Identification of growth patterns of preterm and small-for-gestational age children from birth to 4 years - do they catch up?

Background A legitimate indication for growth hormone (GH) therapy in children born too light or short at birth [small-for-gestational age (SGA)] exists in Germany and the European Union only if special criteria are met. Methods We conducted a longitudinal, multi-centered study on full-term appropriate-for-gestational age (AGA, n=1496) and pre-term born SGA (n=173) and full-term SGA children (n=891) in Germany from 2006 to 2010. We analyzed height, weight, body mass index (BMI) and head circumference. Results Pre-term or full-term born SGA children were shorter, lighter and had a lower BMI from birth until 3 years of age than full-term AGA children. The growth velocity of the analyzed anthropometric measurements was significantly higher in pre-term and full-term SGA children exclusively in the first 2 years of life than in AGA children. The criteria for GH treatment were fulfilled by 12.1% of pre-term SGA children compared to only 1.3% of full-term SGA children. Conclusion For children that do not catch up growth within the first 2 years of life, an earlier start of GH treatment should be considered, because a catch-up growth later than 2 years of life does not exist. Pre-term SGA-born children more frequently fulfill the criteria for GH treatment than full-term SGA children.

Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. METHODS: We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. RESULTS: Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. INTERPRETATION: This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.

Sacral neuromodulation for fecal incontinence and constipation in adult patients with anorectal malformation--a feasibility study in patients with or without sacral dysgenesis.

PURPOSE: The aim of this study was to evaluate both the feasibility and effectiveness of sacral neuromodulation for fecal incontinence and constipation in adult patients who had undergone surgical repair of anorectal malformations (ARM). METHODS: Patients with ARM with or without sacral dysgenesis who presented with fecal incontinence, constipation, or combined symptoms were treated with sacral nerve stimulation (SNS). Success of SNS was assessed by scores preoperatively and after a 3-week test period: Cleveland Clinic Incontinence Score (CCI), Surgical Working Group for Coloproctology (CACP) continence score, German version of the Fecal Incontinence Quality of Life Scale, and Cleveland Clinic Constipation Score (CCCS). The follow-up results of the patients who received a definitive pacemaker were used to evaluate the long-term effect of SNS in patients with ARM. RESULTS: Four patients with fecal incontinence and one patient with constipation (two males, three females; median age 24 years [13; 31]) were treated with SNS between May 2012 and May 2013. Four patients had a normal sacrum; one patient had a sacral dysgenesis. Preoperatively and after the test phase, median CACP continence scores were 8 [1; 10] and 11.5 [3; 16], median CCI 14 [12; 19] and 13 [11; 17], and median Fecal Incontinence Quality of Life Scale improved in all categories. For constipation, CCCSs were 16 and 7. CONCLUSION: Sacral neuromodulation is a feasible treatment modality for adult patients with ARM with a normally developed sacrum. Patients with sacrum dysgenesis are not suited for SNS because a definitive quadripolar electrode could not be anchored in the absence of a sacral bone.

Impact of Coronavirus Disease 2019 (COVID-19) Pandemic on Surgical Site Infection in Patients with Inflammatory Bowel Disease-A Monocentric, Retrospective Cohort Study.

(1) Background: Surgical site infections (SSIs) are a relevant problem with a 25% incidence rate after elective laparotomy due to inflammatory bowel disease (IBD). The aim of this study was to evaluate whether stricter hygienic measures during the COVID-19 pandemic influenced the rate of SSI. (2) Methods: This is a monocentric, retrospective cohort study comparing the rate of SSI in patients with bowel resection due to IBD during COVID-19 (1 March 2020-15 December 2021) to a cohort pre-COVID-19 (1 February 2015-25 May 2018). (3) Results: The rate of SSI in IBD patients with bowel resection was 25.8% during the COVID-19 pandemic compared to 31.8% pre-COVID-19 (OR 0.94; 95% CI 0.40-2.20; p = 0.881). There were seventeen (17.5%) superficial and four (4.1%) deep incisional and organ/space SSIs, respectively, during the COVID-19 pandemic (p = 0.216). There were more postoperative intra-abdominal abscesses during COVID-19 (7.2% vs. 0.9%; p = 0.021). The strictness of hygienic measures (mild, medium, strict) had no influence on the rate of SSI (p = 0.553). (4) Conclusions: Hygienic regulations in hospitals during COVID-19 did not significantly reduce the rate of SSI in patients with bowel resection due to IBD. A ban on surgery, whereby only emergency surgery was allowed, was likely to delay surgery and exacerbate the disease, which probably contributed to more SSIs and postoperative complications.

