Pallister-Killian syndrome is a rare multiple congenital abnormality/mental retardation syndrome caused by mosaic tetrasomy for the short arm of chromosome 12 (12p). The abnormal cell line is not detectable in lymphocyte culture from babies born at full term or older patients, and the diagnosis relies on its detection in skin fibroblasts.1
This unusual genotype was first described by Pallister et al in 1977. 2 The characteristic associated phenotype was subsequently defined by Killian and others3*6 in the 1980s and consists of craniofacial dysmorphism, aberrant scalp hair pattern, hypotonia, developmental delay, and mental retardation. Patchy skin hypopigmentation is a significant but not constant finding.
A few infants with Pallister-Killian syndrome have been reported to have poor vision and/or horizontal pendular nystagmus.5,7,13 However, apart from one case in which pale fundi were observed,10,11 ocular abnormalities that might account for the poor vision nystagmus in these infants have not been reported. We report a second infant with Pallister-Killian syndrome having poor vision and horizontal pendular nystagmus associated with hypopigmentation of the fundí and additionally an abnormal electroretinogram (ERG). We also discuss the possibility that hypopigmentation of the fundi might be a nonspecific sign of chromosomal mosaicism and not directly attributable to the tetrasomy 12p.
The infant boy was born to healthy unrelated parents after an uncomplicated full-term pregnancy. There was no family history of systemic or ocular problems. Shortly after birth, he was noted to be dysmorphic with a prominent forehead, flat nasal bridge, hypertelorism, and small low set ears. A clinical diagnosis of Palli ster- Killian syndrome was confirmed by a skin biopsy that showed mosaic tetrasomy 12p in the fibroblasts.
By 5 months of age, he was showing developmental delay with hypotonia and poor head control. He was of average complexion with brown hair, but had developed an aberrant scalp hair pattern characteristic of PallisterKillian syndrome. Skin pigmentation was normal and no other major congenital anomalies had been discovered (Fig 1).
Although his parents were not concerned by his level of vision, they had noticed his abnormal eye movements from 2 months of age. At 6 months of age, he was referred to us by his pediatrician, who felt his vision was reduced.
Examination confirmed his vision to be poor; he looked to a bright light but would not follow large toys. He had an alternating divergent squint and a horizontal pendular nystagmus. He had hypertelorism, bilateral telecanthus, and bilateral lower Hd entropion. He had brown irides with mild stromal hypoplasia, pupillary miosis, but no iris transillumination.
He subsequently underwent an examination under anesthetic. This showed the media to be clear but revealed marked hypopigmentation of both fundi, which appeared to result from an absence of pigment in both the retinal pigment epithelium (RPE) and choroid. He also had abnormal optic discs that were vertically oval and of a pseudopapillodematous appearance (Fig 2).
Refractive error was OD - 1.50 D, and OS - 1.00 D. It was only possible to perform a minimally dark adapted (5 minutes) single white flash ERG and visually evoked cortical potential (VECP) on the left eye. The ERG A and B wave implicit times were 15.20 ms and 34.00 ms respectively and within normal limits. The A wave amplitude was 35.15 µ-V and the B wave amplitude was 50.78 µ V.
Our laboratory does not have a large enough database to give normal values for an infant of this age; however, by our standards for older ages the B wave was significantly reduced. We would expect at least in excess of 100.00 µ V. The major positive wave of the VECP occurred at 80 ms with an amplitude of 9.15 µ V, which we would consider normal.
FIGURE 1: Appearance of craniofacial dysmorphism at 6 months. Note the characteristic aberrant scalp hair pattern.
Since the first description by Pallister et al of this unusual genotype in two adult patients,2 over 40 cases of Pallister-Killian syndrome have been described, mostly in infants or children.
The craniofacial dysmorphism associated with this syndrome almost universally results in hypertelorism. Telecanthus, epicanthus, and upslanting palpebrai fissures are also common features. Sparse eyebrows and eyelashes have been described in infants with the syndrome,5'7'8 however, the two adults who formed the basis of Pallister's original description had synophrys and ectopie eyebrow or eyelash hairs on the upper lids. These two adult patients aged 19 and 39 years, also had cataracts more marked in the older patient, but congenital cataracts have not been described.
