There are many, rare syndromes associated with lymphatic dysplasia where in the patient will present with lymphedema. Therefore it is useful to include them in the website.

I especially want to express my deep appreciation to Dr. Bruno Chikly for his very kind permission in allowing us to use and reproduce information from his book Silent Waves Theory And Practice Of Lymph Drainage Therapy. His books and works have brought hope and much needed information to countless thousands throughout the world coping with lymphedema and lymphatic disorders.

Also, I want to acknowledge other sources of information.

I have included many entry articles from OMIM, Online Mendelian Inheritance in Man provided by Johns Hopkins University. As a person who has done extensive research and search, I have come to a great respect and admiration for their unending work in presenting top quality information to both professionals and lay people alike.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

Much information has been gathered as well from Pub Med, a section of the National Library of Medicine. A special note of thanks is due them as well for their service to the public.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

Another excellant source of medical information provided by the government is Medline Plus. This is a service of the U.S. National Library of Medicine and the National Institutes of Health

http://www.nlm.nih.gov/medlineplus/

Finally, we must also mention the National Organizations of Rare Disorders. They provide valuable and hard to find information on a vast compendium of rare and little understood diseases and conditions.

http://www.rarediseases.org/

1- Aagenaes (lymphedema-cholestasis) syndrome

2- Distichiasis (lymphedema-distichiasis) syndrome

3- Dahlberg (lymphedema-hypoparathyroidism syndrome)

4- Fabry's disease

5- Gorham-Stout-Haferkamp syndrome

6- Hennekam’s syndrome

7- Klinefelter syndrome

8- Klippel Trenaunay Weber syndrome

9- Maffucci’s syndrome

10- Melkersson - Rosenthal - Miescher syndrome

11- Noonan syndrome

12- Trisomy 10

13- Trisomy 13

14- Trisomy 18

15- Trisomy 21

16- Trisomy 22

17- Turner syndrome

18- Von Recklinghausen’s fibromatosis

19- Yellow nail syndrome

20- Other syndromes associated with lymphatic dysplasia

First description: Aagenaes and associates (Norway), 1968.

OMIM (Online Mendelian Inheritance in Man database) reference number: 214900

Synonyms: Cholestasis-lymphedema-syndrome (CHLS), Lymphedema-cholestasis syndrome (LCS or LCS1), Cholestasis Aagenaes, Cholestasis hereditary Norwegian type.

Genetics: Chromosome 15q. Autosomal recessive inheritance.

Localization: About 2/3 of the cases reported are in Norway.

Onset: usually puberty.

Clinical description:

1- Hepatologic manifestations

Chronic recurrent cholestasis (bile flow obstruction)

Postnatal icterus (jaundice)

The liver may be enlarged; intrahepatic obstructive liver disease and capillary hemangiomata may also occur. The disease may slowly evolve to hepatic cirrhosis and giant-cell hepatitis with fibrosis.

2- Lymphologic manifestations

Lymphedema develops during childhood as a result of lymphatic hypoplasia. This occurs most frequently in the lower extremities, but the condition infrequently affects upper extremities, and rarely the face or lungs.

Distichiasis is defined as a double row of eyelashes (from the Greek distichia, meaning double line).

First description: 1954, University of Houston, Texas.

OMIM (Online Mendelian Inheritance in Man database) reference number: 153400

Genetics: Chromosome 16q24.3. Mutation of the gene FOXC2 (MFH1).

Onset: usually at puberty.

Clinical description:

1- Ophthalmologic manifestations

Distichiasis: the double row of eyelashes may be difficult to identify clinically.

It may be discovered because of an irritation of the cornea, corneal abrasion or in some cases corneal ulceration

Ptosis of the eyelids

Photophobia.

Partial ectropion (eversion of part of an eyelid) of the lateral third of the eyelashes.

2- Lymphologic manifestations

pterygium colli (Webbing of the neck)

Primary lymphedema, often appearing at puberty

Thoracic duct abnormalities

Chylothorax

3. Osteoarticular manifestations

Vertebral segmentation abnormalities: irregularities of end plates, spinal extradural cysts, etc.

Amelogenesis imperfecta (defective dental enamel)

4. Cardiologic manifestations

Congenital heart disease, e.g. tetralogy of Fallot or atrioventricular block Capillary hemangiomata

D- Other associated symptoms:

Cleft palate

Low hairline

First description: Dahlberg P.J., 1983.

