LEOPARD syndrome with recurrent PTPN11 mutation Y279C and different cutaneous manifestations: two case reports and a review of the literature

LEOPARD syndrome (LS) is a heterogeneous disease characterised mainly by cutaneous manifestations. LEOPARD is the acronym for its major features—multiple lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of (male) genitalia, retardation of growth and sensorineural deafness. As clinical manifestations are variable, molecular testing is supportive in the diagnosis of LS. We describe two unrelated LS cases with a common PTPN11 mutation Y279C and with completely different clinical features including distinct changes in skin pigmentation. In patient 1, the first complaint was hyperactive behaviour. First lentigines were presented at birth, but intensive growth began at the age of 2–4 years. Multiple dark lentigines were located mainly on the face and the upper part of the trunk, but the oral mucosa was spared. Patient 2 was born from induced labour due to polyhydramnion, and in the second week of life, mitral valve insufficiency and hypertrophic cardiomyopathy were diagnosed. Rapid growth of lentigines began at the age of 3 years. These are mostly located in the joint areas in the lower extremities; the face and upper trunk are spared from lentigines. In both cases, the rapid growth of lentigines made it possible to shift the diagnosis towards LS. Clinicians should give more consideration to rare genetic syndromes, especially in the case of symptoms from different clinical areas.     

LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria

Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are well-defined entities. The association of both disorders is called neurofibromatosis–Noonan syndrome (NFNS), a disorder that has been related to mutations in the NF1 gene. Both NS and NFNS display phenotypic overlapping with LEOPARD syndrome (LS), and differential diagnosis between these two entities often represents a challenge for clinicians. We report on three patients (two brothers and a not-related patient) diagnosed as having NFNS. They fulfilled NF1 diagnostic criteria and had some features of NS. The three of them had hypertophic cardiomyopathy while neurofibromas, Lisch nodules, and unidentified bright objects on MRI were absent. PTPN11 gene assays revealed a T468M mutation, typical of LS. Thorough clinical examinations of the patients revealed multiple lentigines, which were considered to be freckling in the initial evaluation. We conclude that NF1 clinical criteria should be used with caution in patients with features of NS. Patients with hyperpigmented cutaneous spots associated with cardiac anomalies, even if fulfilling the minimal NF1 criteria for diagnosis, should be strongly considered for LS diagnosis.     

PTPN11 gene mutation in LEOPARD syndrome

The multiple lentigines/LEOPARD syndrome (ML/LS) is a rare and complex genetic syndrome. It is an autosomal dominant disorder with a variable expressivity. The syndrome is mainly characterised by growth retardation, multiple lentigines, and congenital heart diseases with electrocardiographic anomalies, dysmorphia of the face and deafness. The incidence of this pathology is still unknown and a familial inheritance is present in 70% of cases. Some of the ML/LS clinical features are the same as those of the Noonan syndrome (NS), such as congenital cardiac abnormalities, dysmorphia and growth retardation. NS and ML/LS are caused by allele mutations of the PTPN11 gene. We report the case of a 3-year-old girl, who was observed for the presence of widespread lentigines, a 1/6-protosystolic murmur at the mesocardium and growth retardation. The diagnosis of ML/LS was made and thus a molecular analysis of the PTPN11 gene was carried out, directly sequencing the codifying region. The molecular analysis revealed a missense mutation (A836G) in hexone 7 (TYR279CYS) of the PTPNII gene. This mutation is has been observed, at present, in a few cases of ML/LS and Noonan syndrome.     

PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype”

We describe the “LEOPARD syndrome (LS) phenotype” associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, café-au-lait spots and multiple lentigines.     

<Emphasis Type="Italic">PTPN11</Emphasis> Gene Mutation and Severe Neonatal Hypertrophic Cardiomyopathy: What Is the Link?