Influence of Neoadjuvant Therapy on Success of Endoscopic Vacuum Therapy in Anastomotic Leakage after Rectal Resection Because of Rectal Cancer.

Background: For locally advanced rectal cancer, neoadjuvant therapy (NT) is an established element of therapy. Endoscopic vacuum therapy (EVT) has been a relevant treatment option for anastomotic leakage after rectal resection since 2008. The aim was to evaluate the influence of NT on the duration and success of EVT in anastomotic leakage after rectal resection for rectal cancer. Methods: This was a monocentric, retrospective cohort study including patients who underwent rectal resection with primary anastomosis because of histologically proven carcinoma of the rectum in the Department for General and Visceral Surgery of Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin over a period of ten years (2012 to 2022). Results: Overall, 243 patients were included, of which 47 patients (19.3%) suffered from anastomotic leakage grade B with consecutive EVT. A total of 29 (61.7%) patients received NT and 18 patients (38.3%) did not. The median duration of EVT until the removal of the sponge did not differ between patients with and without NT: 24.0 days (95% CI 6.44-41.56) versus 20.0 days (95% CI 17.03-22.97); p = 0.273. The median duration from insertion of EVT until complete healing was 74.0 days with NT (95% CI 10.07-137.93) versus 62.0 days without NT (95% CI 45.99-78.01); p = 0.490. Treatment failure-including early persistence and late onset of recurrent anastomotic leakage-was evident in 27.6% of patients with NT versus 27.8% without NT; p = 0.989. Ostomy was reversed in 19 patients (79.2%) with NT compared to 11 patients (68.8%) without NT; p = 0.456. Overall, continuity was restored in 75% of patients in the long term after EVT. Conclusion: This trial comprised-to our knowledge-the largest study cohort to analyze the outcome of EVT in anastomotic leakage after rectal resection for rectal cancer. We conclude that neoadjuvant therapy neither prolongs EVT nor the time to healing from anastomotic leakage. The rates of treatment failure of EVT and permanent ostomy were not higher when neoadjuvant therapy was used.

Repeatability of anorectal manometry in healthy volunteers and patients.

BACKGROUND: Anorectal manometry is used extensively in the assessment of patients with disorders of the pelvic floor. The present study investigated the repeatability of anorectal manometry in healthy volunteers and patients. PATIENTS AND METHODS: A total of 30 healthy volunteers (15 men and 15 women) and 10 patients with fecal incontinence (4 men and 6 women) underwent perfusion manometry and volumetry. Intraindividual variability was evaluated using the intraindividual correlation coefficient (ICC). Interindividual variability was expressed as the standard deviation from the calculated mean values. RESULTS: We found a high intraindividual correlation for the squeezing pressure (ICC 0.75-0.95), vector volume (ICC 0.88-0.97), and rectal perception (ICC 0.82-0.98). The anal resting pressure showed moderate repeatability (ICC 0.60-0.72). However, with regard to sphincter asymmetry, rectal compliance, and the rectoanal inhibitory reflex, a wide range of variability was found. In the female volunteers, the squeezing pressure and vector volume were lower than in those in the male volunteers. The anal pressure, vector volume, thresholds for urgency, and the maximum tolerable volume were lower in the incontinent patients than in the healthy volunteers. CONCLUSIONS: The squeezing pressure, vector volume, and rectal perception allow a reliable analysis of anal sphincter function. Sphincter asymmetry, rectal compliance, and the rectoanal inhibitory reflex were of limited diagnostic value.

Case report: Life threatening hyponatremia in infants with urinary tract infections: two cases of type III pseudohypoaldosteronism and review of the literature.

