Exploring an objective measure of overactivity in children with rare genetic syndromes.

BACKGROUND: Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates. METHODS: A secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes. RESULTS: M10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex. DISCUSSION: These findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques.

Speech, Language, Hearing, and Otopathology Results From the International Smith-Magenis Syndrome Patient Registry.

PURPOSE: Smith-Magenis syndrome (SMS), a rare, genetically linked complex developmental disorder caused by a deletion or mutation within chromosome 17p11.2, is associated with delays in speech-language development, otopathology, and hearing loss, yet previous studies lack comprehensive descriptions of hearing and communication profiles. Here, analyses of patient registry data expand what is known about speech, language, hearing, and otopathology in SMS. METHOD: International speech-language and hearing registry survey data for 82 individuals with SMS were analyzed using descriptive and inferential statistics. Hearing loss, history of otitis media and pressure equalization (PE) tubes, communication mode, expressive/receptive language, and vocal quality were analyzed for all subjects and subjects grouped by age. Statistical methods included descriptive statistics and Pearson's chi-square tests of independence to test for differences between age groups for each variable of interest. Association analyses included Pearson's correlations. RESULTS: Hearing and otological analyses revealed that 35% of subjects had hearing loss, 66% had a history of otitis media, and 62% had received PE tubes. Speech-language analyses revealed that 60% of subjects communicated using speech, 79% began speaking words at/after 24 months of age, 92% combined words at/after 36 months, and 41% used sign language before speech. There was a significant association between the age that first words were spoken and the age that PE tubes were first placed. Communication strengths noted in more than 40% of subjects included social interest, humor, and memory for people, past events, and/or facts. CONCLUSIONS: Significant delays and impairment in speech-language were common, but the majority of those with SMS communicated using speech by age 6 years. Age was a significant factor for some aspects of hearing loss and communication. Neither hearing loss nor otitis media exacerbated language impairment. These results confirm and extend previous findings about the nature of speech, language, hearing, and otopathology in those with SMS.

A diagnosis of Birt-Hogg-Dubé syndrome in individuals with Smith-Magenis syndrome: Recommendation for cancer screening.

We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.

Caregivers' experience of sleep management in Smith-Magenis syndrome: a mixed-methods study.

BACKGROUND: Smith-Magenis syndrome (SMS) is a rare genetic syndrome associated with a unique profile of early morning waking and daytime sleepiness. Children with SMS evidence high rates of self-injury and aggression and have a preference for adult over peer attention, with strong motivation to interact with a particular caregiver. In addition, people with SMS have lower adaptive functioning skills relative to cognitive abilities and demonstrate high levels of impulsivity. Taken together, these factors may result in individuals being awake overnight requiring vigilant caregiver supervision. Despite these complexities, no study has described the strategies caregivers take to keep their children with SMS safe overnight or considered the impact of these experiences on caregivers or the wider family. METHODS: The current study used a mixed-methods approach to consider sleep management strategies and challenges for caregivers of people with SMS at different ages. Caregivers completed an international online survey about sleep management and related difficulties, use of interventions and access to services and support. Semi-structured interviews were conducted with 14 caregivers in the UK to increase understanding of caregiver experiences and priorities for change in the UK context. Interviews were transcribed verbatim and coded using thematic analysis. RESULTS: Evidence from the online survey (n = 40) revealed wide-ranging impacts of poor sleep on the person with SMS and the wider family. Only 5% of caregivers reported that the sleep problems had no impact on their child, and 76% reported a moderately or extremely significant impact on themselves. For some individual caregivers, sleep management difficulties improved over time whereas for others no change was reported. Weekly respite emerged as the ideal provision for 49% of caregivers, although only 14% had access to this. The majority of caregivers (54%) received no respite. Thematic analysis of qualitative interviews revealed interactions between aspects of the behavioural phenotype of SMS which may contribute to complex and unusual presentations in relation to sleep management and safety. CONCLUSIONS: Caregivers' priorities for sleep management and support were delineated, with key implications for services in terms of the use of SMS-sensitive strategies and respite provision.

Case report: extreme coronary calcifications and hypomagnesemia in a patient with a 17q12 deletion involving HNF1B.