OMIM (Online Mendelian Inheritance in Man database) reference number: 247410

Synonyms: Dahlberg newcomer syndrome.

Genetics: autosomal recessive and X-linked recessive type.

Clinical description:

This syndrome consists mainly of primary lymphopathy of extremities or lungs, progressive renal failure, mitral valve prolapse, brachydactyly (abnormal shortness of toes or fingers) and hypoparathyroidism.

1- Lymphologic manifestations

Primary lymphedema of upper or lower extremities that can develop soon after birth

Pulmonary lymphangiectasia (dilatation of lymph vessels)

2- Nephrologic manifestations

Progressive renal failure that may require kidney transplantation

3- Ophthalmologic manifestations

Cataracts (bilateral)

Ptosis

Telecanthus (increased distance between the inner aspect of the eyelids)

4- Other associated Symptoms

Mitral valve prolapse

Brachydactyly (brachytelephalangy)

Hypoparathyroidism

Hypocalcemia

Hypothyroidism

Broad nasal bridge and lateral displacement of the inner canthi.

Thick skin

Increased body hair

Short stature/dwarfism

First description: Independently described in 1898 by the dermatologist Jonathan Fabry (“purpura haemorrhagica nodularis”) and the surgeon William Anderson (“multiple capillary angiectasis”).

OMIM (Online Mendelian Inheritance in Man database) reference number: 301500

Synonyms:

Anderson-Fabry Disease, alpha - galactosidase A deficiency, angiokeratoma corporis diffusum (universale), cardiovasorenal syndrome, ceramide lactoside lipidosis, ceramide trihexosidase deficiency, GLA deficiency, glyosphingolipidosis, hereditary dystopic lipidosis, lactosyl ceramidosis, Ruiter-Pompen syndrome, Sweeley-Klionsky disease, thesaurismosis hereditaria, thesaurismosis lipoidica, trihexosidase deficiency disease.

Genetics: X-linked lysosomal disorder.

Defect of the gene alpha-galactosidase A (enzyme involved in the biodegradation of lipids) located on the long arm of the X chromosome (Xq22).

Some cases of mutation are likely.

Incidence: 1 case per 117, 000-40,000

Mortality/morbidity: The average age at death is 41 years.

Sex: Fabry’s disease most often affects hemizygous males, but is sometimes found in heterozygous females, who do not display as severe symptoms, or as complete a set.

Age of onset: Generally from childhood to adolescence.

Clinical description:

This disorder leads to a progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids (GSLs) in vascular endothelial lysosomes of the skin, kidneys, heart, nervous system, and blood vessels.

1- Dermatologic manifestations:

          Cutaneous angiokeratoma: maculopapular skin lesions consisting of reddish to dark purple pin-head size spots (dilated capillaries). They could be located anywhere in the body but they are usually located in regions where skin folds and stretching occur. 

          Hypohidrosis, anhidrosis: decreased or absent sweating 

          Teleangiectasia (enlargement of small blood vessels) 

          Rash   

2- Lymphologic manifestation

          Lymphedema in the lower extremities; the etiology is unknown.   

3- Musculoskeletal manifestation

          Acroparesthesia (crises of severe pain, burning, and/or itching in the extremities, associated with fever)   

4- Ophthalmologic manifestations

          Corneal dystrophy 

          Corneal opacities 

          Cataracts   

5- Cardiovascular manifestations

          Angina 

          Coronary artery disease 

          Myocardial ischemia 

          Congestive heart failure 

          Left ventricular hypertrophy 

          Mitral insufficiency 

          Mitral valve prolapse 

          Conduction abnormalities   

6- Neuropsychiatric manifestations

          Stroke 

          Aneurysm 

          Seizures 

          Hemiplegia 

          Hemianesthesia (loss of sense of touch in the right or left half of the body) 

          Aphasia 

          Cerebral hemorrhage. 

          Psychotic behavior   

7- Renal manifestations

          Chronic renal insufficiency 

          Kidney failure   

8- Gastrointestinal manifestations

          Episodes of abdominal or flank pain, diarrhea, or   vomiting 

          Jejunal diverticula 

          Peritonitis   

9- Endocrine manifestations

           Abnromal  growth 

          Delayed onset of puberty.   

10- Other manifestations

          Chronic bronchitis 

          Anemia     

First description: 1955, Gorham and associates.