Noonan syndrome (NS) is an autosomal dominant disorder characterized by multiple dysmorphic features and a broad spectrum of congenital heart defects. Specific mutations of the PTPN11 gene are associated with 50% of the NS cases and 90% of the multiple lentigines/LEOPARD syndrome (ML/LS) cases. These two allelic conditions have several overlapping clinical features. This study describes the association between the Gln510Glu mutation of the PTPN11 gene and lethal progressive hypertrophic cardiomyopathy (HCM) in a newborn with the NS phenotype. The findings confirm the intriguing relationship between site-specific mutations of the PTPN11 gene and rapidly progressive HCM.     

Ruby laser therapy for labial lentigines in Peutz-Jeghers syndrome

Some patients with Peutz-Jeghers syndrome may be disturbed by the appearance of lentigines. Such patients require management of their lentigines as well as their gastro-intestinal polyps. We describe ruby laser therapy of labial lentigines in two children with Peutz-Jeghers syndrome. The response to treatment was excellent and no sequelae or recurrence of the lesions was noted. Conclusion Our experience suggests that ruby laser therapy is safe and a suitable approach for the treatment of labial lentigines in children with Peutz-Jeghers syndrome. Received: 5 August 1997 and revised form: 7 October 1997 / Accepted: 21 October 1997     

Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome

Germline mutations in PTPN11 gene cause Noonan syndrome and the clinically similar LEOPARD syndrome (LS). LS is a rare congenital developmental disorder characterized by multiple lentigines, cardiac abnormalities, facial dysmorphism, retardation of growth, and deafness. Mutations in exons 7 and 12 of the PTPN11 gene can be identified in nearly 90% of patients with LS. PTPN11 gene encodes for an ubiquitously expressed protein tyrosine phosphatase SHP-2 involved in a variety of intracellular signaling processes in development and hematopoiesis. Somatic PTPN11 mutations contribute to leukemogenesis in children with hematologic malignancies including juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplasia. Two cases of leukemia (acute myeloid leukemia) have been reported in children with LS. The authors describe for the first time a girl with genetically confirmed LEOPARD syndrome presenting with common acute lymphoblastic leukemia.     

A modified laparoscopic splenectomy for massive splenomegaly in children with hematological disorder: a single institute retrospective clinical research

Purpose

With the optimal acceptance of its clinical advantages, laparoscopic splenectomy (LS) emerged as a gold standard procedure as compared with open splenectomy (OS). However, it is still controversial and even counted as contraindication for massive splenomegaly. Here, we aim to summarize the experiences, characteristics and trends of modified LS for massive splenomegaly in children with hematological disorders.

Methods

Retrospective series of 57 pediatric patients with massive splenomegaly who underwent splenectomy from March 2007 to December 2011 were designated for this clinical analysis. The main outcome measures were dealt by statistics. For 30 cases of LS, we strictly adhered to the principle of using only three trocars to operate and initial ligation of the splenic artery, followed by retrieving the piecemeal of spleen through an accessory incision of 2?C3?cm at 12?mm trocar port site.

Results

Of the 57 pediatric patients, 27 underwent OS and 30 underwent LS, respectively. Despite the operative time being shorter for OS than for LS (P?<?0.001), the blood loss was lower in LS than in OS (P?<?0.001); the time required for oral intake as well as duration of hospital stay was lower in LS than in OS (P?<?0.001). Post-operatively, 7 (25.9?%) complications occurred in OS and 3 (10?%) in LS. The conversion rate of LS to OS was 13.33?% in four cases till 2009.

Conclusions

Despite the conflicting reports regarding the safety of LS for massive splenomegaly, we demonstrated that our modified laparoscopic splenectomy in the treatment of children with massive splenomegaly in hematological diseases seemed to achieve the fundamental goal of less invasion; it was safe and feasible.     

