Phenotypic Variation in Ophthalmic Manifestations of MIDAS Syndrome

1. Binder HJ. Disorders of absorption. In: Braun- typically involve the face, scalp, neck, Report of Cases. Cases 1 and 2. The wald E, Fauci AS, Isselbacher KJ, Kasper DL, and upper part of the thorax. In ad- twin males were born to a gravida Hauser SL, Longo DL, Jameson JL, eds. Harri- son’s Online. Chap 286. Available at: http://www dition to the ocular and skin find- 1, para 0, healthy 20-year-old single .harrisons.accessmedicine.com. Accessed May 26, ings, there are multiple nonocular ab- mother. The father was unrelated, 2003. 2. Florent C, L’Hirondel C, Desmazures C, et al. In- normalities commonly reported to be and family history was unremark- testinal clearance of ␣1-antitrypsin: a sensitive associated with MIDAS syndrome. able. Complications during the preg- method for the detection of protein-losing enter- Some of these include congenital heart nancy included a positive maternal opathy. Gastroenterology. 1981;81:777-780. 3. Anand R, Tasman WS. Tasman nonrhegmatog- defects, short stature, hypospadias, culture for group B streptococcus enous retinal detachment. In: Ryan SJ, Wilkin- developmental delay, absence of the treated with amoxicillin and supra- son CP, eds. Retina. Vol 3. 3rd ed. St Louis, Mo: Mosby Inc; 2001:2076-2097. corpus callosum, nail dystrophy, and ventricular tachycardia (SVT) of both 4. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi- hydrocephalus. fetuses treated with digoxin. The Harada syndrome. Surv Ophthalmol. 1995;39: The underlying defect in twins were born via an uncompli- 265-292. 5. Snyder DA, Tessler HA. Vogt-Koyanagi-Harada MIDAS syndrome is due to a dele- cated vaginal delivery. Estimated ges- syndrome. Am J Ophthalmol. 1980;90:69-75. tion at Xp22.3. The disease is be- tation was 35 weeks 4 days. Twin 1’s 6. Negi A, Marmor MF. Effects of subretinal and sys- lieved to be transmitted as an X- birth weight was 2.324 kg and twin temic osmolality on subretinal fluid resorption. In- vest Ophthalmol Vis Sci. 1984;25:616-620. linked dominant trait that is lethal 2’s birth weight was 2.350 kg. in the male hemizygous state. This In twin 1, external examina- theory has been supported by the fact tion of the eyelids at birth was normal that there have been no reported in both eyes. Intraocular pressure cases of XY males with this syn- (IOP) obtained with a pneumoto- Phenotypic Variation in drome. The few reported cases of nometer was 36 and 33 mm Hg in the Ophthalmic Manifestations males with MIDAS syndrome have right and left eyes, respectively. Hori- of MIDAS Syndrome 46,XX karyotypes with a deletion of zontal corneal diameter was 7.5 mm (Microphthalmia, Dermal the Xp22.3 region due to an X/Y in each eye. Sclerocornea was noted Aplasia, and Sclerocornea) translocation. Although these pain both eyes. The right and left cor- tients are genotypically female, they neas had central areas of less scleral- The term MIDAS syndrome was are phenotypically male. ized cornea measuring 4 and 5 mm, coined by Happle et al1 in 1993 to de- Recently we examined twin respectively (Figure 1). The fun- scribe the predominant features of a boys and 2 single-birth girls with ge- dus could not be visualized in the genetic disorder with microphthal- netically proven deletion of chro- right eye, but funduscopic examina- mia, dermal aplasia, and sclerocor- mosome Xp22.3. Examination with tion of the left eye showed a flat retina nea. This syndrome has also been the patient under anesthesia, includ- with a grossly normal optic disc and called the “MLS syndrome,” which ing biometry and ultrasonography, macula. Axial length was 15.17 mm stands for “microphthalmia with lin- was performed to detail the ocular in the right eye and 15.44 mm in the ear skin defects.” The dermal aplasia findings associated with this syn- left eye. B-scan ultrasonography find- in MIDAS syndrome consists of lin- drome. Other nonocular abnormali- ings were normal in both eyes. A com- ear erythematous skin defects that ties were also noted. puted tomographic scan and mag-

A B

Figure 1. Patient 1, demonstrating sclerocornea and microphthalmos in the right eye (A) and the left eye (B).

