CLINICAL REPORT
Phenotype of a Child With Angelman Syndrome Born to a Woman With Prader–Willi Syndrome John R. Ostergaard* Department of Pediatrics, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark Manuscript Received: 28 October 2014; Manuscript Accepted: 12 March 2015abstractGroup>
This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader–Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting. Ó 2015 Wiley Periodicals, Inc.
Key words: Angelman syndrome; chromosome 15q11.2-q13
How to Cite this Article: Ostergaard JR. 2015. Phenotype of a child with Angelman syndrome born to a woman with Prader–Willi syndrome. Am J Med Genet Part A 9999A:1–7.
genetically documented PWS [Akefeldt et al., 1999; Schulze et al., 2001; Cassidy and Vats, 2011]. In one, in which the offspring was a genetically and phenotypic normal child, the mother showed maternal uniparental disomy [Akefeldt et al., 1999]. In another case, a deletion of the original paternal chromosome 15q11.2-q13 was transmitted to the offspring [Schulze et al., 2001]. Due to epigenetic mechanisms, all imprints should be erased and rewritten with the maternal imprint, resulting in a girl with a genotype compatible with AS. As expected from previous research, the patient displayed features of AS in early infancy, such as jerky movements and poor sleep, and at the age of 5 months a triphasic high voltage electroencephalography (EEG) pattern was reported [Schulze et al., 2001]. Due to the rarity of this occurrence, we felt that it was important to describe the development of this patient’s phenotype, from early childhood until her current adolescence.
deletion; genetic imprinting; Prader–Willi syndrome
CLINICAL REPORT INTRODUCTION Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are neurodevelopmental conditions caused by a lack of expression of imprinted genes on 15q11.2-q13. AS is caused by a loss or reduction of the functional gene product of UBE3A and is most frequently due to a deletion of the maternally inherited 15q11.2-q13 [Tan et al., 2011; Dagli et al., 2012; Mertz et al., 2013]. The underlying disruption that causes PWS is still unknown. Recently, the focus has mainly been on snoRNAs, which codes for short RNA molecules that are thought to regulate other RNAs in the cell [Sahoo et al., 2008; de Smith et al., 2009; Duker et al., 2010]. The clinical features of PWS include low birth weight, hypotonia, and feeding problems in infancy, followed by developmental delay, obesity, behavioral problems, and hyperphagia during childhood [Butler et al., 2010; Miller et al., 2011; Siemensma et al., 2012]. Fullterm pregnancies have been reported in four individuals with
Ó 2015 Wiley Periodicals, Inc.
The clinical assessment of this patient until age 15 months has previously been reported [Schulze et al., 2001]. In summary, she had normal values for weight, length, and head circumference according to her gestational age and she demonstrated all (100%) of the consistent AS features and the vast majority of the less frequent and associated features [Williams et al., 2006]. Soon after her birth, our patient was placed in family foster care with her biological mother’s sister. She was still living there at age 16 years,
Correspondence to: Professor, John R. Ostergaard, Department of Pediatrics, Centre for Rare Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.a.37080
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2 attended a special school, and, apart from upper airway infections during childhood, her general health has been quite unremarkable. Her growth parameters, according to the Danish references for anthropometric measurements [Tinggaard et al., 2014], are shown in Figure 1. During the first years, her height and weight increased substantially and throughout childhood her height and weight were above þ2SD. Following puberty, her height remained above þ1SD, while her weight stabilized around þ2SD. A BMI chart is shown in Figure 2. Her mother’s height was 152 cm, without the administration of growth hormone, and her father was 180 cm tall. Her head circumference was 1SD until puberty, after which it dropped to 2SD. At the chronological age of 66, 83, and 100 months, her bone age was 82, 113, and 136 months, respectively. The concentration of insulin-like growth factor 1 (IGF-1) was 206 and 278 mg/L at 83 and 100 months and these were within the normal range for age. She had normal parameters for thyroid function, adrenocorticotropic hormone (ACTH), cortisol, prolactin, and insulin, and her menarche occurred at age 12. There were no hematologic abnormalities or signs of liver and kidney dysfunction. She developed a moderate scoliosis, treated by a soft corset. Her body fat distribution, obtained by dual energy X-ray absorptiometry (Fig. 3), was similar to those reported in PWS patients, with most of the fat accumulation in the extra-abdominal areas [Theodoro et al., 2006; Olarescu