Difficulties in diagnosing Marfan's syndrome in childhood and adolescence

BACKGROUND: The diagnosis of Marfan's syndrome in childhood and adolescence is made by the criteria of the Gent nosology, which evaluates genetic data, family history and a spectrum of clinical criteria. Due to the age dependent manifestations of the clinical symptoms, combined with the extreme heterogeneity of Marfan's syndrome diagnosis in early childhood remains sometimes difficult. PATIENTS: Prospectively, we analyzed the clinical symptoms of all patients where Marfan's syndrome was suspected. We evaluated those patients between January 1997 and April 2002 by an interdisciplinary approach. METHODS: We compared the clinical datas of the patients by using the Gent nosology and the Berlin nosolgy. RESULTS: 34 patients underwent full follow-up. The median age was 10,32 years with a range of 0,01 to 37,31 years, 19 patients were male, 15 patients were female. In eight patients Marfan's syndrome could be rouled out, 9 of 26 patients (34,6 %) fullified the criteria of the Gent nosology, in 17 of 26 patients (65,4 %) Marfan's syndrome remained just suspected, but was not fullified by the criteria of the Gent nosology. Concerning the Berlin nosology 14 of 26 patients (53,8 %) fullified the criteria, 12 of 26 patients (46,2 %) failed. Due to the criteria of the Gent nosology 14 patients (53,8 %) fullified the criteria of skeletal involvement, 21 patients (80,8 %) fullified cardiovascular major manifestation, 6 patients (23,1 %) had an ophthalmic major manifestation, and 9 patients (34,6 %) had an affected first degree relative or were genetically determined. CONCLUSIONS: On the basis of the data of our patients the diagnosis of Marfan's syndrome in childhood and adolescence can be made more sensitive by the criteria of the Berlin nosology compared to the Gent nosology. This seems to be caused by the age dependent manifestations of the symptoms. Until diagnostic algorhythms of Marfan's syndrome in childhood remain suboptimal, continuous clinical follow-up for all cases even those only in the case of suspected Marfan's syndrome are necessary to exclude complicated course and to improve outcome.     

The clinical course and echocardiographic features of Marfan's syndrome in childhood

The clinical and echocardiographic manifestations in 25 patients with Marfan's syndrome diagnosed during infancy and childhood (mean [+/- SD] age, 8.1 +/- 4.8 years; range 0 to 16 years) were evaluated. Twenty-one patients (84%) had a midsystolic click, 11 patients (44%) had mitral regurgitation (MR), and five patients (20%) had combined MR and aortic regurgitation (AR). Echocardiography demonstrated mitral valve prolapse in all 25 patients, aortic root dilatation in 20 patients (80%), AR in seven patients (28%), and aortic aneurysm in five patients (20%). During the follow-up period (mean, 5 +/- 4.5 years), progressive AR and aortic aneurysm were documented in four patients, progressive MR in three patients, and progressive aortic root dilatation in two patients. Five patients (22%) died during the follow-up period. Among patients with a positive family history of Marfan's syndrome, MR was less frequent as compared with sporadic cases (29.4% vs 75%, respectively). Progressive cardiovascular involvement was more frequent among patients diagnosed before 10 years of age compared with those diagnosed later (60% vs 12.5%, respectively). Cardiovascular involvement was a common feature of childhood Marfan's syndrome, causing significant morbidity and mortality. Sporadic cases and children diagnosed before 10 years of age represented a particularly high-risk group.     

Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations

BACKGROUND: Paraganglioma (PGL) and phaeochromocytoma (PCC) are chemotherapy and radiation-resistant neuroendocrine tumors that arise from sympathetic tissue, and rarely occur in children. PCC may be associated with predisposing (germline) conditions like the multiple endocrine neoplasia type 2 (MEN2; OMIM 164761), von Hippel-Lindau syndrome (VHL; OMIM 193300), and rarely neurofibromatosis type 1 syndrome (NF1; OMIM 162200) and multiple endocrine neoplasia type 1 (MEN1; OMIM 131100). PGL, on the other hand, may be related to predisposing germline conditions like the familial PGL syndrome and the NF1 syndrome. In adult studies, one of the highest predisposing factors for germline mutation among patients presenting apparently sporadic PCC/PGL was their age at presentation. The aim of this study was to determine the rate of germline mutations among the rare patients presenting with sporadic PGL during childhood. PROCEDURE: In this study, we report the genetic analysis for predisposing conditions for the only three PGL cases retrospectively identified at our pediatric institution in the last 20 years. RESULTS: None had NF1 clinical associated lesions. Mutation screening of genes associated to VHL (VHL), MEN (RET), and familial PGL (SDH-B, -C, and -D) showed that all cases had germline deletions in the SDHB gene. We report a novel mutation, c.778 del C. Importantly, several non-symptomatic relatives were found to be carriers, thus ensuring them a clinical follow-up. CONCLUSION: According to our findings, PGL presenting during childhood represents an early manifestation of an adult disease caused by predisposing germline mutations. These results underline the importance of genetic studies in pediatric PGLs.     

DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome

Embryonal rhabdomyosarcoma (ERMS) is the most common childhood sarcoma and is a component of the familial pleuropulmonary blastoma (PPB)-predisposition syndrome. Using the PPB model, we hypothesized that DICER1 mutations would be found in familial and sporadic forms of ERMS. Blood samples from four children with familial PPB and ERMS, and 52 sporadic ERMS tumors were tested for DICER1 mutations. Germline DICER1 mutations were found in all four patients with familial PPB and 2 of 52 (3.8%) sporadic ERMS had somatic mutations. Our findings confirm the pathogenetic relationship between ERMS and PPB suggesting that ERMS may result from abnormal miRNA regulation.     

Pineal cysts—A benign association with familial retinoblastoma

Patients with familial/heritable retinoblastoma (RB) are at increased risk of developing second malignancies throughout life, including a pineoblastoma (trilateral RB [TRB]) in early childhood. Current guidelines recommend regular surveillance brain imaging for those with heritable RB until 5 years of age. The presence of pineal cysts has been reported in patients with RB. Pineal cysts are thought to arise due to focal degeneration of the pineal gland and can be found incidentally. The finding of pineal abnormalities including cysts in children with RB on imaging is disconcerting, as it raises the possibility of an underlying malignancy, specifically a pinealoblastoma. The authors reviewed the imaging findings and clinical significance of pineal cysts in 69 patients diagnosed with RB at our center between December 1999 and November 2015. Twenty-six patients had pineal cysts found on brain magnetic resonance imaging (MRI) scans performed either at diagnosis or follow-up. Thirty-eight of 69 patients had underlying heritable RB. Nineteen of 38 familial RB patients had a pineal cyst compared with 3 out of 26 with sporadic RB (P = .004). In the majority, the imaging characteristics and size of the cysts remained stable or resolved. In this cohort, pineal cysts were detected at significantly increased frequency in heritable RB. This may be a benign association or may reflect abnormal underlying biology of pineal tissue in individuals highly susceptible to malignancy. Imaging characteristics can be helpful in distinguishing between benign and malignant lesions. The presence of a pineal cyst in patients with unilateral disease may be a useful indicator of underlying heritable RB.     

Epileptic syndromes in childhood and adolescence

The syndromic approach to the diagnosis of epilepsy has been one of the most significant advances in clinical epileptology in the past few decades. An epilepsy syndrome is defined by the clustering of signs and symptoms, including investigational results, which define a unique epilepsy condition. There is no completely satisfactory way of grouping the very large number of epilepsy syndromes that occur in childhood and adolescence. In this paper the following are reviewed: the idiopathic epilepsy syndromes in infancy; the idiopathic focal epilepsies of childhood and the familial (autosomal dominant) focal epilepsies; the idiopathic generalised epilepsies; the symptomatic and probably symptomatic focal epilepsies; and the epileptic encephalopathies. Although a syndrome diagnosis is not possible in all children with epilepsy, where it is, it is likely to offer the best guide to management and prognosis.     

Wilms's tumour and aniridia: clinical and cytogenetic features.

