Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Tuesday, January 31, 2006

Effect of fish oil enriched enteral diet on inflammatory bowel disease, ulcerative colitis and Crohn's Disease

ISSN 1007-9327 CN 14-1219/R World J Gastroenterol 2005 December 21;11(47):7466-7472

Effect of fish oil enriched enteral diet on inflammatory bowel disease tissues in organ culture: Differential effects on ulcerative colitis and Crohn’s disease

Doris Meister, Subrata Ghosh, Gastrointestinal Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom

Correspondence to: Professor Subrata Ghosh, MD (Edin.), FRCP, FRCP(E), Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.

Telephone: +44-20-8383-3266 Fax: +44-20-8749-3436
Received: 2005-03-29 Accepted: 2005-06-02


AIM: To investigate the influence of fish oil enriched enteral diet on intestinal tissues taken from Crohn’s disease (CD), ulcerative colitis (UC) and non-inflamed non-IBD control patients in vitro.

METHODS: Colonoscopic biopsies from patients with active CD (n = 4), active UC (n = 7), and non-inflamed non-IBD control patients (n = 4) were incubated (three dilutions of 1:20, 1:10, and 1:5) with Waymouth’s culture medium and enteral elemental diet (EO28, SHS, Liverpool, UK) modified in the fatty acid composition with fish oil (EF) in an organ culture system for 24 h. In each experimental set-up, incubation with Waymouth's medium alone as control was included. Tissue viability was assessed by adding bromodeoxyuridine (BrdU) to the culture fluid and immunohistochemically staining for BrdU uptake. Cytokine ratio of IL-1ra/IL-1b (low ratio indicative of inflammation) and production of those cytokines as a percentage of medium control were assayed in the culture supernatant.

RESULTS: Incubation of CD-affected tissue with EF (1:20, 1:10, and 1:5) modestly and non-significantly increased IL-1ra/IL-1b ratio as compared with medium control (CD 39.1±16.1; 26.5±7.8, 47.1±16.8 vs control 13.0±2.2), but incubation of UC-affected tissues increased IL-1ra/IL-1b ratio significantly in all three dilutions (UC 69.1±32.2, P<0.05; p =" 0.05;" color="#ff6600">

CONCLUSION: IBD tissues, after incubation with elemental diet modified in its fatty acid composition with fish oil, show an increase in IL-1ra /IL-1b cytokine ratio. This effect of w-3 fatty acid modulation is significantly more marked in UC compared with CD and is accompanied by both a reduction of IL-1β and increase of IL-1ra. The positive direct anti-inflammatory effect of elemental diet with fish oil in tissue affected with UC suggests dietary treatment of UC may be possible.

© 2005 The WJG Press and Elsevier Inc. All rights reserved.

Key words: Inflammatory bowel disease; w-3 fatty acids; Cytokine ratio; IL-1ra/IL-1b; In vitro

Meister D, Ghosh S. Effect of fish oil enriched enteral diet on inflammatory bowel disease tissues in organ
culture: Differential effects on ulcerative colitis and Crohn’s disease.

World Journal of Gastroenterology

Thursday, January 26, 2006

Clinical experience in treatment of port-wine stain with KTP 532 nm laser



Latkowski IT, Wysocki MS, Siewiera IP.

Kliniki Chirurgii Plastycznej w Polanicy Zdroju Akademii Medycznej we Wroclawiu, oraz ze Szpitala Chirurgii Plastycznej w Polanicy Zdroju.

Lesions of port-wine stain (PWS) type are the most commonly occurring vascular malformations of the skin which concerns about 0.3% of the population. These important from aesthetic and psychological points of view capillaries malformations have always been difficult for treatment. Previously applied methods consisting in cryosurgery, dermabrasion, radiation therapy or surgery and skin grafting produced unsatisfactory results. It was only when highly selective lasers were introduced that PWS could be treated effectively and safely. A lot of available lasers and lack of experience of the health care providers result in not always proper qualification of the lesions to the given laser type. The aim of the study was to present a prospective analysis of the efficacy of treatment of PWS vascular malformations by means of KTP 532 nm laser. From January 2003 to May 2005, 155 patients (115 women, 40 men) aged from 2 to 62 years (mean age 18.23) were treated by means of laser at the Plastic Surgery Hospital in Polanica Zdroj, Poland. In the investigated population, the vascular malformation was a component of Sturge-Weber syndrome in 7 patients, Klippel-Trenaunay syndrome--in 2 patients, while in one case it accompanied Recklinghausen disease.

The vascular lesions had not been treated before in majority of cases, while in 37 patients the laser therapy was the continuation of other previously attempted treatment, which included excision and skin grafting, argon laser therapy, radiation therapy and pulsed dye laser treatment. The procedures were performed with at least 4-week intervals without, or under local and in children general anaesthesia. Therapeutic efficacy was evaluated independently by 3 surgeons and a photographer on the basis of Subjective Scoring System (SSS) comparing simultaneously shown pictures of the patients taken prior to and after the last procedure. The outcomes of treatment were classified according to a 4-degree scale: excellent outcome--75-100% improvement, with 100% perceived as eradication of the lesion; good--50-74% improvement; fair--25-49% improvement and poor--less than 25% improvement, including no observable improvement. In 81% of the lesions (126 patients) treatment with KTP 532 nm laser produced significant improvement which was found satisfactory by the patient. excellent outcome of treatment was obtained in 49 patients (31%), good in 42 (27%), fair in 35 (23%).