et al., 2014]. Her total body fat percentage at age 15.5 was 39.2 (Z-score 1.0). Her lean mass index (kg/m2) was 14.8 (Z-score 0.0), and her total bone mineral density (g/cm2) was 0.973 (Z-score 1.0). As seen in Figure 4, her facial phenotype showed many similarities with AS during the first 4 years of life, including a round face, protruding tongue, pointed cheeks, a wide mouth, and mandibular prognathism. As she grew older, the dysmorphic traits disappeared. During ambulation, she only has slightly uplifted flexed arms, her gait is slightly wide based, but not really ataxic and without pronated or valgus-positioned ankles. At age 10 years, she was introduced to an alternative communication device with a point screen and she used this to communicate her wishes regarding activities and food. She used about 30 different signs when she communicated, but she was unable to speak words. When we tested her using the Mullen Scales of Early Learning [Mertz et al., 2014a], we found that her receptive and expressive language abilities at age 12.5 years had reached the level of 19 and 5 months of age, respectively. Her visual reception level was 18 months. The presence of autism or autism spectrum disorders (ASD) was assessed according to the Autism Diagnostic Observation Schedule (ADOS) [Mertz et al., 2014a]. Her scores were lower than the cut-off values for ASD in all ADOS domains, meaning that she demonstrated no signs of autism. The behavioral phenotype for AS includes a happy personality and our patient showed the characteristic outbursts of laughter, often with hand waving. She was obsessed with food, forages for food, and displayed lack of satiety. When we used the Hyperphagia Questionnaire by Dykens et al. [2007] on our patient at age 12.5 years, her score for Hyperphagic Drive (e.g., persistence in asking for food) was 16/20, her score for Hyperphagic Behavior (e.g., stealing food) was 20/25, and her score for Hyperphagic Severity (e.g., the extent that food interferes with everyday functioning) was 9/10.
Self-mutilation, like picking at minor skin lesions, had never been an issue and her pain tolerance and threshold for vomiting were normal. However, her daily life needed to be quite predictable, and she was in need of maintaining uniformity. If that did not happen, she became oppositional, rigid and possessive, and often reacted aggressive to children and adults. This behavior decreased at age 10 years following the administration of Risperidone at 0.75 mg/ 24 hr. Because she found it difficult to fall asleep, she had received melatonin since she was 2 years old and a dose of 4.5 mg enabled her to fall asleep and sleep for 5–6 hr. The maternal deletion 15q11.2-q13 had previously been documented and confirmed by chromosome analysis, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR)based microsatellite analysis [Schulze et al., 2001]. A maternal BP2BP3 deletion was identified by using a methylation-specific multiplex ligation-dependent probe amplification assay EK1 kit (MRCHolland, Amsterdam) and a 4.8 Mb deletion was demonstrated from 23208842 to 26917942 (hg19) using an oligo-array 1000K [Mertz et al., 2013]. These deletion results were identical to her mother’s. In addition, both had a heterozygous 90 kb deletion on chromosome 2q13 (112648398–112738755; hg19) involving MERTK, which is associated with recessive retinitis pigmentosa. Our patient had two atonic seizures at age of 1.5 years, when she was briefly feverish. She was then seizure free for 1 year, despite periods with fever, but at age 2.5 years she had several tonic–clonic, atonic, and myoclonic seizures during another febrile period. Nitrazepam (0.625 mg/24 hr) was initiated and increased 2 months later to 1.25 mg/24 hr. Her nitrazepam was increased to 2.5 mg/ 24 hr, in line with her weight increase, and she had been seizure free for more than 10 years, with the exception of a few, very short atonic attacks when she had a high temperature. Since age 9 years, she has had five attacks during which she suddenly lost muscle tone. All happened when her normal cheerful and happy self was reinforced with a tremendous and uncontrolled outbreak of laughter. During three of these attacks, she lost muscle tone in her limbs for 10–15 sec and collapsed. She was fully conscious and did not display any changes in her complexion during the episodes. She had not experienced excessive daytime sleepiness or other rapid eye movement sleep phenomena, such as sleep paralysis and hypnagogic or hypnopompic hallucinations, and polysomnographic investigations did not show signs of central or obstructive apnea. Due to poor compliance, a multiple sleep latency test could not be performed and for ethical reasons a spinal tap to measure for hypocretin-1 in the cerebrospinal fluid was not performed. A 48 hr ECG monitoring (Holter) did not demonstrate cardiac arrhythmia or conduction disturbances.
