Aarskog syndrome

Aarskog syndrome

Definition Return to top

Aarskog syndrome is an inherited disease characterized by short stature, facial abnormalities, musculoskeletal, and genital anomalies.

Causes, incidence, and risk factors Return to top

Aarskog syndrome is an x-linked recessive genetic disorder. This disorder affects mainly males, although females may have a milder manifestation of some of the features. It is caused by mutations in a gene called FGDY1 found on the X chromosome.

Symptoms

mild to moderate short stature which may not be obvious until the child is between 1 and 3 years old
possible delayed sexual maturation
rounded face
hairline has a "widow's peak"
wide set eyes with droopy eyelids
small nose with nostrils tipped forward
underdeveloped mid-portion of the face
wide groove above the upper lip, crease below the lower lip
delayed eruption of teeth
top portion of the ear folded over slightly
small, broad hands and feet with short fingers and in-curving 5th finger
short fingers and toes with mild webbing
simian crease (single) in palm of hand
protruding belly button
inguinal hernias
"shawl" scrotum, undescended testicles
mild to moderate mental deficiency
eyes have downward palpebral slant
pectus excavatum (mildly sunken chest)

Signs and tests
X-rays will reveal skeletal abnormalities. Genetic testing may be available for mutations in the FGDY1 gene.

Treatment Return to top

Orthodontic treatment may be attempted for some of the facial abnormalities. Trials of growth hormone have not been effective to treat short stature in this disorder.

Support Groups Return to top

The MAGIC Foundation for Children's Growth is a support group for Aarskog syndrome and can be found at www.magicfoundation.org.

Expectations (prognosis) Return to top

Mild degrees of mental slowness may be present, but affected children usually have good social skills. Some males may exhibit reduced fertility.
Complications Return to top

Some recent findings have included cystic changes in the brain and generalized seizures. There may be difficulty growing in the first year of life in up to one-third of cases. Misaligned teeth may require orthodontic correction. An undescended testicle will require surgery.

Calling your health care provider Return to top

Call your health care provider if your child exhibits delays in growth or if you notice any of the irregularities described here. Seek genetic counseling if there is Aarskog syndrome in your family. Seek evaluation by a geneticist if your doctor thinks you or your child may have Aarskog syndrome.

Prevention Return to top

There is no guaranteed prevention. Prenatal testing may be available in cases where a relative has a known mutation.
Update Date: 1/30/2004

Updated by: Douglas R. Stewart, M.D., Division of Medical Genetics, Hospital of the University of Pennsylvania, Philadelphia, PA. Review provided by VeriMed Healthcare Network.

March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains NY 10605
Phone #: 914-428-7100
800 #: 888-663-4637
e-mail: Askus@marchofdimes.com

Medline

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Aarskog syndrome

Synonyms of Aarskog Syndrome
AAS
Aarskog-Scott Syndrome
FGDY
Faciodigitogenital Syndrome
Faciogenital Dysplasia

Disorder Subdivisions

General Discussion

Aarskog syndrome is an extremely rare genetic disorder marked by stunted growth that may not become obvious until the child is about three years of age, broad facial abnormalities, musculoskeletal and genital anomalies, and mild mental retardation.

Organizations related to Aarskog Syndrome

Aarskog Syndrome Parents Support Group
62 Robin Hill Lane;Levittown PA 19055-1411Phone #: 215-943-7131800 #: --e-mail: aarskog1@yahoo.comHome page: N/A

contactcca@ccakids.com

mary@magicfoundation.org

Askus@marchofdimes.com

NAMSIC@mail.nih.gov

National Craniofacial Foundation
3100 Carlisle Street;Dallas TX 75204;Phone #: --800 #: 800-535-3643;e-mail: N/AHome page: N/A

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Pub Med

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NIH/PubMed

Aagenaes Syndrome

AAGENAES SYNDROME

CHOLESTASIS-LYMPHEDEMA SYNDROME

Alternative titles; symbols

CHLSAAGENAES SYNDROMELYMPHEDEMA-CHOLESTASIS SYNDROME; LCS; LCS1Gene map locus 15q

TEXT

In 2 Norwegian kindreds, Aagenaes et al. (1968, 1970) described a syndrome of hereditary recurrent cholestasis and lymphedema. Jaundice became evident soon after birth and recurred in episodes throughout life. Edema in the legs, which was due to hypoplasia of the lymphatic vessels, began at about school age and progressed. In 1 kindred, 16 individuals in 7 interconnected sibships appear to have been affected. One instance of affected mother and daughter may have resulted from the fact that the father was a heterozygote. Aagenaes (1974) described 2 additional unrelated families. In 1 family, with a single affected individual, the parents were first cousins once removed; in the other, nonconsanguineous family, 3 of 6 sibs were affected. Liver histology showed giant cell transformation in infancy and some fibrosis or cirrhosis in later childhood. The family reported by Sharp and Krivit (1971) was also Norwegian, living in Minnesota. Aagenaes (1974) therefore suggested the designation 'hereditary cholestasis of Norwegian type,' when cholestasis is combined with lymphedema.

Morris et al. (1997) reported an affected mother and daughter in a nonconsanguineous family of British origin. Morris et al. (1997) suggested that the most likely explanation was a de novo autosomal dominant mutation in the mother, either allelic with or at a locus distinct from that in the previously described families.

Aagenaes (1998) gave a comprehensive review of the syndrome that bears his name with a description of new cases and follow-up from infancy to adulthood. The original observations (Aagenaes et al., 1968) involved 16 patients from the southwest of Norway. The patients belonged to 7 sibships; consanguinity was frequent, and autosomal recessive inheritance was proposed. Fourteen patients had been diagnosed in Norway since 1970. Nine of these belonged to the first large family reported. Two brothers of consanguineous parents belonged to a small family described in 1974 (Aagenaes, 1974); 2 sibs and 1 other sporadic patient appeared to be unrelated to any of these other families. A complicated pedigree of the original family showing the multiple affected individuals was displayed (Figure 8). Of the 21 patients born before 1970, 11 died in early childhood. Nine of these died in early infancy, mainly of bleeding because of unavailability of vitamin K at the time. Two died of cirrhosis in later childhood. Of the patients born before 1970, 6 women and 4 men survived childhood. One woman died at the age of 50 years, and 9 were still alive at ages ranging from 30 to 61 years. There had been no new Norwegian cases identified in the previous 6 years.

Aagenaes (2001) pointed out that the common denominator of the syndrome that bears his name is a 'relatively generalized' lymphatic anomaly. This appears to indicate that the defect resides in lymphangiogenesis.

Bull et al. (2000) performed a genome screen, using DNA from 8 Norwegian patients with cholestasis-lymphedema syndrome and from 7 unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifested extensive allele and haplotype sharing over a 6.6-cM region on chromosome 15 between markers D15S979 and D15S652.

REFERENCES

1. Aagenaes, O. :
Personal Communication. Oslo, Norway, 2/28/2001.
2. Aagenaes, O. :
Hereditary cholestasis with lymphoedema (Aagenaes syndrome, cholestasis-lymphoedema syndrome): new cases and follow-up from infancy to adult age. Scand. J. Gastroent. 33: 335-345, 1998.PubMed ID : 9605254
3. Aagenaes, O. :
Hereditary recurrent cholestasis with lymphoedema--two new families. Acta Paediat. Scand. 63: 465-471, 1974.PubMed ID : 4857709
4. Aagenaes, O.; Sigstad, H.; Bjorn-Hansen, R. :
Lymphoedema in hereditary recurrent cholestasis from birth. Arch. Dis. Child. 45: 690-695, 1970.PubMed ID : 5477684
5. Aagenaes, O.; Van der Hagen, C. B.; Refsum, S. :
Hereditary recurrent intrahepatic cholestasis from birth. Arch. Dis. Child. 43: 646-657, 1968.PubMed ID : 5702224
6. Bull, L. N.; Roche, E.; Song, E. J.; Pedersen, J.; Knisely, A. S.; van der Hagen, C. B.; Eiklid, K.; Aagenaes, O.; Freimer, N. B. :
Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q. Am. J. Hum. Genet. 67: 994-999, 2000.PubMed ID : 10968776
7. Morris, A. A. M.; Sequeira, J. S. S.; Malone, M.; Slaney, S. F.; Clayton, P. T. :
Parent-child transmission of infantile cholestasis with lymphoedema (Aagenaes syndrome). J. Med. Genet. 34: 852-853, 1997.PubMed ID : 9350821
8. Sharp, H. L.; Krivit, W. :
Hereditary lymphedema and obstructive jaundice. J. Pediat. 78: 491-496, 1971.PubMed ID : 5544157

CONTRIBUTORS

Victor A. McKusick - updated : 10/20/2000Victor A. McKusick - updated : 7/10/1998Michael J. Wright - updated : 6/5/1998

CREATION DATE
Victor A. McKusick : 6/3/1986

EDIT HISTORY
mgross : 3/17/2004

Pub Med

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Cholestasis with lymphedema (Aagenaes syndrome): Genome screen and evaluation of candidate regions. L. Bull1, E. Roche1, K. Eiklid2, C. van der Hagen2, A. Knisely3, O. Aagenaes2, N. Freimer1. 1) UCSF, San Francisco, CA; 2) University of Oslo, Oslo, Norway; 3) University of Texas Medical Branch, Galveston, TX.

