Endochondral ossification in a case of progressive osseous heteroplasia in a young female child.

Progressive osseous heteroplasia (POH) (OMIM 166350) is a rare autosomal dominant condition, characterized by heterotopic ossification of the skin, subcutaneous fat, and deep connective tissue. This condition is distinct from Albright's hereditary osteodystrophy or McCune Albright syndrome (OMIM 103580) and fibrodysplasia ossificans progressiva (OMIM 135100). We present an unusual presentation of POH in a 7-year-old female child. The clinical features included a painful swelling on the left foot, with mechanical complaints. There was no congenital hallux valgus. Family anamnesis was positive in the father. There were subcutaneous ossifications of his left upper arm, right-sided thorax, and lateral side of the right ankle. The father did not allow any radiographs or further examinations. Radiographic examination of the patient revealed ossified subcutaneous plaques on the left foot, lumbar spine, and left scapulae. Additional blood samples were analyzed, revealing no pseudohypoparathyroidism. Sequence analysis of the gene associated with POH, the GNAS1 gene, revealed the heterozygote mutation c.565_568del, previously found in Albright's hereditary osteodystrophy. Histopathological examination of the subcutaneous ossification showed presence of chondrocyte clusters, a feature usually found in fibrodysplasia ossificans progressiva. The combination of the clinical features, the absence of pseudohypoparathyroidism, histology revealing chondrocyte clusters, and the specific GNAS mutation in this patient makes this a truly unusual presentation of POH. The findings in the described case might denote subdivisions of POH. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, and recurrence if excised. We hope to inform pediatricians and orthopedic surgeons to create more awareness of this disorder so that unnecessary treatments can be avoided and proper counseling offered.

The use of medical care and the prevalence of serious illness in an adult Prader-Willi syndrome cohort.

INTRODUCTION: Adults with Prader-Willi syndrome (PWS) have an increased occurrence of several medical conditions. We report on the consequences of high morbidity rates such as prevalence rate of hospital admissions, medication use and surgery in a Dutch cohort of adults with PWS. Special attention is paid to causes and symptoms of serious illness. METHOD: Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with ID. The persons with PWS and their main caregivers were visited at home. Information was collected through semi-structured interviews on 102 adults with PWS. RESULTS: The need for medical care in the neonatal period is associated with hypotonia and feeding problems. Hospital admissions for respiratory tract infections are frequent. During childhood most hospital admissions were due to PWS syndrome specific surgery. During adolescence hospital admissions occurred for scoliosis surgery and endocrine evaluations. At adult age, hospitalization was associated with inguinal hernia surgery, diabetes mellitus, psychosis, erysipelas, water and drug intoxications. In the older group, respiratory infections were again the main reason for hospital admissions. Frequently used medications at adult age included psychotropics, laxatives, anti-diabetics and dermatologic preparations. Abnormal drinking patterns, problems with anesthesia, decreased ability to vomit, abnormal pain awareness and unpredictable fever responses were frequent and often lead to delayed diagnoses of serious conditions. DISCUSSION: People with PWS are frequent users of medical-care. Reasons for hospitalization and medication use are age specific. Knowledge on the different presentation of symptoms in people with PWS is needed. In case of unexplained illness, disturbances of consciousness and behavioral changes in people with PWS, an infection should be ruled out in the first place. Information from this study may help in preventing conditions and recognizing conditions in an early stage. Adequate preventive management and treatment of PWS related morbidity, could reduce medical care use in the long term and could improve quality adjusted life years.

Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.

The psychiatric phenotype in triple X syndrome: new hypotheses illustrated in two cases.

BACKGROUND: Triple X syndrome (47,XXX or trisomy X) is a relatively frequent cytogenetic condition with a large variety of physical and behavioural phenotypes. METHOD: Two adult patients with a triple X karyotype are described. RESULTS: Their karyotype was unknown until some years ago. What these patients have in common is that they were diagnosed with a broader autism phenotype, they were sexually abused, they suffer from psychotic illness and they show challenging behaviour, suicidality and a decline in occupational capacity. DISCUSSION: These gene-environment interactions are discussed. Gene-environment interactions may explain the variety of behavioural and psychiatric phenotypes in triple X syndrome. Ongoing atypical development in adults is hypothesized. CONCLUSIONS: Gene-environment interactions and ongoing atypical development in adults should be taken into account in research concerning the psychiatric phenotype of developmental disorders, especially those involving triple X syndrome.

