Clinical Variability of Pallister–Killian Syndrome in Two Egyptian Patients

Abstract

Pallister–Killian syndrome (PKS) is a rare sporadic genetic disorder caused by a mosaic tetrasomy of chromosome 12p, which mainly manifests with craniofacial dysmorphism, intellectual disability (ID), auditory disturbance, epilepsy, and a variety of congenital malformations. The diagnosis of PKS can be complicated due to the phenotypic variation, and an overlap with other syndromes makes the molecular cytogenetic test necessary for a correct diagnosis. We identified two unrelated patients with typical facial features of PKS, including bitemporal alopecia, hypertelorism, and abnormal ears. Furthermore, the two patients had pigmentary skin anomalies, broad and short hands and fingers, and hypotonia. However, they differed in the degree of ID and ophthalmological findings. Patient 1 showed profound ID and poor macular function, whereas patient 2 had moderate ID and normal fundus. Mosaic tetrasomy of chromosome 12p was found in 40 and 25% of the cells of patients 1 and 2, respectively, by fluorescent in situ hybridization of cultured skin fibroblasts. The higher percentage of mosaic cells with tetrasomy 12p found in patient 1 may explain the severe phenotype. This report expands the clinical manifestations of PKS and highlights the variable expressivity of clinical features in relation to the cytogenetics findings.

Introduction

Pallister–Killian syndrome (PKS) (OMIM#601803) is a well-defined genetic syndrome. PKS presents as a multisystem morphological disorder with characteristic facial features, neurologic abnormalities, skin pigmentation, global developmental delay, and skeletal and other systemic disorders. ^{1 2 3} It is caused by the supernumerary marker chromosome (SMC) isochromosome 12p [i(12p)], which is composed of two short arms of chromosome 12, resulting in tetrasomy 12p. Of the other four known SMC disorders, PKS is the second most common type after Emanuel syndrome and followed by i(18p) and cat-eye syndrome. ⁴

The presence of tissue-limited mosaicism, with very few abnormal cells with i(12p) in the peripheral blood of newborns with PKS, can complicate the diagnosis. Cytogenetic analysis of skin fibroblasts or buccal swabs is often necessary to confirm the diagnosis. Interestingly, with advances in age, the tetrasomy 12p cell line is lost from peripheral blood and skin fibroblasts. ^{5 6}

Clinical Report

Patient 1

The girl was the first child to a consanguineous (first cousins) healthy 23-year-old mother and 30-year-old father (at the birth of their child). Her younger brother is healthy, and there is no history of congenital malformations or mental handicap in the family. She was born after an uneventful pregnancy history at 40 weeks of gestation by elective cesarean section due to premature rupture of membranes. Birth weight, length, head circumference, and Apgar score were not recorded but were mentioned to be normal. She was referred to our clinic at the age of 4 months due to relative macrocephaly and dysmorphic features. Her weight, length, and head circumference were 5,000 g (standard deviation [SD]: –0.8), 61 cm (SD: +0.5), and 41 cm (SD: +0.5), respectively. She presented with large cranium with wide anterior fontanelle, prominent forehead with frontal bossing, sparse scalp hair with bitemporal alopecia, sparse eyebrows, hypertelorism, telecanthus, depressed nose bridge, short nose, long philtrum, large mouth with ‘‘Pallister lip’' (extension of the philtral skin into the vermilion border of the upper lip), thin upper lip, and low-set posteriorly rotated ears ( Fig. 1A ). Hypopigmented streaks over the left arm and thigh were noticed. Neurologic examination revealed generalized muscular hypotonia with hyporeflexia of the deep tendon reflexes.

Fig. 1.

( A ) Patient 1 at the age of 8 months showing frontal bossing, sparse scalp hair with bitemporal alopecia, sparse eyebrows, hypertelorism, telecanthus, depressed nasal bridge, short nose, long philtrum, large mouth with ‘‘Pallister lip’' (extension of the philtral skin into the vermilion border of the upper lip), and thin upper lip. ( B ) Patient 2 at the age of 13 months. Note telecanthus, upturned nostrils, long philtrum, full check, and micrognathia.

