American Journal of M e d i c a l G e n e t i c s 44:61-65 (1992)
Xp22.3 Microdeletion Syndrome With Microphthalmia, Sclerocornea, Linear Skin Defects, and Congenital Heart Defects Noralane M. Lindor, Virginia V. Michels, Daniel A. Hoppe, David J. Driscoll, Jacqueline A. Leavitt, and Gordon W. Dewald Department of Medical Genetics (N.M.L.,V.V.M.),the Sectwn of Laboratory Genetics (DA.€€.,G.W.D.), Department of Pediatrics (D.J.D.),and the Department of Ophthalmology (J.A.L.),Mayo Clinic and Mayo Foundatwn, Rochester, Minnesota We report on an infant girl with congenital erythematous, linear skin lesions on face and neck, bilateral microphthalmia, sclerocornea, cataracts, and a complex cardiac anomaly including atrial septal and ventricular septal defects. This patient had an Xp22.3 microdeletion and a chromosome satellite on the abnormal X p-arm. The abnormal X chromosome was late replicating in peripheral blood lymphocytes and cultured skin fibroblasts. Four other patients with similar congenital anomalies a n d Xp deficiency have been reported previously and are compared with this patient. One patient had an interstitial or terminal deletion, but in others the material translocated to Xp22.3 was variable (Yq material in two patients, a n d Yp material and an unidentifiable satellite in one patient each). Severa1 mechanisms are suggested by which this chromosome abnormality might produce this phenotype in these patients. Our patient is the first with this syndrome to have a congenital heart defect. o 1992 Wiiey-Liss, inc.
KEY WORDS: Xp deletion, pseudoautosomal, dermal hypoplasia, translocation, Y chromosome, cataracts, contiguous gene, hemizygous INTRODUCTION Recently,a new microdeletion syndrome involving the absence of Xp22.3 was described by Al-Gazali et al. 11988, 19901 and Temple et al. [19901. This syndrome has been reported in four patients. It consists of bilateral
Received for publication October 18,1991;revision received January 24, 1992. Address reprint requests to Dr. Virginia V. Michels, Department of Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
O 1992 Wiley-Liss, Inc.
microphthalmia, sclerocornea, and an unusual linear skin lesion that is clinically distinguishable from incontinentia pigmenti and foca1 dermal hypoplasia. This report describes the fifth case of this clinical syndrome involving a similar absence of Xp22.3. Unlike the other four patients, this patient had a severe congenital heart defect and cataracts. These may be additional manifestations of the Xp22.3 microdeletion syndrome. CLINICAL REPORT Clinical Findings This infant was born a t term (weight, 3,530 g; 75th centile) after an uneventful pregnancy and delivery to a 19-year-old gravida 4, para 3 Alaskan woman. At birth, the infant had unusual red, weepy, reticulolinear, nonvesicular skin lesions on her face and neck and bilateral eye abnormalities (Fig. 1). Congestive heart failure developed a t age 2 days. At age 4 weeks, she was transferred to our institution for a h e a e operation. On arrival she weighed 3.19 kg (10th centile) and had a length of 49 cm (5th centile) and occipito-frontal head circumference (OFC) of 34.6 cm (10th centile). The skin over the face was characterized by erythematous, denuded-appearing, linear streaks beginning media1 to the inner canthi and continuing down along the side of the nose, onto the cheeks, and up along the left jaw line to over the left ear. The streaks also continued down the right cheek and jaw line to the neck, where the pattern became less linear and more reticular. The skin on the remainder of the body was normal. Her hair and nails showed no abnormalities. The cardiac lesions were a large malalignment paramembranous ventricular septal defect with an overriding aorta, an additional small muscular ventricular septal defect, a secundum atrial septal defect, and azygous continuation of the inferior vena cava t o the right superior vena cava. In addition, the patient had intermittent junctional rhythm and a wandering atrial pacemaker. Ophthalmologic evaluation showed bilateral microphthalmia, nearly complete sclerocornea, and dense cataracts. Ultrasonography of the globes confirmed the microphthalmia and suggested some choroidal thickening. No cysts were identified. The skin lesions healed with minimal crusting and with the
62
Lindor et al.