However, despite many laser treatments using various energy and pulse duration, there was almost not observable improvement in 19% of the study population (29 patients). The PWS which failed to treatment were most commonly located on the limbs. The results of treatment was poor in 74% of malformations which were located beyond the face and neck (all of them were on the limbs). There was no episodes of scarring or persistent pigmentary changes in any of the patients.


1. KTP (532 nm) laser is an effective and safe tool in the management of capillary malformations of PWS type. 2. The treatment is especially effective in adults and in lesions localized to the face and neck area. 3. Port-wine stain localized on the trunk and extremities often appears to be KTP laser resistant.PMID: 16425790

[PubMed - in process]

Wednesday, January 25, 2006

Vesical Hemangioma in patient with Klippel Trenaunay Weber Syndrome


Urogenital Research Unit, State University of Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil


Klippel-Trenaunay-Weber syndrome is characterized by cutaneous hemangiomas, varicosity and bony hypertrophy of extremities. Urinary tract hemangiomas may occur in 3 to 6% of these patients. This work intends to report a case of a patient with a huge vesical hemangioma, who presented this syndrome. A 5 year-old boy with Klippel syndrome sought our services due to 3 episodes of gross hematuria in the past 30 days. Excretory urography and computerized tomography were performed, indicating the presence of a swelling in vesical dome. An exploratory cystotomy was conducted and the dark colored mass in vesical dome was excised by partial cystectomy. The histopathologic finding confirmed that it was a vesical hemangioma.

Though rare, urinary tract hemangiomas must always be considered in patients with Klippel-Trenaunay syndrome.

Key words: bladder; hemangioma; Klippel-Trenaunay-Weber syndrome; therapeuticsInt Braz J Urol. 2003; 29: 149-50


The Klippel-Trenaunay-Weber syndrome is a syndrome due to vascular malformations, characterized by cutaneous hemangiomas, varicosities and bony hypertrophy of extremities (1). Lesions are present at birth and about 75% of patients manifest symptoms before 10 years old (2). In 3 to 6% of patients, there are urinary tract hemangiomas (3). This work intends to report the case of a patient with this syndrome who presented hematuria caused by a vesical hemangioma.


Male, 5 year-old patient, who presented Klippel-Trenaunay-Weber syndrome, sought the urology service due to 2 episodes of gross hematuria in the past 30 days. Apart from characteristic syndromic changes (cutaneous hemangiomas in lower limbs, hypertrophy of right lower limb and varices in lower limbs), the patient did not present any other relevant finding on physical examination. He was submitted to an ultrasonography of the urinary tract, which revealed a huge mass in vesical dome, with characteristic signs of hemangioma. An excretory urography was made, showing a large filling defect. The assessment was complemented by abdominal and pelvic computerized tomography, which showed a 4.0 x 3.5 cm mass in vesical dome (Figure-1).

Following the analysis of tests, it was decided to perform a partial cystectomy. During exploratory cystotomy, a dark colored mass was seen in vesical dome (Figure-2). The partial cystectomy was made with a safety margin. The histopathologic finding confirmed that it was a vesical hemangioma.


In Klippel-Trenaunay-Weber syndrome, symptoms in genitourinary system occur in the illness’ more severe forms, mainly in patients with visible vascular lesions in trunk and pelvis (2). One of the most frequent symptoms in these patients is hematuria, due to hemangiomas. Vesical hemangiomas have an incidence of less than 1% of the organ’s primary tumors, being, however, the most common connective tissue benign tumor in bladder (3). Painless gross hematuria is a characteristic of this type of tumor, as it was observed in the present case (2). In Klippel-Trenaunay-Weber syndrome, vesical hemangiomas are frequent and preferably located on the bladder’s anterior wall and vesical dome (2). Several treatments are proposed for this lesion: fulguration or endoscopic excision (2), treatment with YAG-Laser (3) and partial cystectomy. Endoscopic excision can lead to profuse bleeding, and is contra-indicated (3), laser treatment is expensive and unavailable in many centers, which makes partial cystectomy the treatment best suited for this type of tumor. Patients with Klippel-Trenaunay-Weber syndrome who present hematuria must be investigated, as they can have urinary tract hemangiomas.


Klein TW, Kaplan GW: Klippel-Trenaunay syndrome associated with urinary tract hemangiomas. J Urol. 1975; 114: 596-600.
Furness III PD, Barqawi AZ, Bisignani G, Decter RM: Klippel-Trenaunay syndrome: 2 case reports and a review of genitourinary manifestations. J Urol. 2001; 166: 1418-20.
Hockley NM, Bihrle R, Bennett III RM, Curry JM: Congenital genitourinary hemangiomas in a patient with the Klippel-Trenaunay syndrome: Management with the Nedymium:Yag-Laser. J Urol. 1989; 141: 940-1.

Received: December 12, 2002
Accepted after revision: March 12, 2003

Correspondence address:Dr. Luciano Alves FavoritoRua Prof. Gabizo, 104 / 201Rio de Janeiro, RJ, 20271-320, BrazilFax: + 55 21 3872-8802

Brazilian Journal of Urology

Tuesday, January 24, 2006

Klippel Trenaunay Weber - Genetics

Klippel-Trenaunay syndrome in a monozygotic male twin: supportive evidence for the concept of paradominant inheritance.

