414 Chapter 22 Congenital Glaucoma Associated with Ocular and Somatic Malformations
Fig. 22.12 HRT LE megalopapilla visual field octopus normal
Phakomatosis 415
Fig. 22.13 a Trabeculectomy piece (H-E, ×100). The trabecular meshwork can be seen, modified by the presence of pseudodiverticular structures that merge and distort the trabeculae. b Trabeculectomy piece (H-E, × 100). In another histological section, the diverticular formations looking like cirsoid vascular structures. c Trabeculectomy piece (H-E, ×1000). One of the pseudodiverticula, coated with an endothelium in its space and with a collagen-type wall
-Macroscopy:
-– Whitish fragment, 3×2×1 mm. Histopathological diagnosis;
–Trabeculectomy, biopsy;
–Ideal surgical limits;
–Mesodermal remnants (diffuse and ligamentous);
–Embryotoxon;
-– Vascular anomaly;
Technique: material included in paraffin prior to MOS observation. Semiserial sections. Stain with H-E, Masson’s trichrome, PAS, reticule, and PAP.
-Microscopy: partial sinusectomy piece of ideal surgical limits including corneoscleral flap, Descemet membrane, Schwalbe line, trabecular meshwork, and Schlemm canal. Abundant (uveal) trabecular meshwork, with presence of melanic pigment in relation to ligamentous structures, where hyaline thickening can be seen in leaves (embryotoxon). Segmented Schlemm canal and numerous vasculartype structures in juxtacanalicular meshwork and scleral furrow. Actually, is a vascular goniodisgenesis.
416 Chapter 22 Congenital Glaucoma Associated with Ocular and Somatic Malformations
Fig. 22.14 Klippel-Trenaunay syndrome in one of the twins
Von Hippel-Lindau’s Retinocerebellar
Hemangioblastomatosis
Glaucoma has been described in some cases of this disease, but as a glaucoma secondary to severe hemorrhagic or exudative-type retinal lesions together with uveitis and cataract.
Summary
Glaucoma may present in the neurofibromatoses when the chamber angle is blocked by the neurofibromatous tissue that may also be found in the ciliary body or when a secondary rubeosis in the chamber angle blocks the outlet pathways.
In Sturge-Weber-Krabbe syndrome, glaucoma may be due to alterations in the chamber angle, just as in congenital glaucoma. At other times, the chamber angle is seen without alterations or with vascular alterations. In the latter case, it is suspected that the interscleral outlet pathways are affected.
Nevus of Ota
Oculodermal melanocytosis was described by Ota in 1939 [23] as an ocular melanocytosis associated with increased pigmentation of the skin in the distribution of the ophthalmic, maxillary, and the mandibular divisions of the fifth cranial nerve. Histologically, the ocular component (melanosis oculi) is increased pigmentation of the uveal tract, sclera, and episclera. The skin component does not consist of true nevus cells; it is composed of dendritic or fusiform cells containing granules of melanin found deep in the dermis. Its incidence is 0.1%–0.5% (Fig. 22.15, Fig. 22.16).
It is generally accepted that ocular melanocytosis is associated with increased uveal melanoma. This asso-
ciation has also been reported with oculodermal melanocytosis and melanomas of the skin, nervous system, and orbit.
Nevus of Ito is histologically similar to nevus of Ota, but involves the area of innervation of the lateral supraclavicular and lateral brachial nerves in the shoulder.
Nevi of Ota may be classified into various types based on extent, ranging from mild ocular involvement only to ocular, periocular, zygomatic, cheek and temple involvement, which can be unilateral or bilateral.
The lesions present as nonpalpable cutaneous pigmentations (black, purple, blue, and brown). The intensity of the pigmentation may appear to vary from day to day.
