|Year : 2022 | Volume
| Issue : 2 | Page : 84-87
The role of behavioral phenotyping in establishing a diagnosis of pseudo-angelman syndrome
Veronica Arora1, Aashita Takkar1, Sameer Bhatia1, Meena Lall1, Praveen Kumar2
1 Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Paediatric Neurology, Sir Ganga Ram Hospital, New Delhi, India
|Date of Submission||10-Mar-2022|
|Date of Decision||27-Apr-2022|
|Date of Acceptance||29-Apr-2022|
|Date of Web Publication||30-May-2022|
Dr. Veronica Arora
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi - 110 060
Source of Support: None, Conflict of Interest: None
Background: Behavioral phenotypes are observable patterns of behavior present in certain genetic syndromes that have distinctive social, linguistic, cognitive, and motor profiles. These may play an important role as pointers toward certain genetic disorders. The recognition of aberrant behavior is important for therapeutic targeting by behavioral modification strategies and medication. The repertoire of behavioral constellations is exhaustive, but common manifestations include aggression, self-injury, autistic features, and a happy demeanor comprising excessive smiling and outbursts of laughter without any preceding triggers. Clinical Description: We describe the approach that was used to establish diagnosis in a boy with a happy disposition, cognitive impairment, and seizures, the firstborn of a couple desiring genetic counseling for their second 7-week pregnancy. After deep phenotyping (identifying overt and concealed dysmorphism, assessment of vision, hearing, behavior, and cognition), a syndrome search was performed by a geneticist using suitable handles. The clinical phenotype of the proband was then matched with the generated list of disorders. The most likely diagnosis Angelman syndrome (AS) was excluded by negative specific genetic testing. Chromosomal microarray identified 2q23.1 microdeletion that is associated with pseudo-AS. Prenatal diagnosis at 16 weeks revealed an unaffected fetus. Management: There is no cure for this syndrome. Affected children benefit from symptomatic intervention provided by a multidisciplinary team including clinical geneticists, pediatricians, pediatric neurologists, developmental pediatricians, and various professional therapists. Conclusions: Behavioral phenotypes aid in establishing diagnosis in certain genetic disorders. A happy disposition coupled with intellectual disability should prompt the clinician to involve a geneticist in management, even if overt dysmorphism is not apparent.
Keywords: Behavioral phenotype, genetic disorder, happy demeanor, MBD5, microdeletion, pseudo-Angelman syndrome
|How to cite this article:|
Arora V, Takkar A, Bhatia S, Lall M, Kumar P. The role of behavioral phenotyping in establishing a diagnosis of pseudo-angelman syndrome. Indian Pediatr Case Rep 2022;2:84-7
|How to cite this URL:|
Arora V, Takkar A, Bhatia S, Lall M, Kumar P. The role of behavioral phenotyping in establishing a diagnosis of pseudo-angelman syndrome. Indian Pediatr Case Rep [serial online] 2022 [cited 2023 Sep 26];2:84-7. Available from: http://www.ipcares.org/text.asp?2022/2/2/84/346263
Behavioral phenotypes are observable patterns of behavior that are present in certain genetic syndromes and have distinctive social, linguistic, cognitive, and motor profiles. These behavioral characteristics may act as pointers toward a specific genetic diagnosis. In addition, they also have a profound impact on the quality of life of the caregivers due to the significant disruption caused at home and outside. For instance, Lesch–Nyhan disease is a monogenic X-linked condition characterized by self-mutilation, aggressiveness, impulsiveness, etc., which can be very difficult for parents to handle. A well-known behavioral phenotype is the one associated with Down syndrome. Although these children are generally cheerful and sociable, they can also display autistic behavior, hyperactivity, obsessive–compulsive behavior, psychosis, etc., Diagnostic dilemmas arise when several syndromes have similar behavioral manifestations. In these cases, a step-by-step logical approach needs to be employed to arrive at the final diagnosis, just as would in a child with hepatosplenomegaly and short stature, which can be caused by multiple etiologies. Deep phenotyping of certain genetic syndromes can aid in deciding the direction of genetic testing, thus saving precious time and costs.
