Sickle cell disease

DEFINITION/OVERVIEW AND ETIOLOGY

Sickle cell disease was first described by James Herrick in 1910 when he found that one of his patients from the West Indies had an anemia with sickle-shaped red blood cells.69 Sickle cell has the distinction of being the first genetic disease to be molecularly characterized, after the discovery that it was caused by a point mutation in the beta globin gene that alters the protein structure so that low oxygen concentrations lead to sickling. It is also one of the first genetic disorders to be used as an example of a heterozygote advantage, as having one copy of the hemoglobin S gene along with one copy of the normal beta hemoglobin gene (sickle cell trait) confers relative resistance to infection by malaria.70 Sickle cell disease originally denoted homozygosity for hemoglobin S (HbSS), which accounts for the majority of sickle cell disease in the US. Subsequently, several other forms of sickle cell disease have been described, all of which involve inheritance of the Hb S gene with another abnormal copy of the beta globin gene.71 These other forms are known as sickle-hemoglobin C disease (HbSC), HbSb+- thalassemia, HbSbo-thalassemia, HbSDPunjab, and HbSO-Arab.

Clinically, the onset of symptoms is in childhood. Severe anemia, caused by sickling of the red blood cells with subsequent hemolysis, leads to shortness of breath, fatigue, and jaundice. Poor growth and development can also result from recurrent attacks. Pain crises result from oxygen deprivation to tissues and organs. These episodes occur when the stiff and sickled red blood cells cannot move easily through the capillaries. These episodes not only cause pain, but can also result in organ damage. The lungs, spleen, kidneys, and brain are particularly susceptible to damage. Pulmonary hypertension as a result of oxygen deprivation has been determined to be a cause of heart failure in about one-third of affected adults.72 This diagnosis is often suspected after the presentation of dactylitis. Pallor, jaundice, pneumococcal sepsis and/or meningitis, splenomegaly with severe anemia, and acute chest syndrome are also clinical conditions that

would lead toward suspecting this diagnosis. Since the sequelae of sickle cell disease can

be so dramatic and incapacitating, screening for this disease is usually performed at birth. Both newborn screening and confirmatory testing use isoelectric focusing or hemoglobin electrophoresis to demonstrate the presence of aberrant beta globin chains. This can also be done with high-performance liquid chromatography. Mutation analyses or complete gene sequencing (especially in cases with the b-thalassemia variants) can also be used to confirm the diagnosis.

Sickle cell anemia is inherited in an AR fashion. The disease can result from either homozygosity for hemoglobin S or from compound heterozygosity with the hemoglobin S gene and other abnormal beta hemoglobin genes. The most common forms are HbSS, HbSC, and sickle beta thalassemia (HbSb+-thalassemia, HbSbo-thalassemia).

Treatment for sickle cell disease is mostly supportive during acute crises and includes hydration, analgesics, oxygen, antibiotics, and transfusions.73 Immunization with the pneumococcal vaccine is very important since splenic sequestration often leads to autosplenectomy and increased susceptibility to infection with pyogenic bacteria. Treatment with hydroxyurea can improve survival and also result in fewer symptomatic pain crises and a decreased need for transfusions. Bone marrow transplantation, although not the standard of care, has been shown to be curative.74

CLINICAL PRESENTATION

Patients with homozygous sickle cell anemia (SS) generally exhibit more severe systemic complications of the disease than patients with SC or S-Thal disease. The converse is true for ocular manifestations. Ocular disease results from intravascular sickling and thrombosis with the retina being primarily affected. Retinal vascular changes can be divided into nonproliferative (non-PSR) and proliferative (PSR). Major vision loss is usually the result of vitreous hemorrhage or retinal detachment, both of which are consequences of PSR. Although uncommon, PSR does occur in adolescents and it should be considered in their medical care.75

Changes of non-PSR include venous tortuosity and salmon patch hemorrhage, an

intraretinal hematoma from sickled erythrocyte occlusion of arterioles and a subsequent blow-out of the vessel wall. It is found in the mid-periphery of the retina and undergoes a color change from bright red to orange, and then finally salmon. Black sunburst is a pigmented, chorioretinal scar in the peripheral retina; it is secondary to scarring from a previous hemorrhage. Finally, angioid streaks, pigmented striae representing breaks in Bruch’s membrane of the retina, are found in non-PSR.