DISCUSSION The present study describes the phenotype development from early childhood to adolescence in a girl with AS following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she demonstrated the typical AS phenotype, but as she grew older, the AS facial phenotype gradually disappeared and indications of PWS phenotypically behavioral traits appeared. The most noticeable trait was her hyperphagia, which was identical to the eating behavior that her foster mother had seen in her own sister,
OSTERGAARD
FIG. 1. Growth charts for height and weight. During the first years of life, our patient’s height and weight increased substantially and throughout childhood her height and weight were above þ2SD. Following puberty, her height remained above þ1SD, while the weight stabilized around þ2SD.
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FIG. 2. BMI chart showing overweight (>85% percentile) through the majority of her childhood.
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FIG. 3. Body composition of the reported individual obtained by dual energy X-ray absorptiometry at age 15.5 years. Her fat accumulation is extra-abdominal, as seen in PWS. She has a moderate scoliosis.
our patient’s birth mother, who has PWS. Abnormal food-related behavior is included on the list of associated findings in the updated consensus diagnostic criteria of AS [Williams et al., 2006]. However, only few studies attempted to define an eating behavioral phenotype in a case-controlled manner [Berry et al., 2005; Mertz
et al., 2014b]. Using selected items from the Developmental Behavior Checklist [Einfeld and Tonge, 1995], Berry et al. [2005] found that one-third of individuals with AS displayed an increased appetite and behavioral orientation to food, compared to one-sixth of the control group. However, the study did not include a specific
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FIG. 4. Facial phenotype of the reported individual during infancy, childhood, and into adolescence. In the first 4 years of her life, she showed many similarities with AS, for example, a round face, protruding tongue, pointed cheeks, wide mouth, and mandibular prognathism. As she grew older, no specific dysmorphic traits were present.
hyperphagia questionnaire and did not take the heterogeneous genetic background of AS into consideration. In a recent population-based study, Mertz et al. [2014b] reported that children with AS due to paternal uniparental disomy (pUPD) presented with significantly increased hyperphagic behavior, severity, and drive in comparison with children with a maternal 15q11.2-q13 deletion or a UBE3A mutation. Accordingly, children with pUPD developed obesity after age 2–3 years, whereas the weight curves representing the other genetic AS groups were within the normal range [Mertz et al., 2014b]. In the present study, the patient’s scores for hyperphagic behavior, severity, and drive were high. In that respect, her phenotype is more in line with AS due to pUPD than a 15q11.2-q13 deletion [Mertz et al., 2014b] and similar to children with PWS [Dykens et al., 2007]. The patient reported here generally demonstrated the cheerful behavior found in AS patients, but her attitude toward others did not reflect the shared enjoyment of interaction that is normally seen in children with AS [Trillingsgaard and Østergaard, 2004; Williams, 2010]. We have found that in unfamiliar surroundings, she with-
drew socially and that her rigid behavior was indicative of a behavior commonly seen in PWS. Her mental impairment was significant, but compared with the levels reported in deleted AS children, her receptive language and visual reception levels were high [Mertz et al., 2014a]. The laughter-induced episodes of postural muscle tone loss were so severe on three occasions that she slumped to the ground. However, as her consciousness was unaffected and she recovered without postictal confusion, these fits may have been due to cataplexy, which is specific to narcolepsy and characterized by a sudden drop of muscle tone triggered by emotional factors. Although any emotion, such as surprise, anger, or fright, can trigger cataplexy, laughter is by far the most common precipitant [Dauvilliers et al., 2007]. In spite of the excessive outbreaks of laughter in individuals with AS, a link between AS and cataplexy has never been reported, whereas narcolepsy and cataplexy are a common feature of PWS [Tobias et al., 2002; Weselake et al., 2014]. In conclusion, the patient demonstrated classic AS features like jerky movements, poor sleep, high voltage EEG patterns, epilepsy,
OSTERGAARD severe developmental delay, and characteristic outbursts of laughter. But this girl, the offspring of a 15q11.2-q13 deleted PWS woman, also presented with several core phenotypic signs of PWS and had more phenotypic signs in common with AS due to pUPD than with AS caused by a 15q11.2-q13 deletion. The latter might be due to a variation in the general AS phenotype [Williams et al., 2006]. However, her features common in PWS patients are hardly a coincidence. If these occurrences are verified by upcoming reports of other children born to women with a paternal 15q11.2q13 deletion, this may open up new aspects of genetic imprinting.
