Leopard syndrome: a report of five cases from one family in two generations

This is the first reported family with Leopard syndrome (LS) from Bosnia and Herzegovina. We report five cases of LS from two generations of the same family. In the present series of patients from one family, all patients carry the same recurrent mutation Y279C in the PTPN11 gene, exhibiting different phenotypes and a variable expression of multiple lentigines. The diagnosis may be on clinical basis as the diagnostic clues of LS are: multiple lentigines and cafè-au-lait-spots, short stature, distinctive face, congenital heart disease, conduction abnormalities, abnormal genitalia, and sensorineural deafness. Conclusion: the clinical diagnosis of LS should be molecularly confirmed in the patient.     

Physiology and treatment of hypertension

Childhood hypertension (HT) is an increasing problem brought about by the epidemic of obesity. This is particularly true in adolescents, where currently Primary HT (PHT) is more common than secondary HT (SHT). The pathophysiology of PHT is complex and involves the interplay of genetic, congenital and environmental factors. It is important that every child with HT has a thorough evaluation so that any secondary cause of HT is identified and managed appropriately. There is increasing role for ABPM in the diagnosis and management of HT. Non-pharmacological therapy should be commenced on all children with hypertension and also those with high normal BP. The decision to initiate antihypertensive therapy should not be based on BP readings alone but should consider the presence or absence of end organ damage and other risk factors such as obesity, kidney disease and family history. Long term studies detailing the outcome of childhood HT and treatment are lacking. Since adult studies have demonstrated that treatment of hypertension leads to improved cardiovascular outcomes, it is imperative that HT is promptly diagnosed and appropriate treatment is commenced to prevent progression of end organ damage.     

Genetic counseling

Genetic counseling is a process of communicating medical aspects about a genetic disorder, especially the information regarding risk of occurrence as recurrence of the disease in the family and preventive options. Accurate diagnosis of the affected member is of paramount importance for genetic counseling. Special genetic investigations like DNA analysis and chromosomal analysis are essential for many cases and especially when prenatal diagnosis is necessary. It is essential for pediatricians to identify cases with genetic disorders or possibly genetic disorders. These cases should be adequately worked up to identify accurate etiology as far as possible. The investigations should be done even if they are not going to make any difference in the outcome of the child. The genetic disorders present not only in neonates, but also in children, stillbirths and fetuses. Hence, autopsy of stillbirth and fetuses terminated after prenatal diagnosis is essential for genetic counseling. The importance of genetic counseling as an integral part of management of genetic disorders has to be realized by all clinicians. Pediatricians with short training can take over the responsibility of providing counseling for common genetic disorders and may need to refer others to genetic centre for counseling and prenatal diagnosis.     

Genetic susceptibility in thyroid autoimmunity

The autoimmune thyroid diseases (AITD) include Graves' disease (GD) which manifests in hyperthyroidism and Hashimoto's thyroiditis (HT), manifesting as hypothyroidism. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens in AITD. Indeed, there is solid epidemiological data to support a strong genetic influence on the etiology of AITD including family and twin studies. Recently, there has been significant progress toward the identification of the AITD susceptibility genes. Several loci (genetic regions) that are linked with AITD have been mapped and in some of these loci putative AITD susceptibility genes have been identified. Some of these loci predispose to a single phenotype (GD or HT), while other loci are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg) and it is likely that the final disease phenotype is a result of an interaction between these loci, as well as environmental influences.     

Triple A syndrome--diagnostic and management issues

The authors present a family with three children affected with triple A syndrome — one had died, one was saved by diagnosis and timely therapy, and one was born after the diagnosis in the second child. The gene for the syndrome has been cloned and genetic counseling should be offered to these families.     

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.     

Genetic analysis of the pedigrees and molecular defects of the GH-receptor gene in the Israeli cohort of patients with Laron syndrome

Out of the 63 patients with Laron Syndrome ( LS) followed in our clinic we were able to perform a genetic analysis on 43 patients belonging to 28 families. Twenty-seven patients were Jews, eight were Arabs, one was Druze, and six were Caucasians from countries other then Israel. Consanguinity was found in 11 families. Molecular analysis of the growth hormone receptor gene was performed in 32 patients and 32 family members. From the study of the pedigrees, as well as the GH receptor gene analysis, we confirmed an earlier report from our group that LS is a recessively inherited disease. One patient with a classical phenotype of LS had a non-classical pattern of inheritance: R43X heterozygosity together with a heterozygous polymorphism G168G; a condition which needs further exploration.     