We describe two female infants at the age of five and six months with urinary tract infections presenting with vomiting and reduced drinking behavior. On laboratory analysis, severe hyponatremia (106 mmol/L and 109 mmol/L) was seen with hyperkalemia and compensated metabolic acidosis. Endocrinological analyses revealed massively increased levels of aldosterone and renin, leading to the diagnosis of type III pseudohypoaldosteronism (PHA). A review of the current literature 2013-2023 revealed 26 type III PHA cases aged up to ten months with reduced drinking behavior, weight loss and/or failure to thrive being the most common clinical presentations. Given the severe presentation of PHA electrolyte measurements in infants with urinary tract infections and/or in infants with congenital anomalies of the kidney and urinary tract (CAKUT) are strongly recommended.

A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes.

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50-60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts.

Twenty years of newborn screening for congenital adrenal hyperplasia and congenital primary hypothyroidism - experiences from the DGKED/AQUAPE study group for quality improvement in Germany.

Congenital primary hypothyroidism (CH) and congenital adrenal hyperplasia (CAH) are targeted by the German and Austrian newborn screening. For both diseases, there are registries for quality improvement, based on standardized observational data from long-term patient follow-up, under the auspices of the DGKED study group. By September 2021, the CH registry HypoDOK includes datasets from 23,348 visits of 1,840 patients, and the CAH registry contains datasets from 36,237 visits of 1,976 patients. Here, we report on the recruitment process, patient characteristics, and research contributions from the registries, and underline that the registries are an important tool to improve patient care and outcomes. Registries for rare conditions should thus be considered as an important public health measure and they should be adequately institutionalized and funded.

Cross-sectional seroprevalence surveys of SARS-CoV-2 antibodies in children in Germany, June 2020 to May 2021.

The rate of SARS-CoV-2 infections in children remains unclear due to many asymptomatic cases. We present a study of cross-sectional seroprevalence surveys of anti-SARS-CoV-2 IgG in 10,358 children recruited in paediatric hospitals across Germany from June 2020 to May 2021. Seropositivity increased from 2.0% (95% CI 1.6, 2.5) to 10.8% (95% CI 8.7, 12.9) in March 2021 with little change up to May 2021. Rates increased by migrant background (2.8%, 4.4% and 7.8% for no, one and two parents born outside Germany). Children under three were initially 3.6 (95% CI 2.3, 5.7) times more likely to be seropositive with levels equalising later. The ratio of seropositive cases per recalled infection decreased from 8.6 to 2.8. Since seropositivity exceeds the rate of recalled infections considerably, serologic testing may provide a more valid estimate of infections, which is required to assess both the spread and the risk for severe outcomes of SARS-CoV-2 infections.

Rectal anatomy after rectopexy: cinedefecography versus MR-defecography.

BACKGROUND: Conventional defecography can reveal abnormalities in patients with evacuatory disorders. With fast dynamic MR imaging systems, MR-defecography has become possible, which does not expose patients to ionizing radiation. The purpose of this study was to assess the correlation of both methods after rectopexy. MATERIALS AND METHODS: Twenty-one consecutive patients underwent abdominal sigmoidectomy and rectopexy due to evacuatory disorders. Postoperatively, all patients were investigated by cineradiographic defecography. Fourteen patients underwent MR-defecography additionally. The results were screened for anorectal angle and pelvic floor position (rest, squeezing, and evacuation). The findings were depicted in Box plot analysis and compared with the Friedman-test. Descent of pelvic organs was also assessed. RESULTS: In MR-defecography, anorectal angle at rest was smaller than in conventional defecography, but there was no difference during squeezing and defecation. Concerning pelvic floor position, during squeezing, MR-defecography illustrated a lower perineum and a broader range of pelvic settings, but no difference at rest and during evacuation. In four patients, MR-defecography visualized a descent of the bladder. However, in four patients with complete evacuation in cineradiography and with no clinical complaints about incomplete evacuation, MR imaging showed deficient evacuation. Overall continence of patients was significantly improved through surgery, but there was no change in sphincter pressure, radial asymmetry, or sphincter length. CONCLUSIONS: In general, with respect to anorectal angle and perineal motility, both methods revealed consistent results. The concomitant depiction of structures in MR-defecography is helpful in the assessment of descent of pelvic organs and permits visualization of enteroceles. However, in 30% of patients, MR-defecography wrongly showed incomplete evacuation.

