Constitutional bone impairment in Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism. In this study, we investigated the bone quality assessed by phalangeal quantitative ultrasound (QUS) and the metabolic bone profiling in a group of patients with NS, to determine whether low bone mineralization is primary or secondary to NS characteristics. Thirty-five patients were enrolled, including 20 males (55.6%) and 15 females (44.5%) aged 1.0-17.8 years (mean 6.4 ± 4.5, median 4.9 years). Each patients was submitted to clinical examination, estimation of the bone age, laboratory assays, and QUS assessment. Twenty-five percent of the cohort shows reduced QUS values for their age based on bone transmission time. Bone measurement were adjusted for multiple factors frequently observed in NS patients, such as growth retardation, delayed bone age, retarded puberty, and reduced body mass index, potentially affecting bone quality or its appraisal. In spite of the correction attempts, QUS measurement indicates that bone impairment persists in nearly 15% of the cohort studied. Our results indicate that bone impairment in NS is likely primary and not secondary to any of the phenotypic traits of NS, nor consistent with metabolic disturbances. © 2017 Wiley Periodicals, Inc.

Improved growth velocity of a patient with Noonan-like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low-dose growth hormone therapy.

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is caused by a heterozygous c.4A>G mutation in SHOC2. Most cases exhibit both growth hormone deficiency (GHD) and growth hormone insensitivity (GHI) and thus require a high dose of growth hormone (GH) therapy (e.g., 35-40 µg/kg/day). We report on a genetically diagnosed NS/LAH patient manifesting severe short stature (-3.85 SDs) with low serum level of IGF1, 30 ng/ml. The peak levels of GH stimulation tests were within the normal range, and GHI was not observed in the IGF1 generation test. However, with low-dose GH therapy (25 µg/kg/day) for two years, IGF1 level and height were remarkably improved (IGF1: 117 ng/ml, height SDs: -2.20 SDs). Further, catch-up of motor development and improvement of the proportion of extending limbs to trunk were observed (the Developmental Quotient score increased from 68 to 98 points, and the relative sitting height ratio decreased from 0.62 to 0.57). Our results suggest that endocrinological causes for short stature are variable in NS/LAH and that GH therapy should be considered as a possible treatment for delayed development in NS/LAH.

Vascular endothelial growth factor (VEGF) levels in short, GH treated children: a distinct pattern of VEGF-C in Noonan syndrome.

CONTEXT: Noonan syndrome (NS) is characterized by short stature and elevated risk of lymphedema. The mechanism underlying lymphedema may be mediated by vascular endothelial growth factors (VEGFs). OBJECTIVE: To assess the effect of growth hormone (GH) treatment on plasma insulin-like growth factor (IGF)-1, VEGF-A and VEGF-C levels in patients with NS as compared to short GH-sufficient children. DESIGN: Retrospective, comparative. SETTING: Endocrinology department of a tertiary pediatric medical center. PATIENTS AND METHODS: Plasma IGF-1, VEGF-A and VEGF-C levels were measured before and during GH treatment in 6 patients with NS and 18 age-matched short subjects (Turner, idiopathic short stature and small for gestational age). MAIN OUTCOME MEASURES: Changes in plasma VEGF and IGF-1 levels. RESULTS: Baseline IGF-1 SDS levels were slightly lower in NS patients compared with controls; IGF-1 response to GH therapy was markedly lower in NS patients compared with controls (p = 0.017). Mean baseline VEGF-A levels were similar in NS patients and controls whilst mean baseline VEGF-C levels were significantly lower in the NS group as compared with controls (p = 0.022). Plasma VEGF-A and VEGF-C levels did not significantly change during GH treatment in the study cohort. No correlation was found between VEGF-C levels and levels of IGF-1, VEGF-A and auxological parameters, either before or during GH administration. CONCLUSION: Children with NS have a distinct growth factor profile including low basal VEGF-C and flattened IGF-1 response to GH. Further studies are needed to confirm our findings and to elucidate the interaction between VEGF-C levels and lymphedema.

Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature.

Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 (PTPN11), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.

GH Responsiveness in Children With Noonan Syndrome Compared to Turner Syndrome.