The first reported case of nevus of Ota associated with choroid melanoma was in 1981 by Hulke [24]. The incidence of nevus of Ota in the white population in general is 0.04% and uveal melanoma has been detected in 1.4% of patients with nevus of Ota in the same population [25, 26]. Using Bayes’ theorem, Singh et al. [27] estimated the risk of developing a melanoma among the white population with ocular and/or oculodermal melanosis as 1 in 400 vs 1 in 13,000 in the general population, and in 90% of cases the uveal melanoma is diagnosed between 31 and 80 years of age.
The glaucoma present in nevus of Ota may be related to the hyperpigmentation of the whole anterior segment, including the trabecular meshwork and the outflow of aqueous humor, including the ciliary pathway. The constant movement of melanic pigment here is also interesting, since this could determine the blockage of the endothelial cells of the trabecular meshwork, following the idea we described about its belonging to Aschoff and Kiyono’s reticuloendothelial system or the Davenport mononuclear phagocytic system. It could thus be recognized as similar to pigmentary glaucomas, from functional saturation of the cells responsible for filtering the aqueous humor.
418 Chapter 22 Congenital Glaucoma Associated with Ocular and Somatic Malformations
Fig. 22.16 Enucleation piece (H-E, ×40). Chamber angle, part of sclera, iris and ciliary body. The marked melanocytosis of the ciliary body and iris can be recognized. The trabecular meshwork and the Schlemm canal show melanic pigment overload
References
1.Van der Hoeve J (1933) Le phakomatoses de Bourneville, de Recklinghausen et de von Hippel Lindau. J Belge Neurol Psychiat 33:752–762
2.Willis RA (1958) The borderline of embryology and pathology. Butterworth, London
3.Recklinghausen FD (1882) Über die multiplen Fibrome der Haut und ihre Beziehungen zu den Neuromen. Festschrift f. R. Virchour. Hirschwald, Berlin
15.Sturge WA (1879) A case of partial epilepsy apparently due to a lesion of one of the vasomotor centres of the brain. Clin Soc Transoct 12:162
16.Weber PP (1922) Right sided hemi-hypotrophy resulting from right-sided congenital spastichemiplegia with a morbid condition of the left side brain, revealed by radiograms. J Neurol 3:134–139
17.Krabbe KH (1934) Facial and meningeal angiomatosis associated with calcifications of the brain cortex, a clinical and an anatomopathologic contribution. Arch Neurol Psychiat Chicago 32:737–755
4.Del Rio Ortega P (1928) del: Tercera participacion al cono18. Bergstrand H, Olivechona H, Tonnis H (1936) Gefäßmiss-
cimiento morfologico y su interpretación funcional de la oligodengroglia. Mem Soc Españ Hist Anat 14:5–121
bildungen und Gefäßgeschwülste des Gehirns. Thieme, Leipzig
5.Schiess-Gemuseus H (1884) Vier FäIle angeborener Ano19. van der Hoeve J (1937) Phakomatoses. Ned T Geneesk 82:
malie des Auges. Grafes Arch Ophthalmol 30:191
6.Lieb WA, Wirth WA (1959) Geeraets. Hydrophtalmus and neurofibromas. Confin Neurol 3:230–247
7.Francois J, Katz C (1961) Association homolatérale d‘hydroptalmie, de la névrome plexiforme de la paupière supérieure et d‘hémihypertrophie faciale dans la maladie de Recklinghausen. Ophthalmologia 142:549–571
8.Maggi C (1962) Neurinoma palpebrale plessiforme e buftalmo. Boll Ocul 41:398–414
4418–4425
20.Stokes JJ (1957) The ocular manifestations of the SturgeWeber Syndrome. South Med J 40:82–80
21.Tosti E (1959) Considerazioni su 4 casi da angiomatosi neuro oculo cutanea. Soc Mal Logic A Tauana 17:
22.Manzitti E, Cocucci D, Mayorga EC, Carrion R (1972) El síndrome de Klipper-Tranaunay y su vinculación con la angiomatosis encefalo-trigeminada de Sturge-Weber. Pren Med Arg 59:340
9.Toselli CE, Volpi D (1963) Gigantismi parziali e facoma23. Ota M (1939) Nevus fusco-coeruleus ophthalmo-maxilaris.
