A New Case - Heterozygote PACS1 Mutation in a Patient with Schuurs-Hoeijmakers Syndrome and a Left Duplex Kidney: Case Report
PACS1 is a rare form of monogenic disorder characterised by intellectual disability, developmental delay, and mild distinctive facial features. The typical facial features include a low hairline on the forehead, eyes that are spaced far apart and slanting downwards, thick eyebrows that may be connected to each other, long eyelashes, large ears that are set low on the head, and gaps between the teeth. Diagnosis is made through a genetic analysis, particularly by whole exome sequencing. Although renal abnormalities are rarely seen in such patients, we present an atypical case of a 33-month-old girl with a left duplex kidney.
Keyword : Down-like face; Duplex kidney; PACS1; Typical facial features
PACS1 gene is found on the long arm of the chromosome 11 (11q13.1-13.2). The mutations showing autosomal dominant inheritance in this gene are known to cause Schuurs-Hoeijmakers syndrome. For the first time, Schuurs-Hoeijmakers et al diagnosed PACS1 as a de novo mutation in two boys who had similar findings and no cognation. The findings included similar typical facial appearance, intellectual and motor disability, and cryptorchidism.1 A de novo c.607C>T (p.R203W) mutation was detected in both boys and their clinical appearance were highly similar. In 2014, three other patients with similar findings and PACS1-associated symptoms were described by Gadzicki et al.2
The only known cause of Schuurs-Hoeijmakers syndrome is the PACS1 mutation. Typical manifestations of this syndrome include intellectual disability, characteristic facial features such as a mouth with down-turned corners, seizures, and cerebral abnormalities. A de novo c.607C>T (p.R203W) mutation is typically seen in PACS1. Also, Miyake N et al reported a de novo missense PACS1 (c.608G>A (p.R203Q) mutation.3 In the case presented in this study, a heterozygous missense c.607C>T (p.R203W) mutation was detected in the PACS1 gene and the patient was diagnosed with whole exome sequencing (WES). Additionally, the patient was detected with a left duplex kidney, which is a rare occurrence in such patients.
A 33-month-old girl with a body weight of 12.8 (10th-25th percentile), height of 90 cm (10th percentile), and a head circumference of 48 cm (10th percentile) presented to the paediatric neurology clinic due to speech retardation and atypical facial appearance. Neuromotor development of the patient was retarded and it was revealed that she could hold her head steady at 4 months, sat without support at 18 months, started to walk at 26 months. Although the patient produced only four meaningful words, she was friendly and good-humoured. Her IQ was revealed to be 54 according to the Denver Developmental Screening Test (DDST). She was the first living child delivered at the third pregnancy of her mother who was 27 years old during the time of delivery. It was also revealed that the mother had been followed up due to oligohydramnios throughout the gestational period and her father was a 32-year-old healthy individual. The parents had no consanguineous relationship. Patient history revealed that the patient had been monitored under mechanical ventilation after birth due to neonatal meconium aspiration syndrome. Moreover, she experienced apnoeic seizures three times in the neonatal period, followed by a focal seizure on her right arm at the age of 3 months. After the age of two, her antiepileptic treatment was discontinued when she had no more seizures. Physical examination revealed hypertelorism, mild ptosis, a large mouth, depressed and wide nasal bridge, long philtrum, flat eyebrows, eyelids drooping downwards, prominent ears, thin upper lip, overlapping toes in the right foot, and pectus excavatum (Figure 1). Additionally, a grade 1/6 systolic ejection murmur was heard. Other system examinations were normal and biochemical analyses were unremarkable. No immunodeficiency was found. A patent foramen ovale (PFO) was detected on electrocardiography (ECG). Renal ultrasonography (US), which was performed due to the presence of recurrent urinary tract infections, revealed a left duplex kidney. Cranial magnetic resonance imaging (MRI) scan was normal and electroencephalography (EEG) was unremarkable. WES revealed a heterozygous de novo missense c.607C>T (p.R203W) mutation in the PACS1 gene.
Abnormal migration of nerve cells resulting from the replacement of arginine by tryptophan in the furin-binding region is considered to play a role in the etiopathogenesis of PACS1, and similar facial findings are explained by zebrafish research.4 However, the presence of similar facial features in other symptoms including Baraitser-Winter syndrome, Cornelia de Lange syndrome, Mowat-Wilson syndrome, and Kabuki syndrome complicates the diagnosis of PACS1 mutations. This challenge can be eliminated by the use of WES analysis, which can also detect the abnormalities accompanying these facial features.
The PACS1 mutation detected in our patient was characterised by intellectual disability, prominent craniofacial characteristics (hypertelorism, mild ptosis, a large mouth, depressed and wide nasal bridge, long philtrum, flat eyebrows, eyelids drooping downwards, prominent ears, and thin upper lip), psychomotor retardation, mild-to-moderate speech retardation, hypotonia, seizures, structural malformations (heart, brain, eyes, kidneys, and bones), and additional congenital anomalies (Tables 1 & 2). The WES analysis performed in our patient detected a heterozygous missense c.607C>T (p.R203W) mutation in the PACS1 gene. This mutation was also shown to be heterozygous in the DNA sequencing analysis performed with the Sanger method. Additionally, the parents were also examined and were found to be normal.
Schuurs-Hoeijmakers et al, in their series of 19 cases aged 2-21 years, found typical facial anomalies in all patients as well as different abnormalities including cardiac abnormalities in 10 patients and renal problems in three patients.4 Additionally, almost half of the patients presented with gastrointestinal problems such as severe feeding, swallowing, and reflux problems. Renal abnormality was seen in only three cases and two of them had right renal duplex anomaly and urethral diverticulum. No vesicourethral reflux was observed.4 In our case, however, had a left duplex kidney and grade IV vesicoureteral reflux. We consider that advanced genetic analyses are helpful for the establishment of diagnosis in these patients, as was in our case. Accordingly, WES analysis appears to be ideal option in the diagnosis of these patients.
Whole exome sequencing (WES) appears to be an ideal method for the diagnosis of patients with moderate intellectual disability, prominent speech retardation, and non-persistent seizures, particularly of patients with similar facial appearance. Patients with PACS1 mutation may rarely present with renal abnormalities, most of which are treatable. The use of social media platforms (e.g. PACS1 groups) by the parents of children diagnosed with PACS1 mutation could be helpful for raising awareness and eliminating concerns among these patients and their parents. Accordingly, by presenting the current case, we aimed to raise awareness among the parents of children with a PACS1 mutation by emphasizing that a PACS1 mutation could be present in syndromic patients with intellectual disability and similar facial appearance and that there could be additional abnormalities in such patients that may require clinical follow-up.
Conflict of Interest
All the authors declare no conflict of interest for this study.
1. Schuurs-Hoeijmakers JH, Oh EC, Vissers LE, et al. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am J Hum Genet 2012;91:1122-7.
2. Gadzicki D, Döcker D, Schubach M, et al. Expanding the phenotype of recurrent de novo variant in PACS1 causing intellectual disability. Clin Genet 2015;88:300-2.
3. Miyake N, Ozasa S, Mabe H, et al. A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome. Clin Genet 2018;93:929-30.
4. Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, et al. Clinical delineation of the PACS1-related syndrome-Report on 19 patients. Am J Med Genet A 2016;170:670-5.