Journal of Pediatric Ophthalmology and Strabismus

SHORT SUBJECTS 

Bilateral Peter's Anomaly in an Infant With 49,XXXXY Syndrome

Kristin G Monaghan, PhD; Patrick J Dennehy, MD; Daniel L VanDyke, PhD; Lester Weiss, MD

Abstract

INTRODUCTION

Peter's anomaly is characterized by central corneal leukomas, posterior corneal defects including localized absence of endothelium and Descemet's membrane, and corneal-iris adhesions.1 The morphology varies from minor corneal leukoma with iridocorneal adhesions and a clear lens, to severe corneal opacification, extensive synechiae between the iris and cornea, cataracts, and glaucoma.

Peter's anomaly can be associated with endocrine, cardiovascular, and genitourinary abnormalities; mental retardation; growth retardation; microcephaly; hearing loss; abnormal ears; cleft lip or palate; and defects of the extremities. Peter's-plus syndrome, probably an autosomal recessive condition, is characterized by typical facies, ear anomalies, and short-limb dwarfism with or without cleft lip or palate and mental retardation.2

Mendelian inheritance has been proposed for Peter's anomaly, and has been associated with teratogen exposures3 and chromosome abnormalities. Hanson et al4 identified a child with sporadic Peter's anomaly and an llplS deletion, and described a family with dominantly inherited Peter's anomaly, and a point mutation in the PAX6 gene, located at Ilpl3.

PAX6 functions as a transcriptional regulator and is expressed in the neural tube, brain, and developing eye.4 Some chromosome abnormalities associated with Peter's anomaly may interrupt a gene or group of genes that interact with PAX6 or other proteins involved in eye morphogenesis. Kivlin et al5 reported two siblings with Peter's anomaly, short-limb dwarfism, and similar facies. One had a balanced translocation, t(2;15)(q21;q26.1), and the other had a normal karyotype. They concluded that Peter's anomaly was inherited as an autosomal recessive trait in this family, and that the translocation was coincidental.

Several autosomal chromosome abnormalities have been reported with Peter's anomaly. Bilateral Peter's anomaly with multiple congenital defects has been reported with deletion 4p-3, deletion 18q3 and trisomy 131. Isolated bilateral Peter's anomaly has been reported with interstitial deletion Ilql4 or Ilq21 in a 5-week-old male.3 Bilateral atypical Peter's anomaly has been associated with duplication 5p6 and trisomy 9 mosaicism.7 Eighty percent of the cases are bilateral; however, unilateral Peter's anomaly with multiple congenital defects has been reported with ring 213 and unilateral atypical Peter's anomaly with deletion 2ql4q21.8 We examined a patient with congenital bilateral Peter's anomaly and a rare variant of Klinefelter's syndrome, 49,XXXXY syndrome.

CASE REPORT

The patient was seen at 5 days of age for evaluation of bilateral, congenital corneal opacities. He was born at 36 weeks gestation to healthy, nonconsanguinous parents. The pregnancy was uneventful, with no known teratogen exposure. There was no family history of congenital eye disease; however, the patient's paternal grandfather had blindness of unknown etiology in his 40s. Birth weight (2154 g) and length (46 cm) were appropriate for gestational age.

Ophthalmologic examination revealed central and steady visual fixation in each eye. Pupils were round, equal, and reactive to light without afferent defect. The eyelids and ocular adenexa were normal. There was a 3mm, wedge-shaped, white corneal opacity in the central cornea of the right eye. A 2-mm, comma-shaped, white corneal opacity was located in the central cornea of the left eye, just nasal to the visual axis. Fine iris processes extended from the iris to the corneal endothelium at the margin of the opacities. The irides were otherwise normal and the lenses were clear. Funduscopic exam in both eyes was normal, with an estimated 20/70 view through the opacity in the right eye and 20/50 view through the opacity in the left eye. There was a venous loop on the optic disc in the left eye. Cyeloplegic retinoscopy was +0.75 sphere in the right eye and +1.25 sphere in the left eye.

At 1 month and again at 5 months of age, normal visual fixation and following movements were demonstrated in…

INTRODUCTION

Peter's anomaly is characterized by central corneal leukomas, posterior corneal defects including localized absence of endothelium and Descemet's membrane, and corneal-iris adhesions.1 The morphology varies from minor corneal leukoma with iridocorneal adhesions and a clear lens, to severe corneal opacification, extensive synechiae between the iris and cornea, cataracts, and glaucoma.

