Albinism
Albinism, from the Latin albus, meaning “white,” is a group of genetic conditions when decreased or absent melanin in the skin, hair, and eyes produces characteristic pale appearance.
In this article:
- What Is Albinism?
- Symptoms
- Skin
- Hair
- Eye color
- Vision
- When to see a doctor
- Causes
- Types of Albinism
- Complications
- Eye complications
- Skin complications
- Social and emotional challenges
- Prevention
- Risk Factors
- Genetic counseling
- Diagnosis
- What is new in research on albinism?
- References
What Is Albinism?
Albinism is rare with estimated at 1:17,000 to 1:20,000 people affected overall. Approximately one in 70 individuals carry an OCA-mutated allele, with the OCA2 mutation being the most common worldwide.
OCA2 is common in sub-Saharan Africa since cultural norms permit consanguineous marriages, allowing prevalence reach 1 in 1000 and a phenomenon called pseudo-dominance where the recessive allele burden is so high in a given family, that the recessive trait is disproportionately represented.
There are other genetic syndromes that have ocular albinism, also very rare:
- Hermansky-Pudlak syndrome (HPS): Prevalence is 1:500,000 worldwide but 1:1800 in Puerto Rico
- Chediak-Higashi syndrome (CHS): Very rare (less than 500 cases published in the past 20 years)
- Angelman syndrome (AS) and Prader-Willi syndrome (PWS): Prevalence of AS (1:12,000 to 20,000) and PWS (1:15,000) are higher than the OCAs. However, only approximately 1% of AS and PWS sufferers have contiguous gene deletions that lead to OCA2-like presentation
- Ocular albinism (OA1): Prevalence is 1:50,000
Symptoms
Early diagnosis is most important to manage ocular symptoms and maximize visual potential, with guidance on general safety and wellbeing, education, self-esteem, and cognitive development.
Skin
Family and providers are not always alerted by hypopigmentation of skin, hair, and eyelashes, except in the context of family members who are constitutionally darker pigmented and the contrast is more striking.
Hair
While blond and red hair is common, and is not a sign of concern, the significant difference in the appearance of the child compared to the rest of the family may be alarming. It is wise to speak with a pediatrician about your concerns.
Eye color
Usually the adult pigment of the eyes establishes at 3-6 month of life, when parents note an unusual pale color of the iris. A very unusual pale iris can be noted soon – taken together with different hair and skin color these might be signs of albino child.
Vision
Ophthalmologist can help confirm the diagnosis with testing on a comprehensive eye exam. Characteristic ocular symptoms are:
- Infantile nystagmus
- Photophobia
- Reduced iris pigment with transillumination
- Reduced retinal pigment
- Visualization of choroidal blood vessels on a fundoscopic exam
- Foveal hypoplasia
- Decreased visual acuity
- Strabismus
- Misrouting of optic nerves on selective VEP exam
When to see a doctor
The earliest detection of the albino syndrome is important for the family. Mother’s eye catches the differences of the eyes, hair and skin first because she spends the most of the time with the baby. You should not feel shy asking a pediatrician about your concerns. A good doctor always listens to the mother’s questions, and will at least arrange a vision screen and an eye exam. In many situations the first problem noted was a nystagmus (constant movement of the eyes from side to side). A degree of nystagmus is normal for newborn babies, but should disappear and get replaced by a fixed gaze within first months of life.
Causes
Melanocytes are cells that reside in the upper skin layers, hair follicles. They contain melanosomes that produce melanin. Interestingly, in the iris cells capable of synthesizing melanin are retinal pigment epithelium which do not come from neural crest origin in the embryo, where melanocytes are developing. Melanin is most known for its role in ultraviolet (UV) protection, but it also has roles in both embryologic development of the ocular structures and oculoneural pathways.
The two most common forms of melanin are eumelanin and pheomelanin. Eumelanin colors skin with black or brown, and plays a role in protecting the skin against ultraviolet radiation damage. Pheomelanin is not UV protective, and people who predominantly have pheomelanin are at risk for severe sunburn, with red or blond hair and light-colored, ruddy skin.
Autosomal recessive inheritance pattern is the most common. It codes the production of the melanin and melanin type.
Types of Albinism
What are the features seen in albinism?
Oculocutaneous albinism
- OCA1: Autosomal recessive. The TYRgene product tyrosinase normally hydroxylates L-tyrosine to L-DOPA and oxidates L-DOPA to DOPAquinone. This serves as the rate-limiting/ step in melanin synthesis. Loss of this function leads to an inability to synthesize melanin.