Fig. 1. A Linear skin lesions on face at 4 weeks of age. B: Eye, showing microphthalmia, sclerocornea, and cataract at 8 weeks of age.
appearance of linear brown streaks of pigmentation. No new skin lesions appeared. Other physical findings included a highly arched palate, proximally implanted thumbs, and bilateral transverse palmar creases. Computed tomography of her head was normal, as was renal ultrasonography. A radiograph of one femur at 2 weeks of age and a complete skeletal survey at 8 weeks of age documented no abnormalities. Audiometric screening, including brain stem evoked responses, was suggestive of a hearing defect. Her postoperative course included one episode of pneumonia and a continued need for supplemental oxygen at the time of dismissal. Her weight a t age 9 weeks was 3,810 g (10th centile).
Laboratory Studies Analysis of GTL-banded chromosomes from peripheral blood and skin fibroblasts showed an abnormal X chromosomethat appeared to be derived from an unbalanced translocation involving an X chromosome and an unidentifiable chromosome that carried a satellite (Fig. 2). The patient’s karyotype was 46,X, - X, + der(X) t(X;?)(p22.3;?). The translocation resulted in loss of Xp22.3. The satellite was Ag-NOR positive and C-band negative, and it stained dully with Q-banding and DAPI banding (Fig. 3 A,B,C,D). With fluorescent in situ hybridization with a generalized human centromeric Drobe for alpha satellite DNA (Oncor, Gaithersburg, MD),no centromeric material was found in the area of
the X p-arm; this result suggests that the breakpoint occurred in the stalk of the satellite (Fig. 3E). Chromosome replication studies showed the abnormal X to be the late-replicating X in 30 of 30 lymphocytes and in 30 of 30 fibroblasts (Fig. 3F). DNA studies from skin fibroblasts for Y-specific probes 472 (Yp11.2)and 50F2 (Yp11.2+p11.3 and Yq11.2) did not show evidence ofY chromatin. The patient’s parents could not accompany their infant to our institution. However, we did obtain blood specimens from each of the parents, and each of their karyotypes was normal. Epstein-Barr virus-immortalized lymphocytes from this infant and her parents have been stored for other possible genetic studies. We have also stored fibroblasts from a skin biopsy specimen from the infant.
DISCUSSION The clinical and laboratory findings of the four other reported patients with the Xp22.3 microdeletion syndrome are compared with the findings in our patient in Table 1. An X;Y translocation was involved in two of these cases, and break and fusion points were at Xp22.3 and Yq11.2 [Al-Gazali et al., 1988, 19901. One other patient was an XX male, in whom Southern blot analysis showed the presence of Yp material [Al-Gazali et al., 19881. The results in this reported XX male imply that the X chromosomes appeared normal and some of the Y chromosome may h&e been transferred to an X
Xp22.3 Microdeletion Syndrome
63
Fig. 2. GTL-banded normal X chromosome on the left and abnor-
mal X chromosome with satellite (arrow) on the right.
chromosome by crossing over in spermatogenesis. Another patient reportedly had an X p-arm terminal deletion that resulted in loss of Xp22.3 [Temple et al., 19901. In our patient, the chromosome satellite on the abnormal X chromosome was probably translocated from a D or G group chromosome. In three of the four reported patients with the Xp22.3 microdeletion syndrome, a Y chromosome was involved. Fig. 3. Special studies on the X chromosome with a satellite in cells we 'Onsidered whether a y chromosome was in- from lymphocytes. A Q-banding. Ag-NOR staining, C: C-banding. in OUr case- The satellite On the abnomal D DAPI banding. E Replication banding. F General centromeric chromosome could have been derived from a Y chromo- probe cocktail (Oncor, Gaithersburg, MD) for alpha satellite DNA. Thusy
TABLE 1. Karyotype and Clinical Findings of Patients With Xp22.3 Microdeletion Syndrome* Case 4 [Al-Gazali et al., 1988,
5 [Al-Gazali et al., 1988,
19901
19901
1 (F'resent case)
2 [Temple et al., 19901
3 [Al-Gazali et al., 1988, 19901
46,X,- X, + der(X)t (X;?)(p22.3;?) Micmphthalmia, OU Selemornea, OU
Xp22.2-tpter
46,XX,t(X;Y)(p22.3;qll.Z) 46,XX.t(X;Y)(p22.3;q11.2) 46,XX male
Microphthalmia, OS Selemcomea, OU
Microphthalmia, OU Comeal opacity, OS
Light perception
Roving eye movement
Perforated comea, OD (4 mo)
Skin
Cataracts, OU Weeping linear skin lesions on face and neck; healed with scarring
Development Birth weight Gmwth
3,530 g, term 5th centile length at b i d
Light perception Raw linear lesions on face and n e e k healed with scarring Normal at 20 months 4,500 g. term
Parental karyotypes Other findings
Normal Roximally implanted thumbs
Findings
-
aansverse palmar crease Complex cardiac defects Low-pitched cry Posible hearing deticit
Normal
Hypoplastic linear skin defecta on face and neck
-
Normal 2,640 g, term < 3rd centile height and weight by 8 months
-
Normal Minor cutaneous ayndactyly Normal steroid sulfatase activity Abnormal X late replicating No CDP
*CDP, chondrodysplasia punctata; OD, right eye; OS, left eye; OU, both eyes.