Cholestasis with lymphedema (CL), or Aagenaes syndrome, was first described in a Norwegian pedigree, in which the disease demonstrates probable autosomal recessive inheritance. Most Norwegian patients come from the same region, and are descended from a couple born circa 1570. CL is characterized by neonatal-onset cholestatic jaundice, accompanied by elevated levels of serum bile acids, bilirubin, and ALAT, and lasting 1-5 years. Recurrent cholestatic episodes occur in later childhood and adulthood. Lymphedema may be apparent at birth, or begin during childhood, and becomes chronic. Studies on urinary bile acids suggest no inborn bile acid metabolism abnormality. To identify the CL gene, we performed a genome screen using DNA from members of the Norwegian pedigree, and 385 autosomal microsatellite markers. A standard linkage analysis was not feasible because the structure of the pedigree is too complex, and too many samples are unavailable. Therefore, we designed a screening strategy to identify genome regions potentially shared identical by descent among several of these distantly related patients; two sib-pairs and a cousin pair were included. We identified candidate regions based on: 1) data consistent with linkage in the two sib pairs, 2) data consistent with linkage in the cousin pair, 3) evidence for marker haplotypes shared by affected individuals, and 4) evidence that particular marker alleles are more frequent than expected on the disease chromosomes. We paid particular attention to 5 regions containing genes previously found to be mutated in forms of hereditary liver disease or lymphedema (BSEP, FLT4, PGY3, FIC1, and JAG1). We have obtained no genetic evidence that CL is due to mutation in any of these candidate genes. We are currently evaluating 20 candidate regions identified in the genome screen on the basis of the genetic criteria outlined above. These regions are being evaluated by additional genotyping of the samples included in the genome screen, as well as in a larger sample of Norwegian CL patients.

Genetics

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Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q.Bull LN, Roche E, Song EJ, Pedersen J, Knisely AS, van Der Hagen CB, Eiklid K, Aagenaes O, Freimer NB.Liver Center Laboratory, San Francisco General Hospital, San Francisco, CA 94110, USA. lbull@medsfgh.ucsf.eduPatients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979-D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor.PMID: 10968776 [PubMed - indexed for MEDLINE]

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Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome.Fruhwirth M, Janecke AR, Muller T, Carlton VE, Kronenberg F, Offner F, Knisely AS, Geleff S, Song EJ, Simma B, Konigsrainer A, Margreiter R, van der Hagen CB, Eiklid K, Aagenaes O, Bull L, Ellemunter H.Department of Pediatrics, University Hospital Innsbruck, the Institute of Medical Biology and Human Genetics, University of Innsbruck, Austria.Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis. A locus, LCS1, has recently been mapped to chromosome 15q in a Norwegian kindred. In a consanguine Serbian Romani family with a neonate who had a combination of lymphedema and cholestasis with features atypical for Norwegian LCS, haplotype and linkage analysis of markers spanning the LCS1 region argue that a second LCS locus may exist. The infant may represent an instance of a previously undescribed lymphedema-cholestasis syndrome.

Publication Types - Pub Med:

Case Reports
PMID: 12712065 [PubMed - indexed for MEDLINE]

Lissencephaly syndrome

Lissencephaly syndrome

#247200
GeneTests,
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MILLER-DIEKER LISSENCEPHALY SYNDROME; MDLS

Alternative titles; symbolsMDSMILLER-DIEKER SYNDROME CHROMOSOME REGION, INCLUDED; MDCR, INCLUDEDGene map locus 17p13.3

TEXT

A number sign (#) is used with this entry because the Miller-Dieker lissencephaly syndrome appears to be caused by deletion of several genes on 17p. Deletion of or mutation in the LIS1 gene (601545) appears to cause the lissencephaly because point mutations have been identified in the disorder isolated lissencephaly sequence (ILS; see 607432). On the other hand, facial dysmorphism and other anomalies in Miller-Dieker patients appear to be the consequence of deletion of additional genes distal to LIS1. Toyo-oka et al. (2003) presented evidence that the gene whose deletion is responsible for the greater severity of Miller-Dieker syndrome compared to isolated lissencephaly is the gene encoding 14-3-3-epsilon (YWHAE; 605066).

(The number 247200 was assigned to this entry when it was first created between the fourth (1975) and eighth (1978) editions of Mendelian Inheritance in Man, on the presumption that the disorder was autosomal recessive. It turns out that both isolated lissencephaly sequence and the Miller-Dieker syndrome are due to haploinsufficiency of one or more genes on 17p; they are autosomal dominant disorders.)

DESCRIPTION

Miller-Dieker lissencephaly syndrome is a chromosomal microdeletion disorder characterized by microcephaly and a thickened cortex with 4 rather than 6 layers. Lissencephaly means 'smooth brain,' i.e., brain without convolutions or gyri.

CLINICAL FEATURES

Miller (1963) described this condition in a brother and sister who were the fifth and sixth children of unrelated parents. The features were microcephaly, small mandible, bizarre facies, failure to thrive, retarded motor development, dysphagia, decorticate and decerebrate postures, and death at 3 and 4 months, respectively. Autopsy showed anomalies of the brain, kidney, heart, and gastrointestinal tract. The brains were smooth with large ventricles and a histologic architecture more like normal fetal brain of 3 to 4 months' gestation.

Dieker et al. (1969) described 2 affected brothers and an affected female maternal first cousin. They also emphasized that this should be termed the lissencephaly syndrome because malformations of the heart, kidneys, and other organs, as well as polydactyly and unusual facial appearance, are associated.

Reznik and Alberca-Serrano (1964) described 2 brothers with congenital hypertelorism, mental defect, intractable epilepsy, progressive spastic paraplegia, and death at ages 19 and 9 years. The mother showed hypertelorism and short-lived epileptiform attacks. Autopsy showed lissencephaly with massive neuronal heterotopia, and large ventricular cavities of embryonic type. (The findings in the mother made X-linked recessive inheritance a possibility.) The patients of Reznik and Alberca-Serrano (1964) may have suffered from a disorder distinct from that described by Miller (1963) and Dieker et al. (1969). All patients with the Miller-Dieker syndrome are severely retarded. None learned to speak. They may walk by 3 to 5 years but spastic diplegia with spastic gait is evident. As in other forms of stationary forebrain developmental anomalies, decerebrate posturing with head retraction emerges in the first year of life. In the case of Norman et al. (1976), 3 sibs were affected and the parents were third cousins.

Dobyns et al. (1983) stated that the most characteristic finding on computerized tomography is complete failure of opercularization of the frontal and temporal lobes, and that this most likely accounts for bitemporal hollowing. (Opercularization is formation of the parts of the lobes that cover part of the insula.) The form of lissencephaly in the Miller-Dieker syndrome was designated classical or type I lissencephaly by Dobyns et al. (1984). It is characterized by microcephaly and a thickened cortex with 4 rather than 6 layers. (Type II lissencephaly has associated obstructive hydrocephalus and severe brain malformations. It is a major manifestation of the HARD plus/minus-E syndrome (236670). The Walker-Warburg syndrome (236670) is the most frequent form of type II lissencephaly (Dobyns et al., 1988). A third form occurs in the Neu-Laxova syndrome (256520). Dobyns et al. (1984) suggested the designation Norman-Roberts syndrome (see 257320) for the disorder associated with type I lissencephaly but distinct from the Miller-Dieker syndrome. A low, sloped forehead and prominent nasal bridge are distinctive to this condition and chromosomes are normal.)

Bordarier et al. (1986) pointed out that agyria was considered a rare malformation until the recent progress in neuroradiology.

Selypes and Laszlo (1988) described the Miller-Dieker syndrome in a 12-year-old boy with a de novo terminal deletion of 17p13. He had growth retardation, microcephaly, ptosis of the left eyelid, low-set ears, prominent philtrum, thin upper lip, clinodactyly of the fifth fingers, and atrial septal defect. Lissencephaly was demonstrated by computerized tomography. MDS is a severe neuronal migration abnormality.

Dobyns et al. (1988) found the most consistent features of the facies in MDLS to be bitemporal hollowing, prominent forehead, short nose with upturned nares, prominent upper lip, thin vermilion border of the upper lip, and small jaw. Agenesis of the corpus callosum was demonstrated by computerized tomography in about 90% of cases. The cerebellum was normal in all. Striking midline calcifications were found in most patients with visible chromosomal change.

Allanson et al. (1998) reported pattern profiles on 5 children with MDLS and 25 children and adolescents with isolated lissencephaly sequence. The patients with ILS at all ages showed reduced head circumference and a wide and flat face with a broad nose and widely spaced eyes. In the age group of 6 months to 4 years of age, there was similarity between the pattern profiles of ILS and MDLS, with a correlation coefficient of 0.812 (p less than 0.001). In MDLS there are a few distinguishing features, including brachycephaly, a slightly wider face, and a considerably shorter nose. Allanson et al. (1998) concluded that given the striking similarity of the pattern profiles, the principal diagnostic discriminators are qualitative features, specifically the tall, furrowed forehead and the long, broad thickened upper lip in MDLS. They also concluded that their observations were consistent with the concept of additional gene(s) telomeric to LIS1 contributing to the facial phenotype of MDLS.

CYTOGENETICS

Dobyns et al. (1983) found a ring chromosome 17 in 1 patient and were prompted to study 2 other cases. They found partial monosomy of 17p13 in one of these. A review of the literature uncovered abnormality of 17p in 5 other patients in 3 families. Sharief et al. (1991) reported a case of MDS associated with ring chromosome 17.