Background: Despite different genetic background, Noonan syndrome (NS) shares similar phenotype features to Turner syndrome (TS) such as short stature, webbed neck and congenital heart defects. TS is an entity with decreased growth hormone (GH) responsiveness. Whether this is found in NS is debated. Methods: Data were retrieved from combined intervention studies including 25 children diagnosed with NS, 40 diagnosed with TS, and 45 control children (all prepubertal). NS-children and TS-girls were rhGH treated after investigation of the GH/IGFI-axis. GH was measured with poly- and monoclonal antibodies; 24hGH-profile pattern analysed by PULSAR. The NS-children were randomly assigned to Norditropin® 33 or 66 µg/kg/day, and TS-girls were consecutively treated with Genotropin® 33 or 66 µg/kg/day. Results: Higher PULSAR-estimates of 24h-profiles were found in both NS-children and TS-girls compared to controls: Polyclonal GHmax24h-profile (Mean ± SD) was higher in both groups (44 ± 23mU/L, p<0.01 in NS; 51 ± 47, p<0.001 in TS; compared to 30 ± 23 mU/L in controls) as was GH-baseline (1.4 ± 0.6 mU/L in NS; 2.4 ± 2.4 mU/L in TS, p<0.01 for both, compared to 1.1 ± 1.2 mU/L in controls). Pre-treatment IGFISDS was 2.2 lower in NS-children (-1.7 ± 1.3) compared to TS-girls (0.6 ± 1.8, p<0.0001). GHmax, IGFI/IGFBP3-ratioSDS, and chronological age at start of GH accounted for 59% of the variance in first-year growth response in NS. Conclusion: Both prepubertal NS-children and TS-girls had a high GH secretion, but low IGFI/IGFBP3 levels only in NS-children. Both groups presented a broad individual response. NS-children showed higher response in IGFI and growth, pointing to higher responsiveness to GH treatment than TS-girls.

Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations.

Reports on Noonan syndrome (NS) have documented multiple types of coagulation defects and bleeding diathesis, and a wide range of clinical presentations. Early studies suggested that a large proportion of NS patients have coagulation defects, whereas more recent reports indicate low rates of coagulopathy. The aim of this study was to evaluate phenotypic characteristics, PTPN11 gene mutations, and hematological and coagulation parameters in 30 clinically diagnosed cases of NS. One of the NS patients had a history of easy bruising; however, his hematological and coagulation tests were normal. None of the other patients had clinical coagulation problems. In the NS group, values for platelet count, activity of factors XI, XII, and protein C were significantly lower than the corresponding means for the control group. However, the results of coagulation tests in the NS group were diagnostically inconclusive and only one patient had clinical signs of coagulopathy. Interestingly, two NS patients had low protein C activity. One of these children had an A1517C mutation and transient myelodysplasia. The other patient had a C1528G mutation in exon 13 that has not been reported previously. Neither of these individuals experienced a thrombotic event or any complication during approximately 3 years of follow-up. For all patients clinically diagnosed with NS, a thorough history of coagulation issues should be taken and first-line coagulation testing should be done to evaluate for bleeding diathesis. However, if these assessments reveal nothing abnormal, complications related to coagulation are unlikely and extensive testing is unnecessary.

Imbalance of plasminogen activator inhibitor type-1 (PAI-1) and tissue plasminogen activator (t-PA) activity in patients with Noonan syndrome.

BACKGROUND: Patients with Noonan syndrome have been reported to have an increased incidence of bleeding with trauma and surgery. Although various abnormalities of hemostasis have been described in reported series, there has been no consistent abnormality described and none have investigated fibrinolytic pathways. METHODS: Fibrinolytic parameters including tissue plasminogen activator (t-PA; activity and antigen), plasminogen activator inhibitor type-1 (PAI-1; activity and antigen), plasminogen (activity and antigen), thrombin-antithrombin complex, prothrombin time (PT), and activated partial thromboplastin time where studied in 12 patients with Noonan syndrome (total of 15 data sets). PT and activated partial thromboplastin time were performed locally whereas the fibrinolytic parameters were performed in a single national reference laboratory. Individual results were compared with published age-appropriate norms and the mean values of the study patients were compared with the midpoint of normal range for each component measured. The ratio of PAI-1/t-PA activity was calculated for each set of results and compared with a "normal" value calculated from the midpoint normal range value for each component. RESULTS: Patients with Noonan syndrome consistently demonstrated an elevation of t-PA activity in relationship to PAI-1 activity and a decreased PAI-1/t-PA ratio (P<0.01 for each comparison). CONCLUSIONS: Patients with Noonan syndrome seem to have an imbalance in fibrinolytic components favoring fibrinolysis. This may be an important contributor to the bleeding noted in these patients.