In this case report, we describe the diagnostic approach that was undertaken in an undiagnosed child with cognitive impairment, epilepsy, neurological abnormalities, and unusual behavior whom we had the chance to encounter. After deep phenotyping, we established a diagnosis of pseudo-Angelman syndrome (AS) due to MBD5 haploinsufficiency. There are very few cases reported globally, and to the best of our knowledge, this is the first one to be reported from India.
| Clinical Description|| |
A healthy nonconsanguineous married couple was referred to the genetics department of our institute for reproductive counseling for their second pregnancy (7 weeks gestational age). They had a significant family history of their firstborn, a 7-year-old boy, having cognitive impairment and behavioral problems since early childhood and epilepsy since the age of 3 years. Although the child had been taken to multiple professionals, a clinical diagnosis had still not been made. The expectant couples' primary concern was whether their next child would be similarly affected. It was decided that we would attempt to establish a diagnosis based on the clinical phenotype and plan genetic testing (as warranted). The feasibility of a prenatal diagnosis would hence be explored accordingly.
The mother reported an uneventful antenatal period in her first pregnancy, with normal perception of quickening and subsequent fetal movements. A boy was born at term through a normal vaginal delivery and he cried immediately at birth. Records showed that at birth, the weight was 2.8 kg, head circumference 36 cm, and length 51 cm, all within normal limits. The perinatal period was normal. Concerns regarding the delayed acquisition of developmental milestones began when it was noted that he still did not hold his neck at 6 months of age. Elicitation of attainment of other milestones that the parents could remember in various domains were as follows: sitting without support at 11 months, standing with support at 24 months, and independent walking at 30 months (gross motor); pincer grasp at 18 months and ability to feed himself independently at 7 years; bisyllables at 30 months and two-word phrases at 4 years (language). The social milestones were also delayed, but the parents were unable to remember specific details. However, regression was not reported in any domain. Currently, at 7 years, he was able to run and speak in short sentences but not tell a story. His social interaction corresponded more with that of a younger child. He had not been sent to school due to his decreased ability to understand and follow instructions and atypical behavior (laughing aloud without reason, hyperactivity, and repetitive hand movements). There was no history of self-injurious behavior or aggression toward others. The child had still not attained a regular sleep pattern which was evident by significant nocturnal awakening and excessive daytime sleepiness. According to the parents, his hearing and vision were apparently normal.
At 3 years of age, he had experienced the first episode of generalized tonic–clonic seizures, which was not associated with fever, trauma, or any infectious illness. Consequently, he had three more episodes till the age of 5 years. He was currently seizure-free for almost 2 years on levetiracetam at 20 mg/kg/day. There was no significant history of any other significant medical illnesses. A three-generation pedigree was obtained, which showed no significant family history [Figure 1]a. The child was immunized for age.
|Figure 1: (a) Three-generation pedigree of the family. (b) Image showing the side profile of the proband showing depressed nasal bridge, micrognathia and prominent ears, and comparatively long limbs. (c) Image showing the frontal profile of the face of the proband at 7 years of age. Note narrow forehead, medial flaring and sparse lateral eyebrows, prominent nasal bridge, anteverted nares, long and smooth philtrum, thin vermillion border, and hypodontia. (d) The array image showing heterozygous deletion in the 2q23.1 cytoband (log R ratio – 0.5)-red box|
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Vital parameters were stable. His weight was 15.6 kg (−3 standard deviation [SD]), height 113 cm (−1.78 SD), head circumference 49 cm (−1.64 SD), and body mass index 13.2 (<5th centile). Facial dysmorphism can be appreciated in [Figure 1]b and [Figure 1]c, which included a narrow forehead, medial flaring and sparseness of the lateral eyebrows, a prominent nasal bridge, anteverted nares, long and smooth philtrum, thin vermilion border, and hypodontia. Significant neurological findings were generalized hypotonia, in the presence of normal power, and normal deep tendon reflexes. There was no ataxia or gait disturbances. The rest of the systemic examinations were normal. The clinical phenotype was that of a dysmorphic child with intellectual disability and epilepsy. Since there were no “dysmorphic handles” pathognomonic of any particular definite or probable syndrome after the preliminary evaluation, we planned subsequent “empirical” workup according to the three main features, intellectual disability/possibly autistic features, epilepsy, and dysmorphism. Investigations and referrals were planned accordingly.