A survey carried out to detect children with aniridia/Wilms''s tumour syndrome identified 8 living and 3 dead children. The incidence of aniridia was found to be 1 in 43 among Wilms''s tumour patients in the UK. The clinical features included complete bilaterial aniridia, cataracts, glaucoma, mental retardation, hyperkinesis, hypospadias, and undescended testes. A high incidence of bilateral tumours (36%), male sex, presentation at a young age, and advanced maternal age appeared to be associated with the syndrome. The 8 living children each had a deletion on the short arm of chromosome 11. In contrast, although 2 patients with sporadic aniridia without Wilms''s tumour had other malformations, neither had genitourinary anomalies, and the only additional problems in patients with familial aniridia were cataracts. Among 49 children with Wilms''s tumour without aniridia ony one had bilateral tumours. No chromosome abnormalities were detected in patients with familial aniridia, nor were they detected in patients with Wilms''s tumour without aniridia or in those with sporadic aniridia without Wilms''s tumour. While many infants with the Wilms''s tumour/aniridia syndrome are clinically diagnosable at birth, chromosome analysis using the elongated chromosome method is especially valuable to confirm the diagnosis in girls with sporadic aniridia and in boys who lack the genitourinary malformations. The presence of an 11p13 deletion confirms the diagnosis of the Wilms''s tumour/aniridia syndrome and indicates a very high risk for the development of Wilms''s tumour.     

婴儿胆汁淤积症的病因研究进展

婴儿胆汁淤积症是一类多因素引起的以高胆红素血症为临床特点的综合征,病因谱广泛,包括感染、中毒、肝内外胆管发育异常及遗传代谢缺陷等.感染、胆道闭锁患儿占胆汁淤积症患儿半数以上,除了常见病因,citrin缺陷症、Alagille综合征、进行性家族性胆汁淤积症等新病因不断被认识,这些疾病临床症状与胆道闭锁相似,预后及治疗各不...     

Familial Evans syndrome: a report of an affected sibship.

PURPOSE: This report describes the clinical course of three siblings, all of whom had Evans syndrome in childhood. PATIENTS: The coexistence of autoimmune hemolytic anemia and thrombocytopenia, in the absence of a known underlying cause, led to the diagnosis of Evans syndrome in a 4-month-old girl and subsequently in her two brothers when they were 4 and 13 years old. RESULTS: The 4-month-old girl had a life-threatening relapsing course unresponsive to corticosteroids, intravenous gamma-globulin, thymectomy, and cyclophosphamide. She eventually responded to splenectomy. Her two brothers had milder disease that responded to corticosteroids. Cytogenetic analyses revealed the presence of a familial Y;15 translocation in all three children and their father. CONCLUSION: There are few reported cases of familial Evans syndrome, and they are usually associated with an inherited congenital abnormality. We report the unusual finding of three siblings with the disease and no known congenital abnormality.     

North American Indian cirrhosis in children: a review of 30 cases

BACKGROUND: North American Indian childhood cirrhosis (NAIC) is a distinct, rapidly evolving form of familial cholestasis found in aboriginal children from northwestern Quebec. This is a retrospective review of the 30 patients treated in Quebec since the discovery of NAIC in 1970. METHODS: The clinical records and histologic samples from 30 patients were reviewed. Extensive metabolic, biochemical, viral, genetic, and radiologic studies were performed in most patients. RESULTS: Genetic analysis suggests autosomal recessive inheritance and a carrier frequency of 10% in this population. Gene mapping studies showed that the NAIC gene is located on chromosome 16q22. Typically, patients have neonatal cholestatic jaundice (70%) or hepatosplenomegaly (20%) with resolution of clinical jaundice by age 1 year but persistent direct hyperbilirubinemia. Portal hypertension was documented in 29 patients (91%). Variceal bleeding (15 patients, 50%) occurred as early as age 10 months. Surgical portosystemic shunting was performed in 13 of these 15 patients (87%); 4 (31%) rebled after 1 to 5 years. Fourteen patients died (47%). In 10 (71%), liver disease was the cause. Four children died of liver failure before liver transplantation became available. In transplanted livers, no recurrence of NAIC was observed after 1 to 10 years. Recognized infectious, metabolic, toxic, autoimmune, and obstructive causes of cirrhosis have been eliminated. The histologic features of NAIC show early bile duct proliferation and rapid development of portal fibrosis and biliary cirrhosis, suggesting a cholangiopathic phenomenon. CONCLUSION: Together with gene mapping studies showing that the NAIC gene is different from those of other familial cholestases, these observations suggest that NAIC is a distinct entity that could be classified as "progressive familial cholangiopathy."     

