Phenotypic Variation in Ophthalmic Manifestations of MIDAS Syndrome(Microphthalmia, Dermal Aplasia, and Sclerocornea)

The term MIDAS syndrome was coined by Happleet al¹ in 1993 to describe the predominantfeatures of a genetic disorder with microphthalmia, dermal aplasia, and sclerocornea. This syndrome has also been called the "MLS syndrome,"which stands for "microphthalmia with linear skin defects." The dermal aplasiain MIDAS syndrome consists of linear erythematous skin defects that typicallyinvolve the face, scalp, neck, and upper part of the thorax. In addition tothe ocular and skin findings, there are multiple nonocular abnormalities commonlyreported to be associated with MIDAS syndrome. Some of these include congenitalheart defects, short stature, hypospadias, developmental delay, absence ofthe corpus callosum, nail dystrophy, and hydrocephalus.

The underlying defect in MIDAS syndrome is due to a deletion at Xp22.3.The disease is believed to be transmitted as an X-linked dominant trait thatis lethal in the male hemizygous state. This theory has been supported bythe fact that there have been no reported cases of XY males with this syndrome.The few reported cases of males with MIDAS syndrome have 46,XX karyotypeswith a deletion of the Xp22.3 region due to an X/Y translocation. Althoughthese patients are genotypically female, they are phenotypically male.

Recently we examined twin boys and 2 single-birth girls with geneticallyproven deletion of chromosome Xp22.3. Examination with the patient under anesthesia,including biometry and ultrasonography, was performed to detail the ocularfindings associated with this syndrome. Other nonocular abnormalities werealso noted.

Cases 1 and 2. The twin males were born toa gravida 1, para 0, healthy 20-year-old single mother. The father was unrelated,and family history was unremarkable. Complications during the pregnancy includeda positive maternal culture for group B streptococcus treated with amoxicillinand supraventricular tachycardia (SVT) of both fetuses treated with digoxin.The twins were born via an uncomplicated vaginal delivery. Estimated gestationwas 35 weeks 4 days. Twin 1's birth weight was 2.324 kg and twin 2's birthweight was 2.350 kg.

In twin 1, external examination of the eyelids at birth was normal inboth eyes. Intraocular pressure (IOP) obtained with a pneumotonometer was36 and 33 mm Hg in the right and left eyes, respectively. Horizontal cornealdiameter was 7.5 mm in each eye. Sclerocornea was noted in both eyes. Theright and left corneas had central areas of less scleralized cornea measuring4 and 5 mm, respectively (Figure 1).The fundus could not be visualized in the right eye, but funduscopic examinationof the left eye showed a flat retina with a grossly normal optic disc andmacula. Axial length was 15.17 mm in the right eye and 15.44 mm in the lefteye. B-scan ultrasonography findings were normal in both eyes. A computedtomographic scan and magnetic resonance images of the orbits showed that bothglobes were small but normal.

In twin 2, on external examination, a small eyelid fissure was notedon the right eye with normal fissures on the left. Examination of the righteye showed anophthalmia. Intraocular pressure obtained with a pneumotonometerwas 26 mm Hg in the left eye. Horizontal corneal diameter was 10 mm in theleft eye. The cornea of the left eye showed peripheral scleralization withdense opacification and vascularization centrally, consistent with Petersanomaly (Figure 2). No details couldbe discerned on funduscopic examination. Axial length of the left eye was16.62 mm, and B-scan ultrasonography findings were normal. A computed tomographicscan and magnetic resonance images showed a normal globe on the left and noglobe on the right.

Examination of the skin of both twins disclosed linear, erythematouslesions consistent with dermal aplasia. The lesions were located on the face,neck, and preauricular area. Several months later, an examination of the skinshowed healing of the lesions with a small amount of scarring.

Both twins had episodes of SVT shortly after birth. Initial echocardiogramsin both twins showed a patent ductus arteriosus, which had spontaneously closedon follow-up echocardiograms. No other cardiac abnormalities were found. Theepisodes of SVT in both twins were well controlled with β-blockers. By6 months of age, all cardiac medications had been discontinued in both twins,without further episodes of SVT.

Both twins were noted to have distal penile hypospadias but otherwisehad normal male genitalia. Chromosomal analysis of the male twins showed a46,XX karyotype with a translocation between the X and Y chromosomes (Figure 3). The probe for the male determinantregion of the Y chromosome was positive, indicating that the region of theY chromosome that determines the male sex was present on the translocatedX chromosome. Because of this translocation, the twins were phenotypicallymale, although genotypically XX or female. Chromosome analysis also showeda deletion at the Xp22.3 site. The karyotype of each of the twins was 46,XX,ishder(X)t(X;Y)(SRY+,Kallmann−, STS). Chromosome analysis was not performedon the patients' parents.