Microphthalmia, OU Orbital cyst, OS (eye enucleatedj
Microphthalmia, OU Corneal opacity. OU
Congenital skin defecta on Linear skin defecta in face and neck reticular pattern on face, neck, and chest Normal 3,900 g, term < 3rd centile height and weight hy 2 years 10 months Normal Hypospadias Midline sacra1 dimple Short stature communicating with spinal dermoid (resected) Anteriorly displaced anus No CDP
64
Lindor et al.
some with a satellite or from a complex translocation involving an X chromosome, a Y chromosome, and an acrocentric chromosome with a satellite. However, the karyotype of our patient’s father was normal, and we have been unable to demonstrate any Y chromosome material in our patient with Southern blot analysis. It may be noteworthy that none of the five known patients with the Xp22.3 microdeletion syndrome were males who had a normal Y chromosome (one patient was an XX male). Although this finding may be due to the small sample size, it may also indicate that this particular X p-arm deletion is lethal in males. This hypothesis needs to be reconciled with a report by Curry et al. [1984], who described two pedigrees with a familia1 Xp22.32 deletion in which three female carriers produced four living sons who were each 46,del(X)(p22,3)Y. Each of these sons was mentally retarded and had ichthyosis and skeletal changes of chondrodysplasia punctata (CDP). Perhaps the deletions in these families involved a different site on the X p-arm than the deletion associated with the Xp22.3 microdeletion syndrome. It may be that deletion of Xp22.3 is not lethal in al1 males and it is only a matter of time until a male with del(X) (p22.3)Ysex chromosome complement is found with the microdeletion syndrome. Severa1 contiguous gene loci have been mapped to Xp22.34pter. Some of the important genes and their map sequence are pter-whort stature+CDP, X-linked recessive-X-linked mental retardation-steroid sulfatase deficiency+Kallmann syndromwcen [Ballabio et al., 19891. The literature provides many examples of patients who have various combinations of these syndromes [Happle, 1979, Manzke et al., 1980, Curry et al., 1984,Ballabio et al., 19891.It is possible that the Xp22.3 microdeletion syndrome involves a different breakpoint than other syndromes mapped to the X p-arm. Those few patients with CDP who have microphthalmia and skin lesions may have a deletion that includes some of the genes in the Xp22.3 microdeletion syndrome. Aicardi syndrome is characterized by chorioretinal defects, agenesis of the Corpus, seizures, and developmental delay [Aicardi et al., 19691 and may also be caused by disruptions of genes at Xp22. Microphthalmia is a frequent associated finding in Aicardi syndrome [Donnenfeld et al., 19901 and is a feature of the Xp22.3 microdeletion syndrome. This could suggest that underlying genetic causes of these two syndromes sometimes overlap. The abnormal X chromosome was late replicating in al1 lymphocytes and fibroblasts examined in our patient. In one other patient with the Xp22.3 microdeletion syndrome, the abnormal X chromosome was also late replicating in 50 of 50 metaphases from peripheral blood. This finding suggests that in these tissues the X p-arm deletion may be lethal to developing cells when the normal X chromosome is inactivated. It is possible that the X chromosome replication pattern is different in cells from the skin lesions. Unfortunately, because the skin lesions in our patient occurred on the face, we did not collect a biopsy specimen to pursue this line of investigation. It is interesting that patients with the Xp22.3 micro-