At the age of 10 months, her weight was 8 kg (mean), length was 71 cm (mean), and occipital frontal circumference was 42 cm (SD: –1.4). She was unable to lift her head, roll over, or sit. Furthermore, she was unable to follow visually or to communicate with the surroundings and had nystagmus. There were no vocalizations and she never laughed. She has been noted to have severe constipation.

Seizures have never occurred, and no additional major external malformations were found. Magnetic resonance imaging (MRI) of the brain demonstrated mild delay in central myelination and hypogenesis of the corpus callosum.

Echocardiography (ECG) revealed a tiny persistent ductus arteriosus but no structural malformations. Ophthalmological investigation revealed albinoid fundus, but the visual evoked potentials showed poor macular function and severe optic nerve dysfunction with moderate conduction delay in the visual pathway. There were no abnormalities in electroencephalogram (EEG).

The girl was evaluated again after 8 months; she made almost no developmental progress and her developmental quotient at that age showed profound delay (18 according to the Vineland test). Skeletal X-ray showed bilateral hip dislocation. Dental examination showed a high-arched V-shaped palate with narrow vault, thick alveolar ridge, thick labial frenum, and delayed eruption. Hearing test revealed bilateral hearing loss.

Patient 2

The 13-month-old boy was the second child of healthy and nonconsanguineous parents. His father and mother were 22 and 32 years old, respectively, when he was born at term by spontaneous vaginal delivery after an uncomplicated pregnancy. Birth weight, length, head circumference, and Apgar score were not recorded. He has an elder healthy sister. He was referred because of dysmorphic features and growth retardation. His weight, length, and head circumference were 6,500 g (SD: –3.3), 69.5 cm (SD: –2.5), and 43.5 cm (SD: –1.8, respectively. He showed dysmorphic facial features including sparse hair and eyebrows, hypertelorism, convergent squint, a wide and depressed nasal bridge, a short nose with wide and anteverted nares, upslanting palpebral fissures, epicanthic folds, full cheeks, a long philtrum, micrognathia, and a tented upper lip ( Fig. 1B ). Additionally, right simian crease, camptodactyly of the fourth and fifth fingers, bilateral undescended testis, and hypopigmented patches in the abdomen were noted. Neurologic examination showed axial hypotonia in the extremities and hyporeflexia of the deep tendon reflexes. No head support was noticed.

ECG and abdominal ultrasonography revealed no other abnormalities. Brain MRI showed hypoplasia of the corpus callosum. Seizures have never occurred, and the EEG revealed no abnormalities. Auditory brainstem response revealed bilateral mild hearing loss.

At the age of 1 year 8 months, he could sit alone but could not crawl. His growth parameters were below 2 standard deviations. Muscular hypotonia persisted. Examination of his fundi was normal. At that age, his developmental quotient showed moderate delay (54 according to the Vineland test). Orodental examination showed severe enamel hypoplasia and hypocalcification and slightly thick alveolar ridge.

Cytogenetic Studies

Chromosome analysis was performed by conventional methods on lymphocytes and showed normal karyotype for both patients. The clinical findings strongly suggested the diagnosis of PKS, for which such reason a fluorescent in situ hybridization (FISH) study of skin fibroblasts was performed.

Short-term fibroblast culture was performed for the skin biopsies from the two patients. After the harvest, slides were prepared and FISH was performed using subtelomeric 12p FISH probe labeled with spectrum orange (Kreatech Diagnostics). The analysis of the slides revealed the presence of four copies of the subtelomere 12p in a mosaic form in both cases: case 1 showed 40% and case 2 showed 25% of the cells with tetrasomy 12p ( Fig. 2 ).

Fig. 2.

Fluorescent in situ hybridization (FISH) using subtelomere 12p spectrum orange applied to the interphase nuclei shows four signals of the probe.

Also, the mother of case 1 was pregnant and FISH was applied to the amniotic fluid sample that gave normal results.