- OCA2: Autosomal recessive. The OCA2gene product is the OCA2 melanosome transmembrane protein P, with unknown function.
- OCA3: Autosomal recessive. The TYRP1gene product is tyrosinase-related protein 1, which is thought to stabilize and modulate the activity of tyrosinase and contribute to melanosome integrity
- OCA4: Autosomal recessive. The SLC45A2gene codes for a solute carrier family 45, member 2 membrane-associated transport protein (MATP) that is thought to transport substances required for melanin biosynthesis into the melanosome.
- OCA5: Autosomal recessive. Gene not yet identified.
- OCA6: Autosomal recessive. The SLC24A5gene (solute carrier family 24, member 5) codes for a Na/K/Ca cation exchange protein with a similar structure to that seen in OCA4. Its function is also thought to be similar.
- OCA7: Autosomal recessive. The LRMDAgene (leucine-rich melanocyte differentiation associated protein) codes for a protein thought to play a role in melanocyte differentiation.
Ocular albinism
Ocular albinism (OA1): X-linked. The GPR143 gene product is a G-protein coupled receptor, a mutation in which yields dysfunctional melanosome biogenesis with resultant “macromelanosomes.”
Albinism related to rare hereditary syndromes
- Hermansky-Pudlak syndrome (HPS): Autosomal recessive. Ten different genotypes have been identified, thus far. The genes corresponding to the subtype of HPS. HPS1 gene (HPS1), AP3B1 gene (HPS2), HPS3 gene (HPS3), HPS4 gene (HPS4), HPS5 gene (HPS5), HPS6 gene (HPS6), DTNBP1 gene (HPS7), BLOC1S3 gene (HPS8), BLOC1S6 gene (PLDN), AP3D1 gene (HPS10). Not all subtypes of the syndrome are identical, but similarities exist. Subjects have oculocutaneous albinism, accumulation of a wax-like fat-protein compound (ceroid lipofuscin) in tissues, especially kidneys and lungs, and bleeding diathesis due to a lack of dense platelet granules leading to abnormal aggregation. Some forms have immunodeficiency (neutropenia) and a hemophagocytic syndrome with AP gene involvement (HPS2, HPS10) due to lysosomal dysfunction. The most severe forms (HPS1, HPS4) are both BLOC-3 protein mutations and associated with pulmonary fibrosis by the thirties and granulomatous colitis.
- Chediak-Higashi syndrome (CHS): Autosomal recessive. The LYST gene codes for a protein that directs delivery of material into lysosomes. Mutations lead to giant cytoplasmic granules (lysosomes) with diminished chemotaxis in leukocytes and platelets. This causes the characteristic increased susceptibility to pyogenic infections, neutropenia, peripheral neuropathy, mild coagulopathy, and hypomelanosis.
- Angelman syndrome (AS) and Prader-Willi syndrome (PWS): Both due to spontaneous (not inherited) partial deletions of chromosome 15q. Albinism occurs because the OCA2 allele located on one Chromosome 15q, making subjects haploinsufficient for OCA2 gene product, protein P. The complete mechanism by which this happens is unexplained since heterozygotes for OCA2 gene mutations producing one nonfunctional copy of protein P still are phenotypically normal. AS is the result of deletion on maternal chromosome 15q or uniparental disomy of chromosome 15 with both copies being of paternal origin. PWS is due to the deletion of paternal chromosome 15q or through uniparental disomy of chromosome 15 with both copies being of maternal origin.
Complications
The two significant results of hypo-melanosis can be divided into dermatological and ophthalmologic consequences. Since eumelanin is photo-protective, albinism leads to increased risk of sun-damage (solar lentigines, actinic keratoses, solar erythema) and UV-associated malignancies (especially squamous cell carcinomas).
Eye complications
- Limited work opportunities where a minimum visual acuity is required
- Difficulty in reading due to uncorrected visual deficits that may lead to educational delays
- Inability to obtain driver’s license due to visual impairment
Skin complications
Squamous cell carcinomas are the most common malignancy in albinism, which can increase the relative risk as much as 1000 times.
Social and emotional challenges
Albinism is a stigma in a society and may play a negative role in the self-esteem and pier relationship of an albino person. Not every country is acceptant of “different” people, which may lead to estrangement and depression. It is important to use every possible resource to help albino child grow happy and self-assured.