Aging in Prader-Willi syndrome: twelve persons over the age of 50 years.

The life expectancy of persons with Prader-Willi syndrome (PWS) has increased in recent years. Because of the paucity of reports on older persons with PWS, the natural history, the onset, and type of age-related problems are poorly understood. Twelve persons with a genetically confirmed diagnosis of PWS aged over 50 years are described (4 deletion; 8 mUPD). Data on physical, behavioral, psychiatric, and aging characteristics were collected through semi-structured interviews with the individuals with PWS and their main carers. Cardiovascular diseases, diabetes, dermatological, and orthopedic problems were common physical complaints in older people with PWS. Functioning in activities of daily living, psychological functioning, physical functions, and care dependence were substantially worse in the older age group (50+) compared to the control group (18-49 years). Seven out of eight persons with mUPD had a history of psychiatric illness. Behavioral problems were observed in the older age group. Given the combination of age-related physical morbidity, physical appearance, behavioral and psychiatric problems, and functional decline in our cohort, we hypothesize that premature aging occurs in PWS. The care for older people with PWS requires a lifespan approach that recognizes the presence, progression, and consequences of specific morbidity. Special medical surveillance of people with PWS from 40 years onwards would ensure that intervention and support is offered with respect to specific areas of decline at the earliest possible time.

Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.

Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice.

Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype-phenotype correlation studies have been performed. A number of general genotype-phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht-Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype-phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype-phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families.

Physical health problems in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage.

Psychiatric illness in a cohort of adults with Prader-Willi syndrome.

Previous studies have suggested an association between PWS and comorbid psychiatric illness. Data on prevalence rates of psychopathology is still scarce. This paper describes a large-scale, systematic study investigating the prevalence of psychiatric illness in a Dutch adult PWS cohort. One hundred and two individuals were screened for psychiatric illness. Case vignettes were written by the first author on 63 individuals with a positive screening on psychopathology according to the interviews, medical history, medication use and behavioural questionnaires. These case vignettes were rated by two psychiatrists specializing in intellectual disability (ID). Psychopathology was divided into four diagnostic categories: bipolar disorder with psychotic symptoms, psychotic illness, depressive illness with psychotic symptoms and depressive illness without psychotic symptoms. Nine out of 53 persons (17%) with a 15q11-13 deletion and 28 out of 44 (64%) persons with maternal uniparental disomy (mUPD) were diagnosed with a current or previous psychiatric illness. Depressive illness with psychotic symptoms was the cause of psychiatric problems in the majority of persons with PWS due to deletion (56%). In the case of mUPD, almost all individuals with histories of psychopathology suffered from psychotic symptoms (85%) with or without affective component. Psychiatric examination should be part of general management of adults with PWS, especially when caused by mUPD. More attention should be paid to the presence of precursor symptoms, indicating a developing psychiatric episode. Longitudinal studies are needed to gain more insight into the natural history of psychiatric illness in adults with PWS.

MLL2 mutation spectrum in 45 patients with Kabuki syndrome.

Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS.

Behavioral phenotype in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by temper tantrums, impulsivity, mood fluctuations, difficulty with change in routine, skinpicking, stubbornness and aggression. Many studies on behavior in PWS are limited by sample size, age range, a lack of genetically confirmed diagnosis of PWS and inconsistent assessment of behavior. The aim of this study was to explore systematically the relation between behavioral problems and age groups, genetic subtypes and BMI categories in an adult PWS population. Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specialized in persons with ID. Behaviors were studied using the Developmental Behavior Checklist for Adults (DBC-A). The forms were completed by the main caregivers of 98 adults with a genetically confirmed diagnosis of PWS. Differences between age groups were statistically significant (ANOVA, p=0.03). DBC-A total scores were higher in the consecutive age groups, with the most behavioral problems in the oldest age groups. Differences between genetic subtypes were also statistically significant (ANOVA, p<0.01). Persons with mUPD had higher total scores on the DBC-A than persons with a deletion. Those with a Type I deletion showed higher total DBC-A scores than persons with a Type II deletion. There were no statistically significant differences in DBC-A total scores between the different BMI categories. Individuals with a BMI<25 had higher scores on the self-absorbed subscale compared to persons with a BMI between 25 and 30. Unlike previous descriptions of the behavioral phenotype in adults with PWS, we did not find a reduction in behavioral problems in older adults. Therefore, special attention should be paid to behavioral problems as part of general management of adults with PWS. Longitudinal studies are warranted to gain more insight into the natural history and course of behavioral problems in adults and older people with PWS over the long term and possible risk and preventive factors.