Metacarpal index in Marfan's syndrome and in constitutional tall stature

The metacarpal index (MCI) in 54 children with constitutional tall stature was mean (SD) 8.65 (0.8) and in 55 with Marfan's syndrome 9.15 (0.9). Indices in both groups showed arachnodactyly and differed from those found in normal individuals (< 7.9). Because the MCI is a poor discriminator patients with tall stature or clinical signs of arachnodactyly should be examined for additional signs of Marfan's syndrome or other hereditary disorders of connective tissue.     

Metacarpal index in Marfan's syndrome and in constitutional tall stature.

The metacarpal index (MCI) in 54 children with constitutional tall stature was mean (SD) 8.65 (0.8) and in 55 with Marfan's syndrome 9.15 (0.9). Indices in both groups showed arachnodactyly and differed from those found in normal individuals (< 7.9). Because the MCI is a poor discriminator patients with tall stature or clinical signs of arachnodactyly should be examined for additional signs of Marfan's syndrome or other hereditary disorders of connective tissue.     

Periodic fever

Periodic fever can be defined as recurrent episodes of fever lasting from a few days to several weeks separated by symptom-free intervals of variable duration, recurring throughout several months. Although these clinical pictures are unusual in clinical practice, in some instances the differential diagnosis with recurrent infections, malignancies and connective tissue diseases is difficult. The aim of this review is to group together these different clinical pictures, which are dispersed in the literature, to obtain an overall and detailed perspective.We classified these processes in two categories: hereditary (familial Mediterranean fever, hyper-IgD syndrome, tumor necrosis factor-receptor-associated periodic syndrome, Muckle-Wells syndrome and familial cold urticaria) and non-hereditary (periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome [PFAPA syndrome], cyclic neutropenia, chronic infantile neurological cutaneous and articular syndrome [CINCA syndrome], Castleman's disease, early onset sarcoidosis and Blau syndrome). Although diagnosis is essentially clinical, in recent years many advances have been made in the knowledge of the molecular and genetic bases of hereditary diseases, which may be of considerable help in establishing the diagnosis and improving treatment.     

Recurrent multifocal periostosis in children. Report of a familial form

Recurrent multifocal periostosis of childhood is an infrequent disease. All cases reported to date have been sporadic. A familial form affecting three siblings is reported herein. Clinical and biologic features were similar to those described in the previously reported cases. This case is of particular interest for two reasons: 1) the pattern of familial clustering suggests autosomal recessive transmission; 2) repeated CT scans were performed in these patients (but not in previously reported cases) and demonstrated early involvement of the three bone layers, suggesting panostosis rather than periostosis.     

Pediatric bilateral spontaneous pneumothoraces in monozygotic twins

Primary spontaneous pneumothorax from subpleural bleb disease is an uncommon occurrence in pediatric patients. This is a rare case of monozygotic twins presenting at alternating intervals with a single-sided spontaneous pneumothorax, only to have it surgically corrected, and to present later with a subsequent contralateral pneumothorax. A review of familial spontaneous pneumothoraces occurring in children was queried for congenital or genetic syndromes. We concluded that a vast majority of pneumothoraces in children, like adults, are not spontaneous and not familial linked. While they are rare, some congenital syndromes have been identified. The HLA haplotype A2 B40, the gene encoding folliculin, Alph-1-antitrypsin, Marfan's syndrome, Ehlers-Danlos syndrome and Birt-Hogg-Dube syndrome have all been associated with familial spontaneous pneumothoraces. Physicians need to counsel family members to ensure appropriate observation and expedited treatment is not delayed.     

