Orchidopexy in children with Prader-Willi syndrome: Results of a long-term follow-up study.

INTRODUCTION: Prader-Willi syndrome (PWS) is a rare (1:20.000) genetic condition affecting both males and females. Among other features, in boys, the syndrome is characterized by cryptorchidism in 86-100% of cases, hypogonadism, delayed puberty and infertility. The aim of the present study is to appraise the results of orchidopexy in this selected population of children. STUDY DESIGN: A follow-up study of children with PWS treated for undescended testes at a single institution over a 20-year period was performed. Patients were identified from a National PWS registry and reviewed at a special follow-up clinic. Data were collected from electronic and hard copies records and reported as median (range). RESULTS: Thirty-three children (1-17 years) were identified. Co-morbidities were present in 22 (66%) and 15 (45%) were on growth-hormone therapy. Six patients (19%) had normal testes palpable in the scrotum; twenty-seven (81%) had undescended testes and required orchidopexy. Thirteen (48%) underwent a bilateral procedure for a total of 40 procedures. A 2-stage Fowler-Stephens orchidopexy was required in 2 (7%) testes. At surgery hypotrophic testes were documented in 6 (22%) patients. Age at orchidopexy was 1.4 years (0.5-5.5). Age at FU was 7.2 years (1.7-17). Length of follow-up is 3.5 years (0.4-14). At follow-up 16 (40%) testes were of normal size and palpable in the scrotum; 7 (17.5%) testes required redo-orchidopexy. All patients (6/33) over 16 years of age that had testosterone levels tested had values below normal limits after successful orchidopexy. CONCLUSIONS: This study evaluates the results of orchidopexy in a large population of children with PWS. At follow-up, only 40% of testes were of normal size and in the scrotum. This information should be taken into consideration for patients' management and pre-operative parents' counseling.

Congenital Methemoglobinemia Type II-Clinical Improvement with Short-Term Methylene Blue Treatment.

We report a case of prophylactic management with methylene blue (MB) in an almost 4-year-old male with congenital methemoglobinemia type II. He has a CYB5R3 compound heterozygote mutation, causing a cytochrome-b(5) reductase deficiency. Since the MB treatment regimen has commenced, his methemoglobin level has been significantly lower. He has shown modest behavioral improvements (as assessed on the Achenbach behavior report scales). There have been no iatrogenic side effects. These findings are encouraging for symptomatic improvement with regular prophylactic MB treatment but represent a single case report, which must be interpreted with caution.

A population-based profile of 160 Australians with Prader-Willi syndrome: trends in diagnosis, birth prevalence and birth characteristics.

Perceived temporal trends in recognition and diagnosis of Prader-Willi syndrome served as the rationale for an updated epidemiological profile of individuals with this syndrome. Data from the Victorian Prader-Willi Syndrome Register were used to explore birth prevalence, birth characteristics, timing of diagnosis, and molecular mechanism, and to identify trends over time. Maternal age, birth gestation, small for gestational age, and sex were compared across molecular mechanisms. Between 1951 and 2012 there were 160 individuals with Prader-Willi syndrome, known to the Victorian Prader-Willi Syndrome Register, who were born in the Australian state of Victoria. The birth prevalence for individuals with a molecular diagnosis of Prader-Willi syndrome was estimated to be 1:15,830 for 2003-2012. Compared to 1973-1981, the decade 2003-2012 saw an increase in the rate of molecular diagnosis from 58% to 96%, more complete identification of the molecular mechanism (42% vs. 83%), earlier molecular diagnosis (1.3 years vs. 8.6 weeks), and a rise in the relative proportion of maternal uniparental disomy from 0% to 45%. One quarter of infants was born preterm and 53% were small for gestational age. This study confirms a temporal change in diagnostic patterns, suggests a greater relative contribution of maternal uniparental disomy as a molecular mechanism, provides a more robust estimate of birth prevalence and provides evidence of in utero growth restriction for this group. These findings have important clinical and health service delivery implications and pave the way for further research in Prader-Willi syndrome.

Prader-Willi syndrome in Victoria: mortality and causes of death.

AIM: The aim of this study was to describe the rates, predictors and causes of mortality in a population sample of individuals with Prader-Willi syndrome (PWS). METHODS: One hundred sixty-three individuals with PWS (90 males and 73 females, ages: 3 weeks to 60 years) were identified from the Victorian PWS Register. Information on demographics, age at diagnosis, genetic mechanism, age at which obesity developed and last known body mass index measurement were extracted. Notification and causes of death were obtained through linkage with Australian national and state of Victoria death indexes. Survival analysis was used to estimate the probability of survival and the effect of obesity on survival. Mortality rate ratios were calculated to investigate the effect of the factors listed above on mortality. RESULTS: Fifteen deaths were recorded (nine males and six females), corresponding to an 87% probability of survival to 35 years. The probability of survival was significantly lower for individuals with known obesity (P= 0.03), but there was no strong evidence for an effect on survival for the other factors studied. Cardiac or respiratory conditions were common causes of death after the age of 15 years. CONCLUSIONS: The effect of known obesity on the probability of survival and the causes of death reported in this and other studies suggest an important association between obesity and early death in adults with PWS. This finding highlights the critical nature of preventative and intervention strategies aimed at minimising the effects of hyperphagia in individuals with PWS.

