Diamond-Blackfan syndrome (congenital hypoplastic anemia) is a rare disorder of pure red cell aplasia. Affected patients do not make red blood cells but continue to have normal or near-normal white cell and platelet counts. The diagnosis is confirmed by an almost complete absence of erythroblasts in the bone marrow. The onset of anemia usually is within the 1st year of life. Treatment with chronic systemic corticosteroid therapy is successful in 75% of affected patients. Some patients, however, are corticosteroid resistant and require repeated transfusions with washed packed red blood cells throughout life, often causing hemosiderosis.1-3
In 10% of cases, there is more than one affected family member, and the occasional reports of consanguinity suggest an autosomal recessive inheritance pattern.4
Associated congenital anomalies with DiamondBlackfan syndrome have been reported in approximately 30% of patients.4 Such anomalies include bilateral double ureters and hydronephrosis, congenital heart defects, extra phalanx, thumb deformities, cleft lip and palate, extra ribs, achondroplasia, abnormal bone development, inverted nipples, and webbed neck.4"5 Short stature is consistently reported, and may be exacerbated by the retarding affects of chronic anemia and/or steroid therapy.2 Ophthalmic anomalies have been infrequently reported but include strabismus, hypertelorism, microphthalmus, and blue sclerae.4'6 Glaucoma and cataracts have been mentioned in the problem lists of four case reports but were not elaborated upon.4,7
We present two cases of infantile glaucoma in patients with the Diamond-Blackfan syndrome. The etiology of the glaucoma was established by gonioscopy revealing trabeculodysgenesis in both cases. To our knowledge, this is the first report describing an association between these two disorders.
Case 1. A 7½-year-old white boy, had been the 3100-gram product of a full-term uncomplicated pregnancy. At birth, the patient was noted to be hydropic with congestive heart failure. He had an initial hemoglobin of 4.0 g/dl. He received a partial exchange transfusion and was begun on prednisone, 2 mg/kg/day. A bone marrow aspirate at 1 month of age revealed a greatly diminished erythroid series with a normal myeloid sériée consistent with the diagnosis of congenital hypoplastic anemia. Despite the corticosteroid therapy, he maintained a suboptimal hemoglobin level and received another blood transfusion 1 month later. A repeated bone marrow aspirate at 2V2 months of age revealed a marked reduction in red blood cell precursors, indicating unresponsiveness to steroids. The patient began a long-term transfusion regimen of frozen red blood cells every 3 to 4 weeks to maintain a minimum hemoglobin level of 10 g/dl. This schedule has continued to the present day. The corticosteroid therapy was discontinued after the second bone marrow aspirate. The patient now undergoes iron chelation therapy with daily infusions of deferoxamine to prevent transfusional hemochromatosis.
FIGURE 1: Patient 1: OD corneal diameter enlargement and edema.
FIGURE 2: Patient 1: OS corneal diameter enlargement and edema.
Except for short stature (10th percentile for height and weight), the patients present systemic findings were within normal limits with no associated congenital anomalies. The patient was developmentally and mentally normal.
The patient first presented to us at 7 months of age for evaluation of bilateral excessive lacrimation and photophobia of 2 months' duration. He had obtained a previous evaluation by an outside ophthalmologist 1½ months before presentation and was treated for presumed bilateral nasal lacrimal duct obstruction. On our initial evaluation, the patient had bilateral hyperemic conjunctiva, enlarged corneal diameters with hazy edema (Figs 1-2), deep anterior chambers, and increased cupping of the optic nerve heads. The patient underwent bilateral trabeculotomies the following day. At the time of surgery, he was noted to have intraocular pressures (IOPs) of 30 mm Hg by pneumotonometry and corneal horizontal diameters of 13 mm bilaterally. Gonioscopy was difficult because of the hazy view but revealed flat, anterior iris insertions into the trabecular meshwork with small iris processes on the trabecular surface bilaterally. Horizontal cup/disc ratios were 0.80 OD and 0.95 OS. Bilateral trabeculotomies were repeated 3 months later because of elevated IOPs and an increase in his corneal diameters to 13.5 mm bilaterally.
Since the second surgical procedure, successive examinations under anesthesia (EUA) have revealed IOPs remaining less than 20 mm Hg bilaterally. His most recent examination at 7% years of age revealed a corrected visual acuity of 6/6 - OD and 6/12 + OS for distance, IOPs of 10 mm Hg bilaterally by pneumotonometry, and cup/disc ratios of 0.50 OD and 0.60 OS. Cycloplegic refraction was -2.00 +2.50 X 90 OD and -5.00 +3.00 X 45 OS.
Case 2. An 8-year-old white girl, had been the 2800-gram product of a 40-week gestation uncomplicated pregnancy. The patient was noted to be anemic and received a blood transfusion in the newborn period. At 1 month of age, the patient was hospitalized because of severe anemia. Bone marrow examination showed an absence of red blood cell precursors with an otherwise normal marrow, consistent with the diagnosis of Diamond-Blackfan syndrome. She received a transfusion of red blood cells at that time, and was given corticosteroid therapy, initially with dexamethasone and later with prednisone. She had an almost immediate response to steroid therapy, with an elevation of reticulocyte count and a rise in hemoglobin level. From that time on, the patient has been maintained on a conservative dosage of prednisone, presently 0.25 mg/day.
At the physical examination, the patient was noted to have "coarse facies" since birth, and weight and height parameters below the third percentile. The patient has not exhibited developmental delay.