Synonyms: Acro-osteolysis syndromes, diffuse cystic angiomatosis of bone, disseminated lymphangiomatosis, thoracic lymphangiomatosis, Gorham-Stout syndrome, Gorham's vanishing bone disease, Hajdu-Cheney syndrome, idiopathic massive osteolysis, idiopathic multicentric osteolysis, massive Gorham osteolysis, phantom bone disease, osteolysis of Martorell, Trinquoste syndrome.

Clinical description:

Studies of about 200 cases have been published in scientific literature.

Osteolysis (bone loss) created by angiomatous tissue (abnormal blood or lymphatic vessel growth)

1- Osteoarticular manifestations

Abnormal vessel growth (angioma = “vessel tumor”) produces areas of osteolysis which may be associated with pathological fractures.

Almost any part of the skeleton can be affected but it is most often found in the cranium (parietal area), upper jaw, maxilla, zygoma and extremities.

2- Lymphologic manifestations

Lymphodysplasia (intraosseous lymphodysplasia or lymphovenous dysplasia)

3- Visceral manifestations

Lymphangiomas of the spleen, or liver, lungs, mediastinum.

First description: 1989, Hennekam and associates.

OMIM (Online Mendelian Inheritance in Man database) reference number: 235510

Synonym: Intestinal lymphangiectasia-lymphedema-mental retardation syndrome.

Genetics: Autosomal recessive inheritance.

Sex ratio: Equal sex ratio.

Clinical description:

About 25 cases have been published in scientific literature.

1- Lymphologic manifestations

1. - mainly due to abnormal lymphangiogenesis

Lymphedema:

1. Peripheral 100%

1. Face: 86%

1. Genital 71%

Lymphangiectasia

1. Intestines 82%

1. Lung 39%

1. Heart 22%

1. Other: kidneys, thyroid (rare)

2- Facial features

Flat face: 100%

Metopic ridge: 31%

Craniostosis (congenital ossification of cranial sutures)

Craniosynostosis (premature ossification of cranial sutures)

Hypertelorism (widely-spaced eyes)

Epicanthal folds

Small mouth

Small ears

3- Cardiovascular manifestations

Congenital heart defects 20%

Blood vessel abnormalities 40%

4- Neuropsychiatric manifestations:

Mental retardation (inconsistent)

Seizures

Convulsions

5- Other associated symptoms

Glaucoma

Dental anomalies

Gingival hypertrophy

Hearing loss

Renal anomalies

Syndactyly (fusion of fingers or toes)

First descriptions: 1895 Richard Altmann, 1934 Walther Berblinger and 1942 Harry Fitch Klinefelter.

Synonyms: Klinefelter-Reifenstein-Albright syndrome, Reifenstein-Albright XXY syndrome, aspermatogenesis-gynecomastia syndrome, chromosome XXY syndrome, medullary gonadal dysgenesis, primary microörchidism, puberal, seminiferous tubule failure, sclerosing tubular degeneration.

Genetics:

1- 47,XXY: approximately 80%-90%.

2- Mosaic patterns: 46,XY/47,XXY, 46,XY/48,XXXY, and 47,XXY/48,XXXY: approximately 10%.

2- Structurally abnormal additional X: about 1%.

Incidence: approximately 1 in 500-700 male births.

Sex ratio: males only.

Clinical description:

1- Endocrine manifestations

A- Growth

Tall stature

Usually disproportionately long in upper and lower extremities (excessive growth in the long bones); the trunk is short in comparison

B- Sexual characteristics

Male hypogonadism (microörchidism - small testes), gynecomastia and sterility (azoöspermia or oligospermia)

Lack secondary sexual characteristics (low androgen production):

Gynecomastia (abnormally large breasts in a male) at late puberty

Testicular dysgenesis: small and firm testicles with low sperm production.

(Penile size is usually normal.)

Infertility/azoöspermia may be present, caused by extensive hyalinization leading to atrophy of the seminiferous tubules.

2- Neuropsychiatric manifestations:

A majority of patients display some minor developmental and learning disabilities.

Language impairment

Behavioral problems

Immaturity

Shyness

Lack of common sense/judgment

Poor self-esteem

Patients’ IQ score is reduced by about15 points for each additional X chromosome, on average.

3- Cardiac and circulatory manifestations

Mitral valve prolapse 55%

Varicose veins 20-40%

4- Odontologic manifestations

Taurodontism (enlargement and deepening of the pulp chambers of the molar teeth): 40% of patients.

Synonyms: Angio-osteohypertrophy syndrome, hyperoxemiating arterio-venous angiomatosis osteohypertrophy.

