Pallister-Killian syndrome

Background

Pallister-Killian syndrome (PKS) is a rare genetic syndrome characterized by multiple dysmorphic features and mental retardation. It is caused by supernumerary isochromosome 12p (tetrasomy 12p) [1,2]. PKS was first described in 1977 by Pallister in adults [3], and later in 1981 by Killian and Teschler Nicola in children with mental retardation, severe dysmorphic features, and skin changes [4]. The syndrome is an example of chromosomal mosaicism, as the abnormality is present only in a fraction of cells examined, and the non-mosaic form of tetrasomy 12p is incompatible with intrauterine survival [5,6]. We here report the first case of PKS diagnosed in our institution in a patient in the second trimester of pregnancy. We hope to contribute to the existing genetic literature on this rare disorder through our case report.

Case Report

A 43-year-old Caucasian woman, Gravida 7 Para 3, with a history of 3 previous first trimester voluntary terminations of pregnancies and no significant personal or family history, presented for genetic counseling secondary to advanced maternal age and an increased risk for Down syndrome of 1/30 based on second trimester biochemical screening. Her previous obstetrical history was unremarkable. She has 3 healthy living children. Ultrasound was consistent with 20 weeks’ gestation. The fetus was noted to have a nuchal fold measuring 6.6 mm, with head circumference, abdominal circumference, and biparietal diameter all >97th percentile, and femur <3rd percentile. There was no hydrocephalus. The maximum vertical pocket of amniotic fluid measured 85 mm. Fetal evaluation was compromised by maternal body habitus; however, the fetal anatomy appeared normal. The patient was offered an amniocentesis based on the increased risk for Down syndrome and ultrasound findings, but declined.

A follow-up scan at 22 weeks gestation revealed a small stomach (Figure 1) and an amniotic fluid index of 22 mm. The remainder of the anatomical survey appeared normal.

At 29 weeks gestation, biparietal diameter and head circumference measured >97th percentile. The long bones, including the ulna, tibia, and fibula, measured <5th percentile, with the femur <3rd percentile (Figure 2). A small stomach was again noted, as well as polyhydramnios with an amniotic fluid index of 433 mm (Figure 3). The patient agreed to genetic testing.

Following consent, amniocentesis was performed, and the amniotic fluid was sent for karyotype and fluorescent in-situ hybridization (FISH) for trisomies 13, 18, and 21.

FISH studies were negative and confirmed a male fetus. The full karyotype was reported as 47, XY, i (12) (p10)/46XY; there was an isochromosome of the short arm of chromosome 12 (tetrasomy 12p) in 14/16 colonies, consistent with PKS. The patient presented at 31.5 weeks gestation in preterm labor with bulging membranes. She was admitted, and tocolysis and antenatal corticosteroids for fetal lung maturity were given. The following day the patient underwent an emergency cesarean section for fetal bradycardia. A viable male infant weighing 2.290 kg with Apgar newborn score of 7 and 8 was delivered.

Postnatally, the physical exam revealed classic phenotypic features of Pallister-Killian syndrome. The infant was noted to have frontal bossing, a flattened nasal bridge, mid-facial hypoplasia with low-set ears, a right upper deciduous tooth, and a grooved palate. The head circumference at birth was at the 10th percentile. Ultrasound of the head postnatally revealed enlarged cisterna magna. The nuchal fold was thickened. Nipples were widely spaced. The infant had left ulnar polydactyly, simian creases, flexion contractures of the right middle finger, and shortened upper extremities. Right inguinal testis and a left intraabdominal testis were noted. The infant had hypotonia, bilateral hearing loss, and respiratory distress syndrome due to prematurity. Ultrasound of the abdomen on the first day of life showed a bilateral dilated renal pelvis and nephrocalcinosis. An echocardiogram done the same day revealed small patent foramen ovale, moderate tricuspid insufficiency, and pulmonary hypertension. The patient subsequently underwent Nissen’s fundoplication and pyloromyotomy for left congenital diaphragmatic hernia and gastro-esophageal reflux disease. A repeat karyotyping with peripheral blood lymphocytes from the infant demonstrated mosaic 47, XY, +i (12) (p10) [1]/46, XY [29], confirming our prenatal diagnosis.

Discussion

Pallister-Killian syndrome (PKS) is a rare, sporadic, polydysmorphic condition, often with highly distinctive features. It is a tissue-limited mosaicism caused by tetrasomy 12p resulting in craniofacial, cardiovascular, renal, genital, and other systemic malformations [5]. Many affected individuals die in utero or postnatally; a few survive into their early 20 s [5]. This condition can be diagnosed prenatally by chorionic villus sampling, amniocentesis, or cordocentesis. Early prenatal diagnosis helps families to choose between continuation and termination of pregnancy, as it poses significant emotional and financial burden. Families may be better equipped to cope with the pregnancy and the care of the infant after birth when they choose to continue pregnancy. However, the diagnosis in our case was delayed until 29 weeks of gestation because the patient had declined genetic testing initially at the time of the first ultrasound.

The abnormality is commonly detected in skin fibroblasts. The diagnosis of PKS can thus be frequently missed due to the tissue-specific nature of mosaicism, and usually is not detected in rapidly dividing cells such as the peripheral blood cells [6,22]. There are very few reported cases in which the isochromosome was diagnosed in peripheral lymphocytes [23]. The detection rate is 0–2% in lymphocytes, 50–100% in fibroblasts, and 100% in amniocytes and bone marrow cells [24]. The genetic confirmation in our infant was obtained postnatally from culturing peripheral blood cells.

Chiesa et al. in 1988 reported the first case diagnosed prenatally based on fetal blood cells after cordocentesis in the second trimester. FISH was used to identify the interphase or the metaphase cells with the isochromosome [17]. About 60 cases of PKS have been recognized prenatally since. Some of the ultrasound findings noted are hydramnios, short limbs, abnormal hands and feet, diaphragmatic hernia, and an absent or small stomach [25] (Table 1). In 2000, Langford et al. reported the first case of PKS after detecting increased nuchal translucency and hydrops during the initial screen for trisomy 21 at 13 weeks gestation [19]. This patient had an increased nuchal fold thickness, with polyhydramnios and short limbs at 20 weeks gestation. The diagnosis was delayed because the patient declined genetic testing. Congenital diaphragmatic hernia is noted in 40% of affected infants [26–28]. The small stomach noted in this case likely represented a diaphragmatic hernia, although no other chest abnormalities were noted. Advanced maternal age is also a contributing factor for tetrasomy 12p. In 1988, Wenger et al. showed that maternal age was significantly higher in people with PKS than in the general population, similar to that of Down syndrome. Advanced maternal age is a contributing risk factor for aneuploidy from meiotic error, as in the case of tetrasomy 12p [29].

Conclusions

PKS is sporadic in nature, but prenatal diagnosis is possible. The first reported case was diagnosed in 2000 after noting an increased nuchal translucency in the first trimester [11]. In our case the findings of increased nuchal fold thickness, short limbs, polyhydramnios, and a small stomach eventually led to the diagnosis of tetrasomy 12p after amniocentesis.