REFERENCES Akefeldt A, Tornhage CJ, Gillberg C. 1999. A woman with Prader–Willi syndrome gives birth to a healthy baby girl. Dev Med Child Neurol 41:789–790. Berry RB, Leitner RP, Clarke AR, Einfeld SL. 2005. Behavioral aspects of Angelman syndrome: A case control study. Am J Med Genet A 132A:8– 12. Butler JV, Whittington JE, Holland AJ, McAllister CJ, Goldstone AJ. 2010. The transition between the phenotypes of Prader–Willi syndrome during infancy and early childhood. Dev Med Child Neurol 52:e88–e93. Cassidy SB, Vats D. 2011. Abstract Presented at the 25th Annual PWSA (USA) Scientific Meeting in Orlando, FL, November 11. Dagli A, Buiting K, Williams CA. 2012. Molecular and clinical aspects of Angelman syndrome. Mol Syndromol 2:100–112. Dauvilliers Y, Arnulf I, Mignot E. 2007. Narcolepsy with cataplexy. Lancet 369:499–511. de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE. 2009. A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Hum Mol Genet 18:3257– 3265. Duker AL, Blake CB, Bawle EV, Person RE, Mahadevan S, Alliman S, Thompson R, Traylor R, Bejjani BA, Shaffer LG, Rosenfeld JA, Lamb AN, Sahoo T. 2010. Paternally inherited microdeletion of 15q11.2 confirms a significant role for the SNORD116C/D box SnoRNA cluster in Prader– Willi syndrome. Eur J Hum Genet 18:1196–1201. Dykens EM, Maxwell MA, Pantino E, Kossler R, Roof E. 2007. Assessment of hyperphagia in Prader–Willi syndrome. Obesity 15:1816–1826. Einfeld SL, Tonge BJ. 1995. The developmental behavior checklist: The development and validation of an instrument to assess behavioral and emotional disturbances in children and adolescents with mental retardation. J Autism Dev Disord 2:81–104.