Prevention
Albinism itself cannot be prevented, while the healthy life with albinism is possible. There is no substitute for lifelong sun protection in albinism, and the importance cannot be overestimated.
Family should be educated on avoidance of prolonged UV light exposure (sun, tanning beds) and avoidance of medications that increase photosensitivity for the affected child. Any outdoor activities, no matter how brief, should be preceded by the application of sunscreen (SPF 30+) with liberal and frequent reapplication (every 2 hours) when in the sun.
Risk Factors
Families with albino child should be counseled on all possible risk factors their child will experience in life.
- Skin cancers. Skin pigmentation varies among individuals and is determined by multiple factors, including the number and metabolic activity of melanocytes in the base layer of the epidermis, the melanogenic activity of melanosomes within these melanocytes, and variations in the number, size, and distribution of melanosomes. In albinos cancerous skin changes may develop de novo or from premalignant actinic lesions, such as actinic keratosis, in which keratinocytes can undergo initial transformation induced by solar radiation. The keratinocytes exhibit different degrees of DNA damage, depending on the intensity and duration of exposure to sunlight.
- Photophobia. Light sensitivity can be managed with dark lensed glasses or hats.
- Eye complications such as nystagmus and strabismus. Ophthalmology follow-up is recommended 2 to 4 times per year (age 1 and 2), 1 to 3 times per year (age 3 to 6), annually (age 5 to 18), then every 2 to 3 years (adults).
- Development delay due to vision problems. Albinos have normal intelligence compared with the general population. There is some delayed visual maturation, which can lead to educational delay if not addressed early enough.
- Depression and ADHD. Furthermore, poor self-image and social alienation can lead to feelings of isolation and depression. Albinos do have an increased rate of attention deficit disorder.
Genetic counseling
Genetics consultation is beneficial to parents of albino children considering future offspring, the patient with albinism and their siblings. Albinism is an absolute homozygote condition with a 100% chance of passing on their defective gene. Coordinated genetic testing of the nonaffected partner is possible if the pathogenic variant is known. This will confirm the offspring have the potential to inherit the condition, if the partner is a carrier of the same pathogenic variant, or just be obligate carriers if the partner has only wild-type genes.
A couple who has already had an albino child has a 25% chance of having another child with albinism, a 50% chance of producing carrier offspring, and 25% of producing non-carrier offspring. This is assuming that one of the parents is not albino, in which case the chance of producing a second albino offspring is 50% after a confirmed albino offspring.
The fact than non-albino siblings have a 67% chance of being carriers is important to convey before they consider childbearing. Of note, if two parents carry genes for different types of albinism (for example, a patient with OCA2 and a carrier for OCA1), no children will be born with albinism, but the children are at risk for being heterozygous for both mutant alleles.
Diagnosis
Diagnosis of the albinism can be very obvious, but many other genetic diseases can present with skin or hair hypopigmentation. So, the diferential diagnosis to rule out other diseases is very important. These include metabolic and nutritional diseases:
- Phenylketonuria
- Homocystinuria
- Histidinemia, Menkes syndrome (copper deficiency), and
- Kwashiorkor
- Tietz syndrome should be considered if hearing is affected
Molecular genetic testing can confirm the diagnosis but is not routinely done. It is expensive and best done using multigene or comprehensive genome sequencing. Clinical diagnosis, especially incorporating a complete ophthalmologic exam, is sufficient.
No specific serological tests or imaging needs to be performed in the diagnosis or routine management of albinism.
What is new in research on albinism?
Is brain also wrong-wired in albinos?
A graph‐theoretic model was applied to explore brain connectivity networks derived from resting‐state functional and diffusion‐tensor magnetic resonance imaging data in 23 people with albinism and 20 controls. They tested for group differences in connectivity between primary visual areas and in summary network organisation descriptors.
Main findings were supplemented with analyses of control regions, brain volumes and white matter microstructure. Significant functional interhemispheric hyperconnectivity of the primary visual areas in the albinism group were found. Second, it was found that a range of functional whole‐brain network metrics were abnormal in people with albinism, including the clustering coefficient.
Based on the results, it was suggested that changes occur in albinism at the whole‐brain level, and not just within the visual processing pathways. It was proposed that their findings may reflect compensatory adaptations to increased chiasmic decussation, foveal hypoplasia and nystagmus.
References
Albinism. Justin R. Federico; Karthik Krishnamurthy. August 28, 2020.