Discussion

The hallmark for suspecting the diagnosis of the PKS is the presence of the characteristic facial features that include craniofacial dysmorphism (prominent forehead, sparse scalp hair, abnormal ears, and short broad nasal bridge) along with skin pigmentation abnormalities, skeletal abnormalities, neurologic abnormalities, and developmental and intellectual disabilities. ^{2 7}

The facial features of our cases are typical for PKS and prompted us to perform the cytogenetics assessment for the cases. However, there are differences between the two cases as regards the neurologic and developmental abnormalities. Case 1 exhibited more severe neurologic and developmental disabilities that included mild delay in central myelination, hypogenesis of the corpus callosum, poor macular function, and severe optic nerve dysfunction with moderate conduction delay in the visual pathway. Mapping the minimal critical regions of the reported PKS cases with neuropathological features strengthens the association between brain abnormalities and PKS. ⁸ However, we speculate that the difference in the severity of the PKS phenotype may be because of the percentage of cells with i(12p). Given that the full PKS phenotype can be observed in individuals carrying partial duplication 12p, it is likely that a subset of genes on 12p is responsible for the PKS phenotype. Moreover, the mosaic percentage is variable and different in skin and brain cells. More recent studies suggested that mosaic dosage is responsible for the pathogenesis of the disease. ²

The pattern of the skeletal abnormalities in our patients is not pathognomonic for the syndrome; polydactly, which is frequently reported in the literature as a constant feature, is not present in our cases. ⁹ On the other hand, the skin pigmentation abnormalities reported in our cases are very characteristic for PKS, and their presence along with the dysmorphic features are highly suggestive of the syndrome; it was reported to be present in more than 50% of the PKS patients. The presence of the hypopigmented streaks reflects the mosaic cytogenetics findings. ^{9 10}

Although epilepsy was reported to affect more than 40% of PK patients, ^{11 12} and Filloux et al ¹³ considered epilepsy as one of the triad and as a constant finding in PKS in association with dysmorphism and cognitive impairment, none of our cases developed epileptic fits or even febrile convulsions and their EEG findings were normal. The absence of seizures in our patients could be explained by their relatively young ages. As reported in the literature, seizures could first present up to 3 years of age and rarely before 12 months, and only very rarely epilepsy is the first presenting symptoms for the syndrome. ¹³ Apart from epilepsy, other neurologic findings detected by clinical examination or neuroimaging are typical for PKS and did not differ from those previously reported.

One of the interesting features in our patients is the absence of major organ affection apart from tiny persistent ductus arteriosus without structural malformations. The major organs affected in PKS, as reported in the literature, are the diaphragmatic hernia and anal atresia. Diaphragmatic hernia was noted in approximately 40% of PKS patients, whereas anal/rectal anomalies were noted in 15%. ¹⁴ However, the cardiovascular involvement, especially septal defects, ranged from 7 to 40%. ¹⁵

In conclusion, our patients with PKS have typical dysmorphic features along with the characteristic skin pigmentation abnormalities that are suggestive of the syndrome. These two features have drawn attention to the diagnosis and the necessity of performing karyotyping. Negative results yielded by peripheral blood analysis led to performing FISH of fibroblasts, which eventually confirmed the diagnosis. Although our patients are lacking major organ involvements and epilepsy, they suffer from severe developmental delay and intellectual dysfunction, which was found to be variable in severity between the two patients. We are uncertain if the variability in the severity between our patients is because of the percentage of the mosaic cell line with i(12p), as previous studies have demonstrated the absence of a correlation between the mosaic ratio and clinical severity due to the difficulty of deducing the mosaic ratio in the organ, whose abnormality directly leads to the symptom such as the brain tissue. ¹⁶ In spite of the recent advance in molecular technologies, the precise underlying molecular mechanism remains to be determined.

Erratum: The last name of the author “Abdelrahman Madian” has been corrected as per Erratum published online on December 4, 2019. DOI of the Erratum is 10.1055/s-0039-3401827.