tosi; l’ipertrofia emifacciale neurofibromatosa con buftalmo omolaterale. Ann Oual 89:791–799
10.Waiter JR, Butler RG (1963) Pigment spots of the iris and ectropion uveae with glaucoma. In: Neurofribromatosis. Am J Ophthalmol 56:964–973
11.Chandler PA, Grant WN (1965) Lectures on glaucoma. Lea and Febiger, Philadelphia, pp 354–356
12.Grant WN, Walton ES (1968) Distinctive gonioscopic findings in glaucoma due to neurofibromatosis. Arch Ophthalmol Chicago 79:127–134.
13.Calixto NE, Carvalho CA (1969) Semiologia do glaucoma congenito. XV Congr Brasil Tal Porto Alegre, pp 105–174
14.Schirmer R (1860) Ein Fall von Te1eangiektasie. Arch Ophthalmol 7:119
Tokyo Med J 63:1243
24.Hulke JW (1861) A series of cases of carcinoma of the eyeball. R Lond Ophthal Hosp Rep 3:279–286
25.Gonder JR, Ezell PC, Shields JA, Augsburger JJ (1982) Ocular melanocytosis. A study to determine the prevalence rate of ocular melanocytosis. Ophthalmology 89:950–952
26.Gonder JR, Shields JA, Albert DM et al (1982) Uveal malignant melanoma associated with ocular and oculodermal melanocytosis. Ophthalmology 89:953–969
27.Singh AD, De Potter P, Bonnie AF et al (1998) Lifetime prevalence of uveal melanoma in white patients with oculo (dermal) melanocytosis. Ophthalmology 105:195–198
This is a syndrome which in 50% of cases is accompanied by glaucoma. It was described for the first time in 1952 by Löwe et al. [1]. It is defined as congenital insufficiency of the renal tubules, with mental retardation,
-nanism, congenital cataract, and glaucoma. Pathological anatomy. Primary congenital nephrop-
- athy with secondary rachitism.
General manifestations. This disease manifests from birth through digestive symptoms: anorexia, vomiting, constipation, and repeated intestinal infections. The children are pale, blond, hypotrophic, and hypotonic. As well as rachitism, the ocular signs are very noticeable: the eyes are sunk in the orbits, bilateral cataract is nearly always present, and it is accompanied by glaucoma in 55% of cases. The rachitism is resistant to the administration of vitamin D
- and there is renal nanism with osteomalacia.
Renal manifestations. Renal anomalies are characterized by deficient ammonia production and hyperaminoaciduria, as a consequence of a reduction in absorption at the renal tubules. There is also a drop in the reabsorption of phosphorus and a loss
Contents
Hyperaminoaciduria: Löwe’s Oculocerebrorenal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Homocystinuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hurler Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Endogenous Ochronosis (Alkaptonuria). Glaucoma Secondary to Luxation of the Lens . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hyperaminoaciduria: Löwe’s
Oculocerebrorenal Syndrome
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Congenital |
23 |
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Glaucoma Associated |
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with Congenital Errors |
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of the Metabolism |
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of calcium by urine that gives rise to secondary hy- |
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perparathyroidism, osteomalacia, etc. This loss of |
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organic acids opens the way to a reduction of the |
421 |
alkaline reserve. |
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Laboratory tests. There is hyperaminoaciduria with |
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- normal amino acid values in the plasma. Sometimes |
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there is also glycosuria. These signs appear after 3 or |
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4 months of age. |
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Ocular manifestations. These basically consist of |
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- a congenital cataract accompanied by congenital |
430glaucoma in 55% of cases. The cataract is generally bilateral. The pupil dilates badly from hypertrophy of the iris, the response to mydriatics is poor, and at times there is nystagmus. The lens may be small (microphakia). Glaucoma generally accompanies the cataract and needs treatment. The chamber angle may appear in the various forms in which it is
-seen in congenital glaucoma.