Sept/Oct 2005 European Journal Dermatology

Hofer T, Frank J, Itin PH.

Winkelriedstrasse 10, Dermatology FMH, CH-5430 Wettingen Switzerland.

Klippel-Trenaunay-syndrome (KTS) (OMIM 149000) is a congenital slow-flow capillary lymphaticovenous malformation often affecting the lower extremities and accompanied by bone and soft tissue hypertrophy. The cutaneous lesions are always surrounded by regions of unaffected skin in a mosaic pattern. Usually, KTS occurs sporadically but rare reports of familial segregation exist, contributing to the ongoing debate on the issue of heredity in this disease. Herein, we report on identical monozygotic male twins discordant for KTS. This observation strongly supports the model of paradominant inheritance that was recently proposed for this and similar disorders.

Publication Types:
Case Reports

Pub Med Abstract


Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis.

Abstract - Cell Mol Life Sci. 2005 Jul

Timur AA, Driscoll DJ, Wang Q.

Center for Molecular Genetics, ND40, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.

Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining 'increased angiogenesis' as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.

Publication Types:

ReviewPMID: 15905966

[PubMed - indexed for MEDLINE]


Identification and molecular characterization of a de novo supernumerary ring chromosome 18 in a patient with Klippel-Trenaunay syndrome.

Abstract - Annual of Human Genetics July 2004

Timur AA, Sadgephour A, Graf M, Schwartz S, Libby ED, Driscoll DJ, Wang Q.

Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular disorder comprised of capillary, venous and lymphatic malformations associated with overgrowth of the affected tissues. In this study, we report the identification of a de novo supernumerary ring chromosome in a patient with mild mental retardation, long tapering fingers, elongated, thin feet and Klippel-Trenaunay syndrome (KTS). The ring marker chromosome was found to be mosaic, present in 24% of cells, and was later shown to be derived from chromosome 18, r(18). Fluorescence in situ hybridization (FISH) was used to define the breakpoints involved in the formation of r(18). The chromosome 18p breakpoint was localized between the markers WI-9619 and D18S1150, which is less than 10 cM to the centromere. The 18q breakpoint was localized between the centromere and BAC clone 666n19, which is a region of less than 40 kb. These data suggest that the r(18) mostly originated from 18p, with an estimated size of less than 10 cM. These studies identify and characterize a new marker chromosome 18, provide insights into the understanding of the relationships between the clinical phenotypes and marker chromosomes, and establish a framework for finding a potential vascular and/or overgrowth gene located on chromosome 18.

Publication Types:

Case Reports

PMID: 15225160

[PubMed - indexed for MEDLINE]


Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome.

Abstract - Nature. 2004 Feb 12;427(6975):592-4.

Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, Chen Q, Szafranski P, Rao S, Wu L, Housman DE, DiCorleto PE, Driscoll DJ, Borrow J, Wang Q.

Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA.

Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.PMID: 14961121

[PubMed - indexed for MEDLINE]

Friday, January 13, 2006

Update on the molecular genetics of vascular anomalies

Update on the molecular genetics of vascular anomalies.

Wang QK.

Department of Molecular Cardiology and Center for Cardiovascular Genetics, Lerner Research Institute/ND 40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Genetic factors play a critical role in the pathogenesis of vascular anomalies. Significant advances have been made in recent years in identifying the genetic and molecular determinants of a variety of vascular anomalies using a molecular genetic approach. Several genes for vascular anomalies have been identified. These genes include AGGF1 for Klippel-Trenaunay syndrome, RASA1 for capillary malformations, KRIT1, MGC4607, PDCD10 for cerebral cavernous malformations, glomulin for glomuvenous malformations, TIE2 for multiple cutaneous and mucosal venous malformations, VEGFR-3, FOXC2, NEMO, SOX18 for lymphedema or related syndromes, ENG, ACVRLK1, MADH4 for HHT or related syndromes, NDP for Coats' disease, Notch3 for CADASIL, and PTEN for Proteus Syndrome. These findings have made genetic testing possible in some clinical cases, and may lead to the development of therapeutic strategies for vascular anomalies. Furthermore, these studies have identified critical genes involved in vascular morphogenesis, and provided fundamental understanding of the molecular mechanisms underlying vasculogenesis and angiogenesis.

PMID: 16379592 [PubMed - in process]

Peho Syndrome

PEHO syndrome



Alternative titles; symbols




Salonen et al. (1991) identified a new form of infantile progressive encephalopathy in 14 patients, 8 of whom were female, from 11 families. The clinical signs included severe hypotonia, convulsions with hypsarrhythmia, profound mental retardation, hyperreflexia, transient or persistent edema, and optic atrophy. Other features included microcephaly and atrophy of the brain, especially in the cerebellar and brain stem areas. Salonen et al. (1991) pictured edema of the hands and tapering of the fingers resembling somewhat the hands in the Coffin-Lowry syndrome (303600). Facial anomalies included a 'pear-shaped' face, protruding lower parts of the earlobes, short nose, and open mouth with curved upper lip. No metabolic abnormality was found.