Hashimoto's Thyroiditis

Hashimoto's Thyroiditis (HT) is the most common cause of thyroid diseases in children and adolescents and it is also the most common cause of acquired hypothyroidism with or without goiter. The linkage between HT and some HLA genes has been reported and a genetic predisposition to thyroid autoimmunity is suggested by observations in twins. There is no direct evidence that infections cause HT in humans, while iodine and iodine containing drugs can precipitate HT in susceptible populations. There is an infiltration of lymphocytes and plasma cells between the follicles followed by their atrophy. The clinical course is variable and spontaneous remission may occur in adolescence. Goiter, menstrual disorders, short stature, constipation, nervousness and exophthalmos have been reported as the most recurrent clinical features of HT. Nevertheless we studied 33 patients with HT, 22 girls and 11 boys aged 4.9-19 years and most of them were euthyroid clinically. Hashimoto thyroiditis is often associated with type 1 diabetes and other autoimmune disorders such as coeliac disease, type 2 and type 3 polyglandular autoimmune disorders. Girls with Turner syndrome may develop HT. Patients with HT have positive antibodies to thyroglobulin and/or to thyroperoxidase in blood. Thyroid function could be normal or abnormal (overt hypothyroidism, subclinical hypothyroidism and hyperthyroidism). Abnormal ultrasound patterns may be present in patients with HT disease as diffuse hypoechogenicity and pseudonodules. L-thyroxine therapy is indicated in HT with hypothyroidism, but periodic re-evaluations are required because HT could be a self-limited disorder in some cases.     

Two pediatric patients with Von Hippel-Lindau disease type 2b: from patient to screening, from screening to patient

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor susceptibility disease characterized by the development of hemangioblastomas of the brain, spinal cord and retina; pheochromocytomas and renal cell carcinoma. The disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3p26-p25. In this paper, we present two patients with VHL disease type 2B confirmed by genetic analysis. Diagnosis in the first patient was based on demonstration of retinal hemangioblastoma in association with bilateral pheochromocytoma. Family screening revealed renal cell carcinoma in her father and uncle. The second patient was discovered during family screening of another index case in adult age. VHL disease should be clinically suspected in any individual with a pheochromocytoma especially when there is bilateral and/or multifocal disease or family history. Screening of patients and at-risk family members for VHL-associated tumors should be essential in management of VHL.     

Obstructive complications of lichen sclerosus

ObjectiveYoung males with lichen sclerosus (LS) commonly present with phimosis; complete urinary obstruction has also been described in this population, but is much rarer. We present the case report of a boy with acute renal failure secondary to urethral obstruction caused by LS, with a review of the literature regarding the occurrence of complete urinary obstruction and renal failure associated with this disease process.Materials and methodsA comprehensive review of the literature was conducted using MEDLINE^® and EMBASE to characterize the association of lichen sclerosus with significant obstructive complications of the urinary tract.ResultsThe true incidence of LS is unknown. Reported rates have ranged from 10% to 95% of boys presenting with phimosis. Our review identified 14 cases of complicated urinary obstruction (seven in children) and two cases of renal failure secondary to lichen sclerosus (both in boys).ConclusionsDistinctive features make this inflammatory process identifiable to the astute physician, such that new onset of phimosis in a school-age boy should raise clinical suspicion of the diagnosis. Successful outcomes, with medical and/or surgical therapy, are commonplace in this cohort. If undiagnosed, however, progression of LS can lead to significant morbidity in the form of renal failure.     

Impact of Childhood Leukemia on Family Planning

Clinical experiences have indicated that family planning is affected by childhood leukemia. To investigate this issue, 130 mothers and fathers of 68 families with a long-term disease-free survivor were studied using interviews and questionnaires concerning the effects of childhood cancer on family planning. In one third of the families, either one or both partners reported that their child's disease affected their reproductive planning in various ways. The most extreme variations included having completed the family before diagnosis but still having another child versus not having completed the family before diagnosis but refraining from further progeny. More than half of the affected families refrained from having further offspring, delineating psychological motives for their decision. For parents whose family planning is affected by their experiences with childhood leukemia, the decision-making process is an extra burden. Therefore we advocate that support for the parents of a child with cancer should include counseling on progeny, in which both genetic and psychological information should be provided.     