Peter's anomaly can be associated with endocrine, cardiovascular, and genitourinary abnormalities; mental retardation; growth retardation; microcephaly; hearing loss; abnormal ears; cleft lip or palate; and defects of the extremities. Peter's-plus syndrome, probably an autosomal recessive condition, is characterized by typical facies, ear anomalies, and short-limb dwarfism with or without cleft lip or palate and mental retardation.2

Mendelian inheritance has been proposed for Peter's anomaly, and has been associated with teratogen exposures3 and chromosome abnormalities. Hanson et al4 identified a child with sporadic Peter's anomaly and an llplS deletion, and described a family with dominantly inherited Peter's anomaly, and a point mutation in the PAX6 gene, located at Ilpl3.

PAX6 functions as a transcriptional regulator and is expressed in the neural tube, brain, and developing eye.4 Some chromosome abnormalities associated with Peter's anomaly may interrupt a gene or group of genes that interact with PAX6 or other proteins involved in eye morphogenesis. Kivlin et al5 reported two siblings with Peter's anomaly, short-limb dwarfism, and similar facies. One had a balanced translocation, t(2;15)(q21;q26.1), and the other had a normal karyotype. They concluded that Peter's anomaly was inherited as an autosomal recessive trait in this family, and that the translocation was coincidental.

Several autosomal chromosome abnormalities have been reported with Peter's anomaly. Bilateral Peter's anomaly with multiple congenital defects has been reported with deletion 4p-3, deletion 18q3 and trisomy 131. Isolated bilateral Peter's anomaly has been reported with interstitial deletion Ilql4 or Ilq21 in a 5-week-old male.3 Bilateral atypical Peter's anomaly has been associated with duplication 5p6 and trisomy 9 mosaicism.7 Eighty percent of the cases are bilateral; however, unilateral Peter's anomaly with multiple congenital defects has been reported with ring 213 and unilateral atypical Peter's anomaly with deletion 2ql4q21.8 We examined a patient with congenital bilateral Peter's anomaly and a rare variant of Klinefelter's syndrome, 49,XXXXY syndrome.

CASE REPORT

The patient was seen at 5 days of age for evaluation of bilateral, congenital corneal opacities. He was born at 36 weeks gestation to healthy, nonconsanguinous parents. The pregnancy was uneventful, with no known teratogen exposure. There was no family history of congenital eye disease; however, the patient's paternal grandfather had blindness of unknown etiology in his 40s. Birth weight (2154 g) and length (46 cm) were appropriate for gestational age.

Ophthalmologic examination revealed central and steady visual fixation in each eye. Pupils were round, equal, and reactive to light without afferent defect. The eyelids and ocular adenexa were normal. There was a 3mm, wedge-shaped, white corneal opacity in the central cornea of the right eye. A 2-mm, comma-shaped, white corneal opacity was located in the central cornea of the left eye, just nasal to the visual axis. Fine iris processes extended from the iris to the corneal endothelium at the margin of the opacities. The irides were otherwise normal and the lenses were clear. Funduscopic exam in both eyes was normal, with an estimated 20/70 view through the opacity in the right eye and 20/50 view through the opacity in the left eye. There was a venous loop on the optic disc in the left eye. Cyeloplegic retinoscopy was +0.75 sphere in the right eye and +1.25 sphere in the left eye.

At 1 month and again at 5 months of age, normal visual fixation and following movements were demonstrated in each eye. There was no objection to occluding either eye. No strabismus was noted. The corneal opacities were unchanged. Cyeloplegic retinoscopy was +1.75 sphere in each eye with good reflexes without scissoring.

At 5 months of age (Fig 1), his developmental milestones were delayed. Length was 56.5 cm, weight 4196 g, and head circumference 38 cm (all <5th percentue after adjustment for prematurity). His left ear measured 4.4 cm and was narrow and elongated compared with the right ear (4 cm). He had short palpebrai fissures with increased inner canthal distance (2.5 cm, >+l SD) and decreased outer canthai distance (6.2 cm, <-2 SD). He had bilateral corneal opacities, broad nasal bridge, intact palate, and umbilical hernia. He had normal genitalia. Palmar creases and digits were normal. Bone age was <2 SD for chronological age. Tests for thyroid and insulin-like growth factor 1 were normal. G-banded karyotype was 49,XXXXY.