Case 3. The first female patient was born toa gravida 1, para 0, healthy 37-year-old mother and her unrelated husbandvia normal spontaneous vaginal delivery. Estimated gestational age was 40weeks, and birth weight was 3.015 kg. There were no complications during thepregnancy or birth.

Results of external examination were normal. The IOP in the right eyeby pneumotonometer was 41 mm Hg. Because the left eye was severely microphthalmic,an accurate IOP measurement was not possible. The right cornea was bulgingcentrally and had a corneal diameter of 10 mm horizontally and vertically.Sclerocornea and diffuse vascularization were present. Centrally, a slightlyless opacified area measuring 6.5 × 4 mm was noted, with a dense, whitearea measuring 4 × 4 mm within this clearer region. The left eye hada corneal diameter of 5 mm horizontally and vertically. Dense sclerocorneawith a central clear zone of 2 mm was evident. No details of the anteriorchamber or fundus could be discerned in either eye. B-scan ultrasonographyfindings in the right eye showed mild vitreous opacification. The retina wasattached with evidence of choroidal thickening. Intraocular structures wereotherwise normal. Ultrasonography could not performed on the left eye becauseof the severity of the microphthalmia.

Examination of the patient's skin showed multiple areas of dermal aplasiaon the face, neck, and upper extremities (Figure 4).

An echocardiogram demonstrated a patent ductus arteriosus with a right-to-leftshunt but normal cardiac function. An ultrasound scan of the head showed asmall intraventricular hemorrhage and moderate hydrocephalus, which requiredno treatment. This patient was also noted to have short fingers and nail dystrophy.Female genitalia were normal.

The patient's karyotype was 46,X,der(X)t(X;Y)(p22.3;q11),ish der(X)t(X;Y)(wcpY+,DYZ1+,DYZ3−,SRY−,STS−). Chromosomal analysis disclosed a translocation betweenthe short arm of one X chromosome and the long arm of a Y chromosome. TheSTS probe, which is specific for the Xp22.3 region, did not hybridize withthe abnormal X homologue, indicating a deletion of the Xp22.3 region. Chromosomeanalysis was performed on the patient's parents and results were normal ineach case.

Case 4. The second female patient was bornto a 27-year-old, gravida 2, para 0 mother and her unrelated husband. Themother had had an ectopic pregnancy in 1993 (approximately 5-6 years beforethe current pregnancy), but otherwise had no significant medical history.The infant was the product of an uncomplicated pregnancy and a normal spontaneousvaginal delivery. Birth weight was 3.892 kg.

Examination of the eyelids showed a slight mongoloid slant, but theywere otherwise normal. Measurement with a Perkins applanator showed an IOPof 11 mm Hg in each eye. The right cornea was flat and oval with a horizontaldiameter of 8.5 mm and a vertical diameter of 5.75 mm. The left cornea wasalso oval with a diameter of 6.75 mm horizontally and 4 mm vertically. Theleft eye had peripheral sclerocornea with a small area of increased claritycentrally. The right eye had a diffusely opaque cornea with a paracentralthinned area and an iridocorneal adhesion at the 4-o'clock position (Figure 5). Partial aniridia was noted inthe left eye with peripheral adhesions of the iris to the cornea. The lensof the right eye was poorly visualized. In the left eye, a remnant of theanterior hyaloid system was seen extending to the posterior aspect of thelens. Under funduscopic examination, the retina of the right eye was not visible,but examination of the left eye showed a normal optic nerve with an attachedretina. A-scan ultrasound measurements demonstrated an axial length of 16.69and 18.46 mm in the right and left eyes, respectively. B-scan ultrasonographyfindings were normal in both eyes.

No skin abnormalities were noted on examination. Results of the patient'scardiac examination and echocardiogram were normal, and she had normal femalegenitalia. By age 3 years, the patient was noted to have short stature.

Chromosome analysis showed a 46,XX karyotype. One X chromosome was normaland the other X chromosome had a translocation involving the distal shortarm of the X chromosome and the long arm of the Y chromosome. This translocationresulted in a deletion of the Xp22.3 region, giving the patient a karyotypeof 46,X,der(X)t(X;Y)(p22.3;q11.2). Results of chromosome analysis performedon each of the patient's parents were normal.

Four patients with genetically proved deletion of chromosome Xp22.3were examined (Table 1). Microphthalmiawas noted in 4 of the 8 eyes (1 of the 4 was anophthalmic). Three of the 4patients had dermal aplasia. Sclerocornea was noted in all 7 eyes, excludingthe anophthalmic eye.