Haltia and Somer (1993) reported the neuropathologic findings in 8 cases: 3 patients in the original group described by Salonen et al. (1991) and 5 others collected from medical records. Two of the 8 patients were sibs. In addition, 1 patient had 1 sib, and another patient had 2 similarly affected sibs. Macroscopically, cerebral and pronounced cerebellar atrophy was seen, the essential histopathologically lesions being confined to the cerebellar cortex and the optic nerve. There was a severe neuronal loss in the inner granular layer of the cerebellum. The Purkinje cells were relatively preserved in number but were small, deformed, and slightly disaligned. Haltia and Somer (1993) found some similarities to congenital cerebellar granular cell hypoplasia and mental retardation (213200); however, mental retardation was less severe, and no epilepsy or optic atrophy was reported.

In a combined neuroradiologic and ophthalmologic study, Somer (1993) found that 10 of 21 possible patients had the true PEHO syndrome according to clinical criteria suggested by the authors. All were abnormal at birth, showing hypotonia, drowsiness, or poor feeding. Head circumference was normal at birth, but usually dropped to 2 SD below average during the first year of life. Visual fixation was either absent from birth or lost during the first months of life. Nine patients had peripheral edema in early childhood. The mean age of onset of infantile spasms was 4.9 months, no motor milestones were ever reached, and patellar reflexes were brisk. Brain stem and somatosensory evoked potentials were abnormal in each case studied, cortical responses of somatosensory evoked potentials could not be elicited, and motor conduction velocities became delayed with age. A total of 19 PEHO patients were found in 14 Finnish families in a pattern consistent with autosomal recessive inheritance. Somer (1993) indicated that cerebellar hypoplasia is a cardinal diagnostic feature of PEHO syndrome and suggested that a PEHO-like syndrome (the same clinical manifestations with only mild supratentorial atrophy) may occur.

Fujimoto et al. (1995) reported 2 affected sibs, a male and a female, born to healthy parents of Japanese descent who fulfilled the necessary diagnostic criteria for the PEHO syndrome established by Somer (1993) but who lacked supportive criteria of peripheral edema. In the female, there was mild elevation of the plasma lactate level only during the first year of life without an accompanying elevation of lactate in the cerebrospinal fluid.

Chitty et al. (1996) described 2 female sibs and 2 unrelated infants (a boy and a girl) with progressive encephalopathy, seizures, which started between 3 days and 13 months of age, characteristic facies, edema of the hands and feet, tapering fingers, and optic atrophy. All 4 patients died between 10 weeks and 34 months of age. Autopsies were declined. MRI, which was performed in 3 cases, showed delay in myelinization but no cerebellar atrophy. The patients reported by Chitty et al. (1996) fit the criteria of PEHO-like syndrome, but noted that the distinction between PEHO and PEHO-like cases remained unclear.

Longman et al. (2003) described 2 sisters with a PEHO-like syndrome. The firstborn had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly, and absence of development. Cranial MRI revealed periventricular white matter changes. Cerebellar hypoplasia, characteristic of true PEHO syndrome, was absent. The MRI changes were interpreted as periventricular leukomalacia due to prenatal ischemia, and a low recurrence risk was suggested. The younger sister was born similarly affected. Longman et al. (2003) noted that the diagnosis of PEHO syndrome is clinical, but cerebellar hypoplasia on neuroimaging is regarded as an additional necessary criterion. A heterogeneous group of PEHO-like patients, who lacked cerebellar hypoplasia but had varying supratentorial abnormalities, had been reported (Somer, 1993; Chitty et al., 1996). The family reported by Longman et al. (2003) was the second report of sibs with a PEHO-like syndrome, and it supported the existence of a distinct, autosomal recessive condition in which neuroimaging abnormalities may be misinterpreted.

Field et al. (2003) noted that few patients fulfilling the diagnostic criteria for PEHO syndrome had been reported outside Finland. Field et al. (2003) reported 5 Australian patients, the first with classic features of PEHO syndrome, and 4 who had a PEHO-like disorder. They suggested that the disorder may be more frequent than would be suggested based on the original diagnostic criteria.


1. Chitty, L. S.; Robb, S.; Berry, C.; Silver, D.; Baraitser, M. :
PEHO or PEHO-like syndrome? Clin. Dysmorph. 5: 143-152, 1996.PubMed ID :
2. Field, M. J.; Grattan-Smith, P.; Piper, S. M.; Thompson, E. M.; Haan, E. A.; Edwards, M.; James, S.; Wilkinson, I.; Ades, L. C. :
PEHO and PEHO-like syndromes: report of 5 Australian cases. Am. J. Med. Genet. 122A: 6-12, 2003.PubMed ID :
3. Fujimoto, S.; Yokochi, F.; Nakano, M.; Wada, Y. :
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome) in two Japanese siblings. Neuropediatrics 26: 270-272, 1995.PubMed ID :
4. Haltia, M.; Somer, M. :
Infantile cerebello-optic atrophy: neuropathology of the progressive encephalopathy syndrome with edema, hypsarrhythmia and optic atrophy (the PEHO syndrome). Acta Neuropath. 85: 241-247, 1993.PubMed ID :
5. Longman, C.; Tolmie, J.; McWilliam, R.; MacLennan, A. :
Cranial magnetic resonance imaging mistakenly suggests prenatal ischaemia in PEHO-like syndrome. Clin. Dysmorph. 12: 133-136, 2003.PubMed ID :
6. Salonen, R.; Somer, M.; Haltia, M.; Lorentz, M.; Norio, R. :
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome). Clin. Genet. 39: 287-293, 1991.PubMed ID :
7. Somer, M. :
Diagnostic criteria and genetics of the PEHO syndrome. J. Med. Genet. 30: 932-936, 1993.PubMed ID :


Victor A. McKusick - updated : 9/25/2003Iosif W. Lurie - updated : 7/26/1996Orest Hurko - updated : 3/9/1996


Victor A. McKusick : 6/4/1991


ckniffin : 5/19/2004tkritzer : 3/19/2004joanna : 3/17/2004carol : 2/18/2004

Pub Med


Diagnostic criteria and genetics of the PEHO syndrome.