Heredity. This is recessive and sex-linked [2, 3], making it an exclusively male disease. The mothers, who are the carriers, sometimes present a punctate cataract. The disease gives the impression that the gene causing the metabolism error has a polyphenic effect that opens the way to the malformation of the chamber angle and of the crystalline lens.
Clinical Case No. 1
A 10-month-old male was brought to the hospital with gastroenteritis. As well as all the general symptoms and the positive laboratory results, he was found to have bilateral cataract and glaucoma. The cataract was extracted in both eyes and the IOP regulated itself spontaneously, remaining the same for 4 years after the operation, when the last check-up was done. A complete description of the clinical picture can be consulted in Elizalde et al. [4]. Figures 23.1, 23.2, and 23.3 illustrate this case.
422 Chapter 23 Congenital Glaucoma Associated with Congenital Errors of the Metabolism
Fig. 23.1 Hyperaminoaciduria, Löwe’s oculocerebro- |
Fig. 23.2 A 10-month-old child with cataract and glaucoma |
renal syndrome |
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Fig. 23.3 X-ray of the bones of the wrist joint. The epiphysis of the radius and the cubit look like a champagne glass, characteristic of rachitism
Hyperaminoaciduria: Löwe’s Oculocerebrorenal Syndrome |
423 |
Differential Diagnosis
Differential diagnosis should be made especially first with Abderhalden-Fanconi syndrome (cystinosis) [5]. This is an error in amino acid metabolism, which may or may not be accompanied by cystine deposits, aminoaciduria, rachitism resistant to vitamin D administration, and generalized and ocular cystinosis.
Ocular cystinosis can be seen by the deposit of birefringent crystals in the cornea, conjunctiva, uvea, sclera, and episclera. Generally, the cornea is cloudy because of the presence of cystine crystals. In one case that was kindly passed to us by Dr. Manzitti for chamber angle puncture, I was able to show the presence of cystine crystals in the aqueous humor. The aqueous humor showed the pentagonal crystals typical of cystine (Fig. 23.4). We made a solution of cystine in alcohol to test their identity, as well as a chromatography.
This is a primary enzyme defect that is inherited recessively. Differential diagnosis should then be made with De Toni syndrome [6]. This is an idiopathic renal acidosis with nephrocalcinosis, late rachitism, and adiposogenital dystrophy. It manifests in aminoaciduria, glycosuria and albuminuria, nephritis, and renal nanism.
The fact that the first of these syndromes contains cystine in the aqueous humor and that in Löwe’s syndrome the aqueous is normal is an additional factor to think about in the polyphenic action of the gene that produces the error in the metabolism in Löwe’s syndrome.
Therapy
If the cataract is bilateral it should be operated. The glaucoma will always be treated surgically if the ocular pressure values are high. In this case, the glaucoma will be operated first. Otherwise the cataract will be operated first.
If glaucoma surgery has to be performed, goniotomy or trabeculotomy will be chosen. Whenever a very young child is found with glaucoma and cataract, the ophthalmologist should think first about Löwe’s syndrome, secondly about an embryopathy (generally rubeola-related), and thirdly glaucoma secondary to an operated congenital cataract. In the first situation, it is hereditary congenital glaucoma, in the second nonhereditary congenital glaucoma, and in the third secondary infantile glaucoma.
Fig. 23.4a–c Typical pentagonal-shape cystine crystals, obtained by crystallizing the aqueous humor, drawn by chamber puncture of a patient with cystinosis. c Cystine crystal obtained from the crystallization of a cystine solution in alcohol
424 Chapter 23 Congenital Glaucoma Associated with Congenital Errors of the Metabolism
Homocystinuria
Homocystinuria is a congenital error of the metabolism for a defect of the cystathionine-synthetase, transmitted by recessive autosomic heredity and shown from infancy fundamentally by luxation of the crystalline lens, reddening of the cheeks, and alterations in the hair and long limbs. A rather deeper analysis enables the mani-
-festations of this disease to be divided as follows: General manifestations. These include neurological disorders such as mental retardation; skeletal alterations such as long limbs (dolichostenomelia) and arachnodactyly; cardiovascular alterations such as dilatation of the arteries and medium-caliber veins; potentially lethal thromboembolisms, which can also occur in small blood vessels from trauma; increased homocystine in urine and blood and reduced cystathionine-synthetase in the liver (puncture biopsy); fine, pale, dry, very altered hair; and
-reddening of the cheeks.