The patient was first evaluated by a glaucoma specialist at 11 months of age for photophobia, excessive tearing, and enlarged corneal diameters with mild haze. She underwent an EUA at 11% months of age. It was noted that she had IOPs of 39 mm Hg OD and 47 mm Hg OS, horizontal corneal diameters of 14.5 mm OD and 15.0 mm OS, deep anterior chambers, and increased cup/disc ratios of 0.9 bilaterally. Ultrasonographic axial lengths of the two eyes were 24.9 mm OD and 24.6 OS. The bilateral gonioscopic appearance of the anterior chamber angles was noted to be abnormal, with an anomalous insertion of the iris to the trabecular meshwork with iris processes. The patient underwent bilateral trabeculotomies without complication. A repeat EUA at 13 months of age revealed persistently elevated IOPs and, therefore, bilateral thermal sclerostomies were performed. An EUA at I1A years of age revealed increased corneal haziness OD. IOPs were 32 mm Hg OD and 20 mm Hg OS. Axial length measurements were 26.0 mm OD and 24.8 mm OS. The OD optic nerve was completely cupped, whereas there was a thin rim of nerve left OS. Revision of the conjunctival bleb OD was performed as the sclerostomy site was discovered to be patent on exploration.
The patient developed subluxated lenses bilaterally over the next 3 months, the right eye greater than the left. Repeated cyclocryotherapy treatments were performed bilaterally in an effort to control her elevated IOPs during the next 2 years. She was also started on a regimen of two topical glaucoma medications, timolol and dipivefrin, during this period, which appeared to better control her IOP in the left eye than in the right. She developed a dense cataract of the right eye by age 7 years. Her most recent axial length measurements were 27.5 mm OD and 26.7 mm OS, and she had a refractive error of - 8.00 diopters OS. A combined trabeculectomy and cataract extraction was proposed to the parents. They continue to contemplate further ocular surgery.
We describe two young patients with the diagnosis of Diamond-Blackfan syndrome and primary developmental glaucoma. Neither patient had a family history of hématologie or ophthalmologic disease. Patient 1 was diagnosed as having Diamond-Blackfan syndrome as a newborn, and he was maintained on chronic transfusion therapy when he was found to be unresponsive to steroid therapy. He received steroid therapy for only the first 2% months of his life. Patient 2 was identified as having Diamond-Blackfan syndrome as a newborn, and she has been maintained on very low doses of corticosteroide. Both patients required multiple surgical procedures to control their glaucoma, with patient 1 responding more successfully than patient 2. Both patients presented for an ophthalmologic evaluation with symptomatic and significant buphthalmos, representing advanced disease. Patient 2 developed subluxated lenses bilaterally which could be due to increased equatorial diameter of her eyes with subsequent zonular tension and breakage, and/or previous intraocular surgery. The cataract that developed in patient 2 could have developed because of the steroid treatment she received and/or from intraocular surgery. Except for the short stature, both patients had no other recognized associated congenital anomalies of Diamond-Blackfan syndrome.
Because these patients were treated with corticosteroids, the possibility of corticosteroid-induced glaucoma is raised. In steroid-induced glaucoma, an excessive deposit of acid mucopolysaccharide, or glycosaminoglycan, is present in the trabeculum.8 It is generally believed that this causes a reduced facility of outflow.9 Systemic corticosteroids have been observed to cause a rapid increase of IOP which falls quickly upon elimination of the steroid.10'11 Although patient 2 is still on steroids, patient 1 only received systemic steroid therapy for the first 2% months of his Ufe and first presented with symptoms of glaucoma 3 months later, which makes it unlikely that there was a persistent steroid affect to produce and sustain his elevated IOPs.
Additionally, it has been shown that degenerative changes in the trabecular meshwork occur in the normal eye with aging.12·13 These changes may account for the decreased ability of the older eye to remove deposited mucopolysaccharide.14 It is generally believed that the younger eye, and especially the infant or juvenile eye, has a higher outflow facility reserve and thus would not develop steroid-induced glaucoma.14 There has been one case report of ACTH-induced glaucoma simulating primary congenital glaucoma in an infant with hypoglycemia.15 However, the patient underwent glaucoma surgery while receiving a tapering steroid dosage, allowing no means to distinguish between possible etiologies of the glaucoma when postoperative evaluations revealed normal IOPs. There also was no description provided of the patient's anterior chamber angle. Concurrent steroid therapy and refractory glaucoma were present in patient 2 as well, but gonioscopic evaluation confirmed the diagnosis of a developmental glaucoma.
That both patients had developmental glaucoma as opposed to secondary corticosteroid-induced glaucoma is supported by the initial EUA findings. Both patients had characteristically deep angles and isolated trabeculodysgenesis with a flat iris insertion just anterior to the scierai spur or at the trabecular meshwork, whereas in the normal infant eye the iris inserts flatly into the angle wall posterior to the scierai spur.16 In the mature angle recess, the surface of the iris turns slightly posteriorly before inserting into the ciliary body.17 This configuration usually develops during the first 6 months of life.17 Both of our patients were older than 6 months when they underwent an initial gonioscopic examination and should, therefore, theoretically have had an adult angle.
In conclusion, we report an association between infantile (primary developmental) glaucoma and DiamondBlackfan syndrome. Corticosteroide are often used to treat this hématologie disease, and this therapy may have exacerbated but did not cause the glaucoma seen in these patients. Both patients had relatively advanced glaucomatous ocular damage at initial presentation to an ophthalmologist. Recognition of the association between the two congenital disorders is important for early diagnosis and treatment of the glaucoma.
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