7 syndrome: Genotype-phenotype correlations. Res Dev Disabil 35: 1742–1747. Mertz LG, Christensen R, Vogel I, Hertz JM, Ostergaard JR. 2014b. Eating behavior, prenatal and postnatal growth in Angelman syndrome. Res Dev Disabil 35:2881–2690. Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, Dykens E, Butler M, Shuster JJ, Driscoll DJ. 2011. Nutritional phases in Prader–Willi syndrome. Am J Med Genet A 155A:1040–1049. Olarescu NC, Jørgensen AP, Godang K, Jurik AG, Frøslie KF, Bollerslev J. 2014. Dual-energy X-ray absorptiometry is a valid method to estimate visceral adipose tissue in adult patients with Prader–Willi syndrome during treatment with growth hormone. J Clin Endocrinol Metab. 99: E1727–E1731. Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL. 2008. Prader–Willi phenotype caused by maternal deficiency for the HBII-85C/D box small nuclear RNA cluster. Nat Genet 40:719–721. Schulze A, Mogensen H, Hamborg-Petersen B, Graem N, Ostergaard JR, Brondum-Nielsen K. 2001. Fertility in Prader–Willi syndrome: A case report with Angelman syndrome in the offspring. Acta Paediatrica 90:455–459. Siemensma EPC, van Alfen-van der Velden AAEM, Otten BJ, Laven JSE, Hokken-Koelega ACS. 2012. Ovarian function and reproductive hormone levels in girls with Prader–Willi syndrome: A longitudinal study. J Clinic Endocrinol Metab 97:e1766–e1773. Tan WH, Bacino CA, Skinner SA, Anselm I, Barbieri-Welge R, BauerCarlin A, Beaudet AL, Bichell TJ, Gentile JK, Glaze DG, Horowitz LT, Kothare SV, Lee HS, Nespeca MP, Peters SU, Sahoo T, Sarco D, Waisbren SE, Bird LM. 2011. Angelman syndrome: Mutations influence features in early childhood. Am J Med Genet A 155A:81–90. Theodoro MF, Talebizadeh Z, Butler MG. 2006. Body composition and fatness pattern in Prader–Willi syndrome: Comparison with simple obesity. Obesity 14:1685–1690. Tinggaard J, Aksglaede L, Sørensen K, Mouritsen A, Wohlfarht-Veje C, Hagen CP, Mieritz MG, Jørgensen N, Wolthers OD, Heuck C, Petersen JH, Main KM, Juul A. 2014. The 2014 danish references from birth to 20 years for height, weight and body mass index. Acta Paediatrica 103:214–224. Tobias ES, Tolmie JL, Stephenson JBP. 2002. Cataplexy in Prader–Willi syndrome. Arch Dis Child 87:170. Trillingsgaard A, Østergaard JR. 2004. Autism in Angelman syndrome: An exploration of comorbidity. Autism 8:163–174. Weselake SV, Foulds JL, Couch R, Witmans MB, Rubin D, Haqq AM. 2014. Prader–Willi syndrome, excessive daytime sleepiness, and narcoleptic symptoms: A case report. J Med Case Rep 8:127.
Mertz LG, Christensen R, Vogel I, Hertz JM, Nielsen KB, Grønskov K, Ostergaard JR. 2013. Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A 161A:2197– 2203.
Williams CA, Baudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers KA, Wagstaff J. 2006. Angelman syndrome 2005: Updated consensus for diagnostic criteria. Am J Med Genet A 140A:413–418.
Mertz LG, Thaulov P, Trillingsgaard A, Christensen R, Vogel I, Hertz JM, Ostergaard JR. 2014a. Neurodevelopmental outcome in Angelman
Williams CA. 2010. The behavioral phenotype of the Angelman syndrome. Am J Med Genet C 154C:432–437.
Phenotype of a Child With Angelman Syndrome Born to a Woman With Prader–Willi Syndrome John R. Ostergaard* Department of Pediatrics, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark Manuscript Received: 28 October 2014; Manuscript Accepted: 12 March 2015abstractGroup>
This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader–Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting. Ó 2015 Wiley Periodicals, Inc.
Key words: Angelman syndrome; chromosome 15q11.2-q13
How to Cite this Article: Ostergaard JR. 2015. Phenotype of a child with Angelman syndrome born to a woman with Prader–Willi syndrome. Am J Med Genet Part A 9999A:1–7.
genetically documented PWS [Akefeldt et al., 1999; Schulze et al., 2001; Cassidy and Vats, 2011]. In one, in which the offspring was a genetically and phenotypic normal child, the mother showed maternal uniparental disomy [Akefeldt et al., 1999]. In another case, a deletion of the original paternal chromosome 15q11.2-q13 was transmitted to the offspring [Schulze et al., 2001]. Due to epigenetic mechanisms, all imprints should be erased and rewritten with the maternal imprint, resulting in a girl with a genotype compatible with AS. As expected from previous research, the patient displayed features of AS in early infancy, such as jerky movements and poor sleep, and at the age of 5 months a triphasic high voltage electroencephalography (EEG) pattern was reported [Schulze et al., 2001]. Due to the rarity of this occurrence, we felt that it was important to describe the development of this patient’s phenotype, from early childhood until her current adolescence.