deletion syndrome have such abnormal ocular and skin development whereas other patients with larger X p-arm deficiencies or monosomy X usually have normal eye development. At least four explanations are possible. First, the normal X chromosome may be inactivated in selected tissues (for example, the eye and skin), and the patient is thus made nullisomic for the dista1 X p-arm genes in these tissues. A second explanation might be that the X chromosome breakpoint disrupts an important structural or regulatory gene that subsequently influences embryogenesis in a dominant fashion. A third explanation is that the abnormal X chromosomeis inactivated in al1 cells, and the individual is made hemizygous for al1 genes on the normal X chromosome. Any deleterious genes carried on this chromosome would be unmasked by this nonrandom lyonization. It seems unlikely that the five known patients with the Xp22.3 microdeletion syndrome each carried the same defective gene on their active X chromosome. hrthermore, no 46,XY males have been reported with this clinical syndrome. A fourth explanation might be related to genomic imprinting. A disturbance of this process might explain the phenotypic differences between patients having cytogenetically similar deletions. Our patient is the only one with the Xp22.3 microdeletion syndrome who had congenital heart defects. This could be a variable finding in the Xp22.3 microdeletion syndrome because of partial penetrance or imprinting [Ross et al., 19911.Although the cardiac anomaly in our patient may be dueto the satellite material translocated to the X chromosome, this explanation seems unlikely because chromosome satellites are not generally thought to have clinically significant genes. It is also possible that the X chromosome breakpoint in our patient is slightly different from that in the other patients and caused a disruption in a gene for normal heart development. Alternatively, this heart anomaly could be due to the unmasking of genes on our patient’s normal X chromosome. The distinct linear skin lesions on the face and neck, bilateral microphthalmia, and sclerocornea appear to be major characteristics of the Xp22.3 microdeletion syndrome. Incontinentia pigmenti (Bloch-S-ilzberger syndrome) and foca1 dermal hypoplasia (Goltz syndrome) are also X-linked disorders with distinctive skin and eye abnormalities. Al-Gazali et al. [19901and Temple et al. U9901 discussed in detail how these syndromes are distinguishable from the Xp22.3 microdeletion syndrome.
REFERENCES Aicardi J, Chevrie J-J, Rousselie F (1969): Le syndrome spasmes en flexion, agenesie calleuse, anomalies chorio-retiniennes. Arch Fr Pediatr 261103-1120. Al-Gazali LI, Mueller RF, Caine A, Antoniou A, McCartney A, Fitchett M, Dennis NR (1990): Two 46,XX,t(X;Y)females with linear skin defeds and congenital microphthalmia: A new syndrome a t Xp22.3. J Med Genet 27:59-63. Al-Gazali LI, Mueller RF, Caine A, Dennis N, Antoniou A, Fitchett M, Insley J, Goodfellow PG, Hultén M (1988): An XX male and two t(X,Y) females with linear skin defects and congenital rnicrophthalmia: A new syndrome a t Xp22.3 (abstract). J Med Genet 25:638-639. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Campbell L, Hamel B,Ferguson-Smith MA, Gimelli G, Fraccaro M, Maraschio
Xp22.3 Microdeletion Syndrome P, Zuffardi O, Guioli S, Camerino G (1989): Contiguous gene syndromes due to deletions in the dista1 short arm of the human X chromosome. Prw Natl Acad Sci USA 8610001-10005. Curry CJR, Magenis RE, Brown M, Lanman JT, Tsai J, O'Lague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro LJ (1984):Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 311:lOlO-1015. Donnenfeld AE, Graham J M Jr, F'acker RJ, Aquino R, Berg SZ, Emanuel BS (1990):Microphthalmia and chorioretinal lesions in a girl with an Xp22.2-pter deletion and partial 3p trisomy: Clinical observations relevant to Aicardi syndrome gene localization. Am J Med Genet 37:182-186.
65
Happle R (1979):X-linked dominant chondrodysplasia punctata. Hum Genet 53:65-73. Manzke H, Christophers E, Wiedemann H-R (1980): Dominant sexlinked inherited chondrodysplasia punctata: A distinct type of chondrodysplasia punctata. Clin Genet 17:97-107. Ross JL, Hall JG, Pfendner EG (1991):The contribution of imprinting to the phenotype in Turner syndrome (abstract). Am J Med Genet 49 Suppl 4:19. Temple IK, Hurst JA, Hing S, Butler L, Baraister M (1990): De novo deletion of Xp22.2-pter in a female with linear skin lesions of the face and neck, microphthalmia, and anterior chamber eye anomalies. J Med Genet 2756-58.