The infant we report had bilateral lower lid entropion, an association that has been described once previously.14 Although not present in our infant, ptosis has been reported in seven cases of Pallister-Killian syndrome.5,7,8,11 The ptosis was bilateral in all but one case. Strabismus is another common ocular association, having been reported in seven cases.5,7,8,12
All but two cases have demonstrated an exotropia as was also present in our infant. An optic disc abnormality, optic disc hypoplasia, has been reported only once in an infant with Pallister-Killian syndrome who also had strabismus but no nystagmus or visual problems and otherwise normal eyes.8 The most severe ocular abnormality to have been described in Pallister-Killian syndrome is microphthalmos, which has been reported in postmortem studies on several infants whose congenital anomalies were so severe as to result in death shortly after birth.15,16
Poor vision has previously been reported in five infants with this syndrome,5,7,9 and in two of the cases7,8 there was an associated horizontal pendular nystagmus. Additionally, three cases10'13 have been reported to have horizontal pendular nystagmus, but with no comment made on the vision. However, in only one of these eight cases has an ocular abnormality that might account for the poor vision and/or nystagmus been described.10,11
FIGURE 2: Fundus appearance age 11 months showing abnormal optic disc and absence of normal fundus pigmentation with the exception of small cuff of pigment around the optic disc.
This was in a 7-month-old girl reported on in the genetic literature who had multiple abnormalities and a horizontal pendular nystagmus, although no comment was made on the vision. She underwent an examination under anesthetic that showed small pupils with iris stromal hypoplasia, pale fundí, but normal optic discs and a normal ERG.
The infant we report on had poor visual fixation, and like this previously reported case, small pupils with iris stromal hypoplasia, hypopigmentation of the fundi, and an associated horizontal pendular nystagmus, which possibly could be attributed to a primary visual defect. Additionally, the electrodiagnostic tests in our infant suggest a normal visual pathway (normal VECP) but more localized reduction in retinal function as reflected in the reduced ERG amplitude.
These findings in this second case of hypopigmentation of the fundi associated with Pallister-Killian syndrome raise the possibility that poor vision resulting from abnormal macular function associated with hypopigmentation of the fundi may be a feature of some cases of this syndrome.
The infant we report on also had an abnormal optic disc appearance and we cannot exclude compromised optic nerve function as a factor in his poor vision. Additionally, it should be considered that Pallister-Killian syndrome is associated with severe mental retardation and frequent other neurologic deficits. It is possible, therefore, that part or all of the reduced vision, and also the nystagmus in this and the other cases, could in fact be secondary to these severe neurologic and cognitive deficits.
Patchy skin hypopigmentation is also an important, but not constant, feature of Pallister-Killian syndrome.5 Pigmentary skin dysplasia including that seen in Pallister-Killian syndrome are now recognized as probable nonspecific markers of genetic mosaicism and not the result of the specific chromosomal abnormality, such as tetrasomy 12p.17
The most spectacular presentation of such a pigmentary skin dysplasia occurs in Hypomelanosis of Ito (HI) with its linear streaks and whorls of hypopigmented skin. No consistent chromosomal abnormality is found in HI, but various forms of chromosomal mosaicism are common.18
The pigmentary dysplasia and other abnormalities seen in HI are postulated to result from a generalized disorder of migration of neural crest cells,19 the cells from which skin melanocytes are derived. Interestingly, abnormal hypopigmentation of the fundi has also been described in some cases of HI.18'20'22
Only three of these cases, to our knowledge, have been reported in the ophthalmic literature, with consequently good descriptions of the appearance of their fundi. In all these cases, a patchy hypopigmentation confined to the RPE was reported.20'22 The pigment cells of the RPE are in fact derived from the neuroepithelium of the developing optic cup and not the neural crest, which in the eye only gives rise to the melanocytes of the choroid and the iris stroma.
Reese and Judisch20 have, however, argued that the additional finding of RPE hypopigmentation in HI implies that the pigmentary dysplasia seen in HI results from a more generalized disturbance affecting melanin production by both neural crest and optic vesicle derivatives and not just a disorder of migration of neural crest cells alone.
The hypopigmentation of the fundi we observed in this case of Pallister-Killian syndrome is different from that which has been described in association with the cases of HI already discussed. It appeared to involve both the RPE and the choroid and affected almost the entire fundus.
Experiments into the development of coat and ocular pigmentation in mice using a retroviral vector carrying the tyrosinase gene to activate melanoblasts in albino embryos have resulted in the development of wide variations of patterns of ocular pigmentation in both the choroid and RPE.23
These experiments suggest that, despite the differences in the pattern of fundal hypopigmentation observed in Pallister-Killian syndrome and HI, they could still be the result of the same generalized disturbance of melanin production, with the differences being attributable to variations in the derivative clones of melanoblasts affected.
We feel it is possible, therefore, that the finding of hypopigmentation of the fundi in both Pallister-Killian syndrome and HI, like the associated skin hypopigmentation in both these syndromes, might simply be a nonspecific marker of chromosomal mosaicism. As with the skin hypopigmentation, fundal hypopigmentation appears not be a constant characteristic of genetic mosaicism and similarly the complex genetic interactions that give rise to it, in some, but not all cases of genetic mosaicism, are not understood.17 If fundal hypopigmentation is a nonspecific sign of chromosomal mosaicism, then if found in a child with other abnormalities including facial dysmorphism and developmental retardation, a search for chromosomal mosaicism should be considered.
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