Leopard syndrome: the potential cardiac defect underlying skin phenotypes.

LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple lentigines and cafe´-au-lait spots, electrocardiographic conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Phenotype overlap complicates clinical discrimination within RASopathies, making the diagnosis of LEOPARD more confusing and challenging. Besides, LEOPARD patients do not usually present with all these typical clinical features, increasing the possibility of underdiagnosis or misdiagnosis.Herein, we report a case of LEOPARD syndrome in a patient who only presented with pigmented skin spots and was initially diagnosed with multiple acquired melanocytic nevi. Subsequent pathological examination confirmed the diagnosis of multiple lentigines rather than melanocytic nevi. A genetic study showed a germline PTPN11 (Tyr279Cys) mutation and raised the suspicion of LEOPARD syndrome. A subsequent ECG examination detected potential cardiac defects and confirmed the diagnosis of LEOPARD. We considered that the potential damage of other systems underlying the skin multiple lentigines should not be ignored. The diagnosis of LEOPARD syndrome in an early stage before cardiac damage has reached a serious and irreversible stage can be meaningful for patients to fully understand the potential risks, complications and prognosis of the disease and to take appropriate precautions to prevent the potential risk of cardiac damage.

Essential role of PTPN11 mutation in enhanced haematopoietic differentiation potential of induced pluripotent stem cells of juvenile myelomonocytic leukaemia.

We established mutated and non-mutated induced pluripotent stem cell (iPSC) clones from a patient with PTPN11 (c.226G>A)-mutated juvenile myelomonocytic leukaemia (JMML). Both types of iPSCs fulfilled the quality criteria. Mutated iPSC colonies generated significantly more CD34+ and CD34+ CD45+ cells compared to non-mutated iPSC colonies in a culture coated with irradiated AGM-S3 cells to which four growth factors were added sequentially or simultaneously. The haematopoietic differentiation potential of non-mutated JMML iPSC colonies was similar to or lower than that of iPSC colonies from a healthy individual. The PTPN11 mutation coexisted with the OSBP2 c.389C>T mutation. Zinc-finger nuclease-mediated homologous recombination revealed that correction of PTPN11 mutation in iPSCs with PTPN11 and OSBP2 mutations resulted in reduced CD34+ cell generation to a level similar to that obtained with JMML iPSC colonies with the wild-type of both genes, and interestingly, to that obtained with normal iPSC colonies. Transduction of the PTPN11 mutation into JMML iPSCs with the wild-type of both genes increased CD34+ cell production to a level comparable to that obtained with JMML iPSC colonies harbouring the two genetic mutations. Thus, PTPN11 mutation may be the most essential abnormality to confer an aberrant haematopoietic differentiation potential in this disorder.

Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B-precursor acute lymphoblastic leukemia.

BACKGROUND: We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians. PROCEDURE: Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346). RESULTS: The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02). CONCLUSIONS: Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL.

[Multiple granular cell tumours in a patient with Noonan's syndrome and juvenile myelomonocytic leukaemia]. / Tumeurs à cellules granuleuses multiples chez un enfant atteint d'un syndrome de Noonan compliqué de leucémie myélomonocytaire juvénile.

BACKGROUND: Granular cell tumour (GCT) is a rare form of tumour comprising Schwann cells. Herein, we report a case of a child presenting Noonan syndrome complicated by juvenile myelomonocytic leukaemia (JMML) and who also developed a multiple form of GCT. We discussed the molecular mechanisms that might account for this association. PATIENTS AND METHODS: A six-year-old boy with Noonan syndrome complicated by JMML presented three asymptomatic subcutaneous nodules on his back, forearm and neck. Histological analysis revealed GCT. A literature review revealed seven cases of Noonan syndrome presenting GCT, none of which were associated with JMML. Mutation of gene PTPN11, via hyperactivation of intracellular Ras signalling may cause the development of GCT and JMML in children presenting Noonan syndrome. DISCUSSION: Detailed clinical examination is recommended in children presenting GCT to screen for multiple forms and for signs of malformation suggestive of a genetic syndrome. Ours is the first case to be described of Noonan syndrome complicated by JMML associated with multiple GCT. This association once again raises the important question of the role of the Ras-MAPK signalling pathway in the development of benign and malignant tumours of solid organs or blood, associated with genetic syndromes.

Anterior Uveitis and Coats Disease in a 16-Year-Old Girl with Noonan Syndrome-A Case Report.

Background: Noonan syndrome (NS) represents a fairly common genetic disorder with a highly variable phenotype. Its features include inherited heart defects, characteristic facial features, short stature, and mild retardation of motor skills. Case presentation: A 16-year-old Caucasian girl with NS reported visual deterioration, photophobia, and pain in the right eye (RE). The initial best-corrected visual acuity (BCVA) was 0.3 in the RE. An examination demonstrated conjunctival and ciliary body hyperemia, keratic precipitates, and flare in the anterior chamber. In addition, post-hemorrhagic floaters, tortuous vessels, and an epiretinal membrane in the RE were present. Diagnosis of unilateral anterior uveitis was made, and this resolved after the use of topical steroids and cycloplegic drops. Due to the presence of retinal telangiectasias and extraocular exudates (consistent with Coats' disease (CD) stage 2A) in the RE, laser therapy was performed. The patient remains under constant follow-up, and after one year, the BCVA in the RE was 0.7. Conclusions: Here, we report the clinical characteristics, genetic findings, and retinal imaging results of a patient with NS. To our knowledge, this is, to date, the first report of an association of NS with a PTPN11 mutation with anterior uveitis and CD.