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Figure 2. Patient 2. The right eye (A) has anophthalmia. The left eye (B) demonstrates a globe of normal size and normal corneal diameter with sclerocornea and dense central corneal opacification consistent with Peters anomaly.

netic resonance images of the orbits patent ductus arteriosus, which had spontaneous vaginal delivery. Esti- showed that both globes were small spontaneously closed on follow-up mated gestational age was 40 weeks, but normal. echocardiograms. No other cardiac and birth weight was 3.015 kg. There In twin 2, on external exami- abnormalities were found. The epi- were no complications during the nation, a small eyelid fissure was sodes of SVT in both twins were well pregnancy or birth. noted on the right eye with normal controlled with ␤-blockers. By 6 Results of external examina- fissures on the left. Examination of months of age, all cardiac medica- tion were normal. The IOP in the the right eye showed anophthal- tions had been discontinued in both right eye by pneumotonometer was mia. Intraocular pressure obtained twins, without further episodes of 41 mm Hg. Because the left eye was with a pneumotonometer was 26 SVT. severely microphthalmic, an accu- mm Hg in the left eye. Horizontal Both twins were noted to have rate IOP measurement was not pos- corneal diameter was 10 mm in the distal penile hypospadias but oth- sible. The right cornea was bulging left eye. The cornea of the left eye erwise had normal male genitalia. centrally and had a corneal diam- showed peripheral scleralization Chromosomal analysis of the male eter of 10 mm horizontally and ver- with dense opacification and vascu- twins showed a 46,XX karyotype tically. Sclerocornea and diffuse vas- larization centrally, consistent with with a translocation between the X cularization were present. Centrally, Peters anomaly (Figure 2). No de- and Y chromosomes (Figure 3). a slightly less opacified area mea- tails could be discerned on fundu- The probe for the male determi- suring 6.5ϫ4 mm was noted, with scopic examination. Axial length of nant region of the Y chromosome a dense, white area measuring 4ϫ4 the left eye was 16.62 mm, and B- was positive, indicating that the re- mm within this clearer region. The scan ultrasonography findings were gion of the Y chromosome that de- left eye had a corneal diameter of 5 normal. A computed tomographic termines the male sex was present mm horizontally and vertically. scan and magnetic resonance im- on the translocated X chromo- Dense sclerocornea with a central ages showed a normal globe on the some. Because of this transloca- clear zone of 2 mm was evident. No left and no globe on the right. tion, the twins were phenotypically details of the anterior chamber or Examination of the skin of both male, although genotypically XX or fundus could be discerned in either twins disclosed linear, erythema- female. Chromosome analysis also eye. B-scan ultrasonography find- tous lesions consistent with dermal showed a deletion at the Xp22.3 site. ings in the right eye showed mild vit- aplasia. The lesions were located on The karyotype of each of the twins reous opacification. The retina was the face, neck, and preauricular area. was 46,XX,ish der(X)t(X;Y) attached with evidence of choroi- Several months later, an examina- (SRY+,Kallmann−, STS). Chromo- dal thickening. Intraocular struc- tion of the skin showed healing of some analysis was not performed on tures were otherwise normal. Ultra- the lesions with a small amount of the patients’ parents. sonography could not performed on scarring. Case 3. The first female pa- the left eye because of the severity Both twins had episodes of SVT tient was born to a gravida 1, para of the microphthalmia. shortly after birth. Initial echocar- 0, healthy 37-year-old mother and Examination of the patient’s diograms in both twins showed a her unrelated husband via normal skin showed multiple areas of der-

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123 45 123 45

6789101112 6789101112

13 14 15 16 17 18 13 14 15 16 17 18

19 20 21 22 XY 19 20 21 22 XY

Figure 3. Karyotypes of patients 1 (A) and 2 (B), obtained by GTG banding with a resolution level of 400 to 550 bands per haploid complement. The karyotype of patient 2 is identical to that of patient 1. Arrows indicate the region of the Y chromosome that is present on the translocated X chromosome.