Traumatic diaphragmatic injuries in infants and children: imaging findings

Objectives. Traumatic diaphragmatic injuries (DI) in infants and children are uncommon and are often associated with multiple severe injuries. Delayed presentation can be life threatening due to organ herniation and strangulation. We present the imaging findings in a relatively large population of children who experienced this rare injury.¶Methods. Medical records of all patients admitted to our Trauma Service from 1977 to 1998 with DI were retrospectively reviewed recording imaging, clinical and surgical or autopsy findings.¶Results. Of sixteen patients with DI (7 females, 9 males; age 3 weeks to 15 years), 14 suffered from blunt trauma secondary to high-energy impact, and 2 from penetrating injuries. Unilateral DI occurred equally on each side, with one bilateral injury. Associated injuries, present in 81 %, included severe head injuries, visceral, mesenteric and vascular injuries and multiple fractures. Six patients died from multiple organ failure (3), head injury (2), and shock (1). Findings in the initial chest X-ray suggested the diagnosis in 13 (81 %) of 16 injuries, and CT demonstrated irregularity and thickening of the diaphragm in 4 out of 7.¶Conclusions. Plain film findings suggested the diagnosis in most; CT and MR were useful adjuncts. High index of suspicion and awareness of the mechanism of injury can lead to prompt diagnosis, early repair, and decreased morbidity and mortality.     

Periodic Fever,Aphthous Stomatitis,Pharyngitis and Cervical Adenitis (PFAPA) Syndrome in Iranian Children First Report of Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR)

Objective: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a nonhereditary idiopathic febrile syndrome belonging to the group of autoinflammatory diseases. No longtime sequel was reported in this disease. Early diagnosis can lead physicians to treatment of this disorder with a short course steroid application and provide satisfaction of the patient’s family. Methods: This study is a prospective review of patients diagnosed with PFAPA syndrome who were registered in Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR) through periodic fever clinic in the Children''s Medical Center, Pediatric Center of Excellence in Tehran, Iran from January 2013 to March 2014. Findings: One hundred thirty patients were registered in our databases. Twenty-one (16.1%) patients including 15 males and 6 females had PFAPA. Normal growth was seen in all patients. The median age at onset was 18 months. The mean duration of fever was 4 days and the mean duration of intervals between fever episodes 21 days. Along with fever, all patients had characteristic symptoms. All patients were asymptomatic between fever episodes. Steroid was used in all patients and causing immediate reduction by 84.61%. Two patients received both steroid and colchicine because of their clinical feature and positive laboratory tests for PFAPA and familial Mediterranean fever. No patient received biological therapy or a tonsillectomy. Conclusion: The long diagnostic delay of PFAPA gives cause to concern indicating a need for greater awareness of the disease so that the diagnosis may be made timely.Key Words: PFAPA syndrome, Periodic fever, Recurrent fever, Children, Autoinflammatory Disorders     

Underestimation of genital lichen sclerosus incidence in boys with phimosis: results from a systematic review

Purpose

Previous histological studies have shown a variable incidence of genital lichen sclerosus (LS). However, the results of these studies were inconsistent. To overcome the limitation of individual studies, we performed this systematic review to explore the true incidence of LS.

Methods

A comprehensive search of Pubmed, Embase, Web of Science and Cochrane Library was performed including cross-referencing independently by two assessors.

Results

A total of 22 articles published from 1980 to 2017 were included in our study. The proportion of LS in those with phimosis had been described in many literature studies, ranging from 2 to 95%. The actual incidence of LS is thought to be clinically underestimated by as much as 50%.

Conclusions

The true incidence of LS in boys is more common than previously realized. LS may be observed in foreskin with or without phimosis. The presence of acquired phimosis may be an aggravating factor in the incidence of LS. The diagnosis LS must be based on biopsy for acquired phimosis because clinical findings underestimated the incidence of LS.

