CHM was first described by Mauthner in 1872,1 who coined this name because he thought that the condition reflected the congenital absence of the choroid. Despite some earlier suggestions that CHM might be a progressive disorder,2,3 Bedell4 was the first to conclude, after thorough review of the literature and on the basis of own observations, that CHM may be defined “as a condition in which the choroid disappears … in a definite uniform manner.” Several authors provided further evidence for progression of this disease,5,6 which was widely accepted after the description of a large Canadian family by McCulloch and McCulloch.7 The concept of CHM as an X-linked disorder with full manifestation in males and minor clinical signs in female carriers was independently worked out by Waardenburg8 and Goedbloed9 on the basis of literature studies and their own observations. Apart from the studies of the McCullochs7,10 and a detailed survey of Sorsby et al.,11 several other large studies such as those of Kurstjens,12 Krill,13 and Kärnä14 have further contributed to the clinical definition of CHM.
Night blindness is usually the first clinical sign of the disorder, and most patients report to have been night-blind since their early childhood.4,14-16 Less frequently, night blindness remains unnoticed before patients are 20 years old.11,15,17,18 Occasionally, it may not be present before the midthirties10,12 or beyond.19
Usually, first signs of visual loss involve the midperiphery. Central vision frequently is preserved until the end stage of the disorder, and often there is also residual vision in the periphery. However, visual fields can vary considerably, even between the two eyes of one patient, and may appear as annular scotomas, tunnel vision, or visual fields of irregular shape. In his study of 45 patients, Kurstjens12 observed large blind spots and reduced equatorial sensitivity, equatorial scotomas, annular scotomas, and central and peripheral temporal remnants as the most frequent findings.
Moderate myopia is more common among patients with CHM than in the normal population. As shown by McCulloch and McCulloch,7 Kurstjens,12 and in particular by Kärnä14 in his large and detailed study, the myopia is progressive and correlated with the course of the disease. Repeatedly, disorders of color vision also have been observed.15,20,21 Jaeger and Grützner22 reported on disturbances in the blue-green range of the spectrum that were correlated with the severity of the disorder. In several patients, these changes resembled protanopia, whereas in others, deuteranopic changes were reported. Additional anomalies included punctiform and fibrillary opacities in the vitreous body.1,7,12 Infrequently, cataract also was present and was mostly of the subcapsular type.12,23,24
According to Krill,13 the fundus changes can be divided into three stages, the first of which consists of pigmentary stippling and fine atrophy of the retinal pigment epithelium (RPE) of the posterior and equatorial parts of the fundus. These findings resemble those seen in female carriers (see below). In the first stage, there is also focal atrophy of the choriocapillary layer and atrophy of the larger choroidal vessels around the optic disc and in the equatorial area. Choroidal vascular atrophy is preceded by depigmentation of the fundus, which reflects the degeneration of the RPE.
In the second stage, the atrophy of the choroid and RPE spreads from the midperiphery inward and from the disc outward. Usually, choroidal vessels of all sizes are involved, but in some cases, only the choroidal capillaries are damaged. The choroidal vessels of the macula are not affected, and pigmentary mottling is no longer seen except in the far periphery. In the third stage of the disorder, atrophy of the choroidal vessels is almost complete except in the far periphery, in the macula, and sometimes near the optic disc. The fundus is yellowish white or greenish white, and attenuation of the retinal vessels may occur at this stage (Fig. 236-1).
Fundus of a CHM patient with a deletion of exons 1 and 2 (patient 1167, see Fig. 236-3) at age 30. Note the severe atrophy of the choroid and RPE affecting the entire fundus except for the macular region and the area surrounding the optic disc. At this stage, retinal arteries are still spared. See Color Plate 19.