Case 4. The second female pa- sound measurements demon- tient was born to a 27-year-old, strated an axial length of 16.69 and gravida 2, para 0 mother and her un- 18.46 mm in the right and left eyes, related husband. The mother had respectively. B-scan ultrasonogra- had an ectopic pregnancy in 1993 phy findings were normal in both (approximately 5-6 years before the eyes. current pregnancy), but otherwise No skin abnormalities were had no significant medical history. noted on examination. Results of the The infant was the product of an un- patient’s cardiac examination and complicated pregnancy and a nor- echocardiogram were normal, and Figure 4. Patient 3 at birth, showing areas of mal spontaneous vaginal delivery. she had normal female genitalia. By dermal aplasia around the nose, on the cheek, Birth weight was 3.892 kg. age 3 years, the patient was noted to and on the neck. Examination of the eyelids have short stature. showed a slight mongoloid slant, but Chromosome analysis showed a mal aplasia on the face, neck, and they were otherwise normal. Mea- 46,XX karyotype. One X chromo- upper extremities (Figure 4). surement with a Perkins applana- some was normal and the other X An echocardiogram demon- tor showed an IOP of 11 mm Hg in chromosome had a translocation in- strated a patent ductus arteriosus each eye. The right cornea was flat volving the distal short arm of the X with a right-to-left shunt but nor- and oval with a horizontal diam- chromosome and the long arm of the mal cardiac function. An ultra- eter of 8.5 mm and a vertical diam- Y chromosome. This translocation re- sound scan of the head showed a eter of 5.75 mm. The left cornea was sulted in a deletion of the Xp22.3 re- small intraventricular hemorrhage also oval with a diameter of 6.75 mm gion, giving the patient a karyotype and moderate hydrocephalus, which horizontally and 4 mm vertically. of 46,X,der(X)t(X;Y)(p22.3;q11.2). required no treatment. This patient The left eye had peripheral sclero- Results of chromosome analysis per- was also noted to have short fin- cornea with a small area of in- formed on each of the patient’s par- gers and nail dystrophy. Female creased clarity centrally. The right ents were normal. genitalia were normal. eye had a diffusely opaque cornea The patient’s karyotype was with a paracentral thinned area and Results. Four patients with geneti- 46,X,der(X)t(X;Y)(p22.3;q11),ishder an iridocorneal adhesion at the cally proved deletion of chromo- (X)t(X;Y)(wcpY+,DYZ1 +,DYZ3−, 4-o’clock position (Figure 5). Par- some Xp22.3 were examined SRY−,STS−). Chromosomal analy- tial aniridia was noted in the left eye (Table). Microphthalmia was noted sis disclosed a translocation be- with peripheral adhesions of the iris in 4 of the 8 eyes (1 of the 4 was tween the short arm of one X chro- to the cornea. The lens of the right anophthalmic). Three of the 4 pa- mosome and the long arm of a Y eye was poorly visualized. In the left tients had dermal aplasia. Sclerocor- chromosome. The STS probe, which eye, a remnant of the anterior hya- nea was noted in all 7 eyes, exclud- is specific for the Xp22.3 region, did loid system was seen extending to ing the anophthalmic eye. not hybridize with the abnormal X the posterior aspect of the lens. Un- Five of the 7 eyes had micro- homologue, indicating a deletion of der funduscopic examination, the cornea, defined as a corneal diam- the Xp22.3 region. Chromosome retina of the right eye was not vis- eter less than 10 mm. One eye was analysis was performed on the pa- ible, but examination of the left eye found to have Peters anomaly. Two tient’s parents and results were nor- showed a normal optic nerve with of the 7 eyes had iridocorneal adhe- mal in each case. an attached retina. A-scan ultra- sions. One eye had partial aniridia

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Figure 5. Patient 4, right eye (A) and left eye (B). Sclerocornea is present in both eyes. The right cornea is scarred diffusely. The central left cornea is partially clear.