Morphological alterations of the enteric nervous system in young male patients with rectal prolapse.

OBJECTIVES: The pathogenesis of rectal prolapse (RP) defined by a circumferential, full-thickness invagination of the rectal wall into the anal canal is controversial. RP is normally encountered in elderly women and attributed to several etiological factors (e.g., advanced age, pudendal nerve injury, laxity of supporting ligaments). RP affecting young male patients is unlikely to be explained by these factors and may be due to a rectal motility disorder. Therefore, the enteric nervous system (ENS) as key regulator of intestinal motility was evaluated by a systematic morphometric analysis. PATIENTS AND METHODS: Full-thickness rectosigmoid specimens obtained from young male patients with symptomatic RP (n = 5) and male controls (n = 15) were processed for conventional histology and immunohistochemistry using anti-HuC/D as pan-neuronal marker. Enteric ganglia, nerve and glial cells were quantified separately in the myenteric (MP) and submucosal plexus (SMP). RESULTS: Compared to controls, patients with RP showed significantly (p < 0.05) increased mean ganglionic area both in MP and SMP, increased mean neuronal content of submucosal ganglia, and nearly threefold higher frequency of submucosal ganglia containing ≥7 neurons. CONCLUSION: The morphometric analysis reveals distinct quantitative alterations of the ENS in young male patients with RP mainly characterized by submucosal hyperganglionosis similar to histopathological features described in intestinal neuronal dysplasia. The data give evidence that RP in this unusual subgroup is associated with morphological changes of enteric ganglia which may contribute to the development of RP and complement established etiological concepts.

Treatment response to cyclophosphamide, rituximab, and bortezomib in chronic immune-mediated sensorimotor neuropathies: a retrospective cohort study.

BACKGROUND: Up to 20% of patients with chronic immune-mediated sensorimotor neuropathies (CIN) do not respond adequately to first-line therapies. However, studies on further treatment are scarce. METHODS: We analyzed retrospectively 200 CIN patients regarding disease characteristics and response to therapy with cyclophosphamide (CYP), rituximab (RTX), and bortezomib (BTZ). Treatment response was defined as improvement or stabilization of inflammatory neuropathy cause and treatment overall disability score (INCAT-ODSS). RESULTS: A total of 48 of 181 patients (26.5%) received therapy with CYP, RTX, or BTZ. The most frequently and first used therapy was CYP (69%). More than 40% of patients needed a second or third treatment. Overall, 71 treatments were applied in 48 patients. The combination of up to all three treatments enhanced the response-rate to 90%. Treatment within 24 months after initial diagnosis resulted in significantly higher response rate than late treatment (79% versus 50 %, p = 0.04, χ 2-test, n = 46) and in lower disability in long-term follow up (INCAT-ODSS 3.8 versus 5.8, p = 0.02, t-test, n = 48). Patients with Lewis-Sumner syndrome (n = 9) and autoantibody mediated neuropathies (n = 13) had excellent response rates after treatment with RTX (90-100%). In contrast, typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) showed a response rate of 64% in CYP, 64% in RTX, and 75% in BTZ. CONCLUSION: Treatment with CYP, RTX, or BTZ was effective in this cohort of CIN refractory to first-line treatment. Our data increase evidence for an early use of these therapies. High efficacy of RTX in Lewis-Sumner syndrome in contrast to typical CIDP suggests a distinct pathophysiology.

Evaluation of the EFNS/PNS diagnostic criteria in a cohort of CIDP patients.