The rate and degree of the atrophy vary, even within families.25,26 For example, McCulloch and McCulloch7 described a completely white fundus in a 7-year-old patient, whereas, on the other hand, changes were very slight in a 45-year-old patient. Not infrequently, conspicuous first-stage changes were found in boys aged between 1 and 4 years.7,12,17,18
Abnormal light and dark adaptation are other early signs of the disorder.12,18,21,27,28 On dark adaptation testing, elevated rod final thresholds are observed, and usually, rod adaptation is disturbed earlier or more profoundly than cone adaptation. Changes generally are correlated with the degree of retinal degeneration.15,24,25
Electroretinographic signs involve both the scotopic and the photopic components. Usually, however, the degeneration follows a rod-cone pattern with reduced rod responses and normal or reduced cone responses.12,14,29,30 Scotopic responses even may disappear totally before the photopic responses become disturbed.12,20 At the terminal stage, the electroretinogram (ERG) is no longer recordable.14,25 In the great majority of patients examined, the electrooculogram (EOG) was abnormal,12,31,32 although a patient with an extinguished ERG but a normal EOG has been described.33 In contrast, Krill13 thought that abnormal ERGs are mostly preceded by changes in the EOG.
Early changes of the choroidal vessels, including capillaries, can be detected by fluorescein angiography. Depending on the severity of the disorder, choroidal capillaries can be absent over large areas,10,16,34,35 and these changes can precede ophthalmoscopic signs considerably.13 Usually, there is macular hyperfluorescence, which is due to degeneration of the RPE.31 In general, changes seen on fluorescein angiography are more extensive than expected from ophthalmoscopic findings.
So far histologic examination of the eyes of CHM patients has been confined to far advanced cases. Absence of the RPE, the choroid, and the photoreceptor outer segments was seen with varying degrees of preservation in the macular region. McCulloch36 reported on thickened and hyalinized choroidal vessels, but these findings were not confirmed by others. In a patient studied by Grützner and Vogel,37 proliferation of the RPE was seen, and a considerable part of the retina was substituted by glial tissue. Gliosis of the inner parts of the retina, doubling of the basal membrane of the RPE, and thickening of Bruch's membrane were observed by Ghosh and McCulloch.38
Clinical Findings in Female Carriers
Female carriers are mostly asymptomatic. Few have minor signs of the disorder, and serious vision impairment is rare.39-42 Berson et al. 43 found ERG abnormalities in 4 of 26 heterozygous females, but 25 of 26 had conspicuous fundus abnormalities such as pigment changes in the periphery closely resembling the fine mottling that is characteristic of initial stages of the disease in males. Histopathologic findings have been reported for 4 cases. The first case was unremarkable.13 In two other female carriers from the same family investigated by Ghosh et al. 44 and MacDonald et al.,45 the RPE was found to be irregular in thickness and pigmentation. Areas of marked atrophy involving both the RPE and photoreceptors were bordered by areas with normal photoreceptors. The choriocapillaris and Bruch's membrane appeared normal. Scanning microscopy of the retina of one carrier female revealed pleomorphic RPE cells and loss of polygonal structure and villi.45 No specific changes in the photoreceptors were found in the latter study. These findings indicate that in the RPE, disruption of the active fluid transport from the retina to the choroid and the delivery of nutrients to the retina may be important in the disease process.
As in males, fundus changes in carrier females are progressive, beginning in the midperiphery and leading to degeneration of the RPE and the choroid, often including the area surrounding the optic disc. Later on, there are numerous white dots scattered throughout the retina, and with increasing age, sclerosis of the choroid is seen. While in general the severity of fundus changes in female carriers is correlated with their age, fundus changes in young heterozygotes may be far more severe than in their carrier mothers.11,13 Variable cellular mosaicism resulting from random inactivation of one of the two X chromosomes in cells of the early female embryo46 may be a major cause of the varying clinical manifestation of CHM in female carriers, but it is of note that in males the clinical picture and the course of the disease are also very variable. Severe manifestation of the disease in females can result from skewed X-inactivation, homozygosity, or disruption of the CHM gene by X-autosome translocations. In females with reciprocal X-autosome translocations, X-chromosome inactivation is nonrandom; usually the normal X is preferentially inactivated, whereas both translocation fragments remain active. Therefore, in line with analogous observations in Duchenne muscular dystrophy, clinical signs of CHM in females with de novo X-autosomal translocations suggested that chromosome breakage had disrupted the only active copy of the CHM gene. This has been confirmed by subsequent molecular analyses.