tients (excluding the anophthalmic Phenotypic Variation in MIDAS Syndrome eye in patient 2) were noted to have various degrees of sclerocornea, but Patient and Eye Microphthalmia Dermal Aplasia Sclerocornea only 4 of the 8 eyes had microphthal- 1 mia (or anophthalmia), and only 3 of OD + + + the 4 patients had dermal aplasia. OS + + + 2 In a review of the literature, OD + + NA there have been 22 case reports of OS − + + patients with a microdeletion at the 3 distal Xp region. Seventeen of the re- OD − + + ported cases were in females,2,3 OS + + + whereas 5 of them were in 46,XX 4 2,4-7 OD − − + males. Previous case reports have OS − − + noted phenotypic variability as seen in our patients. For example, al- Abbreviations: MIDAS, microphthalmia, dermal aplasia, and sclerocornea; NA, not applicable Gazali et al8 in 1990 described a fe- (anophthalmic eye). male patient with peripheral anterior synechiae and collarette and 1 eye had a remnant of the an- mal findings and 1 scan result con- adhesions. Lindor et al9 in 1992 de- terior hyaloid artery visible. Three firmed absence of the globe. cribed an infant with choroidal of the 7 eyes had elevated IOP, 1 eye thickening in both eyes. Other atypi- had a borderline elevated IOP, and Comment. These 4 case studies dem- cal findings reported in patients with 1 eye was too small to obtain an ac- onstrate that the ocular manifesta- MIDAS syndrome include dense curate IOP. The results of dilated tions associated with the deletion of cataracts,9 blepharophimosis,1 and fundus examination were normal in Xp22.3 encompass a broader spec- aphakia.2 To the best of our knowl- 2 of the 7 eyes, and no view was pos- trum of findings than that originally edge, the ophthalmic findings in our sible in 5 eyes. Of the 5 eyes in which described by the MIDAS syndrome. 4 patients not described in previ- there was no view of the fundus, 3 Although our patients had similar ous case reports include Peters eyes had a normal B-scan findings, karyotypes, they exhibited a wide va- anomaly, anophthalmia, partial an- 1 eye was too microphthalmic to ob- riety of ocular findings not included iridia, a remnant of the anterior hya- tain a B-scan, and 1 eye had B-scan in the classic triad of microphthal- loid artery, and vitreous opacity. results that showed mild vitreous mia, dermal aplasia, and sclerocor- Although 5 other 46,XX males opacity with choroidal thickening. nea. In addition, not all of our pa- with the MIDAS syndrome have Computed tomographic scanning tients demonstrated the classic triad been described in the literature, this and magnetic resonance imaging of abnormalities. As shown in the study represents the first case re- were performed on 4 of the 8 or- Table, only patient 1 had all 3 find- port of identical twin boys (cases 1 bits. Three of the 4 scans had nor- ings in both eyes. All eyes of the 4 pa- and 2). These 2 cases demonstrate