Ledbetter (1983) studied the parents of the patients reported by Miller (1963), Dieker et al. (1969), and Norman et al. (1976). The father of Miller's sibs had a 15q;17p translocation; the father of Dieker's patients 1 and 3 had a 12q;17p translocation and both parents of Norman's patient had normal karyotypes. An autosomal recessive form of lissencephaly is suggested also by the parental consanguinity in Norman's case.

Stratton et al. (1984) further narrowed the monosomy to 17p13.3. They also reported prenatal diagnosis. In a patient with MDS and no cytogenetically detectable deletion, vanTuinen and Ledbetter (1987) found evidence of deletion by use of a DNA marker located at 17p13.3. Greenberg et al. (1986) described a family in which the mother had a pericentric inversion of chromosome 17 and 2 of her children had MDS. One of them was shown to carry a recombinant 17 consisting of dup(17q) and del(17p). The patient described by Selypes and Laszlo (1988) had a de novo terminal deletion of 17p13.

Bordarier et al. (1986) reported anatomoclinical observations on a case of partial deletion of 17p. Golgi stains showed many inverted pyramidal cells in the superficial part of the cortex.

Dhellemmes et al. (1988) found a microdeletion of 17p in 1 of 12 cases with lissencephaly. They subscribed to the 4-way classification of lissencephalies proposed by Dobyns et al. (1984): the Miller-Dieker syndrome with abnormality of chromosome 17; the Miller-Dieker syndrome without evident abnormality of chromosome 17; a disorder with manifestations unlike those of the Miller-Dieker syndrome but with familial occurrence and normal chromosomes (Norman-Roberts syndrome); and a form without characteristic facial dysmorphism and without familial occurrence. In the study of Dhellemmes et al. (1988), 1 patient was in category 1 and the other 11 were in category 4.

Dobyns et al. (1991) reviewed the results of their clinical, cytogenetic, and molecular studies in 27 patients with MDS from 25 families. All had severe type I lissencephaly with grossly normal cerebellum and a distinctive facial appearance consisting of prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw. Chromosome analysis showed deletion of band 17p13 in 14 of 25 MDS probands. Studies using probes from the 17p13.3 region detected deletions in 19 of 25 probands tested, including 7 in whom chromosome analysis was normal. When the cytogenetic and molecular data were combined, deletions were detected in 21 of 25 probands. Of the 11 patients in whom parental origin of the de novo deletion was determined, paternal origin was demonstrated in 7 and maternal origin in 4.

De Rijk-van Andel et al. (1991) identified a submicroscopic deletion of 2 DNA markers located at 17p13 in a patient with isolated grade 3 lissencepha
ly. The findings suggested that MDS and isolated lissencephaly have a common etiology.

About 90% of MDS patients have visible or submicroscopic deletions of 17p13.3; Ledbetter et al. (1992) investigated the possibility that some patients with 'isolated lissencephaly sequence' (ILS) had smaller deletions in that chromosomal region. Their studies uncovered 6 submicroscopic deletions in 45 ILS patients with gyral abnormalities ranging from complete agyria to mixed agyria/pachygyria and complete pachygyria. In situ hybridization proved to be the most rapid and sensitive method of deletion detection. The centromeric boundary of these deletions overlapped that of MDS patients, while the telomeric boundary for 4 of them was proximal to that of MDS.

Oostra et al. (1991) studied 5 patients with MDS, 17 patients with isolated lissencephaly sequence, 1 patient with an unclassified form of lissencephaly, and 9 patients with an atypical cortical dysplasia. All patients had normal chromosomes except for a deletion of 17p13.3 in 1 of the 5 MDS patients. The 5 MDS patients showed deletion of markers YNZ22.1 and YNH37.3. Dobyns et al. (1993) reviewed the clinical phenotype, pathologic changes, and results of cytogenetic and molecular genetic studies in 90 probands with lissencephaly, with emphasis on patients with the classic form (type I).

A cryptic translocation in one of the parents of MDS patients had been found using fluorescence in situ hybridization (FISH) (Kuwano et al., 1991). Masuno et al. (1995) described a patient with MDS and a maternal cryptic translocation. Kingston et al. (1996) described a boy who, in addition to lissencephaly and facial features of MDS, had rhizomelic shortening of the limbs, cleft palate, hypospadias, and sacral tail. Banded chromosome analysis did not reveal any abnormality of chromosome 17. FISH studies with the alpha satellite probe D17Z1 and 3 overlapping cosmids from the MDS critical region showed that his mother and grandmother carried a balanced inv(17)(p13.3q25.1). The proband's karyotype was 46,XY,rec(17),dup q,inv(17)(p13.3q25.1)mat. Additional manifestations in the proband were due to distal 17q trisomy. Masuno et al. (1995) and Kingston et al. (1996) stated that FISH analysis is crucial to exclude subtle rearrangements in affected children and their parents.

MAPPING

VanTuinen et al. (1988) found that the genes for myosin heavy chain-2 (160740), tumor antigen p53, and RNA polymerase II (180660), previously mapped to 17p, are not included in the MDS deletion region and therefore are unlikely to play a role in its pathogenesis.

MOLECULAR GENETICS

Ledbetter et al. (1988) described 2 variable number tandem repeat (VNTR) probes that revealed a 15-kb region containing HTF islands that are likely to be markers of expressed sequences. Use of these probes showed homology to chromosome 11 in the mouse. Because of the close location of MDCR to tumor antigen p53 (TP53; 191170) and MYHSA1 (160730) in man, the homologous locus in the mouse is probably close to the corresponding loci in that species. Several neurologic mutants in the mouse map to that region.

In 2 MDS patients with normal chromosomes, a combination of somatic cell hybrid, RFLP, and densitometric studies demonstrated deletion of polymorphic anonymous probes in the paternally derived chromosome 17 (VanTuinen et al., 1988). This demonstration of submicroscopic deletion suggests that all MDS patients may have deletions at the molecular level. In an addendum, the authors stated that 3 additional MDS patients without cytogenetically detectable deletions had been found to have molecular deletions and that 'to date' 13 of 13 MDS patients had molecular deletions. Using anonymous probes, Schwartz et al. (1988) likewise found molecular deletions in 3 MDS patients, 2 of whom had no visible abnormalities of chromosome 17. None of the 3 RFLP loci studied was absent in a case of lissencephaly without MDS.

Ledbetter et al. (1989) found that in all of 7 patients 3 overlapping cosmids spanning more than 100 kb were completely deleted, thus providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region--indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder.

Reiner et al. (1993) cloned a gene called LIS1 (lissencephaly-1) in 17p13.3 that is deleted in Miller-Dieker patients. Nonoverlapping deletions involving either the 5-prime or the 3-prime end of the gene were found in 2 patients, identifying LIS1 as the disease gene. The deduced amino acid sequence showed significant homology to beta subunits of heterotrimeric G proteins, suggesting that it may be involved in a signal transduction pathway crucial for cerebral development. Since haploinsufficiency appears to lead to the syndrome, half the normal dosage of the gene product is apparently inadequate for normal development. It may be that improper proportions of beta and gamma subunits of a G protein disturb formation of the normal protein complex, as in hemoglobin H disease, which is caused by an imbalance in the ratio of alpha- to beta-globin. About 15% of patients with isolated lissencephaly and more than 90% of patients with Miller-Dieker syndrome have microdeletions in a critical 350-kb region of 17p13.3. Genotype/phenotype studies are necessary to explain the phenotypic differences. Neer et al. (1993) commented on the nature of the newly found gene and the usefulness of identifying families of genes and the proteins they encode.

Platelet-activating factor (PAF) is involved in a variety of biologic and pathologic processes (Hanahan, 1986). PAF acetylhydrolase, which inactivates PAF by removing the acetyl group at the sn-2 position, is widely distributed in plasma and tissue cytosols. One isoform of PAF acetylhydrolase present in bovine brain cortex is a heterotrimer comprising subunits with relative molecular masses of 45, 30, and 29 kD (Hattori et al., 1993). Hattori et al. (1994) isolated the cDNA for the 45-kD subunit. Sequence analysis revealed 99% identity with the LIS1 gene, indicating that the LIS1 gene product is a human homolog of the 45-kD subunit of intracellular PAF acetylhydrolase. The results raised the possibility that PAF and PAF acetylhydrolase are important in the formation of the brain cortex during differentiation and development.

Kohler et al. (1995) searched for microdeletions in 17p13.3 in 5 patients with lissencephaly-1, typical features of Miller-Dieker syndrome and apparently normal karyotypes. Analysis of loci D17S5 and D17S379 by PCR and FISH revealed a deletion in 3 of the 5 cases. No deletion was observed in the other 2. Given the almost identical clinical picture of the 5 patients, the great variation in the molecular findings argued against Miller-Dieker syndrome being a contiguous gene syndrome.

Chong et al. (1996) characterized the LIS1 gene (601545), demonstrating the presence of 11 exons. SSCP analysis of individual exons was performed on 18 patients with isolated lissencephaly sequence (ILS; see 607432) who showed no deletions detectable by FISH. In 3 of these patients, point mutations were identified: a missense mutation, a nonsense mutation, and a 22-bp deletion at the exon 9-intron 9 junction predicted to result in a splicing error. The findings confirmed the view that mutations of LIS1 are the cause of the lissencephaly phenotype in ILS and in the Miller-Dieker syndrome. Together with the results of deletion analysis for other ILS and Miller-Dieker syndrome patients, these data are also consistent with the previous suggestion that additional genes distal to LIS1 are responsible for the facial dysmorphism and other anomalies in MDS patients.