     

Liddle syndrome in a Turkish family with heterogeneous phenotypes

Liddle syndrome (LS) is a familial disease characterized by early onset hypertension (HT). Although regarded as rare, its incidence may be greater than expected because the classical findings of hypokalemic metabolic alkalosis with suppressed renin and aldosterone levels are not consistently present. Herein, we present the case of an adolescent boy and maternal relatives who were followed up with misdiagnosis of essential HT for a long duration. Clinical diagnosis of LS was confirmed on genetic analysis. Despite carrying the same mutation, the index patient and the family members manifested heterogeneous phenotypes of the disease including age at presentation, degree of HT, presence of hypokalemia and renal/cardiac complications. LS should be considered in the differential diagnosis of HT in children with a strong family history of HT resistant to conventional treatment; and genetic screening should be performed in these circumstances.     

The genetic etiology in cerebral palsy mimics: The results from a Greek tertiary care center

ObjectiveNon-progressive genetic disorders may present with motor dysfunction resembling cerebral palsy (CP). Such patients are often characterized as CP mimics. The purpose of this work was to delineate the clinical manifestations and molecular findings of CP mimic patients, with the ultimate goal to offer specific disease-modifying therapy and genetic counseling.MethodsRetrospective study of 47 patients diagnosed with CP and no acquired etiology. Chart review of clinical, neuroradiological, biochemical and molecular data was performed.Results31,91% of patients manifested with features resembling dyskinetic CP, 19,14% spastic CP, 10,63% ataxic CP and 38,30% mixed CP. In 23 patients molecular diagnosis was reached and included 5 hereditary spastic paraplegia genes (SPG) in spastic CP mimics; HPRT1, TH, QDPR, DDC in dystonic CP mimics; ADCY5 and NIKX2-1 in choreic CP mimics; CANA1A in ataxic CP mimics; and SPG, PDHA1, NIKX2-1, AT, SLC2A1 and SPR in mixed CP mimics. In 14 patients, the etiological diagnosis led to specific treatment.ConclusionsCP mimics show a number of features that differ from classic CP and can be used as diagnostic clues, including presence of mixed motor features, minor dysmorphic features, oculogyric movements, multiple features of autonomic dysfunction, and acquired microcephaly. A more stringent use of the concept of CP focused on acquired lesions during the perinatal and infancy periods, and excluding disorders that could be of genetic origin, could contribute to a purer use of the term. Identification of a specific genetic cause for CP mimics may in certain cases lead to etiologic treatment.     

Predictors during childhood of future health-related quality of life in adults with Gilles de la Tourette syndrome

BackgroundGilles de la Tourette syndrome (GTS) is a chronic neurodevelopmental disorder characterised by multiple motor and phonic tics and behavioural problems. Patients with GTS of all ages often report a poor health-related quality of life (HR-QOL). The diagnosis of GTS is usually established in childhood but little is known about factors that predict the long-term well-being of patients, especially in the presence of co-morbid behavioural problems.AimTo investigate the childhood predictors of HR-QOL in a cohort of adult patients with GTS.MethodsForty-six patients with GTS aged 6–16 years underwent a baseline standardised clinical assessment of both tics and behavioural symptoms at a specialist GTS clinic. The same patients were re-assessed aged 16 years and above, with a mean follow-up period of 13 years (range 3–25 years), when they completed the Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL), a disease-specific measure of HR-QOL.ResultsTic severity, premonitory urges and family history of GTS were identified as predictors during childhood of a poorer HR-QOL in adults with GTS by multiple linear regression analysis. Specifically, tic severity significantly predicted poor outcome across physical, psychological and cognitive domains of the GTS-QOL, reflecting widespread effects on HR-QOL.ConclusionYoung patients with severe tics associated with characteristic premonitory urges and a family history of tic disorders appear to be at higher risk for poorer HR-QOL as adults. Further prospective research into HR-QOL in GTS is required in order to inform long-term strategic resource allocation.     

Reporting of the incidence of hospitalised injuries: numerator issues

Objectives: To examine and discuss the implications on the incidence of hospitalised injuries of selecting cases from principal diagnosis field only compared with considering all diagnosis fields, the inclusion compared with the exclusion of medical injuries, and the impact of identifying multiple admissions.