Five of the 7 eyes had microcornea, defined as a corneal diameter lessthan 10 mm. One eye was found to have Peters anomaly. Two of the 7 eyes hadiridocorneal adhesions. One eye had partial aniridia and 1 eye had a remnantof the anterior hyaloid artery visible. Three of the 7 eyes had elevated IOP,1 eye had a borderline elevated IOP, and 1 eye was too small to obtain anaccurate IOP. The results of dilated fundus examination were normal in 2 ofthe 7 eyes, and no view was possible in 5 eyes. Of the 5 eyes in which therewas no view of the fundus, 3 eyes had a normal B-scan findings, 1 eye wastoo microphthalmic to obtain a B-scan, and 1 eye had B-scan results that showedmild vitreous opacity with choroidal thickening. Computed tomographic scanningand magnetic resonance imaging were performed on 4 of the 8 orbits. Threeof the 4 scans had normal findings and 1 scan result confirmed absence ofthe globe.

These 4 case studies demonstrate that the ocular manifestations associatedwith the deletion of Xp22.3 encompass a broader spectrum of findings thanthat originally described by the MIDAS syndrome. Although our patients hadsimilar karyotypes, they exhibited a wide variety of ocular findings not includedin the classic triad of microphthalmia, dermal aplasia, and sclerocornea.In addition, not all of our patients demonstrated the classic triad of abnormalities.As shown in Table 1, only patient1 had all 3 findings in both eyes. All eyes of the 4 patients (excluding theanophthalmic eye in patient 2) were noted to have various degrees of sclerocornea,but only 4 of the 8 eyes had microphthalmia (or anophthalmia), and only 3of the 4 patients had dermal aplasia.

In a review of the literature, there have been 22 case reports of patientswith a microdeletion at the distal Xp region. Seventeen of the reported caseswere in females,^2,3 whereas5 of them were in 46,XX males.^2,4-7 Previouscase reports have noted phenotypic variability as seen in our patients. Forexample, al-Gazali et al⁸ in 1990 describeda female patient with peripheral anterior synechiae and collarette adhesions.Lindor et al⁹ in 1992 decribed an infantwith choroidal thickening in both eyes. Other atypical findings reported inpatients with MIDAS syndrome include dense cataracts,⁹ blepharophimosis,¹ and aphakia.² Tothe best of our knowledge, the ophthalmic findings in our 4 patients not describedin previous case reports include Peters anomaly, anophthalmia, partial aniridia,a remnant of the anterior hyaloid artery, and vitreous opacity.

Although 5 other 46,XX males with the MIDAS syndrome have been describedin the literature, this study represents the first case report of identicaltwin boys (cases 1 and 2). These 2 cases demonstrate that, even with identicalgenetic deletions at the Xp22.3 locus, the phenotypes may vary. Patients 1and 2 were similar in that both of them had microphthalmia, sclerocornea,and skin deformities. They also exhibited hypospadias and a mild cardiac abnormalityin the form of SVT. There were, however, several differences in the phenotypesof the twins. Patient 1 had a definite high elevation of IOP, while patient2 had a borderline elevation of pressure. Patient 2 had a small right eyelidfissure and anophthalmia, neither of which was present in patient 1. Microcorneawas present in patient 1, but the corneal diameter of the nonanophthalmicleft eye of patient 2 was normal. These phenotypic differences found in identicaltwin boys with identical karyotypes lend further support to the current hypothesisthat the variations found in MIDAS syndrome may be due to different patternsof X inactivation, or lyonization, rather than due to subtle differences ingenotypes.^4,5 Further researchshould be done to understand more completely how the Xp22.3 deletion is expressedbecause this research may lead to a better understanding of the role of thischromosomal locus in ocular development.

The clinical definition of MIDAS syndrome continues to be modified asmore phenotypic variability is reported. The present study represents oneof the largest case studies detailing the ocular findings in patients withan Xp22.3 deletion and serves to expand the current phenotypes associatedwith this syndrome. Providing additional descriptions of the phenotype shouldaid clinicians in identifying patients with this genetic syndrome and promptearly genetic testing in appropriate patients. It is apparent that the mnemonics"MIDAS syndrome" and "MLS syndrome" do not fully describe this disease. Therefore,consideration should be given to more accurately and genomically referringto the syndrome as the "Xp22.3 microdeletion syndrome."

Dr Kaufman is a recipient of a Career Development Award from Researchto Prevent Blindness Inc, New York, NY.

We thank Arturo Anguiano, MD, for performing the genetic analysis incases 1 and 2.

Correspondence: Dr Zaidman, Department of Ophthalmology, WestchesterMedical Center, Macy Pavilion, Room 1100, Valhalla, NY 10595 (pedkera@aol.com).