Cardoso et al. (2003) completed a physical and transcriptional map of the chromosome 17p13.3 region from LIS1 to the telomere. Using FISH, Cardoso et al. (2003) mapped the deletion size in 19 children with ILS (607432), 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. Cardoso et al. (2003) showed that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, Cardoso et al. (2003) identified 8 genes that are consistently deleted in patients classified as having MDS. These genes include ABR (600365), 14-3-3-epsilon (605066), CRK (164762), MYO1C (606538), SKIP (603055), PITPNA (600174), SCARF1, RILP, PRP8 (607300), and SERPINF1 (172860). In addition, deletion of the genes CRK and 14-3-3-epsilon delineates patients with the most severe lissencephaly grade. On the basis of recent functional data and the creation of a mouse model suggesting a role for 14-3-3-epsilon in cortical development, Cardoso et al. (2003) suggested that deletion of 1 or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with Miller-Dieker syndrome.

DIAGNOSIS

For rapid diagnosis, Batanian et al. (1990) used PCR in connection with probe YNZ22 (D17S5), a highly polymorphic, variable number tandem repeat (VNTR) marker previously shown to be deleted in all patients with MDS, but not in patients with isolated lissencephaly sequence. Analysis of 118 normal persons revealed 12 alleles (differing in copy number of a 70-bp repeat unit) ranging in size from 168 to 938 bp.

Pollin et al. (1999) evaluated the risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the MDS critical region in 17p13.3. Fourteen families were ascertained on the basis of an affected index case. In these 14 families, 38 balanced translocation carriers had 127 pregnancies, corrected for ascertainment bias by the exclusion of all index cases and carriers in the line of descent to the index cases. An abnormal phenotype, an unbalanced chromosome constitution, or both, were found in 33 of the 127 (26%) pregnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with del(17p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9 were unstudied, although MDS with der(17) was usually suspected based on early death and multiple congenital anomalies. When unexplained pregnancy losses, including miscarriages and stillbirths, were excluded from the total, 33 of 99 (33%) pregnancies were phenotypically or genotypically abnormal. The overall risk of abnormal pregnancy outcome of 26% was in the upper range of the reported risk for unbalanced offspring of carrier parents ascertained through liveborn aneuploid offspring. The risk increased to 33% when unexplained pregnancy losses were excluded from the total.

ANIMAL MODEL

The condition of so-called inverted pyramids is observed in the 'reeler' mutation in mice (Landrieu and Goffinet, 1981). The 'reeler' mutation (re) is located on mouse chromosome 5, a chromosome that carries no gene known thus far to be homologous to a gene on human chromosome 17. Thus, there is no support from homology of synteny for the notion that agyria in man is the same as 'reeler' in the mouse.

The conserved sequences identified by Ledbetter et al. (1989) were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, thus extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 cM, into the 17p telomere region.

Yingling et al. (2003) discussed the prospects of using the mouse to model Miller-Dieker syndrome. Null and conditional knockout alleles in the mouse had been generated for Lis1 and Mnt (603039), and null alleles had been produced for Hic1 (603825) and 14-3-3-epsilon. For Lis1 and Pitpn (600174), hypomorphic alleles also existed.

SEE ALSO

Garcia et al. (1978)

REFERENCES

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Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996.
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Clinical and molecular diagnosis of Miller-Dieker syndrome. Am. J. Hum. Genet. 48: 584-594, 1991.PubMed ID : 1671808
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Lissencephaly: a human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. J.A.M.A. 270: 2838-2842, 1993.PubMed ID : 7907669
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Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. Am. J. Med. Genet. 18: 509-526, 1984.PubMed ID : 6476009
12. Dobyns, W. B.; Stratton, R. F.; Parke, J. T.; Greenberg, F.; Nussbaum, R. L.; Ledbetter, D. H. :
The Miller-Dieker syndrome: lissencephaly and monosomy 17p. J. Pediat. 102: 552-558, 1983.PubMed ID : 6834189

13. Dobyns, W. B.; vanTuinen, P.; Ledbetter, D. H. :
Clinical diagnostic criteria for Miller-Dieker syndrome. (Abstract) Am. J. Hum. Genet. 43: A46, 1988.
14. Garcia, C. A.; Dunn, D.; Trevor, R. :
The lissencephaly (agyria) syndrome in siblings: computerized tomographic and neuropathologic findings. Arch. Neurol. 35: 606-611, 1978.
15. Greenberg, F.; Stratton, R. F.; Lockhart, L. H.; Elder, F. F. B.; Dobyns, W. B.; Ledbetter, D. H. :
Familial Miller-Dieker syndrome associated with pericentric inversion of chromosome 17. Am. J. Med. Genet. 23: 853-859, 1986.PubMed ID : 3963054
16. Hanahan, D. J. A. :
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Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor. Nature 370: 216-218, 1994.PubMed ID : 8028668
18. Hattori, M.; Arai, H.; Inoue, K. :
Purification and characterization of bovine brain platelet-activating factor acetylhydrolase. J. Biol. Chem. 268: 18748-18753, 1993.PubMed ID : 8360169
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Miller-Dieker syndrome resulting from rearrangement of a familial chromosome 17 inversion detected by fluorescence in situ hybridisation. J. Med. Genet. 33: 69-72, 1996.PubMed ID : 8825053
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Clinical and molecular genetic findings in five patients with Miller-Dieker syndrome. Clin. Genet. 47: 161-164, 1995.PubMed ID : 7634541
21. Kuwano, A.; Ledbetter, S. A.; Dobyns, W. B.; Emanuel, B. S.; Ledbetter, D. H. :
Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. Am. J. Hum. Genet. 49: 707-714, 1991.PubMed ID : 1897521
22. Landrieu, P.; Goffinet, A. :
Inverted pyramidal neurons and their axons in the neocortex of reeler mutant mice. Cell Tissue Res. 218: 293-301, 1981.PubMed ID : 6167365
23. Ledbetter, D. H. :
Personal Communication. Houston, Texas, 5/27/1983.
24. Ledbetter, D. H.; Ledbetter, S. A.; vanTuinen, P.; Summers, K. M.; Nakamura, Y. :
Two VNTR probes reveal HTF islands and conserved sequences in a microdeletion syndrome. (Abstract) Am. J. Hum. Genet. 43: A111, 1988.
25. Ledbetter, D. H.; Ledbetter, S. A.; vanTuinen, P.; Summers, K. M.; Robinson, T. J.; Nakamura, Y.; Wolff, R.; White, R.; Barker, D. F.; Wallace, M. R.; Collins, F. S.; Dobyns, W. B. :
Molecular dissection of a contiguous gene syndrome: frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated 'island' in the Miller-Dieker chromosome region. Proc. Nat. Acad. Sci. 86: 5136-5140, 1989.PubMed ID : 2740347
26. Ledbetter, S. A.; Kuwano, A.; Dobyns, W. B.; Ledbetter, D. H. :
Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am. J. Hum. Genet. 59: 182-189, 1992.
27. Masuno, M.; Imaizumi, K.; Nakamura, M.; Matsui, K.; Goto, A.; Kuroki, Y. :
Miller-Dieker syndrome due to maternal cryptic translocation t(10;17)(q26.3;p13.3). Am. J. Med. Genet. 59: 441-443, 1995.PubMed ID : 8585563
28. Miller, J. Q. :
Lissencephaly in 2 siblings. Neurology 13: 841-850, 1963.PubMed ID : 14066999
29. Neer, E. J.; Schmidt, C. J.; Smith, T. :
LIS is more. Nature Genet. 5: 3-4, 1993.PubMed ID : 8220419
30. Norman, M. G.; Roberts, M.; Sirois, J.; Tremblay, L. J. M. :
Lissencephaly. Canad. J. Neurol. Sci. 3: 39-46, 1976.PubMed ID : 175907
31. Oostra, B. A.; de Rijk-van Andel, J. F.; Eussen, H. J.; van Hemel, J. O.; Halley, D. J. J.; Niermeijer, M. F. :
DNA analysis in patients with lissencephaly type I and other cortical dysplasias. Am. J. Med. Genet. 40: 383-386, 1991.PubMed ID : 1951447
32. Pollin, T. I.; Dobyns, W. B.; Crowe, C. A.; Ledbetter, D. H.; Bailey-Wilson, J. E.; Smith, A. C. M. :
Risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the Miller-Dieker syndrome (MDS) critical region in chromosome 17p13.3. Am. J. Med. Genet. 85: 369-375, 1999.PubMed ID : 10398263
33. Reiner, O.; Carrozzo, R.; Shen, Y.; Wehnert, M.; Faustinella, F.; Dobyns, W. B.; Caskey, C. T.; Ledbetter, D. H. :
Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 364: 717-721, 1993.PubMed ID : 8355785
34. Reznik, M.; Alberca-Serrano, R. :
Forme familiale d'hypertelorisme avec lissencephalie se presentant cliniquement sous forme d'une arrieration mentale avec epilepsie et paraplegie spasmodique. J. Neurol. Sci. 1: 40-58, 1964.
35. Schwartz, C. E.; Johnson, J. P.; Holycross, B.; Mandeville, T. M.; Sears, T. S.; Graul, E. A.; Carey, J. C.; Schroer, R. J.; Phelan, M. C.; Szollar, J.; Flannery, D. B.; Stevenson, R. E. :
Detection of submicroscopic deletions in band 17p13 in patients with the Miller-Dieker syndrome. Am. J. Hum. Genet. 43: 597-604, 1988.PubMed ID : 2903661
36. Selypes, A.; Laszlo, A. :
Miller-Dieker syndrome and monosomy 17p13: a new case. Hum. Genet. 80: 103-104, 1988.PubMed ID : 3417298
37. Sharief, N.; Craze, J.; Summers, D.; Butler, L.; Wood, C. B. S. :
Miller-Dieker syndrome with ring chromosome 17. Arch. Dis. Child. 66: 710-712, 1991.PubMed ID : 1711306
38. Stratton, R. F.; Dobyns, W. B.; Airhart, S. D.; Ledbetter, D. H. :
New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13. Hum. Genet. 67: 193-200, 1984.PubMed ID : 6745939
39. Toyo-oka, K.; Shionoya, A.; Gambello, M. J.; Cardoso, C.; Leventer, R.; Ward, H. L.; Ayala, R.; Tsai, L.-H.; Dobyns, W.; Ledbetter, D.; Hirotsune, S.; Wynshaw-Boris, A. :
14-3-3-epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nature Genet. 34: 274-285, 2003.PubMed ID : 12796778
40. vanTuinen, P.; Dobyns, W. B.; Rich, D. C.; Summers, K. M.; Robinson, T. J.; Nakamura, Y.; Ledbetter, D. H. :
Molecular detection of microscopic and submicroscopic deletions associated with Miller-Dieker syndrome. Am. J. Hum. Genet. 43: 587-596, 1988.PubMed ID : 3189330
41. vanTuinen, P.; Ledbetter, D. H. :
Construction and utilization of a detailed somatic cell hybrid mapping panel for human chromosome 17: localization of an anonymous clone to the critical region of Miller-Dieker syndrome, deletion 17p13. (Abstract) Cytogenet. Cell Genet. 46: 708-709, 1987.
42. Yingling, J.; Toyo-oka, K.; Wynshaw-Boris, A. :
Miller-Dieker syndrome: analysis of a human contiguous gene syndrome in the mouse. Am. J. Hum. Genet. 73: 475-488, 2003.PubMed ID : 12905154