Use of a patient-controlled stretching device to improve the ankle range of motion.

BACKGROUND: Ankle and subtalar stiffness are widely associated with many foot and ankle conditions and functional deficits. Loss of range of motion, particularly dorsiflexion, results in significant gait dysfunction. A variety of methods have been evaluated to address this problem, including yoga, manipulation, dance training, jogging and static stretching exercises. No tools have been described that effectively and efficiently stretch the ankle and subtalar joint without requiring supervision or assistance of a trained physical therapist. MATERIALS AND METHODS: Twenty-two subjects with varying foot and ankle diagnoses who had little or no improvement in range of motion after traditional assisted physical therapy were recruited from a foot and ankle orthopaedic clinic. The subjects' ankle and subtalar range of motion (ROM) in plantarflexion (PF), dorsiflexion (DF), inversion (INV), and eversion (EVR) were measured using a standard goniometer by a single physiotherapist prior to using the stretching device. The subjects were trained on the proper use of the stretching device and then instructed to use it daily for a 6-week period. Then the same examiner repeated the above measurements. Statistical analysis was performed using a two sample t-test assuming unequal variances. RESULTS: There were statistically significant increases in ROM in all planes tested: DF to PF (p = 0.0052), and INV to EVR (p = 0.018). CONCLUSION: Stretching with the device significantly increased ankle and subtalar ROM. CLINICAL SIGNIFICANCE: The stretching device can be used at home on a regular basis with minimal training and can effectively treat stiffness of the ankle and subtalar joints. It can be cost-effective when compared to use of physiotherapy services.

The "kick-off" position: a new sign for early diagnosis of complex regional pain syndrome in the leg.

BACKGROUND: Complex regional pain syndrome (CRPS) is a clinical entity that develops after a precipitating injury. It involves dysfunction of the sensory, autonomic, and motor systems and frequently is missed on initial presentation. The purpose of this report was to describe a simple clinical sign that can aid in its diagnosis. METHODS: A retrospective review was conducted of 39 consecutive patients with CRPS type I or II seen in a foot and ankle clinic between October, 2001, and May, 2005. The diagnosis was based on clinical findings. RESULTS: Twenty-six patients had type I (67%) and 13 patients had type II (33%) CRPS. The most common nerve involved in type II was the superficial peroneal nerve. Each patient, while sitting on the exam table, held the affected extremity with the knee extended against gravity. When the leg was pushed back to a relaxed and suspended position, the patient eventually involuntarily resumed the extended position. This position in which the patients held their legs was termed the "kick-off" position sign. Nine patients were seen at the foot and ankle clinic within 6 weeks of the initial inciting event and had an established "kick-off" position sign within 3 months from the time of injury. The disappearance of this sign correlated with the subsidence of pain. CONCLUSIONS: Patients with CRPS have variable clinical presentations. The awareness of this simple observation in the right clinical setting should raise the index of suspicion of CRPS in the differential diagnosis. Early treatment of this syndrome is associated with better outcome.

Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (MIM #176270; PWS) is caused by lack of the paternally-derived copies, or their expression, of multiple genes in a 4 Mb region on chromosome 15q11.2. Known mechanisms include large deletions, maternal uniparental disomy or mutations involving the imprinting center. De novo balanced reciprocal translocations in 5 reported individuals had breakpoints clustering in SNRPN intron 2 or exon 20/intron 20. To further dissect the PWS phenotype and define the minimal critical region for PWS features, we have studied a 22 year old male with a milder PWS phenotype and a de novo translocation t(4;15)(q27;q11.2). METHODS: We used metaphase FISH to narrow the breakpoint region and molecular analyses to map the breakpoints on both chromosomes at the nucleotide level. The expression of genes on chromosome 15 on both sides of the breakpoint was determined by RT-PCR analyses. RESULTS: Pertinent clinical features include neonatal hypotonia with feeding difficulties, hypogonadism, short stature, late-onset obesity, learning difficulties, abnormal social behavior and marked tolerance to pain, as well as sticky saliva and narcolepsy. Relative macrocephaly and facial features are not typical for PWS. The translocation breakpoints were identified within SNRPN intron 17 and intron 10 of a spliced non-coding transcript in band 4q27. LINE and SINE sequences at the exchange points may have contributed to the translocation event. By RT-PCR of lymphoblasts and fibroblasts, we find that upstream SNURF/SNRPN exons and snoRNAs HBII-437 and HBII-13 are expressed, but the downstream snoRNAs PWCR1/HBII-85 and HBII-438A/B snoRNAs are not. CONCLUSION: As part of the PWCR1/HBII-85 snoRNA cluster is highly conserved between human and mice, while no copy of HBII-438 has been found in mouse, we conclude that PWCR1/HBII-85 snoRNAs is likely to play a major role in the PWS- phenotype.