Somer M.

Department of Medical Genetics, Vaestoliitto, Finnish Population and Family Welfare Federation, Helsinki.

The PEHO syndrome (progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy) is a recently recognised disorder of unknown biochemical background. Diagnostic features have been found in neuroradiological and neuropathological studies, which show characteristic severe cerebellar atrophy. In combined neuroradiological and ophthalmological studies, 10 out of 21 possible PEHO patients fulfilled the criteria for true PEHO syndrome. All were abnormal at birth showing hypotonia, drowsiness, or poor feeding. Head circumference was normal, but usually dropped to 2 SD below average during the first year of life. Visual fixation was either absent from birth or lost during the first months of life. Nine patients had peripheral oedema in early childhood. The mean age of onset of infantile spasms was 4.9 months. All patients were extremely hypotonic and no motor milestones were reached. Patellar reflexes were brisk. Brain stem and somatosensory evoked potentials were abnormal in each case studied, cortical responses of somatosensory evoked potentials could not be elicited, and motor conduction velocities became delayed with age. Altogether 19 PEHO patients were found in 14 Finnish families. Autosomal recessive inheritance is likely.PMID: 8301648

[PubMed - indexed for MEDLINE]


D I S E A S E : Peho syndrome

Clinical Signs

autosomal recessive inheritance (Very frequent sign)
cerebellum agenesis/hypoplasia (Very frequent sign)
cerebral cortex atrophy (Very frequent sign)
depressed premaxillary region (Very frequent sign)
e.e.g.abnormality (Very frequent sign)
hypereflexia (Very frequent sign) hypotonia (Very frequent sign)
long/large ear (Very frequent sign)
mental retardation (moderate/severe) (Very frequent sign)
microcephaly (Very frequent sign)
mouth held open (Very frequent sign)
optic disc anomaly/atrophy (Very frequent sign)
seizures ( any type) (Very frequent sign)
short/small nose (Very frequent sign)

Other Sites

Finnish Disease Database, Finland

Genetic database. Public : health professionals Site in english

Dysmorphology clinicGenetic counselling clinic

Wednesday, January 04, 2006

Nevo Syndrome

Sotos Syndrome



Nevo et al. (1974) described an inbred Israeli family in which 2 sibs and their cousin had increased growth, kyphosis, prominent forehead, volar edema, spindle-shaped fingers, wrist drop, talipes, hyperbilirubinemia, and generalized hypotonia. Although the authors considered their cases to be an autosomal recessive variant of Sotos syndrome (117550), Cohen (1989) proposed that these patients had a separate entity, which they called the Nevo syndrome. A fourth case was reported by Hilderink and Brunner (1995). Their patient, a boy born to consanguineous parents, had neither lens luxation nor aortic dilatation.

Al-Gazali et al. (1997) described 2 further male cases from unrelated Arab families with features similar to those described by Nevo et al. (1974) but without hyperbilirubinemia. Both had delayed motor development. Cognitive function was normal in one at 2 years 10 months of age. While the other was too young to assess, social responses appeared normal. MRI studies in the older child revealed extreme hyperlordosis of the cervical spine and a wide spinal canal suggestive of dural ectasia.

The patient reported by Dumic et al. (1998) manifested intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large and low-set ears, cryptorchidism, delayed neuropsychologic development, hypotonia, edema and contractures of the hands and feet, a single transverse palmar crease, and tapering digits. After meningococcal sepsis at age 6 months, he remained decerebrate. Thereafter, overgrowth and especially weight gain were markedly accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg. In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed. Dumic et al. (1998) presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his 'overgrowth without growth hormone,' at least in the last 12 months of life after severe brain damage.


Cohen (1989)


1. Al-Gazali, L. I.; Bakalinova, D.; Varady, E.; Scorer, J.; Nork, M. :
Further delineation of Nevo syndrome. J. Med. Genet. 34: 366-370, 1997.PubMed ID :
2. Cohen, M. M., Jr. :
A comprehensive and critical assessment of overgrowth and overgrowth syndromes.In: Harris, H.; Hirschhorn, K. (eds.) : Advances in Human Genetics. Vol. 18. New York: Plenum Press 1989. Pp. 181-303 and 373-376.
3. Dumic, M.; Vukelic, D.; Plavsic, V.; Cviko, A.; Sokolic, L.; Filipovic-Grcic, B. :
Nevo syndrome. Am. J. Med. Genet. 76: 67-70, 1998.PubMed ID :
4. Hilderink, B. G. M.; Brunner, H. G. :
Nevo syndrome. Clin. Dysmorph. 4: 319-323, 1995.PubMed ID :
5. Nevo, S.; Zeltzer, M.; Benderly, A.; Levy, J. :
Evidence for autosomal recessive inheritance in cerebral gigantism. J. Med. Genet. 11: 158-165, 1974.PubMed ID :

Victor A. McKusick - updated : 3/20/1998Michael J. Wright - updated : 7/3/1997

Iosif W. Lurie : 9/26/1996

alopez : 3/23/1998terry : 3/20/1998mimman : 10/3/1997alopez : 8/27/1997alopez : 8/7/1997jamie : 11/1/1996carol : 9/27/1996
Copyright © 1966-2004
Johns Hopkins University


Nevo syndrome.