Ocular manifestations. Luxation of the lens, in general, spherophakic and microphakic, that enables secondary glaucoma, atrophic, fine and translucent iris, colobomas, cystoid degeneration of the retina, retinal detachment, optic atrophy, and strabismus.
After studying this clinical picture, it is clear that it is important to make a differential diagnosis with Marfan’s syndrome. This requires remembering that in homocystinuria heredity is autosomic and recessive and there are mental disorders. In the discussion on alcaptonuria, we presented a picture of differential diagnosis that also contains Marfan’s syndrome and homocystinuria. For this reason, laboratory diagnosis is also important. Bickel and Cleve’s [7] troprussiate test is used. Since homocystine is found only in small quantities in urine, it is detected by placing 3–5 ml of the patient’s urine at room temperature with three to four drops of a fresh solution of 5% sodium nitroprussiate; 2 ml of sodium or potassium cyanide are added at 10%. A positive reaction gives a dark red color. Electrophoresis is also used for the diagnosis.
Medical treatment is currently made with pyridoxine. All the manifestations of the disease improve. When this treatment is used, there is a remarkable difference in the hair before and after, a clear dividing line.
Hurler Syndrome
Hurler syndrome is also known as Pfaundler–Hurler disease, dating from 1920 [8]. This is a metabolism disorder of the mucopolysaccharides, transmitted by recessive inheritance. It is a hyaluronidase deficiency
set off by the accumulation of dermatan sulphate and heparan sulphate, which, as Spellacy et al. [9] show, are deposited in the trabecular meshwork. Its pathogenesis is through deposits of dermatan and heparan sulphate on the trabecular meshwork. The disease manifests itself in the 2nd year of life with lumbar kyphosis and by
-the grotesque appearance of the face and extremities. General manifestations. The clinical signs are disproportionate nanism, alterations in bones and joints, and short stature with a large head. The face has thick lips, a flat nose, broad nostrils, a large tongue, and small teeth. This gives a grotesque appearance, known as gargoylism, from the gargoyles of Gothic cathedrals. There is also hepatosplenomegaly, with voluminous abdomen and inguinal or
-umbilical hernia.
Ocular manifestations. These are mainly at the level of the cornea where superficial and deep whitishgray cloudiness appear. The epithelium and endothelium remain intact. Ellis et al. [10] also describe chorioretinal degeneration, similar to the pigmentary degenerations, atrophy of the optic nerve, and megalocornea. The gargoylism is at times accompanied by moderate glaucoma and at others by buphthalmos. They generally do not survive beyond puberty.
Summary
Löwe’s oculocerebrorenal syndrome, homocystinuria, and Hurler syndrome may be accompanied by glaucoma. In the first case, this is congenital glaucoma, in the second secondary glaucoma, and in the third the cause is unknown.
Endogenous Ochronosis (Alkaptonuria). Glaucoma Secondary to Luxation of the Lens
Among the metabolic diseases affecting the ocular system is alkaptonuria, or ochronosis. The first person to call it ochronosis and to study its pathological anatomy was Virchow, in 1866, and then, in 1904, Osler completed the study and description of the clinical picture.
It is thought that this disease occurs because there is a congenital incapacity to metabolize phenylalanine and tyrosine beyond the homogentisic acid state. This oxidizes, probably from tyrosinase, and becomes melanin or a similar substance that is partly eliminated in urine, with the rest deposited in various tissues, mainly in cartilages, and then in ligaments, tendons, conjunctiva, and sclera.
One of the characteristics of this disorder is that alkapton or homogentisic acid (2-5 dihydroxypheny-