| Management and Outcomes|| |
Thyroid function tests were normal; thyroid-stimulating hormone 2.5 mU/L, and thyroxine (T4) levels 1.2 ng/dL. Magnetic resonance imaging of the brain and electroencephalogram were normal. Ultrasonography (abdomen) and echocardiography did not reveal any concealed congenital anomalies. Structured assessment of vision and hearing assessments did not reveal any impairment.
The child was referred to a developmental pediatrician. Formal cognitive assessment revealed an intelligence quotient of 75 (borderline intelligence). It was observed that the child appeared alert and was extremely interactive with an excessively friendly nature and cheerful disposition. He made eye contact and communicated with the examiners and his parents using short sentences. He was able to follow instructions that were phrased in simple language. It was noted that he exhibited frequent bouts of spontaneous laughter without any triggers. However, there were also some autistic features. The child displayed the inability to appreciate social boundaries (that was out of proportion to the degree of cognitive impairment), hyperactivity (he kept on roaming around the clinic during the evaluation, despite being repeatedly told not to), and hand stereotypies in the form of intermittent hand clapping (without apparent cause) and writhing movements.
A syndrome search was performed by a clinical geneticist using Online Mendelian Inheritance in Man, Pictures of Standard Syndromes and Undiagnosed Malformation, and London Dysmorphology Database. The “handles” that were used were: happy demeanor and seizures. The differential diagnoses included: chromosomal disorders such as Kleefstra syndrome (9q34 deletion), 22q microduplication, and 2q microdeletion; and monogenic disorders that included Pitt–Hopkins syndrome (heterozygous pathogenic variants in TCF4 or a microdeletion involving TCF4), Mowat–Wilson syndrome (heterozygous pathogenic variants in ZEB2), and AS that is due to abnormal methylation at 15q11.2-q13 or a pathogenic variant in UBE3A. The list was then reviewed by applying the clinical, behavioral, and dysmorphism that had been identified in this child.
Out of these, the clinical phenotype of AS was considered the most likely, though typical features such as flat occiput, strabismus, wide mouth, widely spaced teeth, protruding tongue, or prognathia, were not present. However, the methylation specific-multiplex ligation probe amplification was negative for abnormal methylation at 15q11.2-q13, ruling it out completely. We proceeded with the next step in genetic testing, a chromosomal microarray, which revealed pathogenic heterozygous microdeletion of 401 kb at cytoband 2q23.1 encompassing the genes ORC4 and MBD5 [Figure 1]d. This was consistent with 2q23.1 microdeletion, also known as pseudo-Angelman phenotype. Biallelic variants in the ORC4 are known to cause Meier–Gorlin syndrome, characterized by short stature, failure to thrive, distinct dysmorphic facial features, delayed bone age, and absent/hypoplastic patella. Since this child had normal stature and palpable patella, we did not evaluate the ORC4 deletion any further.
The couple underwent genetic counseling for the ongoing pregnancy. They were apprised of the following facts: most of these deletions are de novo; the recurrence risk in the mother's current and subsequent pregnancies was very low; but since germline mosaicism can also lead to recurrence (albeit in a few cases), prenatal diagnosis was nonetheless advisable. The couple agreed to an amniocentesis at 16-weeks' gestation, which revealed an unaffected status of the fetus, and they decided to continue with the pregnancy. The elder son continued follow-up with the developmental pediatrician for the continuation of detailed evaluation and planning of an individualized education plan that would include multidisciplinary interventions.
| Discussion|| |
Behavioral characteristics are often helpful in syndrome identification. In view of the typical handle that helped us establish the diagnosis in this case, we present a brief description of the clinical phenotype of a few genetic disorders that are associated with a “happy” disposition. This behavioral phenotype includes persistent smiling and excessive bouts of spontaneous laughter, both of which occur without any trigger.