deletion; genetic imprinting; Prader–Willi syndrome
CLINICAL REPORT INTRODUCTION Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are neurodevelopmental conditions caused by a lack of expression of imprinted genes on 15q11.2-q13. AS is caused by a loss or reduction of the functional gene product of UBE3A and is most frequently due to a deletion of the maternally inherited 15q11.2-q13 [Tan et al., 2011; Dagli et al., 2012; Mertz et al., 2013]. The underlying disruption that causes PWS is still unknown. Recently, the focus has mainly been on snoRNAs, which codes for short RNA molecules that are thought to regulate other RNAs in the cell [Sahoo et al., 2008; de Smith et al., 2009; Duker et al., 2010]. The clinical features of PWS include low birth weight, hypotonia, and feeding problems in infancy, followed by developmental delay, obesity, behavioral problems, and hyperphagia during childhood [Butler et al., 2010; Miller et al., 2011; Siemensma et al., 2012]. Fullterm pregnancies have been reported in four individuals with
Ó 2015 Wiley Periodicals, Inc.
The clinical assessment of this patient until age 15 months has previously been reported [Schulze et al., 2001]. In summary, she had normal values for weight, length, and head circumference according to her gestational age and she demonstrated all (100%) of the consistent AS features and the vast majority of the less frequent and associated features [Williams et al., 2006]. Soon after her birth, our patient was placed in family foster care with her biological mother’s sister. She was still living there at age 16 years,
Correspondence to: Professor, John R. Ostergaard, Department of Pediatrics, Centre for Rare Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.a.37080
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2 attended a special school, and, apart from upper airway infections during childhood, her general health has been quite unremarkable. Her growth parameters, according to the Danish references for anthropometric measurements [Tinggaard et al., 2014], are shown in Figure 1. During the first years, her height and weight increased substantially and throughout childhood her height and weight were above þ2SD. Following puberty, her height remained above þ1SD, while her weight stabilized around þ2SD. A BMI chart is shown in Figure 2. Her mother’s height was 152 cm, without the administration of growth hormone, and her father was 180 cm tall. Her head circumference was 1SD until puberty, after which it dropped to 2SD. At the chronological age of 66, 83, and 100 months, her bone age was 82, 113, and 136 months, respectively. The concentration of insulin-like growth factor 1 (IGF-1) was 206 and 278 mg/L at 83 and 100 months and these were within the normal range for age. She had normal parameters for thyroid function, adrenocorticotropic hormone (ACTH), cortisol, prolactin, and insulin, and her menarche occurred at age 12. There were no hematologic abnormalities or signs of liver and kidney dysfunction. She developed a moderate scoliosis, treated by a soft corset. Her body fat distribution, obtained by dual energy X-ray absorptiometry (Fig. 3), was similar to those reported in PWS patients, with most of the fat accumulation in the extra-abdominal areas [Theodoro et al., 2006; Olarescu et al., 2014]. Her total body fat percentage at age 15.5 was 39.2 (Z-score 1.0). Her lean mass index (kg/m2) was 14.8 (Z-score 0.0), and her total bone mineral density (g/cm2) was 0.973 (Z-score 1.0). As seen in Figure 4, her facial phenotype showed many similarities with AS during the first 4 years of life, including a round face, protruding tongue, pointed cheeks, a wide mouth, and mandibular prognathism. As she grew older, the dysmorphic traits disappeared. During ambulation, she only has slightly uplifted flexed arms, her gait is slightly wide based, but not really ataxic and without pronated or valgus-positioned ankles. At age 10 years, she was introduced to an alternative communication device with a point screen and she used this to communicate her wishes regarding activities and food. She used about 30 different signs when she communicated, but she was unable to speak words. When we tested her using the Mullen Scales of Early Learning [Mertz et al., 2014a], we found that her receptive and expressive language abilities at age 12.5 years had reached the level of 19 and 5 months of age, respectively. Her visual reception level was 18 months. The presence of autism or autism spectrum disorders (ASD) was assessed according to the Autism Diagnostic Observation Schedule (ADOS) [Mertz et al., 2014a]. Her scores were lower than the cut-off values for ASD in all ADOS domains, meaning that she demonstrated no signs of autism. The behavioral phenotype for AS includes a happy personality and our patient showed the characteristic outbursts of laughter, often with hand waving. She was obsessed with food, forages for food, and displayed lack of satiety. When we used the Hyperphagia Questionnaire by Dykens et al. [2007] on our patient at age 12.5 years, her score for Hyperphagic Drive (e.g., persistence in asking for food) was 16/20, her score for Hyperphagic Behavior (e.g., stealing food) was 20/25, and her score for Hyperphagic Severity (e.g., the extent that food interferes with everyday functioning) was 9/10.