Methods: Analysis of data from the 1999–2000 New South Wales Inpatient Statistics Collection, Australia, including an internal linkage of the same dataset.

Results: Approximately 27.5% of records with a non-injury primary diagnosis include a nature of injury diagnosis in a subsequent diagnostic field. This figure increased to more than half (53%) of discharges for medical injuries. The internal linkage showed that 6.5% of discharges were repeat admissions for the same International Classification of Diseases, 10th revision (ICD-10) injury code and that 13.8% were repeat admissions for any ICD-10 injury code. The proportions of repeat admissions varied according to the type and the mechanism of injury.

Conclusions: Selecting hospitalised injury cases from the principal diagnosis alone would underestimate medical injury cases as well as other injuries occurring in hospital. Repeat admissions should always be considered particularly in the case of thermal injuries, self harm, and medical injuries. Due to the limitations of data linkage, alternative methods need to be developed to identify repeat admissions. Other areas in which further research would be beneficial to a more uniform reporting of injury hospitalisations include better identification of injuries occurring in hospital, a review of ICD-10 injury codes, and the development an ICD-10 based severity measure which can be readily used with hospital discharge data.

     

Primary ciliary dyskinesia presentation in 60 children according to ciliary ultrastructure

Primary ciliary dyskinesia (PCD) is an inherited disease related to ciliary dysfunction, with heterogeneity in clinical presentation and in ciliary ultrastructural defect. Our study intended to determine if there are phenotypic differences in patients with PCD based on ciliary ultrastructural abnormality. In this retrospective study carried out among 60 children with a definitive diagnosis of PCD, we analyzed clinical, radiological, and functional features at diagnosis and at last recorded visit, according to cilia defect (absence of dynein arms: DAD group, n?=?36; abnormalities of the central complex: CCA group, n?=?24). Onset of respiratory symptoms occurred later in the CCA than in the DAD group (9.5 versus 0.5 months, p?=?0.03). Situs inversus was only observed in the DAD group, while respiratory disease in siblings were more frequent in the CCA group (p?=?0.003). At diagnosis, clinical presentation was more severe in the CCA group: frequency of respiratory tract infections (p?=?0.008), rhinosinusitis (p?=?0.02), otitis complications (p?=?0.0001), bilateral bronchiectasis (p?=?0.04), and number of hypoxemic patients (p?=?0.03). Pulmonary function remained stable in both groups, but outcome was better in the CCA than in the DAD group: less antibiotic therapy and hypoxemic patients (p?=?0.004). In conclusion, our results underlined the relationship between the severity of clinical presentation and the ultrastructural ciliary defect.     

Zespół Costello jako przykład rzadkich zaburzeń funkcji szlaku sygnalnego Ras-MAPK: obraz kliniczny i diagnostyka molekularna choroby

Costello syndrome (CS) is a rare congenital disorder with multiple anomalies including characteristic dysmorphic craniofacial features, short stature, failure to thrive, developmental delay, skin anomalies, cardiac and musculoskeletal defects and an increased risk of malignancy. It has been demonstrated that de novo missense mutations in the protooncogene HRAS resulting in increased activation of Ras-MAPK pathway cause Costello syndrome.This paper presents the results of clinical and molecular analysis of Polish CS patients in relation to the worldwide observations. We introduce a group of five unrelated Polish patients aged from 7 months to 17 years with clinical diagnosis of CS. Mutation analysis of HRAS gene revealed heterozygous missense substitutions affecting amino acid 12 of the protein product: c.34G>A (p.G12S) in two and c.35G>C (p.G12A) in three patients. Analysis of the available parental DNA confirmed the mutations as de novo in four cases.The evaluated group represented relatively homogenous Costello phenotype with no significant differences from the classic symptoms of the disease. The most important distinction was the lack of occurrence of malignancies among our patients, which probably results from their young age. Interestingly, in one study case the coexistence of Turner and Costello syndrome was observed.Our results deliver the first important information on the molecular basis of Costello syndrome in Polish population. They indicate that the identified missense mutations in HRAS are known substitutions responsible for CS cases worldwide and confirm that the molecular analysis of HRAS provides a reliable diagnostic test for Polish patients clinically diagnosed with Costello syndrome.     