Dumic M, Vukelic D, Plavsic V, Cviko A, Sokolic L, Filipovic-Grcic B.Department of Pediatrics, University Hospital, Zagreb, Croatia.

We report on a patient with Nevo syndrome manifesting intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large, low-set ears, cryptorchidism, delayed neuropsychological development, hypotonia, adema, contractures of the hands and feet, a single a transverse palmar crease, and tapering digits. After meningococcal sepsis at age 6 months, he remained decerebrate. Thereafter, overgrowth and especially weight gain were extremely accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg. In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed. It is presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his "overgrowth without growth hormone," at least in the last 12 months of life after severe brain damage.

Publication Types:

Case Reports PMID: 9508068 [PubMed - indexed for MEDLINE]



Alternative titles; symbolsCEREBRAL GIGANTISMGene map locus 5q35


A number sign (#) is used with this entry because Sotos syndrome is caused by mutation in the NSD1 gene (606681).


Sotos et al. (1964) described 5 children with a disorder characterized by excessively rapid growth, acromegalic features, and a nonprogressive cerebral disorder with mental retardation. High-arched palate and prominent jaw were noted in several of them. Birth length was between the 90th and 97th centiles in all. Bone age was advanced in most.

Hook and Reynolds (1967) reported that affected children have large hands and feet from birth. Growth is rapid in the first years of life but final height may not be excessive. Bone age is advanced. The skull is large with moderate prognathism. Mild dilation of the cerebral ventricles, nonspecific EEG changes, and seizures have been observed. Poor coordination and mental retardation are features. In 2 patients, Bejar et al. (1970) found abnormal dermatoglyphics, normal growth hormone levels, and high levels of valine, isoleucine and leucine in the blood. The glycine-to-valine ratio seemed particularly useful in distinguishing patients from controls.
Ruvalcaba et al. (1980) found hamartomatous polyps of the intestine and melanin spots of the penis in 2 males with the Sotos syndrome. Halal (1983) reported that the older of the boys she reported with cerebral gigantism had pigmented spots on the genitalia and that the father had been found to have a rectal polyp--findings like those in the 2 unrelated adult males reported by Ruvalcaba et al. (1980).

Kaneko et al. (1987) found congenital heart defects in 5 of 10 patients with typical Sotos syndrome. Noreau et al. (1998) found that 3 of 14 Sotos syndrome patients had congenital heart defects. In a literature review, they found another 17 patients with variable cardiac defects, mostly closure defects, making an overall incidence of approximately 8%.

Goldstein et al. (1988) described 2 unrelated children with macrocephaly, excessive growth, strabismus, hypotonia and developmental delay, and improvement with age.

In a review, Cole and Hughes (1990) emphasized that the handicaps in Sotos syndrome are fewer than previously believed and tend to improve with age. The latter feature makes identification of affected adults difficult. Cole and Hughes (1994) clinically assessed 79 patients with a provisional diagnosis of Sotos syndrome and evaluated their photographs between ages 1 and 6 years. These photographs, together with photographs of first-degree relatives, also at ages 1 to 6 years, were reviewed by 4 clinical geneticists. In 41 probands, but no first-degree relatives, the facial gestalt was thought to be characteristic of Sotos syndrome. Comparison of anthropometric measurements, bone age, and developmental delay in these 41 probands showed marked differences between them and the remaining 38 probands. Length was identified as the most significantly increased prenatal parameter. In childhood, occipitofrontal head circumference (OFC), height, and weight were all increased. OFC remained above the 97th percentile in all but one case throughout childhood and adulthood, whereas height and weight had a tendency to return toward the mean. This 'normalization' was more pronounced in females and was probably related to their early puberty. Early developmental delay and an advanced bone age were seen in 100% and 84% of cases, respectively. Cole and Hughes (1994) suggested that facial gestalt, growth pattern, bone age, and developmental delay are the major diagnostic criteria. Using these criteria, no affected first-degree relatives were identified.

Scarpa et al. (1994) described a sister and brother with macrocrania and coarse face (frontal bossing, highly arched palate, prognathism, pointed chin, large ears). Psychomotor development of the sister, who also had advanced osseous maturation, improved significantly at the age of 7 years. Accelerated growth with normal bone age, optic atrophy, renal agenesis with contralateral double kidney, and significant mental retardation (IQ, 45) were shown in the brother at 3.5 years of age. The father of these children was tall, with macrocrania and large hands and feet. He had had learning difficulties in school and was a manual laborer. Scarpa et al. (1994) suggested that these children and their father showed different manifestations of Sotos syndrome. Allanson and Cole (1996) presented anthropometric evaluation of the head in 45 patients with Sotos syndrome between age 1 and 25 years. With increasing age, the face lengthens and the chin becomes more striking.