PSR is secondary to repeated episodes of ischemia from peripheral arterial occlusions, which then give rise to neovascularization. Neovascularization commonly occurs in the peripheral retina, but can also be seen on the optic disc. The five stages of change are:

•Stage 1: a graying appearance to the retina (retinal ischemia), which is secondary to peripheral arterial occlusion.

•Stage 2: arteriolar– venular anastomsis.

•Stage 3: neovascular fronds grow on the retinal surface. They resemble a marine invertebrate, hence their name ‘sea fan neovascularization’.

•Stage 4: vitreous hemorrhage caused by neovascular traction on the retinal vessels.

•Stage 5: retinal detachment. This usually occurs as a result of traction from the neovascular tufts. Retinal ischemia can also cause retinal thinning, hole formation, and subsequent retinal detachment.

Other changes that occur are:

•Conjunctiva vessel tortuosity, which conveys a comma-shaped appearance to the capillaries.

•Iris atrophy.

•Branch and central retinal artery occlusion.

•Pseudotumor cerebri has been reported 76 and should be suspected in sickle cell patients who present with severe headaches that are unexplained by their disease.

MANAGEMENT/TREATMENT

Monitoring for changes with sickle cell disease should start by 10 years of age. A complete peripheral fundus examination is imperative. Fluorescein angiography may be necessary to delineate the early stages of the disease. Once PSR has been identified, laser photocoagulation helps stop the complications of vitreous hemorrhage and the subsequent retinal detachment. Laser photocoagulation does not, however, stop the progression of new PSR, so careful monitoring is imperative.

The presence of sickle cell hemoglobinopathies, including sickle cell trait, is a significant risk factor for complications associated with traumatic hyphema.77 Increased IOP occurs secondary to obstruction of the aqueous outflow by the sickled erythrocytes. If uncontrolled, it can lead to central retinal artery occlusion, and optic atrophy. Re-bleeds also occur more frequently. Surgical intervention or topical antifibrinolytic therapy with aminocaproic acid may be necessary.

Albinism

DEFINITION/OVERVIEW AND ETIOLOGY

There are several genetic conditions that result in the phenotype of oculocutaneous albinism (Table 16, see page 212). All of these conditions affect pigmentation of the hair, skin, and eyes (249). Genetically, there is variability in the amount of residual pigment formed by melanocytes, which can be used to distinguish the different syndromes;78 these result from mutations that affect the formation of the pigment. Hermansky–Pudlak syndrome79 and Chediak–Higashi syndrome80 result from defective intracellular organelle formation and lysosomal trafficking, respectively. These lead to abnormal pigment production. A number of different genes are involved and all conditions are inherited in an AR manner.

The management of these disorders revolves around sun avoidance, skin protection, and routine ophthalmologic care. Hermansky– Pudlak syndrome has an associated bleeding dyscrasia because of platelet dysfunction. Desmopressin has been used, as has vitamin E. Chediak–Higashi syndrome is generally fatal, and without bone marrow transplantation, death will usually occur before the age of 7 years. This is related to increased susceptibility to infection and malignant lymphoma. Although bone marrow transplantation improves survival by decreasing the frequency and severity of infection, it does not prevent progression of neurologic symptoms.81

CLINICAL PRESENTATION

Visual acuity and nystagmus vary according to the type of albinism. The spectrum ranges from poor vision (worse than 20/200) in the tyrosinase-negative albino to minimally impaired (20/40–20/60) in brown albinos. In the past, the degree of visual impairment was thought to correlate with the amount of pigment in the eye. However, recent studies have shown that diminished vision is more closely related to the severity of the foveal hypoplasia.82 Nystagmus is present within the first few months of age and its severity is also dependent upon the type of albinism, ranging from severe to observable only at the slit-lamp.It usually begins with a pendular form that changes to a jerk form as fixation improves.

Both foveal hypoplasia and nystagmus contribute to these children’s visual impairment.