Self-mutilation, like picking at minor skin lesions, had never been an issue and her pain tolerance and threshold for vomiting were normal. However, her daily life needed to be quite predictable, and she was in need of maintaining uniformity. If that did not happen, she became oppositional, rigid and possessive, and often reacted aggressive to children and adults. This behavior decreased at age 10 years following the administration of Risperidone at 0.75 mg/ 24 hr. Because she found it difficult to fall asleep, she had received melatonin since she was 2 years old and a dose of 4.5 mg enabled her to fall asleep and sleep for 5–6 hr. The maternal deletion 15q11.2-q13 had previously been documented and confirmed by chromosome analysis, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR)based microsatellite analysis [Schulze et al., 2001]. A maternal BP2BP3 deletion was identified by using a methylation-specific multiplex ligation-dependent probe amplification assay EK1 kit (MRCHolland, Amsterdam) and a 4.8 Mb deletion was demonstrated from 23208842 to 26917942 (hg19) using an oligo-array 1000K [Mertz et al., 2013]. These deletion results were identical to her mother’s. In addition, both had a heterozygous 90 kb deletion on chromosome 2q13 (112648398–112738755; hg19) involving MERTK, which is associated with recessive retinitis pigmentosa. Our patient had two atonic seizures at age of 1.5 years, when she was briefly feverish. She was then seizure free for 1 year, despite periods with fever, but at age 2.5 years she had several tonic–clonic, atonic, and myoclonic seizures during another febrile period. Nitrazepam (0.625 mg/24 hr) was initiated and increased 2 months later to 1.25 mg/24 hr. Her nitrazepam was increased to 2.5 mg/ 24 hr, in line with her weight increase, and she had been seizure free for more than 10 years, with the exception of a few, very short atonic attacks when she had a high temperature. Since age 9 years, she has had five attacks during which she suddenly lost muscle tone. All happened when her normal cheerful and happy self was reinforced with a tremendous and uncontrolled outbreak of laughter. During three of these attacks, she lost muscle tone in her limbs for 10–15 sec and collapsed. She was fully conscious and did not display any changes in her complexion during the episodes. She had not experienced excessive daytime sleepiness or other rapid eye movement sleep phenomena, such as sleep paralysis and hypnagogic or hypnopompic hallucinations, and polysomnographic investigations did not show signs of central or obstructive apnea. Due to poor compliance, a multiple sleep latency test could not be performed and for ethical reasons a spinal tap to measure for hypocretin-1 in the cerebrospinal fluid was not performed. A 48 hr ECG monitoring (Holter) did not demonstrate cardiac arrhythmia or conduction disturbances.
DISCUSSION The present study describes the phenotype development from early childhood to adolescence in a girl with AS following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she demonstrated the typical AS phenotype, but as she grew older, the AS facial phenotype gradually disappeared and indications of PWS phenotypically behavioral traits appeared. The most noticeable trait was her hyperphagia, which was identical to the eating behavior that her foster mother had seen in her own sister,
OSTERGAARD
FIG. 1. Growth charts for height and weight. During the first years of life, our patient’s height and weight increased substantially and throughout childhood her height and weight were above þ2SD. Following puberty, her height remained above þ1SD, while the weight stabilized around þ2SD.