Opitz et al. (1998) reported affected mother and daughter. The mother was described as a large infant and 'as tall as her teacher in school.' Her adult height was 185.4 cm, and she had mandibular prognathism and a prominent pointed chin. The daughter showed a prominent forehead with sparseness of frontal hair and a 'ruddy' or flushed complexion, especially of the nose and perioral area. She had prominent features of the congenital hypotonia/lymphedema sequence with hypermobile joints, especially at the knees and ankles, lymphedema nails (especially toenails), and a high total ridge count (TRC) of the fingertip dermatoglyphics. The mother also had a high TRC and a receding frontal hairline.

Robertson and Bankier (1999) reported 3 children with anthropometric and dysmorphologic features of classic Sotos syndrome in association with redundant skin folds, joint hypermobility, and, in 2 of the 3, vesicoureteric reflux. Robertson and Bankier (1999) thought the associated features suggested a coexisting connective tissue disorder. All the patients had a normal bone age. Although Sotos syndrome in its classically described form was not present, Robertson and Bankier (1999) concluded that this entity might reflect a related, perhaps allelic, condition.

Tumor Formation

Maldonado et al. (1984) reported the association of malignant tumors in Sotos syndrome. Nance et al. (1990) described a 15-month-old child with Sotos syndrome and a paraspinal neuroblastoma. From this and other evidence, they concluded that children with this disorder may be at an increased risk for developing tumors. Gorlin et al. (1990) estimated a risk of 3.9% of benign or malignant tumors in Sotos syndrome. The same excess of neoplasms is present in other overgrowth syndromes. Le Marec et al. (1999) reported that one of a monozygotic twin pair, both of whom had Sotos syndrome, developed a diffuse gastric carcinoma containing signet ring cells at the age of 26. The young age of occurrence of this gastric carcinoma suggested a genetic factor. Leonard et al. (2000) reported 2 children with Sotos syndrome who had benign sacrococcygeal teratomas. Given that Sotos syndrome and sacrococcygeal teratoma are rare events, the authors suggested that these tumors may be due to the effects of overgrowth on tumor development.


Opitz et al. (1998) discussed the differentiation of 2 overgrowth syndromes, Sotos syndrome and Weaver syndrome (277590), and the question of whether the similarities are sufficient to consider them 1 entity. They noted that vertebrate development is constrained into only a very few final or common developmental pathways; therefore, no developmental anomaly seen in humans is unique to ('pathognomonic of') one syndrome. Possible phenotypic differences between the syndromes of Sotos and Weaver pointed out by Opitz et al. (1998) were the following: the Sotos syndrome may be a cancer syndrome, whereas the Weaver syndrome is not (although a neuroblastoma had been reported in the latter disorder). In Sotos syndrome there is remarkably advanced dental maturation; this is rarely commented on in Weaver syndrome. In Weaver syndrome, there are more conspicuous contractures and a facial appearance that experts find convincingly different from that in Sotos syndrome. Opitz et al. (1998) favored allelic heterogeneity as the explanation for the similarities between Sotos and Weaver syndromes. They suggested that mapping and isolation of the causative gene or genes would settle the issue.

Differential Diagnosis

Schaefer et al. (1997) concluded that neuroimaging findings of Sotos syndrome are distinct enough to allow differentiation of this syndrome from other mental retardation syndromes with macrocephaly. The most common abnormality of the cerebral ventricles was prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). The supratentorial extracerebral fluid spaces were increased for age in 70% of the patients and the fluid spaces in the posterior fossa were increased in 70% also. A variety of midline abnormalities were noted but anomalies of the corpus callosum were almost universal.


Fryns (1988) referred to cases of the fragile X syndrome (309550) in which Sotos syndrome had been diagnosed; he therefore suggested that this disorder be designated the Sotos sequence or the mental retardation-overgrowth sequence.


Most reported cases of Sotos syndrome have been sporadic and may represent new dominant mutations. Hook and Reynolds (1967) reported a concordant set of affected identical twins. Hooft et al. (1968) described cerebral gigantism in 2 first cousins. Nevo et al. (1974) described affected brother and sister and their affected double first cousin in an inbred Arab family in Israel. Two of the 3 showed generalized edema and flexion contractures of the feet at birth. This may represent a distinct disorder; see Nevo syndrome (601451). Hansen and Friis (1976) described affected mother and child. Zonana et al. (1976) described affected mother and 2 children (male and female). The mother's father may have been affected. Zonana et al. (1977) reported 3 families showing vertical transmission and equal severity in males and females; no male-to-male transmission was observed. As an addendum, they commented on a fourth instance of affected mother and son. Smith et al. (1981) observed affected mother and daughter--the presumed fifth instance of dominant inheritance. The mother had primary hypothyroidism due to Hashimoto disease. Halal (1982) reported a family in which the father and 2 of his sons were affected. She knew of no other instance of documented male-to-male transmission. Winship (1985) described a 'Cape Coloured' family with affected father and 4 children by 2 different, unrelated wives. Presumed Sotos syndrome was described in a mother and 2 daughters by Bale et al. (1985). They suggested that instances of seemingly autosomal recessive inheritance may be examples of incomplete penetrance, gonadal mosaicism, or genetic heterogeneity. Minor changes in 2 mothers of 2 unrelated affected infants reported by Goldstein et al. (1988) suggested dominant inheritance of a Sotos sequence. Brown et al. (1998) described a pair of 5-year-old male monozygotic twins who were discordant for Sotos syndrome.