CONTRIBUTORS

Victor A. McKusick - updated : 10/13/2003Victor A. McKusick - updated : 6/9/2003Ada Hamosh - updated : 5/9/2003Victor A. McKusick - updated : 8/31/1999Michael J. Wright - updated : 2/12/1999Iosif W. Lurie - updated : 8/6/1996

CREATION DATE

Victor A. McKusick : 6/3/1986

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Lissencephaly syndrome

Lissencephaly Network - Support

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Lymphedema People

Microcephaly Chorioretinopathy Syndrome

Clinical:

Microcephaly (head is smaller than normal), chorioretinal dysplasia, retinal fold with microcephaly and microphthalmosmental retardation.

Genetics: Autosomal recessive; indication of X-linkage.

Other indications observed in this disorder include: congenital lymphedema and/ora delay in the maturation of the lymphatic system, lymphedema nails (usually in the toes), coarseness of the hair follicles over the dorsum of the hands and feet. While normal intelligence was the more common pattern, there also have been unusually high incidences of slow learning, mental retardation or attention deficit disorder. Psychomotor development is normal.

The most extensive clinical study was involving 5 members of a Chinese family, involving 4 generations, giving clear indications of familial (male) transmission (Leung 1985).

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Alternative titles; symbols

RETINAL FOLDS WITH MICROCEPHALY AND MICROPHTHALMOS, INCLUDED

TEXT

The combination of microcephaly and lymphedema and that of microcephaly and chorioretinopathy (156590) are autosomal dominant traits. There are reports also of autosomal recessive microcephaly with chorioretinopathy (251270); Kozma et al. (1996) reported a possible incidence of autosomal recessive microcephaly-lymphedema. Although microcephaly-lymphedema and microcephaly-chorioretinopathy have been considered 2 separate autosomal dominant entities, Feingold and Bartoshesky (1992) and Angle et al. (1994) each reported on 2 unrelated sporadic cases with microcephaly, lymphedema, and chorioretinal dysplasia. Fryns et al. (1995) reported on another sporadic case with microcephaly, pedal lymphedema, and chorioretinal dysplasia with retinal folds.

In 5 members of 4 generations of a Chinese family, Leung (1985) described the combination of microcephaly and lymphedema. The lymphedema was present at birth or began soon after birth. Intelligence was normal. Male-to-male transmission was observed. Crowe and Dickerman (1986) described congenital lymphedema in association with microcephaly in a young boy and his maternal uncle. The mother, maternal grandmother and a sister of the grandmother had microcephaly. The pattern was consistent with X-linkage but may have been indicative of autosomal recessive inheritance with reduced expression in females; the proband's mother, grandmother, and great aunt were microcephalic. In an accompanying editorial, Opitz (1986) made many useful comments. Congenital lymphedema is frequent and represents delay in the maturation of the lymphatics and delay in clearing of the lymphedema regularly present in the fetus. 'Lymphedema nails,' i.e., white nails, especially in the toes, is a persisting sign. Coarseness of the hair follicles over the dorsum of the hands and feet and first phalanges where edema was present earlier is another sign. Unusual persistence of fetal lymphedema is usually associated with congenital hypotonia which clears faster than the lymphedema. What Opitz (1986) called the 'congenital lymphedema facies' (thick tissues, full cheeks, underdeveloped bridge of nose and supraorbital ridges, thick epicanthal folds, bilateral ptosis with thick lids, and micrognathia) is seen with many syndromes. Lymphedema in the hands causes thick volar tissues and later numerous white lines seen on palm prints and with a magnifying glass. Change in the pattern of hair may be seen in other areas of the body in addition to the nape of the neck, e.g., in the forearms. Leung (1987) emphasized the intellectual normality in these cases.

Jarmas et al. (1981) described 2 brothers with severe microcephaly, microphthalmos, retinal folds, and visual deficit. Their mother was also microcephalic and showed mild mental retardation. Young et al. (1987) reported a retarded boy with microcephaly, microphthalmos, and retinal folds. His mother and sister showed microphthalmos and the sister was also microcephalic. Angle et al. (1994) pointed out that the patients of Jarmas et al. (1981) and Young et al. (1987) had lymphedema in addition to microcephaly and chorioretinal dysplasia.

Feingold and Bartoshesky (1992) described 2 unrelated boys with microcephaly, lymphedema, and chorioretinal changes. They concluded that their patients had the same entity as did the patients reported by Leung (1985) and also those reported by McKusick et al. (1966). This seems unlikely in view of the fact that the patients of Leung (1985) had a dominant disorder and the patients of McKusick et al. (1966) clearly had a recessive disorder (see 251270). They stated that in the patients of McKusick et al. (1966)'no lymphedema or mental retardation was present.' It is true that no lymphedema was present, but mental retardation of fairly profound degree was a striking feature. Angle et al. (1994) presented 2 unrelated boys with microcephaly, lymphedema, and chorioretinal dysplasia. Kozma et al. (1996) described a sister and brother from a nonconsanguineous Saudi family who, in addition to severe microcephaly (without mental retardation) and lymphedema, had attention deficit disorder. One brother was more severely affected, and X-linked dominant inheritance could not be excluded.

Strenge and Froster (1998) described a boy with congenital microcephaly and lymphedema. He also had short stature, a feature that had not been described as part of this syndrome, even though it was present in 1 patient reported by Fryns et al. (1995). Bilateral limb lymphedema with lymphedema toenails was still present at age 2 years. At the age of 4 years, the lymphedema began decreasing. At the age of 8 years, lymphedema was restricted to the surface of the toes and the distal part of both feet. His height was at the 3rd centile; the occipital-frontal circumference was 48 cm (less than 3rd centile). Psychomotor development was normal.

Limwongse et al. (1999) provided follow-up on the family reported by Crowe and Dickerman (1986) which was considered to have the microcephaly-lymphedema syndrome. They found chorioretinal dysplasia with variable visual deficit in multiple relatives, supporting the concept that the combination of microcephaly, lymphedema, and chorioretinopathy constitutes a single autosomal dominant genetic entity with variable expression. In an editorial comment on the report by Crowe and Dickerman (1986), Opitz (1986) suggested that the facial characteristics of their proband at birth and during childhood resembled those of other patients with disorders associated with congenital lymphedema. Limwongse et al. (1999) noted a striking similarity between the facial characteristics of their proband at age 14 years and those of the 11-year-old patient of Sadler and Robinson (1993). Both patients had prominent ears, broad nasal bridge, broad and large nasal tip with anteverted nares, prominent full lips, and pointed chin.