Genetics: Gene may be located on 5q or p11.

Sex ratio: Females are affected approximately twice as often as males.

Clinical description:

K-T can be characterized by a triad of symptoms (Gloviczki et al., 1991):

Hemangioma (port-wine stain): 95%

Hypertrophy of bones and soft tissues: 93% (limb hypertrophy: 67%)

Varicose veins 76%

Approximately 65% of patients have all 3 symptoms (according to a Mayo Clinic study of 252 patients, with KTS between January 1956 and January 1995)

1- Vascular manifestations

Vascular dysplasia: port-wine stains, cavernous hemangioma, varicose veins, arteriovenous malformations, lymphedema and lymphangiomata.

A- Hemangiomata

Port-wine stain or “birthmark” (cutaneous capillary malformations) often in the lateral aspect of the limb present with a well demarcated linear border. These cutaneous capillary malformations usually do not spontaneously regress or enlarge.

B- Varicose veins and venous dysplasia

Venous varicosities developed in 79% of cases (Muluk et al., 1995)

Typically a large lateral superficial vein seen at birth.

Varicosities may be quite extensive. Generally sparing the saphenous distribution, they more usually affect the popliteal or femoral veins, and sometimes both.

Associated deep venous abnormalities can lead to serious complications, and may include aneurysmal dilatation, hypoplasia, aplasia and absent or incompetent valves.

C- Arteriovenous fistulae, the main feature distinguishing Klippel-Trenaunay syndrome from Parkes-Weber (see below), are rarely found in the affected extremity of K-T patients.

D- Lymphodysplasia:

Lymphodysplasia and resulting primary lymphedema of the extremities (most commonly the legs) is seen in K-T

These can be either aplasia, dysplasia or hyperplasia / lymphangiectasia of the lymph vessels; they can be treated like any other primary lymphedema.

Lymphangioma occurs in about 8% of these patients.

2- Osteoarticular manifestations

Soft tissue and bony hypertrophy

It usually evolves during the first years of life and manifests commonly in one lower extremity or the other (71%). It occurs less frequently bilaterally (20%) or in the upper extremity (25%) [Gloviczki et al., 1991].

It can lead to complications such as postural abnormalities or vertebral scoliosis.

Differential diagnosis:

It is often difficult to distinguish between K-T syndrome and K-T-W or Parkes Weber syndrome. The absence of arteriovenous fistulae and the presence of low-velocity venous malformations inclines the physician to a diagnosis of Klippel-Trenaunay rather than Parkes Weber.

Complications of K-T:

The can include ulcerations, bleeding, cellulitis, deep vein thrombosis and pulmonary embolism.

Involvement of viscera (e.g. lungs, liver, kidneys or large intestine) can produce specific complications such as spontaneous rupture of hemangioma and internal bleeding.

The Kasabach-Merritt syndrome is a medical emergency in K-T patients. It involves thrombocytopenia, caused by the trapping of platelets in an expanding cavernous hemangioma, and occasionally excessive consumption of clotting factors, resulting in internal bleeding (e.g. in internal organs, the head and neck area, or the extremities).

First description: Angelo Maffucci, 1881, Naples, Italy.

Synonyms: Achondromatosis with hemangiomata, chondrodysplasia angiomatosis syndrome, chondrodystrophy and vascular hamartoma syndrome, chondrodystrophy with angiomatosis, cutaneous dyschondroplasia-dyschromia syndrome, dyschondroplasia-angiomatosis syndrome, dyschondrodysplasia-haemangiomas syndrome; Kast’s disease, Maffucci-Kast syndrome, multiple enchondromatosis syndrome.

Genetics: inheritance unknown.

Sex ratio: Both sexes affected but males more frequently.

Clinical description:

Benign tumors of cartilage (enchondromas), associated with multiple cavernous hemangiomata.

1- Osteoarticular manifestations

Nodular tumors usually develop before puberty and continue to evolve later. They can lead to fracture, unequal length of the extremities and disharmonious segmental hypertrophy of the body.

Dyschondroplasia of the hands is common (89%) in Maffucci’s syndrome, but they can be found in almost any bone.

2- Vascular manifestations

Hemangiomata in the skin of the limbs and in the viscera: eyes, pharynx, tongue, meninges, and intestines.