Deficits in size-adjusted bone mass in children with Alagille syndrome

OBJECTIVES: To describe bone status in children with Alagille syndrome (AGS) and healthy control children adjusted for age, gender and height (HT), and to identify dietary intake and AGS-related factors associated with bone status. METHODS: Prepubertal children with AGS and healthy controls comparable in age and ethnicity were evaluated. Subjects were > or =4 years of age, prepubertal and had whole body (WB) and/or lumbar spine (LS) dual energy X-ray absorptiometry (DXA) scans of acceptable quality. Anthropometric (weight, HT), diet and AGS-specific data (e.g., coefficient of fat absorption, labs, liver transplantation) were also collected. Bone area (BA), bone mineral content (BMC) and HT were log transformed for best fit. Bone data were analyzed unadjusted, adjusted for gender, age and HT, and as HT-specific z-scores. RESULTS: AGS and control groups were similar in age, pubertal status and ethnicity. Children with AGS were small-for-age, had decreased BA and BMC-for-age, and decreased WB BA and BMC-for-HT z-scores compared to healthy controls. Prevalence of low BMC-for-HT z-scores (< -2) among AGS subjects was 20% for the WB and 39% for the LS. Bone mineralization was positively related to fat absorption but not dietary intake. CONCLUSIONS: Children with AGS have deficits in bone size and bone mass relative to body size. Modifiable factors, such as treatment of malabsorption should be explored as an early focus of AGS care to prevent bone fragility.     

Diagnosis and treatment of Wilson's disease

Wilson's disease (WD) has moved on from being a recognized syndrome that was uniformly fatal to a curative disease for which the genetic basis has been discovered. Most pediatric patients present with hepatic manifestations, but some may have neurologic or psychiatric features. Clinical and biochemical screening, including liver biopsy for hepatic copper analysis, remain the standard for diagnosis, but haplotype analysis for siblings is now available and should be considered for family screening when possible. Lifelong medical therapy remains the mainstay of treatment, but treatment preferences are changing from penicillamine to alternative agents such as trientine and zinc. OLT remains lifesaving for those with fulminant WD and those in whom initial medical therapy fails. The future will probably see the application of rapid and accurate molecular diagnostic testing for this disorder and new therapeutic modalities such as hepatocyte transplantation, gene replacement therapy, and gene modification.     

Genetic counseling. Indications, problems and prospects

From their personal experience, the authors demonstrate that, in spite of increased requests in general, couples in underprivileged socio-cultural classes are insufficiently concerned by genetic counselling; on the contrary it is too often requested by women who are already pregnant. They emphasize the necessity of providing information to all at risk couples and the essential part taken by family doctors. They discuss the difficulties of geneticists when consulters do not express a real question or wait to be given a rule of behaviour. Antenatal diagnosis (proposed to 2 of every 5 couples in 1983) changed the concept of genetic counselling by replacing a probability (the risk) by a certainty (the child presents with the disease or is normal). However, one should not look to either genetic counselling or antenatal diagnosis for a considerable decrease in the incidence of affected children.     

Sonographic evaluation of pediatric localized scleroderma: preliminary disease assessment measures

Background

Our earlier work in the ultrasonograpy of localized scleroderma (LS) suggests that altered levels of echogenicity and vascularity can be associated with disease activity. Utrasound is clinically benign and readily available, but can be limited by operator dependence. We present our efforts to standardize image acquisition and interpretation of pediatric LS to better evaluate the correlation between specific sonographic findings and disease activity.

Methods

Several meetings have been held among our multi-center group (LOCUS) to work towards standardizing sonographic technique and image interpretation. Demonstration and experience in image acquisition were conducted at workshop meetings. Following meetings in 2007, an ultrasound measure was developed to standardize evaluation of differences in echogenicity and vascularity. Based upon our initial observations, we have labeled this an ultrasound disease activity measure. This preliminary measure was subsequently evaluated on over 180 scans of pediatric LS lesions. This review suggested that scoring levels should be expanded to better capture the range of observed differences. The revised levels and their definitions were formulated at a February 2009 workshop meeting. We have also developed assessments for scoring changes in tissue thickness and lesion size to better determine if these parameters aid evaluation of disease state.

