Two Sisters with Angelman Syndrome: A Case Series Report.

Angelman syndrome (AS) is known as an intellectual disability related to speech impairment, ataxia and behavioral uniqueness, including a combination of frequent laughter and smiling, apparent happy demeanor, excitable personality and hypermotor behavior. In this report, we present a 5-year-old girl with AS associated with atypical clinical manifestations, including developmental dysplasia of the hip and simian line in the right hand, and her elder sister with AS. Even if any gene mutation cannot be demonstrated, it should be kept in mind that different mutations may exist in the cases that are the suggestive of clinical AS. Therefore, AS patients can be exposed to special education, and their quality of life can be elevated.

INTRODUCTION

Angelman syndrome (AS) is characterized by severe intellectual disability with major speech impairment, ataxia, and behavioral–emotional disorder, including a combination of frequent laughter and smiling, apparent happy demeanor, excitable personality, and hypermotor behavior.[1] AS is seen in 1 in 12,000–20,000 of the population.[2] The characteristic morphological facial features are broad mouth, widely spaced teeth, prognathia, protruding tongue, strabismus, and deep-set eyes. In addition, microcephaly and seizures are commonly accompanying signs.[3] Although the history at prenatal period and birth shows normality in general, developmental delays are first noted at around the sixth month of life with delayed attainment of developmental milestones without loss of skills. Behavioral uniqueness includes a combination of frequent laughter, smiling, and apparent happy demeanor in older children. However, the unique clinical features of AS become manifested after thefirst year of life, and it can take several years before the correct clinical diagnosis is made.[4]

In this report, we present a 5-year-old girl with AS associated with atypical clinical manifestations, including developmental dysplasia of the hip and simian line in the right hand, and her elder sister with AS.

On the familial history, patient 1 was found out to be born at postterm with the induction of birth following an uneventful pregnancy. Birth parameters were within normal ranges. Strabismus was noted at the sixth month, and developmental milestones were delayed. The patient sat unsupported at the 12th month and walked independently at the 28th month with unsteady, wide-based gait and flexed arms. There was no speech development. Although the patient developed tonic seizures at the 30th month of life, any anticonvulsant therapy was found out not to be started. The patient was operated because of the developmental dysplasia of the hip at the age of 3.

At the age of 5, the patient was admitted to our clinic due to myoclonic seizure caused by high fever. As other accompanying symptoms, the patient displayed sleep disturbances, stereotypies, and a happy disposition with frequent and inappropriate smiling and laughter. On the physical examination, her height was detected as 104 cm (10th to 25th percentile), weight as 16 kg (10th to 25th percentile), and head circumference as 49 cm (25th to 50th percentile). Subtle dysmorphic facial features, such as a large mouth, widely spaced teeth, deep-set eyes, strabismus, and upslanting palpebral fissures, were noted [Figure 1]. A simian line was remarkable in her right hand. The clinical investigation revealed normal metabolic, hematologic, and biochemical laboratory profiles. Although hearing test result was normal, the patient failed to utter any word. The electroencephalography (EEG) showed generalized large-amplitude, slow-wave activity with paroxysmal spike-waves. The sisters we presented were also genetically evaluated and consulted, but no mutation was determined.

Figure 1

Case 1

The patient was diagnosed with AS, based on clinical and laboratory findings. Valproic acid treatment was started, and the patient was sent to a special school, meeting the needs of students with disability. The patient had no repeated seizure attack during a 12-month follow-up period after anticonvulsive therapy was started.

Patient 2 was the elder sister of patient 1. On the familial history, patient 2 was found out to be born at term after an uneventful pregnancy. The birth parameters were within normal ranges. The patient sat unsupported at the 10th month of life and walked independently at the 24th month. As with her sister, this patient had also no speech development. Furthermore, she had febrile seizure at the seventh month. The patient had no repeated seizures after anticonvulsive therapy was started. The impression of patient 2 seemed to be better than that of her sister. She did not attend a special needs school. She had a happy demeanor with smiling and laughter, and a hyperactive behavior. Her height was 152 cm (10th percentile), weight was 57 kg (50th to 75th percentile), and head circumference was 52 cm. Clinical examination revealed dysmorphic features with macrostomia, widely spaced teeth, deep-set eyes, and upslanting palpebral fissures [Figure 2]. “Duck-walk gait” was also remarkable.

Figure 2

Case 2

DISCUSSION

The patients presented in this report have classical phenotypic manifestations of AS, including severe intellectual disability with major speech impairment, subtle ataxia, seizures, behavioral disorders with happy dispositions, frequent and inappropriate smiling, and sleep disturbance. AS is known to be caused by different genetic defects with similar consequences in terms of neurological development and behavior. Maternal deletion (15q11-q13), characterized by the loss of one part of the chromosome, occurs in 75%–80% patients.[5] The sisters we presented were also genetically evaluated and consulted, but no mutation was determined. We consider that our patients were probably affected by a genetic defect we failed to determine.

Most patients with AS present with epilepsy and suggestive EEG patterns, which may be used as diagnostic criteria. Both of our patients also displayed epileptic attacks, and whereas patient 1 had pathological EEG findings, patient 2 was exposed to no EEG investigation. Unprovoked and provoked seizures may coexist in patients with AS. In our two cases, seizures were also precipitated by fever. Epilepsy is often more severe in patients with the deletion of chromosome 15q11-q13, including genes coding for Gamma-aminobutyric acid type A (GABAA) receptor subunits, than in those in other molecular classes.[6] This is consistent with generally milder neurobehavioral features in patients without a deletion. No deletion of chromosome 15q11-q13 was detected in both of our cases, and their seizures did not repeat. So, we consider that our patients were from a different molecular class.

In a study conducted by Valente et al.,[7] valproic acid was reported to improve the seizure control in 19 patients undergoing either monotherapy or polytherapy, especially when associated with clonazepam or phenobarbital. The type or number of seizures was not the predictive of remission or better response to antiepileptic drug treatment. The seizures observed in our cases were taken under control after valproic acid therapy was started.

Although all seizure types are reported in AS, generalized seizures, atypical absences, and myoclonic seizures are predominant. Epilepsy might be related to abnormal GABA-mediated transmission due to the lack of Ubiquitin-protein ligase E3A (UBE3A) expression or other factors.[8] Our first case had also myoclonic seizure, whereas the type of seizure in the second case was unknown.

The majority of cases with AS are sporadic. Nevertheless, several reports have shown that AS may recur with a familial transmission, and the incidence of familial AS cases has been estimated to be 7% in two extensive surveys.[9] Our patients were also two sisters. Patient 1 was born at postterm with the induction of birth following an uneventful pregnancy and underwent an operation of developmental dysplasia of the hip. To our knowledge, this is the first report describing such anomalies in patients with AS. We cannot conclude, however, whether these clinical findings are related to AS or are incidental.

In conclusion, AS should be taken into account in the differential diagnosis of infants with delayed developmental milestones, seizures, and frequent and inappropriate smiling, and additional abnormalities such as strabismus, developmental dysplasia of the hip, large mouth, widely spaced teeth, deep-set eyes, strabismus, and upslanting palpebral fissures should be investigated. The patient should metabolically and neurologically be assessed, and if necessary, EEG and genetic investigation should be performed.

Even if 15q11-q13 deletion gene mutation cannot be demonstrated, it should be kept in mind that different mutations may exist in the cases that are the suggestive of clinical AS. Therefore, patients with AS can be exposed to special education, and their quality of life can be elevated.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.