Platelet Dysfunction in Noonan and 22q11.2 Deletion Syndromes in Childhood.

INTRODUCTION: An underlying thrombocytopathy seems to be responsible for hemorrhagic symptoms in patients diagnosed with 22q11.2 deletion syndrome (22q11DS) or Noonan syndrome (NS). In 22q11DS, it is explained by a defect in the membrane glycoprotein (GP) complex Ib-V-IX. The cause of thrombocytopathy in NS remains unclear. AIM: The objective is to study the incidence of thrombocytopathy in pediatric patients diagnosed with 22q11DS or NS assessing the utility of ISTH-BAT questionnaire and laboratory techniques. MATERIALS AND METHODS: Prospective study between March and December 2018 in children (2-18 years old) diagnosed with 22q11DS or NS. Hemorrhagic symptoms using ISTH-BAT score, total cell blood count, platelet indices, PFA-200 closure times, and platelet aggregation were evaluated in all patients and membrane GP expression in 22q11DS patients. RESULTS: Nearly 70% of NS patients (n = 22) had a platelet aggregation defect without thrombocytopenia. A defect of platelet aggregation with adenosine diphosphate (ADP) and epinephrine was the most frequent pattern. A statistically significant inverse correlation between closure times and aggregation with arachidonic acid (p = 0.049, p = 0.043) and epinephrine (p = 0.021, p = 0.035), and ADP (p = 0.117, p = 0.05) was found. Total 5 out of 29 patients diagnosed with 22q11DS had macrothrombocytopenia; more noteworthy in older patients. Twenty-six patients showed an impairment in ristocetin-induced platelet aggregation that correlated with prolonged collagen/epinephrine (p = 0.034) and collagen/ADP (p = 0.01). A significant association between ISTH-BAT score >3 and closure times (p = 0.022, p = 0.002) and aggregation defect with ristocetin (p = 0.043) was also demonstrated. CONCLUSION: Most NS and 22q11DS patients show an impairment of platelet aggregation that correlates with closure times. In 22q11DS patients, these results were also related to hemorrhagic symptoms.

Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency.

Context Abnormalities in the hypothalamo-pituitary-gonadal axis have long been reported in Noonan syndrome (NS) males with only few data available in prepubertal children. Objective The aim of this study was to describe the gonadal function of NS males from childhood to adulthood. Design It is a retrospective chart review. Patients and methods A total of 37 males with a genetically confirmed diagnosis of NS were included. Clinical and genetic features, as well as serum hormone levels (LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B) were analysed. Results Of the 37 patients, 16 (43%) children had entered puberty at a median age of 13.5 years (range: 11.4-15.0 years); age at pubertal onset was negatively correlated with BMI SDS (r = -0.541; P = 0.022). In pubertal boys, testosterone levels were normal suggesting a normal Leydig cell function. In contrast, NS patients had significant lower levels of AMH (mean SDS: -0.6 ± 1.1; P = 0.003) and inhibin B (mean SDS: -1.1 ± 1.2; P < 0.001) compared with the general population, suggesting a Sertoli cell dysfunction. Lower AMH and inhibin B levels were found in NS-PTPN11 patients, whereas these markers did not differ from healthy children in SOS1 patients. No difference was found between cryptorchid and non-cryptorchid patients for AMH and inhibin B levels (P = 0.43 and 0.62 respectively). Four NS-PTPN11 patients had a severe primary hypogonadism with azoospermia/cryptozoospermia. Conclusions NS males display Sertoli cell-specific primary testicular insufficiency, whereas Leydig cell function seems to be unaffected.

Noninvasive prenatal screening for fetal common sex chromosome aneuploidies from maternal blood.