REFERENCES

1. Angle, B.; Holgado, S.; Burton, B. K.; Miller, M. T.; Shapiro, M. J.; Opitz, J. M. :
Microcephaly, lymphoedema, and chorioretinal dysplasia: report of two additional cases. Am. J. Med. Genet. 53: 99-101, 1994.PubMed ID : 7856652
2. Crowe, C. A.; Dickerman, L. H. :
A genetic association between microcephaly and lymphedema. Am. J. Med. Genet. 24: 131-135, 1986.PubMed ID : 3706402
3. Feingold, M.; Bartoshesky, L. :
Microcephaly, lymphedema, and chorioretinal dysplasia: a distinct syndrome? Am. J. Med. Genet. 43: 1030-1031, 1992.PubMed ID : 1415329
4. Fryns, J. P.; Smeets, E.; Van den Berghe, H. :
On the nosology of the 'primary true microcephaly, chorioretinal dysplasia, lymphoedema' association. Clin. Genet. 48: 131-133, 1995.PubMed ID : 8556819
5. Jarmas, A. L.; Weaver, D. D.; Ellis, F. D.; Davis, A. :
Microcephaly, microphthalmia, falciform retinal folds and blindness. Am. J. Dis. Child. 135: 930-933, 1981.PubMed ID : 7293993
6. Kozma, C.; Scribanu, N.; Gersh, E. :
The microcephaly-lymphoedema syndrome: report of an additional family. Clin. Dysmorph. 5: 49-54, 1996.PubMed ID : 8867659
7. Leung, A. K. C. :
Dominantly inherited syndrome of microcephaly and congenital lymphedema. Clin. Genet. 27: 611-612, 1985.PubMed ID : 4017282
8. Leung, A. K. C. :
Dominantly inherited syndrome of microcephaly and congenital lymphedema with normal intelligence. (Letter) Am. J. Med. Genet. 26: 231 only, 1987.PubMed ID : 3812569
9. Limwongse, C.; Wyszynski, R. E.; Dickerman, L. H.; Robin, N. H. :
Microcephaly-lymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance. Am. J. Med. Genet. 86: 215-218, 1999.PubMed ID : 10482868
10. McKusick, V. A.; Stauffer, M.; Knox, D. L.; Clark, D. B. :
Chorioretinopathy with hereditary microcephaly. Arch. Ophthal. 75: 597-600, 1966.PubMed ID : 5936364
11. Opitz, J. M. :
On congenital lymphedema. (Editorial) Am. J. Med. Genet. 24: 127-129, 1986.PubMed ID : 3706401
12. Sadler, L. S.; Robinson, L. K. :
Chorioretinal dysplasia-microcephaly-mental retardation syndrome: report of an American family. Am. J. Med. Genet. 47: 65-68, 1993.PubMed ID : 8368255

13. Strenge, S.; Froster, U. G. :
Microcephaly-lymphedema syndrome: report of a family with short stature as additional manifestation. Am. J. Med. Genet. 80: 506-509, 1998.PubMed ID : 9880217

14. Young, I. D.; Fielder, A. R.; Simpson, K. :
Microcephaly, microphthalmos, and retinal folds: report of a family. J. Med. Genet. 24: 172-184, 1987.PubMed ID : 3573001

CONTRIBUTORS

Victor A. McKusick - updated : 2/10/2000

Victor A. McKusick - updated : 1/15/1999Iosif W. Lurie - updated : 7/26/1996

Crohn's Disease

An email I received yesterday ask me if there was a tie in between lymphedema and Crohn's Disease. On the face of it, you would think not, however a closer examination of the two conditions reveals a distinct tie in.

I include a quote from renown British lymphedema expert Dr. Peter Mortimer in an article for Lymphovenous Canada:

"It is my belief that many of the types of edema that we see associated with treatment of cancer and other conditions such as Crohn's disease and some arthritic conditions, are in fact related to an underlying genetic weakness in lymph drainage which already exist. If you take Crohn's disease, for example, the pathology of Crohn's disease is effectively lymphedema of the gut. Gastroentologists don't call it that, but that is what it is."

There are two clinical features specifically of Crohn's that can lead to and are associated with lymhpedema.

First is granulomatous lymphangitis. Secondly is hyperplaysia of the lymphatics similar to that in lymphangiectasia. Both of these affet the lymphatics and subsequent have lymphedema presenting as an accompanying complication.

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CROHN'S DISEASE

Background

This is one half of inflammatory bowel disease, its partner is ulcerative colitis. The presenting symptoms are varied including fever, mild diarrhea, and abdominal pain. The attacks may be episodic lasting weeks to months. Bleeding, especially in patients with colon involvement, may occur. Crohn's disease differs from ulcerative colitis in being able to involve the entire gastrointestinal tract from mouth to anus. In addition, a number of organ systems may be involved (see clinical presentations).

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION

SYNONYMS Terminal ileitis, Regional enteritis, Granulomatous colitis, Crohn's colitis, inflammatory bowel disease

INCIDENCE 3/100,000 in USA

Clinical features of Crohn's disease: a clinical study of one hundred patients found in an unselected population.Kangas E, Matikainen M, Auvinen O, Harju E, Inkovaara J, Maki M.Int Surg 1986 Oct-Dec;71(4):256-9 Abstract quote

One hundred patients (mean age 34 years, range from 12 to 70 years) were treated at Tampere University Hospital during the thirteen year period, 1972-1984. Our hospital takes responsibility for the treatment of patients with Crohn's disease found in an unselected population of 400,000 inhabitants.

In 73% of cases Crohn's disease was diagnosed before the age of forty. The mean interval between the first clinical signs and the diagnosis was 3.3 years. In 57% of the patients the diagnosis was reached within one year. In nine patients the primary diagnosis was colitis ulcerosa. Most patient were anemic and were in the state of inflammation and/or catabolism suggested by low blood hemoglobin concentration and high ESR and CRP values on admission. Three percent of the patients had macroscopic Crohn's disease in all parts of the gastrointestinal tract, whereas 22% had it only in the small intestine and 18% only in the colon. Fifty of the hundred patients had lesions in the terminal ileum and 20% in the anus. The specific finding for the present series was a high frequency of rectal lesions, in 29% of the patients.

Histologically the condition was more often (P less than 0.001) revealed by the laparatomy specimen than the endoscopic biopsy, which gave a positive histology more often (P less than 0.001) in the lower than in the upper gastrointestinal tract. No gastrointestinal malignancies were found.

AGE-RANGE AND MEDIAN

Peak 2-3rd decadesMinor peak in 6-7th decades

SEX (MALE:FEMALE) Females slightly more common

GEOGRAPHIC DISTRIBUTION Whites:Nonwhites 2-5:1 Smoking Jewish et

DISEASE ASSOCIATIONS CHARACTERIZATION

CALCIPHYLAXIS

Calciphylaxis in a patient with Crohn's disease in the absence of end-stage renal disease.

Barri YM, Graves GS, Knochel JP.

Department of Medicine, Presbyterian Hospital of Dallas, TX 75231, USA

Am J Kidney Dis 1997 May;29(5):773-6 Abstract quote

Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification previously described in patients with end-stage renal disease and hyperparathyroidism. Early diagnosis may be important in improving the poor outcome in these patients since early intervention may forestall the development of life-threatening complications.

We describe a patient with Crohn's disease complicated by short-bowel syndrome and modest renal insufficiency (not requiring renal replacement therapy) who developed calciphylaxis. It appears that longstanding Crohn's disease and the short-bowel syndrome accelerated the development of calciphylaxis as the chronic renal disease was not end stage. Considering the possibility of calciphylaxis in this setting may avoid delaying the diagnosis and its consequences.

LUPUS ERYTHEMATOSUS

Fatal evolution of systemic lupus erythematosus associated with Crohn's disease.

Chebli JM, Gaburri PD, de Souza AF, Dias KV, Cimino KO, de Carvalho-Filho RJ, Lucca FA.

Division of Gastroenterology, Department of Medicine, Juiz de Fora University, School of Medicine, Juiz de Fora, MG, BrazilA

rq Gastroenterol 2000 Oct-Dec;37(4):224-6 Abstract quote

The authors describe the case of a young Brazilian woman who was treated of ileocolonic Crohn's disease sparing rectum, as confirmed by colonoscopy and histopathological examination.

After a 4-year course of sulfasalazine treatment, she presented with skin facial lesions in vespertilio, fever, arthralgias and high titers of anti-ANA and LE cells. A sulfasalazine-induced lupus syndrome was diagnosed, because after sulfasalazine withdrawal and a short course of prednisone, the clinical symptoms disappeared and the laboratory tests returned to normal. Mesalazine 3 g/day was started and the patient remained well for the next 3 years, when she was again admitted with fever, weakness, arthralgias, diplopy, strabismus and hypoaesthesia in both hands and feet, microhematuria, haematic casts, hypocomplementemia and high titers of autoimmune antibodies.

A diagnosis of associated systemic lupus erythematosus was made. Although a pulsotherapy with methylprednisolone was started, no improvement was noticed. A cyclophosphamide trial was tried and again no positive results occurred. The patient evolved to severe clinical manifestations of general vasculitis affecting the central and peripheral nervous system and lungs, having a fatal evolution after 2 weeks.

Although uncommon, the association of both disease may occur, and the authors call attention to this possibility, making a brief review of literature

PSORIASIS

Connections between psoriasis and Crohn's disease.

Najarian DJ, Gottlieb AB.

University of Virginia School of Medicine, and the Clinical Research Center, University of Medicine and Dentistry of New Jersey-The Robert Wood Johnson Medical School.

J Am Acad Dermatol. 2003 Jun;48(6):805-21. Abstract quote The prevalence of psoriasis in patients with Crohn's disease (CD) is higher than chance would allow if they were mutually exclusive diseases. A close examination reveals genetic and pathologic connections between these diseases. An appreciation for the role of tumor necrosis factor-alpha in both diseases has proven very important.

Increased levels of this inflammatory cytokine have been measured in CD lesions, and in 1997 a clinical trial demonstrated the response of this disease to infliximab, a monoclonal antibody specific for tumor necrosis factor-alpha. A subsequent clinical trial evaluated infliximab in a patient with CD and psoriasis, another disease in which increased levels of tumor necrosis factor-alpha are seen in lesions.