Lymphangiomata and lymphangiosarcomata

Phlebangiectasia (venous dilatatons)

3- Dermatologic manifestations

Vitiligo

Pigmented nevi

First descriptions: Lothar von Frankl-Hochwart in 1891. Described by Melkersson in 1928. Rosenthal described the plicated tongue in 1931.

Synonyms: Rosenthal's syndrome II, Melkersson-Rosenthal-Schuermann syndrome, Rossolimo’s syndrome, Miescher’s cheilitis, Melkersson’s syndrome.

Genetics: May be related to chromosome 9 (9p11).

Autosomal dominant inheritance with variable expressivity.

Sex ratio: Affects men and women equally.

Clinical description:

1- Classical manifestations

Chronic edema of the lips (granulomatous edema, also called cheilitis granulomatosa, cheilitis glandularis, cheilitis granulomatosis, essential granulomatous macrocheilitis) and other part of the face (chin, eyelids)

Peripheral recurrent facial paralysis

Hypertrophic plicated tongue (lingua plicata, “scrotal tongue”)

2- Other manifestations:

Mild lymphatic hyperplasia (usually with very little fibrosis)

Headaches / migraines

Ptosis of the eyelids

Optic neuritis.

First descriptions: First reported by Kolinski in 1883. In 1930 Ullrich described this disorder, followed by Henry Turner 8 years later.

In 1971 this syndrome was completely described by Jacqueline Noonan, MD, Professor of Pediatrics in Kentucky, and the syndrome was officially named “Noonan syndrome”.

OMIM (Online Mendelian Inheritance in Man database) reference number: 163950

Synonyms: Male Turner syndrome, female pseudo-Turner syndrome, pseudo Ullrich-Turner syndrome, Turner's phenotype with normal karotype, Ullrich-Noonan syndrome, XX Turner phenotype syndrome.

Genetics: Autosomal dominant disorder with variable expression.

In 33-50% of cases Noonan syndrome is caused by a mutation of the gene PTPN11 (which encodes the protein tyrosine phosphatase SHP-2) located on chromosome 12 (12q 24).

Sex ratio: Both sexes are affected equally

Incidence: approximately 1 in 1,000 to 2,500 births.

Clinical description:

Noonan syndrome (NS) is clinically similar to Turner syndrome but with a normal number of chromosomes.

1. Craniofacial manifestations

Triangular face

Down-slanting upper eyelids (95%)

Thickened helix (90%)

Low posterior hairline (55%)

High arched palate (45%),

Micrognathia (small jaw) in 25%,

Low-set, posteriorly-rotated ears

Hypertelorism (widely-spaced eyes)

Webbed neck (pterygium colli)

2. Endocrine manifestations:

Growth retardation

Short stature or dwarfism

Sexual development:

          A. Males 

                      Cryptorchidism (undescended testicles) (60%) 

                      Small testes. 

          B. Females 

                      Normal fertility   

3. Musculoskeletal manifestations

Cubitus valgus (50%)

Superior pectus carinatum (90-95%) (“pigeon breast”)

Inferior pectus excavatum (concave chest, “funnel breast”)

Vertebral/sternal anomalies

low-set widespaced nipples

Dental malocclusion (35%)

Short curved fingers with blunt fingertips (30%),

Scoliosis (10%)

Joint hyperextensibility and hypotony

4. Cardiovascular manifestations

Pulmonary valve stenosis (50%)

Hypertrophic cardiomyopathy (20-30%)

Atrial septal defects (10-20%)

Asymmetric septal hypertrophy (10%)

Ventral septal defects (5-15%)

Persistent ductus arteriosus (3%).

Tetralogy of Fallot

5. Lymphologic manifestations (20%)

Distal chronic lymphedema of dorsal surface of the feet. This can be the first clinical symptom of NS.

Genital lymphedema

Intestinal lymphangiectasia

Pulmonary lymphangiectasia

Cervical cystic hygroma (benign lymphatic tumors of the neck)

Hydrops fetalis (fetal edema)

6. Neurobehavioral manifestations

Mild-moderate mental retardation (33%)

Gross motor developmental delay (25%)

Speech and language developmental delay (20-30%)

Verbal performance discrepancy (15%)

Seizures (13%)

7. Hematologic manifestations

Coagulation defects (33%)

1. Partial deficiency of factor XI:C, XII:C, and VIII:C

1. Thrombocytopenia

1. Von Willebrand disease

Splenomegaly (50%)

Hepatosplenomegaly (25%)

8. Ophthalmologic manifestations

Strabismus (about 55%)

Myopia

Amblyopia

Nystagmus.