Objective To explore the feasibility of high-throughput massively parallel genomic DNA sequencing technology for the noninvasive prenatal detection of fetal sex chromosome aneuploidies (SCAs). Methods The study enrolled pregnant women who were prepared to undergo noninvasive prenatal testing (NIPT) in the second trimester. Cell-free fetal DNA (cffDNA) was extracted from the mother's peripheral venous blood and a high-throughput sequencing procedure was undertaken. Patients identified as having pregnancies associated with SCAs were offered prenatal fetal chromosomal karyotyping. Results The study enrolled 10 275 pregnant women who were prepared to undergo NIPT. Of these, 57 pregnant women (0.55%) showed fetal SCA, including 27 with Turner syndrome (45,X), eight with Triple X syndrome (47,XXX), 12 with Klinefelter syndrome (47,XXY) and three with 47,XYY. Thirty-three pregnant women agreed to undergo fetal karyotyping and 18 had results consistent with NIPT, while 15 patients received a normal karyotype result. The overall positive predictive value of NIPT for detecting SCAs was 54.54% (18/33) and for detecting Turner syndrome (45,X) was 29.41% (5/17). Conclusion NIPT can be used to identify fetal SCAs by analysing cffDNA using massively parallel genomic sequencing, although the accuracy needs to be improved particularly for Turner syndrome (45,X).

Noonan syndrome: partial factor XI deficiency.

Among the multiple extracardiac abnormalities seen in the Noonan syndrome, several authors have mentioned an unexplained bleeding tendency. In 1983 Kitchens and Alexander reported on a partial deficiency of coagulation factor XI in four patients with Noonan syndrome. We examined 9 patients with Noonan syndrome and 9 of their 18 parents (3 of them also had Noonan syndrome). Four Noonan patients were found to have a partial deficiency of factor XI (30-65%). The Noonan patients had a mean factor XI level of 67%, significantly lower than the normal parents (mean level of 109%). Our study suggests a relationship between Noonan syndrome and a partial deficiency of factor XI.

Reproductive failure in a patient with neurofibromatosis-Noonan syndrome.

We report on a 39-year-old man with neurofibromatosis-Noonan syndrome and long-standing infertility. Comprehensive testing did not uncover any significant endocrine abnormalities, but the testicular seminiferous epithelium was found to be severely compromised. While the occasional association of neurofibromatosis with signs of Noonan syndrome has been reported, reproductive failure has not been previously described in this condition.

Platelet dysfunction in Noonan's syndrome. A case with a platelet cyclooxygenase-like deficiency and chronic idiopathic thrombocytopenic purpura.

Individuals with Noonan's syndrome are likely to have one or more coagulation abnormalities: complex platelet function defects, partial Factor XI deficiency, or von Willebrand's disease. A distinctive platelet function defect has not been identified. The authors describe a 24-year-old women with Noonan's syndrome, chronic idiopathic thrombocytopenic purpura (ITP), and a platelet function defect characterized by a greater than 15-minute bleeding time, failure of aggregation and release with 10 microM ADP, 10 microM epinephrine, 750 microM arachidonic acid or 0.019 g/L collagen. A mixture of aspirin-treated platelets with the patient's platelets failed to correct the defect. Addition of 2.5 microM U46619 (a PGG2 analogue) corrected the aggregation and release defect. An electron microscopic analysis failed to reveal structural abnormalities. Thus, the platelet function defect in this patient appears to be a functional deficiency of cyclooxygenase. The presence of autoantiplatelet antibodies in a clinical setting consistent with chronic ITP raises the possibility that the defect may be acquired.

Defective growth hormone (GH) secretion and short-term treatment in Noonan syndrome.

Auxological and endocrine data from 12 prepubertal children (3 males, 9 females) with Noonan syndrome (NS) were compared with those of 15 children with constitutional short stature (CSS), 20 children with partial GH deficiency (GHD), and 6 children with Turner syndrome (TS). Four children with NS were treated with human growth hormone (hGH) (n = 4) (25 units/m2 week, divided on daily s.c. doses). In children with NS, the peak serum GH response to clonidine (5.4 +/- 2.7 ug/L) and glucagon (7.4 +/- 3.4 ug/L) were significantly lower than those for children with CSS (14.8 +/- 3.4 and 12.8 +/- 2.8 ug/L respectively). Nine out of the 12 (75%) children with NS did not mount normal GH peak (10 ug/L or more) after provocation. The 12-h integrated GH secretion in the 3 children with NS who had normal GH response to provocation (2.7 +/- 0.7 ug/L) was markedly lower compared to that for children with CSS (6.7 +/- 1.2 ug/L). The serum insulin-like growth factor-1 (IGF-I) concentrations were lower in children with NS (67 +/- 32 ng/ml) vs CSS (165 +/- 35 ng/ml), but not different from those for GHD children (59 +/- 33 ng/ml). In 4 children with NS, hGH therapy for a year increased height growth velocity from 4.1 +/- 0.3 cm/yr to 7.4 +/- 0.6 cm/yr and height standard deviation score (Ht SDS) from -2.2 +/- 0.6 to -1.45 +/- 0.3. This growth acceleration was accompanied by an increase in IGF-I concentration (from 52 +/- 21 ng/ml to 89 +/- 25 ng/ml). In summary, these results prove a defect of the GH secretion in children with NS and suggest that GH therapy has an important role in the management of their short stature.