Scientists noticed the marked skin improvement of this patient and later demonstrated the efficacy of infliximab for psoriasis in a randomized, double-blind, placebo-controlled trial. Thus, an appreciation for connections between psoriasis and CD can suggest novel therapeutic strategies with ensuing benefits to patients. This article reviews epidemiologic, genetic, and pathologic connections between psoriasis and CD and discusses pharmaceuticals targeting inflammatory mediators common to each disease. (J Am Acad Dermatol 2003;48:805-21.) Learning objective: At the completion of this learning activity, participants should understand how psoriasis and Crohn's disease are related at epidemiologic, genetic, and pathological levels and should appreciate how to use this knowledge to treat these diseases.

PATHOGENESIS CHARACTERIZATION

GENERAL

Molecular Discoveries Alter Our View of Inflammatory Bowel Disease A Review From Scientific, Clinical, and Laboratory Perspectives

Eric B. Staros, MD

Am J Clin Pathol 2003;;119:524-539 Abstract quote Within the past decade, knowledge of the molecular basis of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis, has advanced owing to the explosive growth of research involving the human genome.

Furthermore, a shared interest between molecular biologists and clinical researchers has contributed to an emerging understanding of IBD. Nucleotide-binding oligomerization domain 2 (NOD2) belongs to an apoptotic regulatory family of genes and has been linked to CD. In addition, research into nuclear factor kappa B (NF–kappa B), the proteasome, interleukins, and tumor necrosis factor alpha has improved our understanding of IBD. Our understanding of these molecules and other scientific discoveries offers hope for new diagnostic tests and therapeutic agents.

In the future, genetic markers will predict disease susceptibility, therapeutic responsiveness, and long-term sequelae of modern therapeutics. Also on the horizon, molecular markers promise to define disease heterogeneity, thereby providing a rational basis for patient-specific therapies. The molecular discoveries that are changing our views of IBD will affect the clinician, the laboratory professional, and the patient.

BACTERIAL 16S rRNA

Cutaneous manifestations of Crohn's disease, its spectrum, and its pathogenesis: intracellular consensus bacterial 16S rRNA is associated with the gastrointestinal but not the cutaneous manifestations of Crohn's disease.

Crowson AN, Nuovo GJ, Mihm MC Jr, Magro C. Central Medical Laboratories, Winnipeg, Manitoba, Canada

Hum Pathol. 2003 Nov;34(11):1185-92 Abstract quote.

The classic pathology of skin disease discontinuous from the inflamed gastrointestinal (GI) tract in patients with Crohn's disease (CD) includes pyoderma gangrenosum (PG), erythema nodosum (EN), and so-called metastatic Crohn's disease. The purpose of this study was two-fold: First, we explored the full spectrum of cutaneous lesions associated with Crohn's disease, and second, we sought to explore a potential molecular basis of the skin lesions in patients with CD.

In this regard, we analyzed skin and GI tract biopsies from affected patients for the consensus bacterial SrRNA to determine whether direct bacterial infection was associated with either condition. Formalin-fixed, paraffin-embedded sections were studied and correlated to clinical presentation and histories from 33 patients with CD. Consensus bacterial RNA sequences were analyzed using an RT in situ PCR assay on both skin biopsy and GI biopsy material. The GI tract material included biopsies from 3 patients who had skin lesions and from 7 patients in whom there were no known skin manifestations. There were 8 cases of neutrophilic dominant dermal infiltrates, including pyoderma gangrenosum, 6 cases of granuloma annulare/necrobiosis lipoidica-like lesions, 5 cases of sterile neutrophilic folliculitis, 5 cases of panniculitis, 4 cases of vasculitis, 2 cases of psoriasis, 2 cases of lichenoid and granulomatous inflammation, and 1 case of classic metastatic CD. Intracellular bacterial 16S rRNA was detected in 8 of 10 tissues of active CD in the GI tract, of which 3 of the cases tested were from patients who also developed skin lesions at some point in their clinical course; in contrast, none of the skin biopsies had detectable bacterial RNA.

The dermatopathological manifestations of CD discontiguous from the involved GI tract mucosa have in common a vascular injury syndrome, typically with a prominent extravascular neutrophilic and/or histiocytic dermal infiltrate. In addition, this study, the first to document in situ intracellular consensus bacterial SrRNA in the GI tract in CD, suggests that hematogenous dissemination of viable microbes is not associated with the cutaneous manifestations of this disease. Bacteria do, however, appear to play a role in bowel lesions of patients with CD.

CYTOKINES

Role of cytokines in the pathogenesis of inflammatory bowel disease.

Papadakis KA, Targan SR.

Division of Gastroenterology, Cedars-Sinai Medical Center, University of California, Los Angeles 90048, USA.

Annu Rev Med 2000;51:289-98 Abstract quote

Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn's disease.

Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn's disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor necrosis factor-alpha) antibody have shown marked clinical benefit in the majority of patients with Crohn's disease, verifying the importance of TNF-alpha in the pathogenesis of Crohn's disease.

In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn's disease but not in ulcerative colitis.

Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles

.....

Comparative Studies of the Colonic In Situ Expression of Intercellular Adhesion Molecules (ICAM-1, -2, and -3), 2 Integrins (LFA-1, Mac-1, and p150,95), and PECAM-1 in Ulcerative Colitis and Crohn's Disease

Ben Vainer, M.D.; Ole Haagen Nielsen, M.D., D.M.Sc.; Thomas Horn, M.D., D.M.Sc.

From the Department of Medicine M (B.V., O.H.N.), Division of Gastroenterology, Glostrup Hospital; and the Department of Pathology (T.H.), Herlev Hospital, University of Copenhagen, Denmark.

Am J Surg Pathol 2000;24:1115-1124 Abstract quote

A dysregulated local immune defense with a constant influx of leukocytes provides a basis for continuous intestinal inflammation in ulcerative colitis (UC) and Crohn's disease (CD). Cell adhesion molecules are pivotal for the migration of leukocytes from the circulation toward the colonic epithelium.

A study quantifying the cells expressing intercellular adhesion molecules (ICAMs), 2 integrins, and platelet–endothelial cell adhesion molecule-1 (PECAM-1) in the colon was performed to illustrate the leukocyte migration pathway in inflammatory bowel disease.

Serial colonic sections (10 UC, 10 CD, and 10 controls) were stained immunohistochemically for ICAM-1, ICAM-2, ICAM-3, CD11a, CD11b, CD18, and PECAM-1. Cell adhesion molecule expression was evaluated quantitatively with reference to topographic localization. In UC, polymorphonuclear leukocytes (PMNs) in contact with the crypt epithelium and in crypt abscesses expressed CD11b. CD tissue was characterized by CD11a-, CD11c-, and ICAM-1-expressing cells. ICAM-1 was detected on endothelial cells, leukocytes, and apical parts of epithelial membranes, whereas ICAM-2 was expressed on basal epithelial membranes. Most infiltrating leukocytes expressed ICAM-3, whereas perivascular mononuclear cells expressed PECAM-1. Interestingly, the epithelial basement membrane in UC stained for CD18.

In conclusion, CD11b, CD18, and ICAM-2 seem to be important for PMN transepithelial migration in UC, whereas CD11a, CD11c, ICAM-1, and ICAM-3 seem central in leukocyte locomotion and aggregation in CD. Differentiated upregulation of cell adhesion molecules is suggested to be essential for the diversities between UC and CD.

MYCOBACTERIUM

Absence of Mycobacterium avium subsp. paratuberculosis in the microdissected granulomas of Crohn's disease.

Baksh FK, Finkelstein SD, Ariyanayagam-Baksh SM, Swalsky PA, Klein EC, Dunn JC.

1Department of Pathology, Lancaster General Hospital, Lancaster, PA, USA

Mod Pathol. 2004 Oct;17(10):1289-94. Abstract quote

The etiology of Crohn's disease remains unknown with inflammatory, infectious, and/or genetic causes suspected. Granulomatous inflammation is a characteristic feature of the disorder, resembling the tissue response to mycobacterium. Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent in Johne's disease, a chronic ulcerative intestinal condition in cattle, and has been implicated as a likely candidate.

We carefully microdissected the granulomas from the paraffin-embedded resection specimens of 18 patients with well-established Crohn's disease. The DNA obtained was PCR amplified for the IS900 and IS1311 repeat elements of MAP, PCR product size maintained at 101 and 124 base pairs, respectively. Archival tissue from bovine Johne's disease was used as a positive control. MAP-specific DNA, confirmed by sequencing and comparison with prototype strain sequence, was appropriately amplified from the positive control.

None of the Crohn's disease cases yielded a positive amplification product, failing to support a role for the organism in the pathogenesis of this illness.

NOD2 GENE

The Nod2 gene in Crohn's disease: implications for future research into the genetics and immunology of Crohn's disease.

Cho JH. Department of Medicine (GI), University of Chicago Hospitals, Illinois 60637, USA.

Inflamm Bowel Dis 2001 Aug;7(3):271-5 Abstract quote

The association of the Nod2 gene on chromosome 16 with increased susceptibility to Crohn's disease holds the promise of catalyzing fundamental genetic and therapeutic advances.

Coding region variants in the leucine-rich repeat region of Nod2 may affect host interactions with bacterial lipopolysaccharide. Genetic differences in pattern-recognition proteins (such as Nod2) of the innate immune system represent an increasingly important paradigm for understanding host-environment interactions. The central problem for complex disease gene identification through genome-wide searches has been that of locus heterogeneity; it is hoped that this heterogeneity will recede with the identification of Nod2, as the first pieces of a puzzle accelerate placement of subsequent pieces.

The potential for genetic approaches to positively impact the treatment of Crohn's disease and ulcerative colitis is unparalleled among complex, multigenic disorders

YERSINIA

Pathogenic yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease.