Different distribution of the genetic subtypes of the Prader-Willi syndrome in the elderly.

The Prader-Willi syndrome (PWS) is a genetic disorder caused by the absent expression of the paternal copy of maternally imprinted genes in chromosome region 15q11-13. The frequencies of different subtypes in PWS are usually given in literature as 70% deletion, 25-30% maternal uniparental disomy (mUPD) and 3-5% others (imprinting centre (IC) defects and translocations). Little is known about factors that influence the frequency of genetic subtypes in PWS. The study sample comprised 102 adults with clinically and genetically confirmed PWS, contacted through the Dutch Prader-Willi Parent Association and through physicians specialized in treating persons with intellectual disabilities. Genetic testing showed 55 persons (54%) with a paternal deletion, 44 persons (43%) with an mUPD and 3 persons (3%) with a defect of the IC. The observed distribution in our study differed from that in literature (70% deletion, 30% mUPD), which was statistically significant (z-score: P<0.05). This was mainly caused by a higher proportion of mUPD in the advanced age groups. Differences in maternal age and BMI of persons with PWS could not explain the differences in distribution across the age groups. Our study population had a much broader age range, compared with other studies, because of a predominance of elderly people (40+ years) with PWS. In other studies, these elderly persons might have been undiagnosed and/or underreported because of a lack of genetic diagnosis. The results underline both the need for correct genetic diagnosis in all persons with PWS and adjustment of the guidelines for preventive management in adulthood.

Dementia in a woman with Prader-Willi syndrome.

We report on a 58-year-old woman with Prader-Willi syndrome (PWS) and dementia. This case report illustrates a new research area in older adults with PWS. Dementia might be associated with PWS. In the case of dementia, more clinical studies are warranted to observe whether premature Alzheimer changes or indications of other dementia forms indeed occur more prevalent in people with PWS.

Triple X syndrome: a review of the literature.

The developmental and clinical aspects in the literature on triple X syndrome are reviewed. Prenatal diagnosis depends on karyotyping. The incidence is 1 of 1000 females. At birth, 47,XXX girls have a lower mean birth weight and a smaller head circumference. Triple X diagnosis was not suspected at birth. The maternal age seems to be increased. Toddlers with triple X syndrome show delayed language development. The youngest girls show accelerated growth until puberty. EEG abnormalities seem to be rather common. Many girls show motor-coordination problems and auditory-processing disorders are not rare. Scoliosis is probably more common in adolescent cases. The IQ levels are 20 points below that of controls, and verbal IQ is lowest. The girls struggle with low self-esteem and they need psychological, behavioural and educational support. They perform best in stable families. After leaving school they seem to feel better. In adults, premature ovarian failure seems to be more prevalent than in controls. MRIs of the brain seem to show decreased brain volumes. The 47,XXX women most often find jobs that reflect their performance abilities. Psychotic illness seems to be more prevalent in triple X adult women than in controls. Psychotic disorders respond well to psychotropic drugs. Triple X adults suffer more frequently from cyclothymic and labile personality traits. Research on triple X syndrome may yield more insight into brain and behaviour relations, developmental psychopathology, auditory-processing disorders, EEG disorders, personality and psychotic disorders, etc.

The C20orf133 gene is disrupted in a patient with Kabuki syndrome.

