiel, Ingmar, et al. ‘Periodontal Conditions in Patients with Marfan Syndrome – a Multicenter Case Control Study’. BMC Oral Health, vol. 13, Oct. 2013, p. 59. PubMed Central, https://doi.org/10.1186/1472-6831-13-59.

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8. ‘Neurofibromatosis 1’. NORD (National Organization for Rare Disorders), https://rarediseases.org/rare-diseases/neurofibromatosis-type-1-nf1/. Accessed 9 Jan. 2023.

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9. ‘Neurofibromatosis 2’. NORD (National Organization for Rare Disorders), https://rarediseases.org/rare-diseases/neurofibromatosis-2/. Accessed 9 Jan. 2023.

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10. Abdolrahimzadeh, Barmak, et al. ‘Neurofibromatosis: An Update of Ophthalmic Characteristics and Applications of Optical Coherence Tomography’. Clinical Ophthalmology (Auckland, N.Z.), vol. 10, May 2016, pp. 851–60. PubMed Central, https://doi.org/10.2147/OPTH.S102830.

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11. Adams, E. G., et al. ‘Multiple, Unilateral Lisch Nodules in the Absence of Other Manifestations of Neurofibromatosis Type 1’. Case Reports in Ophthalmological Medicine, vol. 2011, 2011, p. 854784. PubMed Central, https://doi.org/10.1155/2011/854784.

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12. Nishi, Takeshi, et al. ‘A Case of Pancreatic Neuroendocrine Tumor in a Patient with Neurofibromatosis-1’. World Journal of Surgical Oncology, vol. 10, July 2012, p. 153. PubMed Central, https://doi.org/10.1186/1477-7819-10-153.

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13. Zaheryany, Seyed Mohammad Salar, et al. ‘Idiopathic Thrombocytopenia and Neurologic Manifestations in A Young Female Leading to the Diagnosis of Wilson’s Disease’. Iranian Journal of Psychiatry and Behavioral Sciences, vol. 6, no. 2, 2012, pp. 96–99. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940014/.

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