The most common syndrome (incidentally considered in this case as well) is AS. In addition to the laughter and smiling, it is characterized by cognitive impairment, autistic features, the aforementioned dysmorphism, ataxia, hand flapping, seizures, microcephaly, and fair complexion. The combination of the ataxia, unusual gait, and happy disposition leads it to be referred to as “happy puppet” syndrome. The tuning fork test is a reliable bedside test for identification; affected children respond to the sound of a struck tuning fork with a wide smile, outburst of laughter, and tendency to lean toward the vibrating tuning fork.
Pseudo-AS or 2q23.1 microdeletion, which was identified in this case, is due to MBD5 haploinsufficiency. The manifestations include developmental delay, seizures, and the behavioral phenotype that encompasses hyperactivity, autism spectrum disorder, self-injury, aggression, and social withdrawal, in addition to the happy demeanor. The dysmorphic features include a broad forehead, highly arched eyebrows, short nose, depressed and wide nasal bridge, downturned corners of the mouth, everted vermilion of the lower lip, tented and thin vermilion of the upper lip. Skeletal abnormalities (small hands and feet, fifth finger clinodactyly, brachydactyly, sandal gap, etc.) and cardiovascular anomalies (atrial and ventricular septal defects) have been reported in a few cases. Antiepileptic drugs are routinely utilized for seizure control in the 80% of affected children who have seizures. Feeding difficulty and constipation are reported in infancy in 90% due to the associated hypotonia, and may require consultation with a nutritionist. Medication may be considered for aggressive behavior on a case-to-case basis. Sleep disturbances are managed by strict sleep hygiene and drugs such as melatonin and trazodone. The clinical and behavioral phenotype in the proband was consistent with published literature and confirmed by the genotype.
Christianson syndrome due to 2q23.1 microdeletion is also referred to as X-linked AS due to its close resemblance to AS (happy disposition, ataxia, and epilepsy). However, the distinct dysmorphism (microcephaly, long, and narrow face with prominent nose, jaw, ears, and open mouth with uncontrolled drooling), abnormal eye movements, the absence of tuning fork response, and less affected intellect are important differentiating features.
The following descriptions are of a few less commonly known syndromes associated with a happy demeanor. Pitt–Hopkins syndrome (caused by heterozygous pathogenic variants in TCF4 or a microdeletion involving TCF4) can be differentiated by the presence of typical facial features, which include deep-set eyes, wide nasal root, short philtrum, and full upper and lower vermilion. In addition, they may display an unusual breathing pattern. The dysmorphism seen in Mowat–Wilson syndrome (due to heterozygous pathogenic variants in ZEB2) comprises a prominent pointed chin, low-hanging columella, open mouth expression, and uplifted earlobes. Gastrointestinal disorders (Hirschsprung's disease and chronic constipation) and structural heart defects may also be seen. Kleefstra syndrome results from heterozygous deletion at chromosome 9q34.3 (that includes at least part of EHMT1) or a heterozygous intragenic pathogenic variant of EHMT1, affected individuals have Down syndrome such as facies and cognitive impairment (with severe speech delay) with prominent neurological involvement. Glass syndrome (due to either de novo heterozygous mutations in the SATB2 gene or de novo heterozygous deletions of chromosome 2q32-q33) is characterized by pre-and postnatal growth retardation, short stature, dental anomalies, and ectodermal abnormalities (skin, hair, and nail).
In conclusion, behavioral phenotypes aid in the clinical characterization of various syndromic genetic disorders. A happy disposition in a child with intellectual disability should prompt the clinician to consult a geneticist and developmental pediatrician to delineate the cognitive and behavioral dimensions. These not only help in the planning of the intervention and behavior modification strategies but also direct the sequence of genetic testing.
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's mother (proband is a minor) has given her consent for her child's images and other clinical information to be reported in the journal. The concerned family understands that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that name and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.
We acknowledge the patient and the family for participating in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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