Hemostatic abnormalities in Noonan syndrome.

BACKGROUND: A bleeding diathesis is a common feature of Noonan syndrome, and various coagulation abnormalities have been reported. Platelet function has never been carefully investigated. METHODS: The degree of bleeding diathesis in a cohort of patients with Noonan syndrome was evaluated by a validated bleeding score and investigated with coagulation and platelet function tests. If ratios of prothrombin time and/or activated partial thromboplastin time were prolonged, the activity of clotting factors was measured. Individuals with no history of bleeding formed the control group. RESULTS: The study population included 39 patients and 28 controls. Bleeding score was ≥2 (ie, suggestive of a moderate bleeding diathesis) in 15 patients (38.5%) and ≥4 (ie, suggestive of a severe bleeding diathesis) in 7 (17.9%). Abnormal coagulation and/or platelet function tests were found in 14 patients with bleeding score ≥2 (93.3%) but also in 21 (87.5%) of those with bleeding score <2. The prothrombin time and activated partial thromboplastin time were prolonged in 18 patients (46%) and partial deficiency of factor VII, alone or in combination with the deficiency of other vitamin K-dependent factors, was the most frequent coagulation abnormality. Moreover, platelet aggregation and secretion were reduced in 29 of 35 patients (82.9%, P < .01 for all aggregating agents). CONCLUSIONS: Nearly 40% of patients with the Noonan syndrome had a bleeding diathesis and >90% of them had platelet function and/or coagulation abnormalities. Results of these tests should be taken into account in the management of bleeding or invasive procedures in these patients.

IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene.

BACKGROUND: Short stature represents one of the main features of children with Noonan syndrome. The reason for impaired growth remains largely unknown. OBJECTIVE: To assess GH and IGF1 secretion in children with Noonan syndrome. PATIENTS: 12 prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene [7 males, 6 females; median age, years: 8.6 (range 5.1-13.4)] were studied; 12 prepubertal children with short stature (SS) [7 males, 5 females; median age, years: 8.1 (range 4.8-13.1)] served as the control group. MEASUREMENTS: GH secretion after arginine stimulation test; IGF1 generation test by measurement of IGF1 levels before and after recombinant GH (rGH) administration (0.05 mg/kg/day for 4 days). RESULTS: Baseline and stimulated peak values of GH were not significantly different between the two groups. At +120 minutes, GH levels remained significantly higher (p = 0.0121) in comparison with baseline values in children with Noonan syndrome. Baseline IGFI levels in patients and in SS controls were not significantly different, in contrast to values after the rGH generation test [205 ng/mL (interquartiles 138.2-252.5 ng/mL) and 284.5 ng/mL (interquartiles 172-476 ng/mL), respectively; p = 0.0248]. IGF1 values were significantly related to height (baseline: r = 773, p = 0.0320; peak: r = 0.591, p = 0.0428) in children with Noonan syndrome. CONCLUSIONS: Blunted increase of IGF1 after the rGH generation test was present in children with Noonan syndrome due to mutations in the PTPN11 gene in comparison with SS children. This finding may be due to partial GH resistance in the former likely related to altered Ras-MAPK signaling pathway.

Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, multiple dysmorphisms and congenital heart defects. A myeloproliferative disorder (NS/MPD), resembling juvenile myelomonocytic leukemia (JMML), is occasionally diagnosed in infants with NS. In the present study, we performed a functional evaluation of the circulating hematopoietic progenitors in a series of NS, NS/MPD and JMML patients. The different functional patterns were compared with the aim to identify a possible NS subgroup worthy of stringent hematological follow-up for an increased risk of MPD development. We studied 27 NS and 5 JMML patients fulfilling EWOG-MDS criteria. The more frequent molecular defects observed in NS were mutations in the PTPN11 and SOS genes. The absolute count of monocytes, circulating CD34+ hematopoietic progenitors, their apoptotic rate and the number of circulating CFU-GMs cultured in the presence of decreasing concentrations or in the absence of granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated. All JMML patients showed monocytosis>1,000/µl. Ten out of the 27 NS patients showed monocytosis>1,000/µl, which included the 3 NS/MPD patients. In JMML patients, circulating CD34+ cells were significantly increased (median, 109.8/µl; range, 44-232) with a low rate of apoptosis (median, 2.1%; range, 0.4-12.1%), and circulating CFU-GMs were hyper-responsive to GM-CSF. NS/MPD patients showed the same flow cytometric pattern as the JMML patients (median, CD34+ cells/µl, 205.7; range, 58-1374; median apoptotic rate, 1.4%; range, 0.2-2.4%) and their circulating CFU-GMs were hyper-responsive to GM-CSF. These functional alterations appeared 10 months before the typical clinical manifestations in 1 NS/MPD patient. In NS, the CD34+ absolute cell count and circulating CFU-GMs showed a normal pattern (median CD34+ cells/µl, 4.9; range, 1.3-17.5), whereas the CD34+ cell apoptotic rate was significantly decreased in comparison with the controls (median, 8.6%; range, 0-27.7% vs. median, 17.6%; range, 2.8-49.6%), suggesting an increased CD34+ cell survival. The functional evaluation of circulating hematopoietic progenitors showed specific patterns in NS and NS/MPD. These tests are a reliable integrative tool that, together with clinical data and other hematological parameters, could help detect NS patients with a high risk for a myeloproliferative evolution.

Bleeding diathesis in Noonan syndrome: is acquired von Willebrand syndrome the clue?

INTRODUCTION: Noonan syndrome (NS) is characterized by dysmorphic facies, short stature and congenital heart defects. Various haemostatic disorders have been described in NS patients, but not all were related to bleeding, which itself is present in up to 65%. Several subgroups of NS - especially those with PTPN11 mutation - are associated with pulmonary stenosis. As it is known that some heart defects are prone to a shear stress related destruction of the von Willebrand factor as an important haemostatic component, we aimed to find out, whether the pulmonary stenosis could be responsible for such a mechanism in NS patients. PATIENTS, METHODS AND RESULTS: We investigated the haemostatic system in 15 children with genetically proven NS (14 with PTPN11, one with SOS1 mutation). Platelet count, basic coagulation parameters, fibrinogen and antithrombin were normal in all patients, none had a relevant reduction of coagulation factor activities. Five patients had pulmonary valve stenosis with systolic gradients>60 mmHg. In three of them a deficiency of the high molecular weight multimers and a pathologic collagen-binding capacity were detected, suggesting acquired von Willebrand syndrome. Nine of our patients indicated a relevant bleeding diathesis and complained of easy bruising, three reported spontaneous gum bleeding. IN CONCLUSION: the destruction of the von Willebrand factor could explain the bleeding in some of the NS patients with pulmonary valve stenosis. Our finding is of clinical relevance since most of these patients require either interventional cardiac catheterization or open heart surgery which may be complicated by the haemorrhagic tendency.

45,X maleness: clinical and cytogenetic features in two patients.

45,X maleness is a very rare disorder. We report on 2 new 45,X males aged 9 10/12 and 39 years, respectively. The boy presented for developmental delay, while the man was referred to us because of infertility. Both patients showed short stature (boy -2.29 SDS, man -4.05 SDS) and an unbalanced translocation of Yp, including SRY, onto the long arm of chromosome 10 and short arm of chromosome 14, respectively. The growth pattern of the 2 patients and literature data suggest the presence of a specific growth gene in the pericentrometric region of Yq. In addition, developmental delay in some 45,X males may be related to specific deletion of telomeric autosome regions, but involvement of gene(s) on the Y chromosome may play a role as well. Albeit in the boy inhibin B levels were in the normal range for age, azoospermia was demonstrated in the adult, supporting that infertility is a feature of adult 45,X men with AZFa-c deletion.