Xp22.3 Microdeletion Syndrome With Microphthalmia, Sclerocornea, Linear Skin Defects, and Congenital Heart Defects Noralane M. Lindor, Virginia V. Michels, Daniel A. Hoppe, David J. Driscoll, Jacqueline A. Leavitt, and Gordon W. Dewald Department of Medical Genetics (N.M.L.,V.V.M.),the Sectwn of Laboratory Genetics (DA.€€.,G.W.D.), Department of Pediatrics (D.J.D.),and the Department of Ophthalmology (J.A.L.),Mayo Clinic and Mayo Foundatwn, Rochester, Minnesota We report on an infant girl with congenital erythematous, linear skin lesions on face and neck, bilateral microphthalmia, sclerocornea, cataracts, and a complex cardiac anomaly including atrial septal and ventricular septal defects. This patient had an Xp22.3 microdeletion and a chromosome satellite on the abnormal X p-arm. The abnormal X chromosome was late replicating in peripheral blood lymphocytes and cultured skin fibroblasts. Four other patients with similar congenital anomalies a n d Xp deficiency have been reported previously and are compared with this patient. One patient had an interstitial or terminal deletion, but in others the material translocated to Xp22.3 was variable (Yq material in two patients, a n d Yp material and an unidentifiable satellite in one patient each). Severa1 mechanisms are suggested by which this chromosome abnormality might produce this phenotype in these patients. Our patient is the first with this syndrome to have a congenital heart defect. o 1992 Wiiey-Liss, inc.
KEY WORDS: Xp deletion, pseudoautosomal, dermal hypoplasia, translocation, Y chromosome, cataracts, contiguous gene, hemizygous INTRODUCTION Recently,a new microdeletion syndrome involving the absence of Xp22.3 was described by Al-Gazali et al. 11988, 19901 and Temple et al. [19901. This syndrome has been reported in four patients. It consists of bilateral
Received for publication October 18,1991;revision received January 24, 1992. Address reprint requests to Dr. Virginia V. Michels, Department of Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
O 1992 Wiley-Liss, Inc.
microphthalmia, sclerocornea, and an unusual linear skin lesion that is clinically distinguishable from incontinentia pigmenti and foca1 dermal hypoplasia. This report describes the fifth case of this clinical syndrome involving a similar absence of Xp22.3. Unlike the other four patients, this patient had a severe congenital heart defect and cataracts. These may be additional manifestations of the Xp22.3 microdeletion syndrome. CLINICAL REPORT Clinical Findings This infant was born a t term (weight, 3,530 g; 75th centile) after an uneventful pregnancy and delivery to a 19-year-old gravida 4, para 3 Alaskan woman. At birth, the infant had unusual red, weepy, reticulolinear, nonvesicular skin lesions on her face and neck and bilateral eye abnormalities (Fig. 1). Congestive heart failure developed a t age 2 days. At age 4 weeks, she was transferred to our institution for a h e a e operation. On arrival she weighed 3.19 kg (10th centile) and had a length of 49 cm (5th centile) and occipito-frontal head circumference (OFC) of 34.6 cm (10th centile). The skin over the face was characterized by erythematous, denuded-appearing, linear streaks beginning media1 to the inner canthi and continuing down along the side of the nose, onto the cheeks, and up along the left jaw line to over the left ear. The streaks also continued down the right cheek and jaw line to the neck, where the pattern became less linear and more reticular. The skin on the remainder of the body was normal. Her hair and nails showed no abnormalities. The cardiac lesions were a large malalignment paramembranous ventricular septal defect with an overriding aorta, an additional small muscular ventricular septal defect, a secundum atrial septal defect, and azygous continuation of the inferior vena cava t o the right superior vena cava. In addition, the patient had intermittent junctional rhythm and a wandering atrial pacemaker. Ophthalmologic evaluation showed bilateral microphthalmia, nearly complete sclerocornea, and dense cataracts. Ultrasonography of the globes confirmed the microphthalmia and suggested some choroidal thickening. No cysts were identified. The skin lesions healed with minimal crusting and with the
62
Lindor et al.