DISCUSSION

49,XXXXY is a variant of Klinefelter's syndrome (47,XXY) with an incidence of 1/85,000. The phenotype is characterized by microcephaly, coarse facies, hypertelorism, epicanthal folds, upslanting palpebrai fissures, broad nasal bridge, low-set or malformed ears, and mandibular prognathism. To our knowledge, anterior segment anomalies have not been reported with Klinefelter's syndrome or its variants. Cleft palate or bifid uvula are common. Skeletal anomalies include radioulnar synostosis, clinodactyly of the fifth digit, minor malformations of the vertebral column, short stature, and delayed bone age. Cardiac defects may be present. The genitalia are often hypoplastic with cryptorchidism, defective prepubertal development of seminiferous tubules, hypoplastic Leydig cells, and absent germ cells.9 Moderate-to-severe mental retardation is typical. Like men with Klinefelter's syndrome, 49,XXXXY males are more deficient in speech and language abilities than nonverbal skills.10

Peter's anomaly in our patient may have been caused by the sex chromosome abnormality or autosomal recessive inheritance unrelated to the aneuploidy. Although a new dominant mutation is possible, autosomal dominant inheritance is unlikely as neither parent is affected. A higher copy number of genes that normally escape inactivation along the X chromosome may be involved in the abnormalities that occur with the 49,XXXXY genotype. Perhaps one of these genes is involved in the normal development of the anterior segment of the eye.

Aneuploidy may result in unusually high expression, interrupt normal ocular embryogenesis, and result in Peter's anomaly. If this scenario is correct, because 49,XXXXY is a sporadic event unrelated to parental age, the recurrence risk to our patient's parents would be nominal. If the Peter's anomaly occurred independently of the aneuploidy, in a recessive inheritance pattern, then the recurrence risk to his parents is 25%. Therefore, the chance of this anomaly occurring in future pregnancies of our patient's parents may be as high as 25%.

In affected individuals where chromosome abnormalities are due to parental chromosome rearrangements, the recurrence risk for Peter's anomaly would be different. In families where there is autosomal dominant inheritance of Peter's anomaly, the recurrence risk is 50%.

To our knowledge, this is the first report of Peter's anomaly associated with any sex chromosome abnormality. The lack of a consistent karyotype abnormality associated with Peter's anomaly suggests that there are multiple genetic or environmental effects associated with its development.

Fig 1: Patient at 5 months. Note bilateral corneal opacities, short palpebrai fissures, and broad nasal bridge.

Fig 1: Patient at 5 months. Note bilateral corneal opacities, short palpebrai fissures, and broad nasal bridge.

As demonstrated with PAX6, chromosome abnormalities can be used to identify genes related to Peter's anomaly. This will improve counseling because recurrence risks will be more accurately calculated. We recommend a genetics evaluation or detailed family history and karyotype for all patients with Peter's anomaly, whether it occurs with multiple congenital defects or as an isolated malformation.

REFERENCES

1. Yanoff M, Fine BS. Ocular Pùthology, A Text and Atlas. Philadelphia, Pa: Harper and Row; 1982:41-311.

2. Hennekam RCM, Van Schooneveld MJ, Ardinger HH, et al. The Peter'sPlus syndrome: description of 16 patients and review of the literature. Clinical Dysmorphohgy, 1993;2:283-300.

3. Trabousli EI, Maumenee IH. Peter's anomaly and associated congenital malformations. Aren Ophthalmol. 1992; 110: 1739- 1742.

4. Hanson IM, Fletcher JM, Jordan T, Brown A, Taylor D, Adams RJ, Punnett HH, Heyningen V. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peter's anomaly. Nature Genetics. 1994;6:168-173.

5. Kivlin JD, Fineman RM, Crandall AS, Olson RJ. Peter's anomaly as a consequence of genetic and nongenetic syndromes. Arch Ophthalmol. 1986; 204:61-64,

6. Dichtl A, Joñas JB, Neumann OH. Atypical Peter's anomaly associated with partial trisomy Sp. Am J Ophthalmol. 1995;120:541-543.

7. Ginsberg J, Soukup S, Ballard ET. Pathologic features of the eye in trisomy 9. J Pediatr Ophthalmol Strabismus. 1982; 19:37-41.

8. Frydman M, Steinberger J, Shabtai F, Katznelson, MB, Varsano I. Interstitial deletion 2ql4q21. Am J Med Genet. 1989;34:476-479.

9. Hamerton JL. Human Cytogenetics, General Cytogenetics. New York, NY: Academic Press, Ine; 1971:37-51.

10. Sheridan MK, Radlinski SS, Kennedy MD. Developmental outcome in 49,XXXXY Klinefelter's syndrome. Developmental Medicine and Child Neurology. 1990:32:528-546.

10.3928/0191-3913-19980301-11

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