Results

We have standardized our protocol for acquiring ultrasound images of pediatric LS lesions. A wide range of sonographic differences has been seen in the dermis, hypodermis, and deep tissue layers of active lesions. Preliminary ultrasound assessments have been generated. The disease activity measure scores for altered levels of echogenicity and vascularity in the lesion, and other assessments score for differences in lesion tissue layer thickness and changes in lesion size.

Conclusions

We describe the range of sonographic differences found in pediatric LS, and present our efforts to standardize ultrasound acquisition and image interpretation for this disease. We present ultrasound measures that may aid evaluation of disease state. These assessments should be considered a work in progress, whose purpose is to facilitate further study in this area. More studies are needed to assess their validity and reliability.     

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.     

Clinical Suspicion of Maturity Onset of Diabetes of the Young in Pediatric Patients Diagnosed with Diabetes Mellitus

Type 1 diabetes remains the predominant form of diabetes in the pediatric population, while the incidence of type 2 diabetes has increased, paralleling the increase in obesity. Another form of diabetes, Maturity Onset Diabetes of the Young (MODY), should also be considered especially in those whose clinical presentation is atypical for type 1 and type 2 diabetes. Although testing for MODY is a challenge, testing in appropriate patients and family members should be standard of care. Knowledge of the genetic etiology of the type of diabetes will enable appropriate treatment and optimize outcomes, allow more accurate prediction of disease progression, as well as allow screening for and the diagnosis of MODY in family members.     

先天性肾上腺皮质增生症1例CYP21A2基因突变分析

该文检测了1例先天性肾上腺皮质增生症（CAH）小儿及其父母CYP21A2基因突变,复习该病的临床特征、治疗监测及分子遗传机制。采用QIAGEN Blood DNA Mini kit提取外周血DNA,根据CYP21A2基因与其假基因间的基因序列差异设计高特异性的PCR引物,用PrimeSTAR DNA聚合酶（TAKARA） 扩增CYP21A2基因全长,并对扩增产物进行直接测序,分析检测CYP21A2基因突变。 该患儿36 日龄,临床诊断为CAH（21-羟化酶缺乏失盐型）,至1岁6个月龄进行了基因诊断证实。该先证者为CYP21第2内含子c.293-13C位点突变,先证者为纯合子,其父母均为杂合子。该病尽早确诊及规范治疗,可避免发生失盐危象,减少病死率;避免骨龄老化,改善成年终身高;避免成年后生育功能障碍。通过对CAH分子遗传机制的了解,可提高对该病的再认识,优化确诊方法;同时对于先证者家系的携带者诊断及遗传咨询具有重要的临床价值。     

蛋白聚糖型脊柱骨骺干骺端发育不良1 例报告

目的探讨ACAN基因突变引起的常染色体隐性遗传疾病蛋白聚糖型脊柱骨骺干骺端发育不良(SEMD)的临床和基因诊断。方法回顾分析1例SEMD患儿的临床资料和基因检测结果,并复习相关文献。结果 7岁矮小女性患儿,排除生长激素缺乏症、特发性矮小、甲状腺功能低下等常见矮小病因后,结合家族史及临床表现,高度疑似SEMD。经知情同意后,患儿经高通量测序基因检测,证实为ACAN基因c.512CT纯合突变,符合蛋白聚糖型SEMD诊断;父母特定位点基因分析,均为杂合子。结论临床上特殊类型矮小患儿高度怀疑SEMD时,应尽早行基因检测以明确诊断。     

Prenatal diagnosis of Gaucher disease using next‐generation sequencing

In the prenatal diagnosis of Gaucher disease (GD), glucocerebrosidase (GBA) activity is measured with fetal cells, and gene analysis is performed when pathogenic mutations in GBA are identified in advance. Herein is described prenatal diagnosis in a family in which two children had GD. Although prior genetic information for this GD family was not obtained, next‐generation sequencing (NGS) was carried out for this family because immediate prenatal diagnosis was necessary. Three mutations were identified in this GD family. The father had one mutation in intron 3 (IVS2 + 1), the mother had two mutations in exons 3 (I[‐20]V) and 5 (M85T), and child 1 had all three of these mutations; child 3 had none of these mutations. On NGS the present fetus (child 3) was not a carrier of GD‐related mutations. NGS may facilitate early detection and treatment before disease onset.