Lamps LW, Madhusudhan KT, Havens JM, Greenson JK, Bronner MP, Chiles MC, Dean PJ, Scott MA.

Am J Surg Pathol 2003 Feb;27(2):220-7 Abstract quote Previously, we detected pathogenic (invasive) DNA in the appendices of two patients who later developed Crohn's disease (CD).

This subsequent investigation is the first to evaluate a series of specimens from CD patients for the presence of pathogenic DNA. A total of 54 intestinal resection specimens from 52 patients with confirmed CD were evaluated.

Lesional tissue was tested by polymerase chain reaction analysis for the presence of genes occurring only in pathogenic Primer pairs are specific for each species, with no known cross reactions with other bacteria. Forty normal bowel specimens, 30 cases of acute appendicitis, and 50 cases of various active colitides served as disease controls. Medical records were reviewed following polymerase chain reaction and histologic evaluation. A total of 17 of 54 resections (31%) contained DNA by polymerase chain reaction. Mesenteric lymph nodes were also positive in eight of these cases.

All controls were negative. -positive patients had carried the diagnosis of CD for a median of 10 years before resection (range 1 month to 40 years).

We report the first documentation of DNA in a series of CD cases. Further studies are needed, including serial study, over time, of -positive CD patients, as well as prospective studies of newly diagnosed CD patients for evidence of infection. Like previous studies associating infectious organisms with CD, much work remains to elucidate whether the presence of DNA is an epiphenomenon or actually a factor in the pathogenesis of CD.

LABORATORY/ RADIOLOGIC/ OTHER TESTS CHARACTERIZATION

Barium enema-radiology

String sign-characteristic narrowing of the small bowel lumen

Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup.

Vasiliauskas EA, Plevy SE, Landers CJ, Binder SW, Ferguson DM, Yang H, Rotter JI, Vidrich A, Targan SR.

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.Gastroenterology 1996 Jun;110(6):1810-9 Abstract quote

BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCA) have been consistently detected in a subgroup of patients with Crohn's disease (CD). This study was designed to determine whether serum ANCA expression in patients with CD characterizes an identifiable clinical subgroup.

METHODS: The study population consisted of 69 consecutive patients with an established diagnosis of CD as determined by a combination of characteristic clinical, radiographic, endoscopic, and histopathologic criteria. Sera from the patients were analyzed for the presence of ANCAs using the fixed neutrophil enzyme-linked immunosorbent assay (ELISA) assay. Perinuclear ANCA (pANCA)-positive and cytoplasmic ANCA (cANCA)-positive results by ELISA were confirmed by indirect immunofluorescence staining. Clinical profiles of the ANCA-positive patients with CD were compared with those of patients with CD not expressing ANCA (ANCA-negative).

RESULTS: pANCA-positive patients with CD have endoscopically and/or histopathologically documented left-sided colitis and symptoms of left-sided colonic inflammation, clinically reflected by rectal bleeding and mucus discharge, urgency, and treatment with topical agents. One hundred percent of patients with CD expressing pANCA had "UC-like" features.

CONCLUSIONS: In patients with CD, serum pANCA expression characterizes a UC-like clinical phenotype. Stratification of CD by serum pANCA provides evidence of heterogeneity within CD and suggests a common intestinal mucosal inflammatory process among a definable subgroup of patients with CD and UC expressing this marker

.....

Tumor necrosis factor-alpha in serum of patients with inflammatory bowel disease as measured by a highly sensitive immuno-PCR.

Komatsu M, Kobayashi D, Saito K, Furuya D, Yagihashi A, Araake H, Tsuji N, Sakamaki S, Niitsu Y, Watanabe N.

Division of Laboratory Diagnosis, Department of Clinical Laboratory Medicine, Sapporo Medical University, School of Medicine, South-I, West-16, Chuo-ku, Sapporo 060-8543, Japan.

Clin Chem 2001;47(7):1297-301 Abstract quote

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION The significance of serum concentrations of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of inflammatory bowel disease (IBD) is uncertain. We measured TNF-alpha in serum from IBD patients by immuno-PCR to analyze the relationship between TNF-alpha and pathophysiologic state in IBD.

METHODS: Serum samples were collected from 54 healthy blood donors, 29 patients with ulcerative colitis (UC; 46 samples), and 7 patients with Crohn disease (CD; 8 samples). DNA label was generated by PCR amplification using biotinylated primer and was bound with streptavidin to biotinylated third antibody. TNF-alpha sandwiched by antibodies was detected by PCR amplification of the DNA label.

RESULTS: TNF-alpha could be measured in all samples. The median serum concentration in IBD patients overall was approximately 390-fold higher than in healthy donors (median increase, 380-fold for UC, 640-fold for CD). The median serum TNF-alpha concentration was 1.7-fold higher in the active stage of UC than in the inactive stage (P <0.05),

CONCLUSIONS: Sensitive measurement of serum TNF-alpha could provide an important pathophysiologic marker for the presence and activity of IBD.

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

Site of involvement

Small intestine alone 40%

Small and large intestine 30%

Colon alone 30%

GASTROINTESTINAL TRACT

Characteristic skip lesions with diseased segments of bowel interspersed with normal segments, leading to cobblestone mucosa

Mesenteric fat wraps around bowel forming creeping fat

Intestinal wall is thickened and rubbery with narrowing of the lumen

Aphthous ulcers, focal mucosal ulcers, in early disease, leading to linear ulcers

Numerous fissures and sinus tract formation

.....

Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn's disease.

Ruuska T, Vaajalahti P, Arajarvi P, Maki M.

Department of Clinical Medicine, University of Tampere, Finland.

J Pediatr Gastroenterol Nutr 1994 Aug;19(2):181-6 Abstract quote Eighty-eight consecutive children with inflammatory bowel disease were studied, and upper gastrointestinal endoscopy was performed in 80 of them as one of the initial investigations before commencing medical or nutritional treatment.

Forty-one children were found to have Crohn's disease and 47, ulcerative colitis. Upper gastrointestinal endoscopy revealed pathology in 32 (80%) cases of Crohn's disease, esophagitis in 16, and esophageal ulcer in two, nonspecific gastritis in 22, duodenitis or duodenal ulcer in 18, and Helicobacter pylori infection in two cases. Granulomas were detected in 10 patients in the upper gastrointestinal tract: one esophageal, eight gastric, and three duodenal. Of the ulcerative colitis patients, seven had esophagitis, one had esophageal ulcer, 17 had nonspecific gastritis, two had gastric ulcers, two had duodenal ulcers, and five had H. pylori infection; altogether 30 (75%) yielded pathological findings. Radiological studies using barium meal revealed pathology in only eight of all inflammatory bowel disease cases. Symptoms at admission were not conclusive for definite diagnosis because 63% of patients with Crohn's disease had signs of colitis (such as diarrhea, bloody diarrhea) compared to 94% of ulcerative colitis patients.

Upper gastrointestinal endoscopy may be used to achieve a specific diagnosis, thus being helpful when planning treatment. Also a considerable incidence of nonspecific gastritis, duodenitis, and esophagitis with or without concomitant H. pylori infection may be anticipated in children suffering from both ulcerative colitis and Crohn's disease.

EXTRAGASTROINTESTINAL

EYE

Uveitis

JOINTS

Migratory polyarthritis

Sacroiliitis

Ankylosing spondylitis

LIVER

Hepatic sclerosing cholangitis

Noninfectious lung pathology in patients with Crohn's disease.

Casey MB, Tazelaar HD, Myers JL, Hunninghake GW, Kakar S, Kalra SX, Ashton R, Colby TV.

Am J Surg Pathol 2003 Feb;27(2):213-9 Abstract quote Lung involvement in Crohn's disease is not well characterized. We reviewed our experience with 11 lung biopsies (seven wedge and four transbronchial) from patients with Crohn's disease to study this association further. Negative cultures, special stains for organisms Gomori-methenamine-silver [GMS], acid fast), and polymerase chain reaction for (four cases) were required for inclusion. The group included five women and six men with a mean age of 47 years (range 13-84 years).

A diagnosis of Crohn's disease preceded the lung disease in nine patients. In two patients the diagnosis of Crohn's disease followed the diagnosis of their pulmonary disease 1 and 15 months later. Radiologically, eight patients had diffuse infiltrates, two had bilateral nodular infiltrates, and one had a mass. Chronic bronchiolitis with nonnecrotizing granulomatous inflammation was present in four patients, one of whom was taking mesalamine. Two patients had an acute bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague granulomatous features. One patient on mesalamine had cellular interstitial pneumonia with rare giant cells. Four patients demonstrated organizing pneumonia with focal granulomatous features, two of whom were taking mesalamine, and one of these two responded to infliximab (anti-tumor necrosis factor) monoclonal antibody therapy.

Noninfectious pulmonary disease in patients with Crohn's disease has variable histologic appearances, including granulomatous inflammation and airway-centered disease resembling that seen in patients with ulcerative colitis. Drugs may contribute to pulmonary disease in some patients.

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION Site of involvement Small intestine alone 40%Small and large intestine 30%Colon alone 30%

GASTROINTESTINAL TRACT Characteristic skip lesions with diseased segments of bowel interspersed with normal segments, leading to cobblestone mucosa

Mesenteric fat wraps around bowel forming creeping fat

Intestinal wall is thickened and rubbery with narrowing of the lumen

Aphthous ulcers, focal mucosal ulcers, in early disease, leading to linear ulcers

Numerous fissures and sinus tract formation

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