OBJECTIVE: To evaluate the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) in a cohort of patients diagnosed and treated for CIDP in a tertiary university hospital. METHODS: In a monocentric retrospective study of 203 CIDP patients, diagnosed according to expert opinion, we evaluated the EFNS/PNS diagnostic criteria. Clinical course and nerve conduction studies (NCS) over 1 year from first referral were studied. Secondarily, we compared the clinical and paraclinical characteristics, including nerve ultrasound, of patients who failed with those who fulfilled the criteria in order to identify clinically relevant differences. RESULTS: At 1 year, 182 (89.7%) patients fulfilled the criteria (156/76.9% definite, 22/10.8% probable, and 4/2% possible). Twenty-one (10.3%) patients did not because the electrodiagnostic criteria remained negative. These still showed signs of demyelination but did not reach the cut-off values. They also presented typical, albeit less pronounced, multifocal nerve enlargement in ultrasonography. Mean disability at presentation and 1 year after was significantly lower. Most importantly, a relevant proportion of these patients also responded to therapy (6/21 = 28.6% vs. 82/182 = 45.3% of those fulfilling the criteria). INTERPRETATION: CIDP diagnosis could be established for 89.7% of patients over the course of 1 year using EFNS/PNS criteria. The remaining patients (10.3%) presented with milder disability, less accentuated demyelination, but otherwise similar characteristics and still considerable probability of treatment response. Failure to fulfill diagnostic criteria should not automatically preclude treatment. Nerve ultrasound should be considered as a complementary diagnostic tool to detect signs of inflammation in CIDP.

Guideline Adherence and Registry Recruitment of Congenital Primary Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (HypoDok).

Neonatal screening for congenital primary hypothyroidism (CH) is mandatory in Germany but medical care thereafter remains inconsistent. Therefore, the registry HypoDok of the German Society of Pediatric Endocrinology and Diabetology (DGKED) was analyzed to evaluate the implementation of evidence-based guidelines and to assess the number of included patients. Inclusion criteria were (i) date of birth between 10/2001 and 05/2020 and (ii) increased thyroid-stimulating hormone (TSH) at screening and/or confirmation. The cohort was divided into before (A) and after (B) guideline publication in 02/2011, to assess the guideline's influence on medical care. A total of 659 patients were analyzed as group A (n = 327) and group B (n = 332) representing 17.5% and 10.3% of CH patients identified in the German and Austrian neonatal screening program during the respective time period. Treatment start and thyroxine doses were similar in both groups and consistent with recommendations. Regular follow-ups were documented. In the first three years of life, less than half of the patients underwent audiometry; developmental assessment was performed in 49.3% (A) and 24.8% (B) (p < 0.01). Documentation of CH patient care by pediatric endocrinologists seemed to be established, however, it reflected only a minority of the affected patients. Therefore, comprehensive documentation as an important instrument of quality assurance and evidence-based medicine should be legally enforced and officially funded in order to record, comprehend, and optimize care and outcome in patients with rare diseases such as CH.

Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement.

OBJECTIVE: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). DESIGN: Combined cross-sectional and retrospective clinical study. METHODS: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. RESULTS: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. CONCLUSIONS: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

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.

Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome.

BACKGROUND: Patients with mutations or deletions of the Short Stature Homeobox-containing(SHOX) gene have variable degrees of growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX deficiency remain short in adulthood. Growth hormone (GH) treatment improves short-term linear growth; however, there are no data on GH treatment effects on final height. PATIENTS: In a retrospective study, we assessed the relative effects of GH on final height gain in patients with SHOX deficiency (n = 14; 12 females) and Turner syndrome (TS) (n = 158). Patients were included if they fulfilled the following criteria: genetically-confirmed SHOX deficiency or TS, baseline height SDS <1.5, GH treatment started at Tanner stage < or =2, duration of GH treatment >2 years, and final height attained. RESULTS: Both groups of patients were short at baseline (height SDS [mean +/- SD]: SHOX deficiency, -3.3 +/- 0.9; TS, -2.9 +/- 0.8). Height SDS gain from baseline to final height was significant for each patient group (SHOX deficiency, 1.1 +/- 0.7; TS, 1.2 +/- 0.8; p < 0.001); however, it was not significantly different between groups (p = 0.708). CONCLUSIONS: Patients with SHOX deficiency receive similar final height benefit from GH treatment to those with TS.

Quality of Life of Short-Statured Children Born Small for Gestational Age or Idiopathic Growth Hormone Deficiency Within 1 Year of Growth Hormone Treatment.

Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency (n = 65), born small for gestational age (n = 58), and idiopathic short stature (n = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.