BACKGROUND: 17q12 deletion syndrome encompasses a broad constellation of clinical phenotypes, including renal magnesium wasting, maturity-onset diabetes of the young (MODY), renal cysts, genitourinary malformations, and neuropsychiatric illness. Manifestations outside of the renal, endocrine, and nervous systems have not been well described. CASE PRESENTATION: We report a 62-year-old male referred to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) who presented with persistent hypermagnesiuric hypomagnesemia and was found to have a 17q12 deletion. The patient exhibited several known manifestations of the syndrome, including severe hypomagnesemia, renal cysts, diabetes and cognitive deficits. Coronary CT revealed extensive coronary calcifications, with a coronary artery calcification score of 12,427. Vascular calcifications have not been previously reported in this condition. We describe several physiologic mechanisms and a review of literature to support the expansion of the 17q12 deletion syndrome to include vascular calcification. CONCLUSION: Extensive coronary and vascular calcifications may be an extension of the 17q12 deletion phenotype, particularly if hypomagnesemia and hyperparathyroidism are prevalent. In patients with 17q12 deletions involving HNF1B, hyperparathyroidism and hypomagnesemia may contribute to significant cardiovascular risk.

Using a Functional Analysis Followed by Differential Reinforcement and Extinction to Reduce Challenging Behaviors in Children With Smith-Magenis Syndrome.

Smith-Magenis syndrome (SMS) is a genetic disorder, commonly caused by a 17p11.2 deletion, affecting the Retinoic Acid Induced 1 gene. It affects approximately 1 in 25,000 individuals, with over 90% engaging in challenging behaviors. Function-based treatments, using the principles of applied behavior analysis, have consistently been shown to decrease challenging behaviors exhibited by individuals with developmental delays. However, additional research is needed to determine the effects of these interventions with specific diagnostic subsets, including SMS. The current study identified the function of challenging behavior for 2 children with SMS and found a function-based treatment, consisting of differential reinforcement and extinction, reduced challenging behavior for both.

A cross-syndrome cohort comparison of sleep disturbance in children with Smith-Magenis syndrome, Angelman syndrome, autism spectrum disorder and tuberous sclerosis complex.

BACKGROUND: Sleep disturbance is common in children with neurodevelopmental disorders, with high rates identified in children with Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC). Phenotypic sleep profiles for these groups may implicate different pathways to sleep disturbance. At present, cross-group comparisons that might elucidate putative phenotypic sleep characteristics are limited by measurement differences between studies. In this study, a standardised questionnaire was administered across groups affording comparison of the prevalence and profile of sleep disturbance between groups and contrast to chronologically age-matched typically developing (TD) peers. METHODS: The modified version of Simonds and Parraga's sleep questionnaire, adapted for use in children with intellectual disabilities, was employed to assess sleep disturbance profiles in children aged 2-15 years with SMS (n = 26), AS (n = 70), ASD (n = 30), TSC (n = 20) and a TD contrast group (n = 47). Associations between sleep disturbance and age, obesity, health conditions and overactivity/impulsivity were explored for each neurodevelopmental disorder group. RESULTS: Children with SMS displayed severe night waking (81%) and early morning waking (73%). In contrast, children with ASD experienced difficulties with sleep onset (30%) and sleep maintenance (43%). Fewer children with ASD (43%) and AS (46%) experienced severe night waking compared to children with SMS (both p < .01). Higher sleep-disordered breathing scores were identified for children with SMS (p < .001) and AS (p < .001) compared to the TD group. Sleep disturbance in children with AS and TSC was associated with poorer health. Children experiencing symptoms indicative of gastro-oesophageal reflux had significantly higher sleep-disordered breathing scores in the AS, SMS and ASD groups (all p < .01). A number of associations between overactivity, impulsivity, gastro-oesophageal reflux, age and sleep disturbance were found for certain groups. CONCLUSIONS: These data reveal syndrome-specific profiles of sleep disturbance. The divergent associations between sleep parameters and person characteristics, specifically symptoms of gastro-oesophageal reflux, overactivity and impulsivity and age, implicate aetiology-specific mechanisms underpinning sleep disturbance. The differences in prevalence, severity and mechanisms implicated in sleep disturbance between groups support a syndrome-sensitive approach to assessment and treatment of sleep disturbance in children with neurodevelopmental disorders.

Reversed gender ratio of autism spectrum disorder in Smith-Magenis syndrome.

Background: A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most consistent findings in autism spectrum disorder (ASD).Lately, the interest in studying ASD in genetic disorders has increased, and research has shown a higher prevalence of ASD in some genetic disorders than in the general population.Smith-Magenis syndrome (SMS) is a rare and complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2 or a mutation on the retinoic acid induced 1 gene. The disorder is characterised by intellectual disability, multiple congenital anomalies, obesity, neurobehavioural abnormalities and a disrupted circadian sleep-wake pattern. Methods: Parents of 28 persons with SMS between 5 and 50 years old participated in this study. A total of 12 of the persons with SMS were above the age of 18 at the time of the study. A total of 11 came from Sweden and 17 were from Norway.We collected information regarding the number of autism spectrum symptoms using the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS). Adaptive behaviour was also measured using the Vineland Adaptive Behavior Scale II. The level of intellectual disability was derived from a review of the medical chart. Results: We found significant gender differences in ASD symptomatology using the SCQ and SRS questionnaires. We found approximately three females per male above the SCQ cutoff. The same differences were not found in the intellectual level and adaptive behaviour or for behavioural and emotional problems.Gender had an independent contribution in a regression model predicting the total SCQ score, and neither the Vineland Adaptive Behavior Scale II nor the Developmental Behaviour Checklist had an independent contribution to the SCQ scores. Conclusion: We found a clear reversed gender difference in ASD symptomatology in persons with SMS. This may be relevant in the search for female protective factors assumed to explain the male bias in ASD.