Noonan syndrome: rhGH treatment and PTPN11 mutation.

OBJECTIVE: To analyze the clinical data and genetic characteristics of Noonan syndrome, both the effect and side effects of recombinant human growth hormone (rhGH) treatment. METHODS: We collected clinical data from 8 children with Noonan syndrome diagnosed from November 2017 to June 2021. The diagnosis was clarified by exome second-generation sequencing and parental PCR-NGS validation and interpretation of the preceding evidence, and growth hormone therapy was administered. Of the cases, four males and four females were seen for slow height growth and the median age at diagnosis was 8 years 7 months (1 year 7 months to 12 years 6 months). RESULTS: Here, 7 children were treated with rhGH. Compared to the pre-treatment period, the growth rate increased after rhGH treatment [3.7 ± 0.5 cm/year before treatment and 8.0 ± 1.0 cm/year after treatment, p < 0.01], with the maximum growth rate between 3 and 6 months of treatment and decreasing with the duration of treatment thereafter. The growth hormone treatment was discontinued and the orthopedic consultation was ordered with regular follow-up, which was considered to be related to the PTPN11 mutation. CONCLUSION: Noonan syndrome is characterized by slow growth, short stature, mental retardation, peculiar facial features, structural heart abnormalities and abnormal bone metabolism. and osteochondroma was found after case 2 rhGH treatment. Genetic examination is mostly caused by PTPN11 mutation. It is recommended to pay attention to bone metabolism abnormalities before growth hormone treatment, especially in children with PTPN11 mutations.

Molecular characterization of canine SHP2 mutants and anti-tumour effect of SHP2 inhibitor, SHP099, in a xenograft mouse model of canine histiocytic sarcoma.

Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic neoplasm. Mutations in src homology 2 domain-containing phosphatase 2 (SHP2; encoded by PTPN11), which recently have been identified in canine HS tumour cells, could be attractive therapeutic targets for SHP099, an allosteric inhibitor of SHP2. Here, molecular characteristics of wild-type SHP2 and four SHP2 mutants (p.Ala72Gly, p.Glu76Gln, p.Glu76Ala and p.Gly503Val), including one that was newly identified in the present study, were investigated. Furthermore, in vivo effects of SHP099 on a HS cell line carrying SHP2 p.Glu76Ala were examined using a xenograft mouse model. While SHP2 Glu76 mutant cell lines and SHP2 wild-type/Gly503 mutant cell lines are highly susceptible and non-susceptible to SHP099, respectively, a cell line carrying the newly identified SHP2 p.Ala72Gly mutation exhibited moderate susceptibility to SHP099. Among recombinant wild-type protein and four mutant SHP2 proteins, three mutants (SHP2 p.Ala72Gly, p.Glu76Gln, p.Glu76Ala) were constitutively activated, while no activity was detected in wild-type SHP2 and SHP2 p.Gly503Val. Activities of these constitutively activated proteins were suppressed by SHP099; in particular, Glu76 mutants were highly sensitive. In the xenograft mouse model, SHP099 showed anti-tumour activity against a SHP2 p.Glu76Ala mutant cell line. Thus, there was heterogeneity in molecular characteristics among SHP2 mutants. SHP2 p.Glu76Ala and perhaps p.Glu76Gln, but not wild-type SHP2 or SHP2 p.Gly503Val, were considered to be oncogenic drivers targetable with SHP099 in canine HS. Further studies will be needed to elucidate the potential of SHP2 p.Ala72Gly as a therapeutic target of SHP099 in canine HS.

Spinal cord glioblastoma multiforme in a patient with Noonan syndrome: A clinical report.

INTRODUCTION: Currently, there are only 3 reported cases of central nervous system malignancies in patients with Noonan syndrome in the literature, all of which are intracranial pathologies. To our knowledge, there are no cases of spinal cord glioblastoma multiforme reported in the literature. CASE DESCRIPTION: We describe the case of a 12-year-old girl with Noonan syndrome who presented with back pain and new onset neurological deficits and was found to have a spinal cord lesion. T10-L1 laminoplasty with safe maximal resection was done. Postoperative pathological analysis identified this lesion as a high-grade astrocytoma consistent with glioblastoma multiforme. CONCLUSIONS: Spinal cord glioblastoma multiforme is a rare occurrence in the general population, particularly in a patient with an underlying diagnosis of Noonan syndrome. Patients with spinal cord tumors can present with a multitude of clinical signs and symptoms and treatment should not be delayed.

Juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML), a rare myeloid malignancy that occurs in young children, is considered a clonal disease originating in pluripotent stem cells of the hematopoietic system. The pathogenesis of JMML involves disruption of signal transduction through the RAS pathway, with resultant selective hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating factor. Progress has been made in understanding aspects of the molecular basis of JMML. How these molecular mechanisms may lead to targeted therapeutics and improved outcomes remains to be elucidated. Allogeneic hematopoietic stem cell transplant is the only curative option for children with JMML, and it is fraught with frequent relapse and significant toxicity.

LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation.

In LEOPARD syndrome, mutations affecting exon 13 of the PTPN11 gene have been correlated with a rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy (HCM). This is a report of early onset severe HCM in an infant with LEOPARD syndrome and an unusual mutation in exon 13, showing genotype-phenotype correlation.