Acute Leukemia in an Infant with Marfan's Syndrome: A Case Report

We describe a familial case of Marfan's syndrome with associated intrathoracic stomach detected during the neonatal period. The patient developed a primitive leukemia at 3 months of age. Acute leukemia in a patient with Marfan's syndrome has not previously been reported.     

Recurrent parotitis of childhood

BACKGROUND: Recurrent parotitis (RP) of childhood is a rare condition of unknown aetiology, probably immunologically mediated. OBJECTIVE: To review the clinical presentation, diagnosis and management of RP of childhood. METHODS: Retrospective study from 1983 to 2004 of children diagnosed with RP of childhood at a tertiary children's hospital. RESULTS: We identified 53 children, 37 (70%) male and 16 (30%) female. The age of onset was biphasic, with peaks at 2-5 years of age and at 10 years. The commonest symptoms were swelling (100%), pain (92.5%) and fever (41.5%). Symptoms usually lasted 2-7 days with a median of 3 days. The mean frequency was 8 episodes per year. The diagnosis was often delayed, >1 year in 70% of patients, maximum 8 years. The most common diagnoses, before the definitive diagnosis of RP, were mumps (21%), 'infection' (15%) and stones (11%). Sialogram (57%) and/or ultrasound (41%) showed sialectasis in 81% of patients. Over half the patients (54%) were given antibiotics at least once to treat the parotitis. Two children had hypogammablobulinaemia, one child had human immunodeficiency virus infection, and one child had Sjogren's syndrome. Two children had high titre antinuclear antibodies. CONCLUSIONS: Recurrent parotitis had a biphasic age distribution. The major clinical features that distinguish it from other causes of parotid swelling are the lack of pus and recurrent episodes. A clinical diagnosis can often be confirmed by ultrasound. Antibiotics do not have a role in treatment. Affected children should be screened for Sjogren's syndrome and immune deficiency.     

Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma

Hepatoblastoma is the most common primary liver tumor in childhood and occurs more commonly in families with familial adenomatous polyposis. Germline mutations of the gene responsible for familial adenomatous polyposis--adenomatous polyposis coli (APC)--are described in patients with hepatoblastoma even without a family history. We investigated children presenting with apparently sporadic hepatoblastoma between 1991 and 2004. Blood samples were available from 29 children (18 boys) whose conditions were diagnosed at a median age of 22 months (range 6-119 months). No germline APC mutations were found, which does not support the need for routine screening in sporadic hepatoblastoma in the absence of a suggestive family history of colorectal cancer or suspicion of familial adenomatous polyposis.     

Marfan's syndrome and the heart.

In recent years, there have been many advances in the treatment of cardiac disease in children with Marfan's syndrome. Early diagnosis, meticulous echocardiographic follow-up and multidisciplinary assessment are essential. Medical treatment with beta-blockers is probably helpful in most children with aortic root dilatation. Research on TGFbeta signalling and the potential treatment role of TGFbeta antagonists may lead to exciting new treatments, but the results of clinical trials are awaited. In managing the cardiovascular complications of Marfan's syndrome, the paediatrician has to walk a difficult path. On the one hand, restrictive lifestyle advice and drugs may need to be prescribed, often in the context of a family history of major surgery or even sudden death. On the other hand, it is essential to encourage the often asymptomatic child to develop and mature as normally as possible.     

De novo facioscapulohumeral muscular dystrophy defined by DNA probe p13E-11 (D4F104S1).

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition with variable age of onset and severity. Identification of a de novo DNA fragment by probe p13E-11 (D4F104S1) established the diagnosis of new mutation FSHD in 27 of 31 sporadic cases. The clinical data for these certain new mutation cases were as follows: 13 boys, 14 girls; mean age of onset 6.8 years; significant leg weakness in 19/27 (70%) (8/27 (30%) used wheelchairs at a mean age of 17.7 years); high tone sensorineural deafness in 10/27; visual acuity and direct ophthalmoscopy were normal. Congenital facial diplegia and sensorineural deafness in three children suggest that infantile FSHD is not a genetically separate disorder from FSHD. Ascertainment bias may explain the difference in severity between this group and typical familial cases. Molecular analysis for FSHD should be considered in children with either congenital or early onset facial weakness or diplegia.