The possibility of uniparental disomy in Sotos syndrome was investigated by Smith et al. (1997). Using 112 dinucleotide repeat DNA polymorphisms, they examined parental inheritance of all autosomal pairs, except chromosome 15, in 29 patients with Sotos syndrome. All informative cases showed biparental inheritance and no cases of UPD were found.


In a study of the metacarpophalangeal pattern profile (MCPP) in Sotos syndrome, Butler et al. (1985) found no evidence of heterogeneity and developed a diagnostic tool using MCPP variables, which they suggested may be useful.


Schrander-Stumpel et al. (1990) described a 6-year-old boy with Sotos syndrome who also had a de novo, apparently balanced translocation, t(3;6)(p21;p21). They suggested that the autosomal dominant gene for the Sotos syndrome may be located either at 3p21 or 6p21. Tsukahara and Kajii (1991) could find no abnormality in high resolution-banded chromosomes from 5 patients. Involvement of genes at 3p21 was also suggested by the case reported by Cole et al. (1992); a 22-year-old female with Sotos syndrome, a nonsmoker, died of small cell lung carcinoma (182280) for which genetic determinants in the 3p21 region are suggested by loss-of-heterozygosity studies. Maroun et al. (1994) reported the case of a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between 5q and 15q: 46,XX,t(5,15)(q35;q22). They thus suggested 5q35 or 15q22 as the site of an autosomal dominant gene determining Sotos syndrome.

Faivre et al. (2000) reported a child with apparent Sotos syndrome and mosaicism for partial duplication of the short arm of chromosome 20 (46,XY,dup(20)(p12.1-p11.2)[12]/46,XY[66]). The somatostatin receptor-4 (SSTR4; 182454) gene is located at 20p11.2, encompassed by the duplication. The authors proposed that a dosage effect of this gene might be responsible for some of their patient's clinical findings.

Imaizumi et al. (2002) described a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8, 46,XX,t(5;8)(q35;q24.1), in a 15-month-old girl with a typical Sotos syndrome phenotype. They proposed that a gene responsible for this disorder is located in the distal long arm region of chromosome 5.


In patients with Sotos syndrome harboring a chromosomal translocation, Kurotaki et al. (2002) isolated the NSD1 (606681) gene from the 5q35 breakpoint. They identified 1 nonsense, 3 frameshift, and 20 submicroscopic deletion mutations of NSD1 among 42 sporadic cases of Sotos syndrome. The results indicated that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.

To the 42 cases of Sotos syndrome reported by Kurotaki et al. (2002), Kurotaki et al. (2003) added 70 more cases, 53 of whom were Japanese. Among the 112 total cases, they identified 50 microdeletions (45%) and 16 point mutations (14%). They noted a large difference between Japanese and non-Japanese patients in the frequency of microdeletions, which occurred in 49 (52%) of the 95 Japanese but in only 1 (6%) of the 17 non-Japanese. Most of the microdeletions were confirmed to be identical by FISH analysis. Kurotaki et al. (2003) identified highly homologous sequences, i.e., possible low copy repeats, in regions flanking proximal and distal breakpoints of the common deletion. This suggested that low copy repeats may mediate the deletion. The frequency of such low copy repeats seemed to vary in different populations, and thus the differences in frequency of microdeletions between Japanese and non-Japanese cases may have been caused by patient selection bias.

In a Finnish father and son with Sotos syndrome, Hoglund et al. (2003) identified a heterozygous mutation in the NSD1 gene (606681.0009). The authors noted that the findings in this family confirm that familial Sotos syndrome is caused by mutation in the NSD1 gene.
Beckwith-Wiedemann syndrome (BWS;
130650) is, like Sotos syndrome, an overgrowth syndrome. Deregulation of imprinted growth regulatory genes within the 11p15 region is the major cause of BWS. Similarly, defects of the NSD1 gene account for more than 60% of cases of Sotos syndrome. Owing to the clinical overlap between the 2 syndromes, Baujat et al. (2004) investigated whether unexplained cases of Sotos syndrome could be related to 11p15 anomalies and, conversely, whether unexplained BWS cases could be related to NSD1 deletions or mutations. Two 11p15 anomalies were identified in a series of 20 patients with Sotos syndrome, and 2 NSD1 mutations (606681.0011-606681.0012) were identified in a series of 52 patients with BWS. The results suggested that the 2 disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the 11p15 region.
Turkmen et al. (2003) screened the NSD1 gene for mutations in 20 patients and 1 familial case with Sotos syndrome, 5 patients with Weaver syndrome, 6 patients with unclassified overgrowth and mental retardation, and 6 patients with macrocephaly and mental retardation. They identified 19 mutations, 17 previously undescribed, in 18 Sotos patients and the familial case (90%). The best correlation between the molecular and clinical findings was for facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. Turkmen et al. (2003) found no mutations of the NSD1 gene in the patients with Weaver syndrome or other overgrowth phenotypes and concluded that the great majority of patients with Sotos syndrome have mutations in NSD1.


Boman and Nilsson (1980); Dodge et al. (1983); Stephenson et al. (1968)


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PubMed ID : 889595

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