Fig. 1. A Linear skin lesions on face at 4 weeks of age. B: Eye, showing microphthalmia, sclerocornea, and cataract at 8 weeks of age.
appearance of linear brown streaks of pigmentation. No new skin lesions appeared. Other physical findings included a highly arched palate, proximally implanted thumbs, and bilateral transverse palmar creases. Computed tomography of her head was normal, as was renal ultrasonography. A radiograph of one femur at 2 weeks of age and a complete skeletal survey at 8 weeks of age documented no abnormalities. Audiometric screening, including brain stem evoked responses, was suggestive of a hearing defect. Her postoperative course included one episode of pneumonia and a continued need for supplemental oxygen at the time of dismissal. Her weight a t age 9 weeks was 3,810 g (10th centile).
Laboratory Studies Analysis of GTL-banded chromosomes from peripheral blood and skin fibroblasts showed an abnormal X chromosomethat appeared to be derived from an unbalanced translocation involving an X chromosome and an unidentifiable chromosome that carried a satellite (Fig. 2). The patient’s karyotype was 46,X, - X, + der(X) t(X;?)(p22.3;?). The translocation resulted in loss of Xp22.3. The satellite was Ag-NOR positive and C-band negative, and it stained dully with Q-banding and DAPI banding (Fig. 3 A,B,C,D). With fluorescent in situ hybridization with a generalized human centromeric Drobe for alpha satellite DNA (Oncor, Gaithersburg, MD),no centromeric material was found in the area of
the X p-arm; this result suggests that the breakpoint occurred in the stalk of the satellite (Fig. 3E). Chromosome replication studies showed the abnormal X to be the late-replicating X in 30 of 30 lymphocytes and in 30 of 30 fibroblasts (Fig. 3F). DNA studies from skin fibroblasts for Y-specific probes 472 (Yp11.2)and 50F2 (Yp11.2+p11.3 and Yq11.2) did not show evidence ofY chromatin. The patient’s parents could not accompany their infant to our institution. However, we did obtain blood specimens from each of the parents, and each of their karyotypes was normal. Epstein-Barr virus-immortalized lymphocytes from this infant and her parents have been stored for other possible genetic studies. We have also stored fibroblasts from a skin biopsy specimen from the infant.
DISCUSSION The clinical and laboratory findings of the four other reported patients with the Xp22.3 microdeletion syndrome are compared with the findings in our patient in Table 1. An X;Y translocation was involved in two of these cases, and break and fusion points were at Xp22.3 and Yq11.2 [Al-Gazali et al., 1988, 19901. One other patient was an XX male, in whom Southern blot analysis showed the presence of Yp material [Al-Gazali et al., 19881. The results in this reported XX male imply that the X chromosomes appeared normal and some of the Y chromosome may h&e been transferred to an X
Xp22.3 Microdeletion Syndrome
63
Fig. 2. GTL-banded normal X chromosome on the left and abnor-
mal X chromosome with satellite (arrow) on the right.
chromosome by crossing over in spermatogenesis. Another patient reportedly had an X p-arm terminal deletion that resulted in loss of Xp22.3 [Temple et al., 19901. In our patient, the chromosome satellite on the abnormal X chromosome was probably translocated from a D or G group chromosome. In three of the four reported patients with the Xp22.3 microdeletion syndrome, a Y chromosome was involved. Fig. 3. Special studies on the X chromosome with a satellite in cells we 'Onsidered whether a y chromosome was in- from lymphocytes. A Q-banding. Ag-NOR staining, C: C-banding. in OUr case- The satellite On the abnomal D DAPI banding. E Replication banding. F General centromeric chromosome could have been derived from a Y chromo- probe cocktail (Oncor, Gaithersburg, MD) for alpha satellite DNA. Thusy
TABLE 1. Karyotype and Clinical Findings of Patients With Xp22.3 Microdeletion Syndrome* Case 4 [Al-Gazali et al., 1988,
5 [Al-Gazali et al., 1988,
19901
19901
1 (F'resent case)
2 [Temple et al., 19901
3 [Al-Gazali et al., 1988, 19901
46,X,- X, + der(X)t (X;?)(p22.3;?) Micmphthalmia, OU Selemornea, OU
Xp22.2-tpter
46,XX,t(X;Y)(p22.3;qll.Z) 46,XX.t(X;Y)(p22.3;q11.2) 46,XX male
Microphthalmia, OS Selemcomea, OU
Microphthalmia, OU Comeal opacity, OS
Light perception
Roving eye movement
Perforated comea, OD (4 mo)
Skin
Cataracts, OU Weeping linear skin lesions on face and neck; healed with scarring
Development Birth weight Gmwth
3,530 g, term 5th centile length at b i d
Light perception Raw linear lesions on face and n e e k healed with scarring Normal at 20 months 4,500 g. term
Parental karyotypes Other findings
Normal Roximally implanted thumbs
Findings
-
aansverse palmar crease Complex cardiac defects Low-pitched cry Posible hearing deticit
Normal
Hypoplastic linear skin defecta on face and neck
-
Normal 2,640 g, term < 3rd centile height and weight by 8 months
-
Normal Minor cutaneous ayndactyly Normal steroid sulfatase activity Abnormal X late replicating No CDP
*CDP, chondrodysplasia punctata; OD, right eye; OS, left eye; OU, both eyes.