Other Disorders Associated with CHM and Differential Diagnosis
Apart from a variety of ocular symptoms that are interpreted as direct or indirect manifestations of the fundamental defect, association of CHM with various other diseases has been reported. Sensorineural hearing loss was found in 10 of the patients studied by McCulloch and McCulloch7 and in 1 of Scobee's patients.6 One of the patients of Dachevzkaya and Polonsky47 was mute, and Murdoch16 described a patient with congenital hearing loss. CHM also has been described in combination with dwarfism,48 but the absence of night blindness in this patient and of fundus changes in the mother render the diagnosis of CHM in this case rather unlikely. CHM-like symptoms also have been observed in a family with a complex, apparently X-linked disorder including anhidrotic ectodermal dysplasia, skeletal abnormalities, and mental retardation49 and in patients with chorioretinopathy and pituitary dysfunction.50,51 CHM also was diagnosed in a 33-year-old man with leukoencephalopathy and arylsulfatase A pseudodeficiency,52 as well as in two brothers with hereditary motor neuropathy.53 In another CHM case, the patient also suffered from a pinealoma.54 The molecular relationship, if any, between these disorders and CHM has not yet been clarified, but in the family described by Van den Bosch,49 both a deletion and an inversion disrupting the CHM and anhidrotic ectodermal dysplasia genes have been excluded (H van Bokhoven, JAJM van den Hurk, HH Ropers, FPM Cremers, unpublished observation, 1998). In contrast, deletions on the proximal long arm of the X chromosome have been identified as the primary defect in a variety of patients with CHM, mental retardation, deafness, and other features. As discussed below, molecular characterization of these deletions and the above-mentioned X-autosome translocations in female patients has been instrumental for fine mapping of the CHM gene and, eventually, its isolation by positional cloning.
The differential diagnosis of CHM includes gyrate atrophy (MIM 258870; see Chap. 83), which clinically may be almost identical with CHM. Apart from characteristic circular lesions seen in the fundus of most patients with gyrate atrophy, distinguishing features are the mode of inheritance, which for gyrate atrophy is autosomal recessive, and the elevated plasma ornithine level in these patients, which is due to a defect in the enzyme ornithine aminotransferase.55,56 In early stages of the disease, CHM is sometimes indistinguishable from X-chromosomal recessive retinitis pigmentosa (RP) (MIM 602772), but in these patients, follow-up studies and examination of affected relatives will establish the diagnosis.57 Nevertheless, in a large American family with Italian ancestry, the male proband was diagnosed by an experienced retina specialist at the ages of 3 and 15 years as having X-linked RP. Obligate carriers, however, demonstrated radially oriented clumping of the RPE, which is characteristic of CHM. Haplotype analysis of X-chromosomal markers excluded linkage of the gene defect with markers from the XRP2 and XRP3 regions on the short arm of the X chromosome and showed cosegregation with markers pJ59 and DXS1002 situated close to the CHM gene at Xq21.58 An A→T transversion in exon 14 of the CHM gene was found that leads to a C-terminal 99-amino-acid truncation of the predicted CHM protein. This result shows that CHM mutations could be involved in other so-called XRP families. Not infrequently, autosomal dominant RP (see Chap. 235) is diagnosed in female CHM carriers because of similar funduscopic findings. In contrast to the situation in autosomal dominant RP, in which funduscopic changes are accompanied by alterations of the ERG and narrowed visual fields, ERG and visual fields are normal in most CHM carriers.14,57 Other similar diseases include Bietti crystalline retinal dystrophy59 (MIM 210370) and acquired retina damage due to thioridazine toxicity.60 Ocular symptoms similar to CHM also have been seen in patients with mitochondrial myopathies.57,61