Kabuki syndrome (KS) is a rare, congenital mental retardation syndrome. The aetiology of KS remains unknown. Four carefully selected patients with KS were screened for chromosomal imbalances using array comparative genomic hybridisation at 1 Mb resolution. In one patient, a 250 kb de novo microdeletion at 20p12.1 was detected, deleting exon 5 of C20orf133. The function of this gene is unknown. In situ hybridisation with the mouse orthologue of C20orf133 showed expression mainly in brain. The de novo nature of the deletion, the expression data and the fact that C20orf133 carries a macro domain, suggesting a role for the gene in chromatin biology, make the gene a likely candidate to cause the phenotype in this patient with KS. Both the finding of different of chromosomal rearrangements in patients with KS features and the absence of C20orf133 mutations in 19 additional patients with KS suggest that KS is genetically heterogeneous.

Skin abnormalities in individuals with macrocephaly: Cowden disease from a dermatologist's point of view.

Cowden disease is a rare autosomal dominant disorder characterized by multiple hamartomas and (malignant) tumors affecting major organs including the breast, thyroid, endometrium, brain, skin and mucosa. Diagnostic criteria as formulated by the International Cowden Consortium serve as a guideline to clinically identify patients in which Cowden disease is suspected. However, the spectrum of abnormalities associated with PTEN mutations is very broad, such that the term PTEN hamartoma tumor syndrome (PTHS) is often used. The diagnostic criteria for Cowden disease do not always serve to reliably identify patients who fall within the PTHS spectrum. Therefore, it is important that clinicians are aware of features that should raise the suspicion of such a syndrome. To illustrate this point, we present three patients with clinical features of the PTEN hamartoma tumor syndrome spectrum. These patients have macrocephaly in common. Two of them meet the criteria for Cowden disease; one patient refused mutation analysis, while mutation analysis in the other patient revealed no PTEN mutation. The third patient does not meet the criteria for Cowden disease; however, genetic analysis showed a pathogenic mutation in the PTEN gene. Dermatologists regularly encounter the (muco-)cutaneous abnormalities that can be seen in PTEN hamartoma tumor syndrome. These findings combined with a (family) history of internal malignancy or a macrocephaly should raise the suspicion of PTHS, even in the absence of classical Cowden criteria.

REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.

Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.

Shprintzen-Goldberg syndrome associated with a novel missense mutation in TGFBR2.

Shprintzen-Goldberg syndrome (SGS) is a rare disorder characterized by a Marfan-like habitus, mental retardation and craniosynostosis. Cardiac abnormalities, such as aortic root dilation have also been noted as well as several skeletal abnormalities. Its nosological status is unclear as it is hard to delineate SGS from similar disorders, such as Furlong, Marfan type II, Camurati-Engelmann and Loeys-Dietz syndromes. It has been suggested that these conditions represent a phenotypical spectrum associated with aberrant TGF-beta signalling. In support of this notion, we found a novel TGFBR2 missense mutation in a patient with features of SGS.

Healthcare transition in persons with intellectual disabilities: general issues, the Maastricht model, and Prader-Willi syndrome.

In current healthcare, transitional healthcare is a very important and timely issue. Thanks to the major advances made in medical care and technology, many children with childhood onset diseases and/or genetic syndromes survive to adulthood. These children are at risk of not being provided with adequate healthcare as they reach adulthood. Healthcare transition is an essential part of healthcare provision, referred to as the shift from one type of healthcare to another. In Maastricht, we developed a transition/out clinic led by a medical doctor specialized in persons with intellectual disability (ID), together with a clinical geneticist. We aim to coordinate healthcare issues based on guidelines if available. Also questions concerning living, daily activities, relations, sexuality, and sterilization can be discussed. The aging process of persons with ID has been a topic of interest in recent years. Little is known about the aging process of people with specific syndromes, except for persons with Down syndrome. We present some data of a recent questionnaire study in persons with Prader-Willi syndrome. In only 50% in persons with a clinical diagnosis genetic test results could be reported. The majority of persons were obese. Diabetes mellitus, hypertension, skin problems, sleep apnea, and hormonal problems like osteoporosis and hypothyroidism were common. Psychiatric problems were frequent, especially in the persons with uniparental disomy. Osteoporosis and sleep apnoea seem to be underestimated. Further longitudinal research is necessary for a better understanding of the aging process in PWS.