Microphthalmia, OU Orbital cyst, OS (eye enucleatedj
Microphthalmia, OU Corneal opacity. OU
Congenital skin defecta on Linear skin defecta in face and neck reticular pattern on face, neck, and chest Normal 3,900 g, term < 3rd centile height and weight hy 2 years 10 months Normal Hypospadias Midline sacra1 dimple Short stature communicating with spinal dermoid (resected) Anteriorly displaced anus No CDP
64
Lindor et al.
some with a satellite or from a complex translocation involving an X chromosome, a Y chromosome, and an acrocentric chromosome with a satellite. However, the karyotype of our patient’s father was normal, and we have been unable to demonstrate any Y chromosome material in our patient with Southern blot analysis. It may be noteworthy that none of the five known patients with the Xp22.3 microdeletion syndrome were males who had a normal Y chromosome (one patient was an XX male). Although this finding may be due to the small sample size, it may also indicate that this particular X p-arm deletion is lethal in males. This hypothesis needs to be reconciled with a report by Curry et al. [1984], who described two pedigrees with a familia1 Xp22.32 deletion in which three female carriers produced four living sons who were each 46,del(X)(p22,3)Y. Each of these sons was mentally retarded and had ichthyosis and skeletal changes of chondrodysplasia punctata (CDP). Perhaps the deletions in these families involved a different site on the X p-arm than the deletion associated with the Xp22.3 microdeletion syndrome. It may be that deletion of Xp22.3 is not lethal in al1 males and it is only a matter of time until a male with del(X) (p22.3)Ysex chromosome complement is found with the microdeletion syndrome. Severa1 contiguous gene loci have been mapped to Xp22.34pter. Some of the important genes and their map sequence are pter-whort stature+CDP, X-linked recessive-X-linked mental retardation-steroid sulfatase deficiency+Kallmann syndromwcen [Ballabio et al., 19891. The literature provides many examples of patients who have various combinations of these syndromes [Happle, 1979, Manzke et al., 1980, Curry et al., 1984,Ballabio et al., 19891.It is possible that the Xp22.3 microdeletion syndrome involves a different breakpoint than other syndromes mapped to the X p-arm. Those few patients with CDP who have microphthalmia and skin lesions may have a deletion that includes some of the genes in the Xp22.3 microdeletion syndrome. Aicardi syndrome is characterized by chorioretinal defects, agenesis of the Corpus, seizures, and developmental delay [Aicardi et al., 19691 and may also be caused by disruptions of genes at Xp22. Microphthalmia is a frequent associated finding in Aicardi syndrome [Donnenfeld et al., 19901 and is a feature of the Xp22.3 microdeletion syndrome. This could suggest that underlying genetic causes of these two syndromes sometimes overlap. The abnormal X chromosome was late replicating in al1 lymphocytes and fibroblasts examined in our patient. In one other patient with the Xp22.3 microdeletion syndrome, the abnormal X chromosome was also late replicating in 50 of 50 metaphases from peripheral blood. This finding suggests that in these tissues the X p-arm deletion may be lethal to developing cells when the normal X chromosome is inactivated. It is possible that the X chromosome replication pattern is different in cells from the skin lesions. Unfortunately, because the skin lesions in our patient occurred on the face, we did not collect a biopsy specimen to pursue this line of investigation. It is interesting that patients with the Xp22.3 micro-