Foveal hypoplasia is always present. Clinically, it is identified by the absence of the foveal pit, absence of the macula lutea pigment, absence of the normal hyperpigmentation of the foveal pigment epithelium, and failure of the retinal vasculature to wreath the fovea. Grading of the fovea with optical coherence tomography (OCT) has provided better predictive values for vision than iris transillumination and macular transparency.82 Multifocal ERG has shown results suggesting a homogeneous density of cone photoreceptors across the central retina consistent with anatomic studies showing arrest of postnatal macular development.83

Hypopigmentation of the fundus varies with the type of albinism and the race of the child (250). At the extreme end, complete choroidal vasculature is visible because of the absence of retinal pigment. Less affected patients will have minimal retinal pigment dilution.

Transillumination of the iris occurs in all forms of albinism, but varies in degree (251, 252). In tyrosinase-negative albinos, the iris transillumination can be visualized by applying a light source to the lower lid, which will produce the classic ‘pink eyed’ appearance. With lesser degrees of iris transillumination, examination at the slitlamp will be necessary. Iris transillumination is often the only identifiable feature that aids in the diagnosis of albinism in children with nystagmus and minimally decreased hair and skin pigment. The color of the iris varies from pale blue to brown. Photophobia is typically present and secondary to the iris hypopigmentation.

Visual pathway abnormalities are also known to occur. There is misrouting of temporal axons to the contralateral visual cortex, secondary to reduced melanin biosynthesis. The normal ratio of crossed to uncrossed fibers is 53:47.84 Patients with albinism have fibers of 20% or more originating from the temporal retinacrossing at the chiasm that project to the contralateral hemisphere. This hemispheric asymmetry becomes evident in monocular visually evoked cortical potentials (VECPs) and, if the typical clinical features are lacking, can help in the diagnosis of albinism.

Binocular vision is reduced. Guo et al. (1989) proposed that the abnormal decussation of the optic nerve fibers may be the cause of this reduction.84 Because albinos have reduced

Oculocutaneous albinism Type 4

Iris transillumination very variable Retinal pigment variable

Vision = normal to 20/400

At birth, hair color ranges from silvery white to light yellow

More common in Japanese population

Hypopigmentation of skin

stereopsis and binocular vision, which primarily provide a feedback signal that helps establish and maintain proper alignment, strabismus is common with an overall prevalence of 40%.

High refractive errors are common with myopia, hyperopia, and astigmatism being described.

Torticollis or anomalous head positions (AHPs) occurs. Children adopt these head positions to facilitate their null point (the position of gaze with the least nystagmus and best visual acuity). Children with albinism have relatively normal neurodevelopmental behavior and academic performance, regardless of the degree of visual impairment; however, they did have a higher prevalence of attention deficit hyperactivity disorder (ADHD) in one study.85

MANAGEMENT/TREATMENT

Typically, infants are directed to the ophthalmologist when nystagmus is noted and vision is not age appropriate. The diagnosis can be quite obvious if the child’s skin and hair are hypopigmented, while at other times iris transillumination needs to be confirmed at the slit-lamp. Occasionally, a VECP is necessary to establish the diagnosis. Genetic referral is appropriate for the benefit of the child and the parents. Spectacle correction of high refractive errors is also appropriate and has been proven to improve visual acuity as well as binocular alignment and torticollis.86 Separate sunglasses or photochromic lenses will help the photophobia.

Surgical correction of strabismus should be undertaken. Previous investigations have confirmed the efficacy of horizontal muscle recession, resections, or both (Anderson– Kestenbaum procedure), to treat the anomalous head positions produced by nystagmus.87 Four-muscle horizontal tenotomy has also been shown to improve

nystagmus waveforms and broaden the range of gaze angles, or null points.88,89 These studies

have led to more recent investigations which have shown the benefit of combining tenotomies with nystagmus or strabismus recession procedures.90 Although these studies have focused primarily on infantile nystagmus, the benefits can be extrapolated to albinos with nystagmus.

Finally, the role of the pediatrician and ophthalmologist in directing the parents to seek help in school is very important. Albinos typically have average intelligence; however, their ability to learn may be hampered by their visual disability. An individual education plan will identify each child’s needs and provide them with special services to help them succeed.