Brief clinical report: A genetic association between microcephaly and lymphedema

We discuss a family in which microcephaly and lymphedema are co-segregating as an apparently autosomal or X-linked dominant trait. A review of each malformation is presented with reference to the known genetic patterns of each. This combination of microcephaly and lymphedema may be a unique syndrome, previously undescribed because of subtleties of expression in affected individuals.     

Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations

Mutations in the vascular endothelial growth factor receptor 3 gene, VEGFR3/FLT4, have been identified in a subset of families with hereditary lymphedema type I or Milroy disease (MIM 153100). Individuals carrying a VEGFR3 mutation exhibit congenital edema of the lower limbs, usually bilaterally and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, upturned toenails, and hydrocele. In this study, we report the first de novo VEGFR3 mutation in a patient with sporadic congenital lymphedema. We also describe three other families with a VEGFR3 mutation. In each family, one individual had an atypical clinical presentation of hereditary lymphedema type I, whereas the others had the classical VEGFR3 mutation-caused phenotype. The atypical presentations included pre-natal pleural effusion, spontaneous resorption of lymphedema and elephantiasis. Three of the four identified mutations were novel. These data show that de novo VEGFR3 mutations may be present in patients without family history of congenital lymphedema. This has implications for follow-up care, as such individuals have nearly a 50% risk for occurrence of lymphedema in their children. Our findings also indicate that although most patients with a VEGFR3 mutation have the well-defined phenotype for hereditary lymphedema type I, there are exceptions that should be considered in genetic counseling. Because VEGFR3 mutation can cause generalized lymphatic dysfunction and can thus result in hydrops fetalis, VEGFR3 screening should be added to the investigation of cases of hydrops fetalis of an unknown etiology.     

Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family

A second multigeneration family with hereditary lymphedema (LE) secondary to a variant in the planar polarity gene, CELSR1, is described. Dominant inheritance of the variant was discovered using whole-exome sequencing and confirmed by Sanger sequencing. In contrast to heterozygous males, all heterozygous females showed LE during physical examination albeit variable in severity and age of onset. Lymphscintigraphy in affected females showed previously undescribed lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.     

Spectrin mutations in hereditary elliptocytosis and hereditary spherocytosis

Hereditary elliptocytosis (HE), its aggravated form hereditary pyropoikilocytosis (HPP), and hereditary spherocytosis (HS) designate a set of congenital hemolytic syndromes. The responsible mutations lie in several genes encoding proteins of the red cell membrane. In particular, they involve the SPTA1 and SPTB genes that encode erythroid spectrin α- and β-chains, respectively. In situ, spectrin is a α₂β₂ fibrillar tetramer resulting from the head-to-head self-association of two αβ dimers. In HE, the 24 known α-chain mutations lie in the self-association site or its vicinity, whereas the 17 β-chain mutations occur in the self-association site itself (record of November 30, 1995). Allele α^LELY (LELY: Low Expression LYon) is found in ethnic groups remote from one another with a uniform frequency (20–30% of all α-alleles). It allows an expanded expression of any HE α-allele located in trans and results in severe HE or in HPP. In HS, a number of spectrin mutations have been recorded recently. Allele α^LEPRA (LEPRA: Low Expression PRAgue) would occur in a recurrent fashion. © 1996 Wiley-Liss, Inc.     

Exclusion mapping of the benign hereditary chorea gene from the Huntington's disease locus: report of a family

A Greek family is presented in which seven members suffered from benign hereditary chorea (a rare autosomal dominant non-progressive chorea without dementia). All patients and three informative healthy relatives were submitted to DNA analysis using probes from loci linked to Huntington's disease. The results confirm one previous suggestion that these two disorders are not allelic and that they should be considered as two distinct genetic entities.     

Microcephaly,lymphedema, and chorioretinal dysplasia: Report of two additional cases

In recent years, several patients with microcephaly, lymphedema and chorioretinal dysplasia have been described. We have studied two additional patients with similar findings. The question of whether microcephaly with lymphedema and microcephaly with chorioretinal dysplasia and lymphedema are distinct entities remains unanswered. Identification of other patients in the future may provide additional information. © 1994 Wiley-Liss, Inc.     

Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity

In 1978, Price introduced the concept of indeterminate colitis to describe cases in which colonic resections had been undertaken for chronic inflammatory bowel disease (CIBD), but a definitive diagnosis of either of the classical types of CIBD, ulcerative colitis and Crohn's disease, was not possible. This was especially apposite in cases of acute fulminant disease of the colorectum. More recently, the term indeterminate colitis has been applied to biopsy material, when it has not been possible to differentiate between ulcerative colitis and Crohn's disease. In our opinion, and in those of other workers in this field, the term should be restricted to that originally suggested by Price. This then provides a relatively well-defined group of patients in whom the implications and management of the disease are becoming much clearer. Cases where there are only biopsies with CIBD, but equivocal features for ulcerative colitis and Crohn's disease, should be termed 'CIBD, unclassified', 'equivocal/non-specific CIBD' or IBD unclassified (IBDU), in line with recent recommendations. When the diagnosis is correctly restricted to colectomy specimens, there is now good evidence that the majority of cases will behave like ulcerative colitis. Furthermore, the diagnosis should not be a contraindication to subsequent pouch surgery. When the latter is undertaken, surgeons and patients can expect an increased complication rate, compared with classical ulcerative colitis, especially of pelvic sepsis, but most patients fare well. Only very occasional patients, around 10%, will eventually be shown to have Crohn's disease. This review describes the pathology of cases appropriately classified as indeterminate colitis and the implications of that diagnosis. It also highlights recent advances in its pathological features, clinical management and its immunological and genetic associations.     

FOXC2 truncating mutation in distichiasis,lymphedema, and cleft palate

We report a family showing autosomal-dominant segregation of upper- and lower-eyelid distichiasis (double row of eyelashes) in seven affected relatives over three generations, in addition to below-knee lymphedema of pubertal onset (lymphoedema proecox) in three. Two children had cleft palate in addition to distichiasis, but without the previously reported association with the Pierre-Robin sequence. Other ophthalmologic anomalies included divergent strabismus and early-onset myopia. This family was found to be completely linked to markers mapped to 16q24.3 and thereby proposed to be allelic to the distichiasis-lymphedema syndrome (DL, MIM 153400), although pterygium colli, congenital heart disease, or facial dysmorphism were not features found here. As FOXC2/FKLH14 mutations were found to underlie DL and diverse hereditary lymphedema conditions, this gene was examined by sequence analysis. An out-of-frame deletion (914-921del) was identified and found to segregate with the disease, further highlighting the phenotypic heterogeneity of lymphedema conditions linked to FOXC2 truncating mutations. Whether such heterogeneity is related to genotype-phenotype correlation, a hypothesis not primarily supported by the apparent loss-of-function mechanism of the mutations, or governed by modifying genes, remains to be determined.     

Hartnup disease presenting as hereditary spastic paraplegia and severe peripheral neuropathy

Hartnup disease cases were rare, and the genotype–phenotype correlation was not fully understood. Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the SLC6A19 gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Magnetic resonance imaging showed mild bilateral cerebellar atrophy and thinning of the thoracic spinal cord. Electromyogram detected mixed sensorimotor polyneuropathy in lower limbs. Sural nerve biopsy and pathological study indicated the moderately reduced neural fibers in the periphery nerves. Urinary amino acid analysis showed increased levels of multiple neutral amino acids. Moreover, muscle strengths in the lower limbs and the walking ability have been improved in both cases (MRC 3/5 to 4/5 in Patient 1; walking distance elongated from 50 to 100 m in Patient 2) after the treatment with oral nicotinic acid and intravenous injection of multiple amino acids. Exome sequencing revealed and confirmed the existence of the novel compound heterozygous SLC6A19 mutations: c.533G>A (p.Arg178Gln) and c.1379-1G>C mutations in patient1, and c.1433delG (p.Gly478AlafsTer44) and c.811G>A (p.Ala271Thr) in patient 2. Taken together, these findings expanded the clinical, neuroimaging, pathology, and genetic spectrum of Hartnup disease. However, the co-existence of HSP and peripheral neuropathy was only inferred based on clinical observations, and pathological and molecular studies are needed to further dissect the underlying mechanisms.     

Postmastectomy lymphangiosarcoma: a reappraisal of the concept—a critical review and report of an illustrative case

The syndrome of postmastectomy lymphangiosarcoma (LAS) has been universally accepted since it was first outlined by Stewart & Treves (1948), except for a small number of authors who concluded that the neoplasms arising in the chronic lymphoedematous arms were in fact due to retrograde spread from the original breast carcinoma (Laffargue, Pinet & le Go 1960, Giannardi, Pelù & Zampi 1960, Giannardi & Pelù 1961, Delarue 1962, Salm 1963, Laugier, Olmos, Hunziker & Orusco 1973), but their views have been largely ignored. A case is reported in whom neoplastic arm lesions appeared 27 years after mastectomy and were due, in our opinion, to recent metastases from a new primary Carcinoma of the lung. The validity of the entire concept of LAS is re-examined.     

Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3

Hereditary lymphedema type I (HL-I), also known as Milroy disease, is an autosomal dominant disorder characterized by typical phenotype of infantile onset lower-limb lymphedema accompanied by variable expression of recurrent episodes of cellulites, toenail changes, and papillomatosis. Mutations in the vascular endothelial growth factor receptor 3 (VEGFR3), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb lymphedema. Wide intrafamilial phenotypic variability included two asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication, yet unreported, of chronic degenerative joint disease of the knees. This report broadens the known “classic” phenotype of HL-I.     

Synergic effect of compression therapy and controlled active exercises using a facilitating device in the treatment of arm lymphedema

Trial design: A randomized controlled trial was performed to evaluate the effect of the combination of compression therapy with active exercising using a facilitating apparatus on arm lymphedema. Method: Twenty women with a mean age of 63.3 years were evaluated; all had lymphedema resulting from breast cancer treatment. The inclusion criterion was a difference of 200 mL in size between arms. The apparatus used, called ''pulley system'', is a vertical iron wheel fixed on a support at a distance of 10 cm from the patient''s body. Participants were submitted to two series of active exercises using this facilitating device, one series using a compression sleeve and the other without. Each series consisted of four 12-minute sessions of exercises separated by 3-minute rest intervals. Volumetry was performed before and after each series of exercises. The paired t-test was utilized for statistical analysis (p-value < 0.05). Results: A significant mean reduction (p-value < 0.007) and non-significant mean increase (p-value < 0.2) in volumes were observed during exercising with and without compression, respectively. Conclusion: Controlled active exercising utilizing a facilitating apparatus while wearing a compression sleeve reduces the size of lymphedematous arms.     

Primary lower limb lymphedema: a focus on its functional, social and emotional impact

Primary lymphedema is a rare, chronic and distressing condition with negative effects on physical, social and emotional level. The purpose of these reports was to present and discuss two different cases of primary lower limb lymphedema with a focus on its physical and mental impact and on some qualitative aspects of patients' self-reported experiences. The patients were recruited as they used occasional services within the University Hospital of Heraklion (Crete, Greece). The functional and mental impact of primary lymphedema was measured using the generic Medical Outcome Study short form-36 questionnaire and open-ended questions led to give more emphasis to patients' experiences. The analysis of short form-36 results in the first patient disclosed a significant functional impairment with a minor impact of the condition on emotional and social domains. For the second patient quality of life scores in the emotional and social domains were affected. Our findings support further the statement that physicians should pay full attention to appraise the patient's physical and emotional condition. General practitioners have the opportunity to monitor the long-term impact of chronic disorders. Posing simple open-ended questions and assessing the level of physical and mental deficits in terms of well-being through the use of specific metric tools can effectively follow-up rare conditions in the community.     

Venous malformation may be a feature of EXT1-related hereditary multiple exostoses: A report of two unrelated probands

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondroma (HMO), is an autosomal dominant disorder caused by pathogenic variants in exostosin-1 or -2 (EXT1 or EXT2). It is characterized by the formation of multiple benign growing osteochondromas (exostoses) that most commonly affect the long bones; however, it may also occur throughout the body. Although many of these lesions are clinically asymptomatic, some can lead to chronic pain and skeletal deformities and interfere with adjacent neurovascular structures. Here, we report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME.     

Exceptions to the rule: Case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi‐gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified.     

The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees

Leber hereditary optic neuropathy (LHON) is characterized by acute or subacute bilateral visual loss, and affects mostly young males. The most common mitochondrial DNA mutation responsible for LHON worldwide is G11778A. Despite different genetic backgrounds, which are believed to influence the disease expression, most features of LHON are quite common in different populations. However, there seem to be a few ethnic-specific differences. Analyses of our 30 G11778A LHON pedigrees in Thailand showed some characteristics different from those of Caucasians and Japanese. In particular, our pedigrees showed a lower male to female ratio of affected persons (2.6:1) and much higher prevalence of G11778A blood heteroplasmy (37% of the pedigrees contained at least one heteroplasmic G11778A individual). Heteroplasmicity seemed to influence disease manifestation in our patients but did not appear to alter the onset of the disease. The estimated overall penetrance of our G11778A LHON population was 37% for males and 13% for females. When each of our large pedigrees were considered separately, disease penetration varied from 9 to 45% between the pedigrees, and also varied between different branches of the same large pedigree. Survival analysis showed that the secondary LHON mutations G3316A and C3497T had a synergistic deleterious effect with the G11778A mutation, accelerating the onset of the disease in our patients.