Mental retardation and distinctive facial features with or without cardiac defects (MRFACD) syndrome is a type of syndromic intellectual disability (ID) caused by heterozygous variants in the
The study was conducted according to the Declaration of Helsinki Principles. Written informed consent was obtained from the legal representatives of the patient and the study protocol was approved by the Bioethics Committee of the Institute of Mother and Child, Warsaw, Poland (number 30/2012).
A detailed description of the materials and methods used for this study can be found in the supplementary material of this article.
The patient is a 7-year-old boy with severe ID, born to young, non-consanguineous parents after 41 weeks of gestation in an uncomplicated second pregnancy. The first pregnancy had ended by a miscarriage in the 10th week. The patient’s birth weight was 2,300 g (5c<), height 50 cm (25c–50c) and head circumference 32 cm (5c<). His Apgar scores were 7, 9 and 10 points in the 1st, 3rd and 5th min, respectively. He had congenital pneumonia. Brain ultrasound examination performed at the age of 8 months revealed wide lateral ventricles. From the beginning, the child had had axial hypotonia with distal spasticity. He was able to sit at 13 months and walk at about 3 years of age, but his gait was atactic. He presented dysmorphic features such as open mouth with the protruding tongue, wide mouth, high forehead, hypotelorism, biparietal narrowing, sparse hair in the temporal region, discrete telecanthus, bulbous nasal tip, short philtrum, proximal thumbs without ability to catch, first toes curved laterally and an additional nipple on the left side (Fig. S1C–E in Supplementary Material). He had convergent strabismus and astigmatism. At the age of 7, he did not develop speech at all. He had behavioural problems – autoagression (biting hands) and stereotypic movements. Magnetic resonance imaging (MRI) of the brain revealed typical terminal zones of unfinished myelination posteriorly and asymmetric ventricles. The Virchow–Robin spaces were detectable in the same location (Fig. S1B in Supplementary Material). Array CGH (aCGH) taken as primary genetic testing had shown the presence of a 170-kb maternally derived deletion in 22q12.3 (32,323, 842-32,494,686)[hg18]. This deletion encompasses the
(A) Sanger sequencing confirmed the nonsense variant c.5941C>T in the patient. (B) Axial and coronal brain MRI showing terminal zones of unfinished myelination posteriorly and asymmetric ventricles as well as the Virchow-Robin spaces in the same location. (C) Facial features, (D) hands and (E) feet anomalies in patient at 7 years of age.
Whole exome sequencing identified a heterozygous single nucleotide substitution c.5941C>T (NM_015335.4) at exon 27 in the
Further Sanger sequencing of the c.5941C>T variant in the patient’s family confirmed the absence of mutation in both parents, indicating its
MRFACD is a genetic disorder caused by molecular defect of the
In this study, we describe a patient with severe ID, developmental delay, absence of speech, dysmorphic features and hypotonia. Due to the presence of the
Recently, Torring et al. have summarized clinical presentation of the disease in 69 patients with the
Comparison of major clinical features and their frequency in patients with likely pathogenic variants in the
Clinical feature | Number of patients | This study patient | |
---|---|---|---|
Clinical findings | ID or DD | 69/69 | +(severe ID and DD) |
Speech delay | 68/69 | +(no speech) | |
Hypotonia | 46/66 | +(axial hypotonia) | |
Coordination problems | 20/60 | +(stereotypic movements, wide-based gait) | |
Congenital heart defects | 12/64 | – | |
Autistic features | 16/69 | – | |
Abnormal brain MRI | 26/58 | +(lateral ventricles asymmetry, wider posterior part of the left ventricle) | |
Seizures | 10/63 | – | |
Behavioural problems | 16/51 | +(self-destructive behaviour – biting hands) | |
Strabismus | 3/24 | +(convergent strabismus – esotropia) | |
Dysmorphic features | Depressed/flat nasal bridge | 19/33 | +(flat nasal bridge) |
Broad/prominent forehead | 16/21 | +(prominent frontal eminence) | |
Bulbous nasal tip | 50/67 | + | |
Upslanting palpebral fissures | 26/65 | +(slight epicanthic folds) | |
Low seat ears | 17/33 | – | |
Bitemporal narrowing | 8/33 | – | |
Horizontal eyebrows | 7/33 | + | |
Macrosomia | 14/33 | + | |
Macroglossia | 9/33 | – |
Hypotonia, speech delay and brain abnormalities in MRI are quite common among these patients (70%, 99% and 45%, respectively). Also, dysmorphic features such as bulbous nasal tip, depressed/flat nasal bridge, upslanting palpebral fissures and abnormal chin have been previously reported in patients with the
Our findings support the conclusion that the phenotype of patients with loss-of-function variants in the
Pathogenic variants in
MRFACD is characterized by clinical heterogeneity – our patient, besides intellectual disability, developmental delay and hypotonia, presented self-destructive behaviour, strabismus and complete absence of speech, findings that are not common in patients with
As the intellectual disability is not a pathognomonic feature and MRFACD shares clinical characteristics with other ID syndromes, it seems that NGS-based analysis should be applied to make a definite diagnosis.