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FIG. 2. BMI chart showing overweight (>85% percentile) through the majority of her childhood.
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FIG. 3. Body composition of the reported individual obtained by dual energy X-ray absorptiometry at age 15.5 years. Her fat accumulation is extra-abdominal, as seen in PWS. She has a moderate scoliosis.
our patient’s birth mother, who has PWS. Abnormal food-related behavior is included on the list of associated findings in the updated consensus diagnostic criteria of AS [Williams et al., 2006]. However, only few studies attempted to define an eating behavioral phenotype in a case-controlled manner [Berry et al., 2005; Mertz
et al., 2014b]. Using selected items from the Developmental Behavior Checklist [Einfeld and Tonge, 1995], Berry et al. [2005] found that one-third of individuals with AS displayed an increased appetite and behavioral orientation to food, compared to one-sixth of the control group. However, the study did not include a specific
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FIG. 4. Facial phenotype of the reported individual during infancy, childhood, and into adolescence. In the first 4 years of her life, she showed many similarities with AS, for example, a round face, protruding tongue, pointed cheeks, wide mouth, and mandibular prognathism. As she grew older, no specific dysmorphic traits were present.
hyperphagia questionnaire and did not take the heterogeneous genetic background of AS into consideration. In a recent population-based study, Mertz et al. [2014b] reported that children with AS due to paternal uniparental disomy (pUPD) presented with significantly increased hyperphagic behavior, severity, and drive in comparison with children with a maternal 15q11.2-q13 deletion or a UBE3A mutation. Accordingly, children with pUPD developed obesity after age 2–3 years, whereas the weight curves representing the other genetic AS groups were within the normal range [Mertz et al., 2014b]. In the present study, the patient’s scores for hyperphagic behavior, severity, and drive were high. In that respect, her phenotype is more in line with AS due to pUPD than a 15q11.2-q13 deletion [Mertz et al., 2014b] and similar to children with PWS [Dykens et al., 2007]. The patient reported here generally demonstrated the cheerful behavior found in AS patients, but her attitude toward others did not reflect the shared enjoyment of interaction that is normally seen in children with AS [Trillingsgaard and Østergaard, 2004; Williams, 2010]. We have found that in unfamiliar surroundings, she with-
drew socially and that her rigid behavior was indicative of a behavior commonly seen in PWS. Her mental impairment was significant, but compared with the levels reported in deleted AS children, her receptive language and visual reception levels were high [Mertz et al., 2014a]. The laughter-induced episodes of postural muscle tone loss were so severe on three occasions that she slumped to the ground. However, as her consciousness was unaffected and she recovered without postictal confusion, these fits may have been due to cataplexy, which is specific to narcolepsy and characterized by a sudden drop of muscle tone triggered by emotional factors. Although any emotion, such as surprise, anger, or fright, can trigger cataplexy, laughter is by far the most common precipitant [Dauvilliers et al., 2007]. In spite of the excessive outbreaks of laughter in individuals with AS, a link between AS and cataplexy has never been reported, whereas narcolepsy and cataplexy are a common feature of PWS [Tobias et al., 2002; Weselake et al., 2014]. In conclusion, the patient demonstrated classic AS features like jerky movements, poor sleep, high voltage EEG patterns, epilepsy,
OSTERGAARD severe developmental delay, and characteristic outbursts of laughter. But this girl, the offspring of a 15q11.2-q13 deleted PWS woman, also presented with several core phenotypic signs of PWS and had more phenotypic signs in common with AS due to pUPD than with AS caused by a 15q11.2-q13 deletion. The latter might be due to a variation in the general AS phenotype [Williams et al., 2006]. However, her features common in PWS patients are hardly a coincidence. If these occurrences are verified by upcoming reports of other children born to women with a paternal 15q11.2q13 deletion, this may open up new aspects of genetic imprinting.
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