Sleep Complaints and the 24-h Melatonin Level in Individuals with Smith-Magenis Syndrome: Assessment for Effective Intervention.

AIMS: Individuals with Smith-Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep clinic for the first time. METHODS: At intake, caregivers of 50 children and nine adults with SMS were surveyed about the sleep pattern and potential melatonin administration. Sampling of salivary melatonin levels was performed. RESULTS: At intake, exogenous melatonin was used by 16 children (27.1% of sample; 56.3% male) with mean age 6.8 ± 2.8 years, whereas 34 children (57.6%; 7.5 ± 4.8 years old; 64.7% male) and nine adults (15.3%; 36.8 ± 15.3 years old; 44.4% male) were not taking melatonin at intake. Participants were reported to have problems with night waking and early awakenings regardless of melatonin administration. Overall, moderate to high levels of salivary melatonin at noon were found in individuals with SMS. In particular, children with SMS showed a disrupted melatonin pattern. Furthermore, the endogenous melatonin level, age, and gender may potentially interact, yielding the severity range of sleep disturbances reported in SMS. CONCLUSION: Treatment of sleep problems in SMS is complex, and our findings may support person-centered sleep and medication management. Future clinical trials including larger groups may shed light on such approaches.

Non-invasive ventilation for sleep-disordered breathing in Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterised by behavioural disturbances, intellectual disability and early onset obesity. The physical features of this syndrome are well characterised; however, behavioural features, such as sleep disturbance, are less well understood and difficult to manage. Sleep issues in SMS are likely due to a combination of disturbed melatonin cycle, facial anatomy and obesity-related ventilatory problems. Sleep disorders can be very distressing to patients and their families, as exemplified by our patient's experience, and can worsen behavioural issues as well as general health. This case demonstrates the successful use of non-invasive ventilation in treating underlying obesity hypoventilation syndrome and obstructive sleep apnoea. As a consequence of addressing abnormalities in sleep patterns, some behavioural problems improved.

Smith-Magenis Syndrome: Face Speaks.

Smith-Magenis syndrome is a well delineated microdeletion syndrome with characteristic facial and behavioral phenotype. With the availability of the multi-targeted molecular cytogenetic techniques like Multiplex Ligation Probe Amplification and cytogenetic microarray, the cases are diagnosed even without clinical suspicion. Here, the authors present clinical features of nine Indian cases of Smith-Magenis syndrome. Characteristic facial phenotype including tented upper lip, broad forehead, midface hypoplasia, short philtrum and upslant of palpebral fissure is obvious in the photographs. The behavioral variations were seen in some of the cases but were not the presenting features. The characteristic facial phenotype can be an important clinical guide to the diagnosis.

Individuals with Smith-Magenis syndrome display profound neurodevelopmental behavioral deficiencies and exhibit food-related behaviors equivalent to Prader-Willi syndrome.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder associated with intellectual disability, sleep disturbances, early onset obesity and vast behavioral deficits. We used the Behavior Problems Inventory-01 to categorize the frequency and severity of behavioral abnormalities in a SMS cohort relative to individuals with intellectual disability of heterogeneous etiology. Self-injurious, stereotyped, and aggressive/destructive behavioral scores indicated that both frequency and severity were significantly higher among individuals with SMS relative to those with intellectual disability. Next, we categorized food behaviors in our SMS cohort across age using the Food Related Problems Questionnaire (FRPQ) and found that problems began to occur in SMS children as early as 5-11 years old, but children 12-18 years old and adults manifested the most severe problems. Furthermore, we evaluated the similarities of SMS adult food-related behaviors to those with intellectual disability and found that SMS adults had more severe behavioral problems. Many neurodevelopmental disorders exhibit syndromic obesity including SMS. Prader-Willi syndrome (PWS) is the most frequent neurodevelopmental disorder with syndromic obesity and has a well-established management and treatment plan. Using the FRPQ we found that SMS adults had similar scores relative to PWS adults. Both syndromes manifest weight gain early in development, and the FRPQ scores highlight specific areas in which behavioral similarities exist, including preoccupation with food, impaired satiety, and negative behavioral responses. SMS food-related behavior treatment paradigms are not as refined as PWS, suggesting that current PWS treatments for prevention of obesity may be beneficial for individuals with SMS.