Ollier disease: benign tumours with risk of malignant transformation. A review of 17 cases

AimTo review Ollier disease, an uncommon disease, in order to understand the clinical symptoms, diagnosis, correct treatment, and risk factors in order to prevent malignant transformation.Materials and methodsSeventeen cases of Ollier disease were treated between 1976 and 2006. The variables studied included: age at diagnosis and onset of malignant transformation, location of the lesion, family association with other tumours, radiological findings, treatment for the different lesions, metastatic lesions and survival. We excluded patients with Chondrosarcoma without previous diagnosis of Ollier disease. All malignant transformations were assessed by histopathology studies and radiological images.ResultsWe include 16 cases of Ollier's and 1 of Maffucci's syndrome. The median age at diagnosis for patients having malignant transformation was 45 years, whereas the average age at diagnosis for patient without progression to malignancy was 11 years. Pathological fractures, dysmetria and deformities led to the diagnosis in young people. Benign lesions were treated with minor surgery. There were five malignancy transformations in four patients (23.5%), with the distal femur being the most frequent location for transformation to grade I chondrosarcoma. Surgery was the treatment in all of them. We found no family association with other tumours.ConclusionsMultiple enchondromatosis is a benign disease with a high risk of malignant transformation above 40 years old. Bone scintigraphy is the best tool for detecting multiple lesions and malignant transformation. Radical surgery is the only way to improve survival, and this is the reason why early diagnosis is essential.     

New X linked mental retardation syndrome

IntroductionResearching inherited mental retardation, from a diagnostic and aetiological point of view, is a great challenge. A particular type of mental retardation is the one linked to the X chromosome which is classified under syndromic and non-syndromic types, according to the presence or absence of a specific physical, neurological or metabolic pattern associated with mental retardation.Patients and methodFive generations of a family have been studied with eight males suffering from mental retardation. Six of these males were clinically tested using anthropometric indicators and genetic tests: high resolution karyotypes, fragile X research, linkage and MID1 and PQBP1 gene studies.ResultsAlong with mental retardation, the clinical study showed a pattern of microcephaly, micrognathia, osteoarticular and genital anomalies, short stature and other less frequent malformations. The linkage study mapped the possible causal gene of this mental retardation syndrome and multiple congenital abnormalities in the Xp11.23-q21.32 segment, with a LOD score of 2. As far as we know, a medical profile, similar to the one these patients have, linked to this X segment has not been described.ConclusionsWe suspect that this family has a “new syndrome” of mental retardation and multiple congenital anomalies linked to the X chromosome.     

Brief resolved unexplained event: Severity-associated factors at admission in the pediatric emergency ward

ObjectiveA brief resolved unexplained event (BRUE) is a recent clinical entity that has now replaced the term “infant discomfort”. Despite the availability of recent recommendations, identification of patients requiring further examination remains difficult.MethodWe aimed to identify factors associated with severe pathology and/or recurrence by studying the medical files of 767 patients admitted to the pediatric emergency department of a French university hospital for a BRUE.ResultsOverall, 255 files were studied; 45 patients had a recurrence and 23 patients had a severe diagnosis. The most frequently found etiology was gastroesophageal reflux in the benign diagnosis group and apnea or central hypoventilation in the severe diagnosis group. Prematurity (p = 0.032) and time since last meal >1 h (p = 0.019) were the main factors associated with severe disease. Most of the routine examination results remained non-contributive to the etiology.ConclusionAs prematurity is a factor associated with severe diagnosis, special attention should be given to this population, without subjecting them to multiple tests, since the main complication was found to be apnea or central hypoventilation. Prospective research is needed to establish the usefulness and prioritization of diagnostic tests for infants who are at “high risk” of experiencing a BRUE.