deletion syndrome have such abnormal ocular and skin development whereas other patients with larger X p-arm deficiencies or monosomy X usually have normal eye development. At least four explanations are possible. First, the normal X chromosome may be inactivated in selected tissues (for example, the eye and skin), and the patient is thus made nullisomic for the dista1 X p-arm genes in these tissues. A second explanation might be that the X chromosome breakpoint disrupts an important structural or regulatory gene that subsequently influences embryogenesis in a dominant fashion. A third explanation is that the abnormal X chromosomeis inactivated in al1 cells, and the individual is made hemizygous for al1 genes on the normal X chromosome. Any deleterious genes carried on this chromosome would be unmasked by this nonrandom lyonization. It seems unlikely that the five known patients with the Xp22.3 microdeletion syndrome each carried the same defective gene on their active X chromosome. hrthermore, no 46,XY males have been reported with this clinical syndrome. A fourth explanation might be related to genomic imprinting. A disturbance of this process might explain the phenotypic differences between patients having cytogenetically similar deletions. Our patient is the only one with the Xp22.3 microdeletion syndrome who had congenital heart defects. This could be a variable finding in the Xp22.3 microdeletion syndrome because of partial penetrance or imprinting [Ross et al., 19911.Although the cardiac anomaly in our patient may be dueto the satellite material translocated to the X chromosome, this explanation seems unlikely because chromosome satellites are not generally thought to have clinically significant genes. It is also possible that the X chromosome breakpoint in our patient is slightly different from that in the other patients and caused a disruption in a gene for normal heart development. Alternatively, this heart anomaly could be due to the unmasking of genes on our patient’s normal X chromosome. The distinct linear skin lesions on the face and neck, bilateral microphthalmia, and sclerocornea appear to be major characteristics of the Xp22.3 microdeletion syndrome. Incontinentia pigmenti (Bloch-S-ilzberger syndrome) and foca1 dermal hypoplasia (Goltz syndrome) are also X-linked disorders with distinctive skin and eye abnormalities. Al-Gazali et al. [19901and Temple et al. U9901 discussed in detail how these syndromes are distinguishable from the Xp22.3 microdeletion syndrome.
REFERENCES Aicardi J, Chevrie J-J, Rousselie F (1969): Le syndrome spasmes en flexion, agenesie calleuse, anomalies chorio-retiniennes. Arch Fr Pediatr 261103-1120. Al-Gazali LI, Mueller RF, Caine A, Antoniou A, McCartney A, Fitchett M, Dennis NR (1990): Two 46,XX,t(X;Y)females with linear skin defeds and congenital microphthalmia: A new syndrome a t Xp22.3. J Med Genet 27:59-63. Al-Gazali LI, Mueller RF, Caine A, Dennis N, Antoniou A, Fitchett M, Insley J, Goodfellow PG, Hultén M (1988): An XX male and two t(X,Y) females with linear skin defects and congenital rnicrophthalmia: A new syndrome a t Xp22.3 (abstract). J Med Genet 25:638-639. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Campbell L, Hamel B,Ferguson-Smith MA, Gimelli G, Fraccaro M, Maraschio
Xp22.3 Microdeletion Syndrome P, Zuffardi O, Guioli S, Camerino G (1989): Contiguous gene syndromes due to deletions in the dista1 short arm of the human X chromosome. Prw Natl Acad Sci USA 8610001-10005. Curry CJR, Magenis RE, Brown M, Lanman JT, Tsai J, O'Lague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro LJ (1984):Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 311:lOlO-1015. Donnenfeld AE, Graham J M Jr, F'acker RJ, Aquino R, Berg SZ, Emanuel BS (1990):Microphthalmia and chorioretinal lesions in a girl with an Xp22.2-pter deletion and partial 3p trisomy: Clinical observations relevant to Aicardi syndrome gene localization. Am J Med Genet 37:182-186.
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Happle R (1979):X-linked dominant chondrodysplasia punctata. Hum Genet 53:65-73. Manzke H, Christophers E, Wiedemann H-R (1980): Dominant sexlinked inherited chondrodysplasia punctata: A distinct type of chondrodysplasia punctata. Clin Genet 17:97-107. Ross JL, Hall JG, Pfendner EG (1991):The contribution of imprinting to the phenotype in Turner syndrome (abstract). Am J Med Genet 49 Suppl 4:19. Temple IK, Hurst JA, Hing S, Butler L, Baraister M (1990): De novo deletion of Xp22.2-pter in a female with linear skin lesions of the face and neck, microphthalmia, and anterior chamber eye anomalies. J Med Genet 2756-58.