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 that, even with identical genetic de- Dr Kaufman is a recipient of a Ca- Report of a Case. A previously letions at the Xp22.3 locus, the phe- reer Development Award from Re- healthy 81-year-old woman devel- notypes may vary. Patients 1 and 2 search to Prevent Blindness Inc, New oped mandibular pain with chew- were similar in that both of them had York, NY. ing, low-grade fevers, night sweats, microphthalmia, sclerocornea, and We thank Arturo Anguiano, MD, and proximal limb mylagias. She de- skin deformities. They also exhib- for performing the genetic analysis in nied headache or visual changes. ited hypospadias and a mild car- cases 1 and 2. There were no abnormalities on re- diac abnormality in the form of SVT. Correspondence: Dr Zaidman, sults of physical examination, and There were, however, several differ- Department of Ophthalmology, her temporal arteries were pulsa- ences in the phenotypes of the twins. Westchester Medical Center, Macy Pa- tile and neither indurated nor ten- Patient 1 had a definite high eleva- vilion, Room 1100, Valhalla, NY der. A chest radiograph was unre- tion of IOP, while patient 2 had a 10595 ([email protected]). markable. The only abnormality on borderline elevation of pressure. Pa- routine laboratory testing was mi- 1. Happle R, Daniels O, Koopman RJ. MIDAS syn- tient 2 had a small right eyelid fis- drome (microphthalmia, dermal aplasia, and croscopic hematuria. Her condi- sure and anophthalmia, neither of sclerocornea): an X-linked phenotype distinct tion did not improve after a trial of which was present in patient 1. Mi- from Goltz syndrome. Am J Med Genet. 1993; 47:710-713. antibiotics for the presumed diag- crocornea was present in patient 1, 2. Stratton RF, Walter CA, Paulger BR, Price ME, nosis of sinusitis. Three weeks af- but the corneal diameter of the Moore CM. Second 46,XX male with MLS syn- ter onset of symptoms, an erythro- drome. Am J Med Genet. 1998;76:37-41. nonanophthalmic left eye of pa- 3. McLeod SD, Sugar J, Elejalde BR, Eng A, Lebel cyte sedimentation rate of 131 mm/h tient 2 was normal. These pheno- RR. Gazali-Temple syndrome. Arch Ophthal- and a C-reactive protein level of 7.9 typic differences found in identical mol. 1994;112:851-852. mg/dL prompted referral for neuro- 4. Lindsay EA, Grillo A, Ferrero GB, et al. Microph- twin boys with identical karyo- thalmia with linear skin defects (MLS) syn- ophthalmic consultation and bi- types lend further support to the cur- drome: clinical, cytogenetic, and molecular char- opsy. Although no abnormalities rent hypothesis that the variations acterization. Am J Med Genet. 1994;49:229-234. 5. Kono T, Migita T, Koyama S, Seki I. Another ob- were found on the examination re- found in MIDAS syndrome may be servation of microphthalmia in an XX male: mi- sults, we performed a biopsy of the due to different patterns of X inac- crophthalmia with linear skin defects syn- left temporal artery. drome without linear skin lesions. J Hum Genet. tivation, or lyonization, rather than 1999;44:63-68. The biopsy specimen was due to subtle differences in geno- 6. Paulger BR, Kraus EW, Pulitzer DR, Moore CM. fixed and serially sectioned. Micro- types.4,5 Further research should be Xp microdeletion syndrome characterized by pa- scopic examination (Figure) thognomonic linear skin defects on the head and done to understand more com- neck. Pediatr Dermatol. 1997;14:26-30. showed a normal temporal artery pletely how the Xp22.3 deletion is 7. Kobayashi M, Kiyosawa M, Toyoura T, Tokoro in all sections, but several small expressed because this research may T. An XX male with microphthalmos and sclerocornea. J Pediatr Ophthalmol Strabismus. 1998; adjacent arteries included in the lead to a better understanding of the 35:122-124. biopsy specimen showed granulo- role of this chromosomal locus in 8. al-Gazali LI, Mueller RF, Caine A, et al. Two matous angiitis. 46,XX,t(X;Y) females with linear skin defects and ocular development. congenital microphthalmia: a new syndrome at The patient’s symptoms im- The clinical definition of MIDAS Xp22.3. J Med Genet. 1990;27:59-63. proved with oral prednisone therapy, syndrome continues to be modified 9. Lindor NM, Michels VV, Hoppe DA, Driscoll DJ, but further investigations prompted Leavitt JA, Dewald GW. Xp22.3 microdeletion as more phenotypic variability is re- syndrome with microphthalmia, sclerocornea, by persistent hematuria resulted in ported. The present study repre- linear skin defects, and congenital heart de- the diagnosis of Wegener granulo- sents one of the largest case studies fects. Am J Med Genet. 1992;44:61-65. matosis. detailing the ocular findings in patients with an Xp22.3 deletion and Comment. As demonstrated by this serves to expand the current pheno- case, symptoms, signs, and even his- types associated with this syn- A “Negative” Temporal tologic findings classically associ- drome. Providing additional descrip- Artery Biopsy, Positive ated with GCA can be found with tions of the phenotype should aid for Arteritis other systemic vasculitides. Fea- clinicians in identifying patients with tures attributed to GCA, such as jaw this genetic syndrome and prompt Ophthalmologists often participate claudication, amaurosis fugax, and early genetic testing in appropriate pain the diagnosis and treatment of an erythrocyte sedimentation rate tients. It is apparent that the mne- patients with giant cell arteritis greater than 100 mm/h, have been monics “MIDAS syndrome” and (GCA), typically when the diagno- seen in patients with Wegener “MLS syndrome” do not fully de- sis is heralded by a central retinal granulomatosis.1-3 Like patients with scribe this disease. Therefore, con- artery occlusion or ischemic optic GCA, patients with Wegener granu- sideration should be given to more ac- neuropathy. However, even in the lomatosis can improve with corti- curately and genomically referring to absence of eye symptoms or signs, costeroid treatment, at least ini- the syndrome as the “Xp22.3 micro- ophthalmologists may be asked to tially. However, patients with deletion syndrome.” examine the patient and perform a Wegener granulomatosis who are biopsy of the temporal artery. The misdiagnosed as having GCA and Catherine J. Cape, MD microscopic findings in the who are treated only with cortico- Gerald W. Zaidman, MD patient described herein bear on steroids may develop acute renal fail- Allen D. Beck, MD the technique of temporal artery ure and respiratory tract disease.4 Adam H. Kaufman, MD biopsy. When faced with a “positive” tem-

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