Dermatologic features of Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is characterized by distinctive facial and skeletal features, developmental delay, cognitive impairment, and behavioral abnormalities, including self-injurious behaviors. We aimed to investigate whether cutaneous features are common in SMS. We performed a complete skin examination in 20 young SMS patients. Skin features secondary to self-injurious behavior, such as bites, abrasions, dystrophic scars, limited spots of hyperkeratosis, anomalies of the nails, and whitlows, were found in the majority of patients. Acral pachydermia and fissured plantar keratoderma were common. Xerosis was constant and associated with extensive keratosis pilaris in the majority of patients. Dermatofibromas were frequent in older patients. The hair was dense and shiny, with an unusual hairline. Eyelash trichomegaly and heavy brows were common, as well as folliculitis on the back. The skin features of SMS have rarely been reported in the literature. Some of these are the consequence of neurobehavioral features, but some cutaneous features and abnormalities of appendages have not been reported in other related syndromes. Skin manifestations of SMS are varied, sometimes induced by self-injurious behavior and sometimes more specific. It remains to be determined whether the combination of the two kinds of signs could contribute to early diagnosis of the syndrome.

Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptive daytime behavior have been linked to an abnormal circadian rhythm of melatonin with a diurnal instead of nocturnal secretion of this hormone. SMS provides a demonstration of a biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate the generation of circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2, may cause the inversion of the melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS may also affect entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nuclei), or synthesis and release of melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening.

Potocki-Lupski syndrome with teratologic dislocation of the hip: a case report.

Potocki-Lupski syndrome results from the duplication of chromosome 17 band p11.2. This is the first report of a case of Potocki-Lupski syndrome with teratologic dislocation of both hips. The diagnosis was made by chromosomal analysis. The association between Potocki-Lupski syndrome and musculoskeletal disorders may help elucidate the etiology and prognosis of the syndrome.

Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect: first report from China.

Smith-Magenis syndrome (SMS) is a rare syndrome with multiple congenital malformations, including development and mental retardation, behavioral problems and a distinct facial appearance. SMS is caused by haploinsufficiency of RAI1 (deletion or mutation of RAI1). We describe an eight-year-old female Chinese patient with multiple malformations, congenital heart defect, mental retardation, and behavioral problems (self hugging, sleeping disturbance). High-resolution genome wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in chromosome region 17p11.2. This chromosome region contains RAI1, a critical gene involved in SMS. To the best of our knowledge, this is the first report of an SMS patient in mainland China.

Siblings of individuals with Smith-Magenis syndrome: an investigation of the correlates of positive and negative behavioural traits.

BACKGROUND: Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder that affects approximately one out of 25,000 births worldwide. To date, no research has been conducted to investigate how having an individual with SMS in a family is a positive or negative influence on siblings. METHODS: To investigate this question we conducted a study involving 79 siblings and 60 parents of individuals with SMS to assess perceptions of how having a sibling with SMS positively and negative influence siblings' behavioural traits. RESULTS: Our findings show that age of siblings of individuals with SMS was associated with a significant increase in positive behavioural traits and a significant decrease in negative behavioural traits. Additionally, siblings who perceive benefits from having a sibling with SMS demonstrate significantly more positive behavioural traits and significantly fewer negative behavioural traits. Parents accurately assess the changes in sibling behavioural traits with age, and parents who perceive their child as having experienced benefits from the sibling relationship report that siblings demonstrate significantly more positive behavioural traits and significantly fewer negative behavioural traits. CONCLUSIONS: Our research shows that although individuals experience difficulties as a result of having a sibling with SMS, overall, siblings tend to fare well and parents appreciate both the positive and negative behavioural effects that result from having a sibling with SMS.

Definition of a critical genetic interval related to kidney abnormalities in the Potocki-Lupski syndrome.

Potocki-Lupski syndrome is a genomic disorder caused by duplication of 17p11.2. It is characterized by failure to thrive, intellectual disability, hypotonia, and behavioral difficulties. Structural renal anomalies have been observed in <10% of affected individuals. We present detailed clinical and molecular data on six patients with Potocki-Lupski syndrome, two of whom had renal abnormalities, and investigate the prevalence of kidney abnormalities in the mouse model for the syndrome. In contrast to affected humans, the mouse model does not demonstrate a renal phenotype. Comparison of the duplicated segment in patients with Potocki-Lupski syndrome and the renal phenotype and the syntenic duplicated region in the mouse model allowed us to suggest a 0.285 Mb critical region, including the FLCN gene that may be important for development of renal abnormalities in patients with this duplication.