9. Dermatologic manifestations

Large finger pads (67%)

Neurofibromatosis.

10. Otologic manifestations

Mild hearing loss or deafness (12%)

Genetics: presence of an additional chromosome 10.

Incidence: 1.8% of all spontaneous abortions

Clinical description:

All cases of trisomy 10 are mosaic, i.e., the defect is not present in all cells. Babies born live with the condition have usually a very short life expectancy.

Clinical manifestations include: mental and growth retardation, cryptorchidism (undescended testicles), hypertelorism (increased distance between the eyes), marked plantar and palmar furrows and congenital heart defects.

First described by: Klaus Patau, 1960.

Synonyms: Chromosome 13 trisomy syndrome, trisomy 13, Patau syndrome

Bartholin-Patau syndrome, trisomy 13-15, trisomy D.

Genetics: presence of an additional chromosome 13.

Incidence: approximately 1 in 4,000-10,000 birth.

Mosaic trisomy 13 about 5% of cases.

Clinical description:

Most usually do not survive the first 3-6 months of life.

Severe mental retardation is common

Holoprosencephaly (forebrain defect), sloping forehead

Microcephaly

Wide sagittal suture and fontanelles

Cleft lip/palate

Cardiac defects (atrial or ventricular septal defects, dextroposition of the heart)

Kidneys defects (hydronephrosis, hydroureter)

Polydactyly; clinodactyly (condition in which the little finger is curved toward the ring finger)

Hypertelorism

Deformed ears

Single umbilical artery

Deafness

First description: John Edwards, 1960.

Synonyms: Edwards syndrome, trisomy E, trisomy 16-18.

Genetics: Presence of an additional 18th chromosome.

In 95% of the cases it is a pure trisomy, in 3% it is mosaic and 2% of translocations. (rearrangements of chromosomal material.)

Incidence: Approximately 1 in 3,000-8,000 births.

About ninety percent of these patients do not survive the first year.

Clinical description:

1. Craniofacial manifestations

Microcephaly

Low set malformed ears

Micrognathia (small jaw)

Hypertelorism

Cleft lip/palate

Webbed neck

Cystic hygroma or nuchal edema/thickening

Choroid plexus cysts

Large cisterna magna (increased intracranial space outside the posterior brain)

Cerebellar hypoplasia

Seizures

2. Other manifestations

Cardiac abnormalities (90%): ventricular septal defect, trial septal defect, patent ductus arteriosus

Lung abnormalities

Kidney and ureter abnormalities

Hypertension

Spina bifida

Scoliosis

Eye abnormalites

Hearing loss

Omphalocele (herniation of abdominal contents in the umbilical area)

First descriptions: 1838, Jean Etienne Esquirol. John Down, 1866.

Synonyms: Trisomy 21, mongolism, congenital acromicria syndrome. mongoloid idiocy, mongolism, trisomy G, Langdon-Down syndrome, Langdon Down disease, morbus Down.

Genetics: presence of an additional chromosome 21.

Incidence: approximately 1 in 700 births.

Risk increases with the age of the mother.

Clinical description:

1. Craniofacial and neurologic manifestations

Mental retardation is present almost 100 % of the time in these individuals, ranging from very mild to severe

Microcephaly, short head

Sloping forehead

Flat nasal bridge, flattened nose

Protruding, enlarged, fissured tongue

Upward slanting eyes

Epicanthal fold (rounded fold of skin at the inner corners of the eyes)

Low-set ears

Small ear canals

Short neck

Nuchal edema/thickening

Webbed neck

2. Musculoskeletal manifestations

Hands:

1. Short and broad hands with short fingers

1. abnormal palmar creases (“simian crease”)

1. shortening of the middle phalanx of the fifth digit resulting in clinodactyly

Atlanto-axial subluxation

3. Cardiologic manifestations

Occurrence: in 50% to 85% of Down syndrome individuals.

Endocardial cushion abnormalities, ventricular septal defects, mitral valve abnormalities.

4. Gastrointestinal manifestations

Esophageal atresia (obstruction of the esophagus)

Duodenal atresia (obstruction of the duodenum)

Anorectal malformations (imperforate anus)

Hirschsprung’s disease

5. Nephrologic manifestations

Renal pyelectasis (dilation of the renal pelvis) (25%)

6. Other manifestations

Premature aging,

Alzheimer’s disease

Acute myeloid leukemia.

Delayed puberty, early menopause

Hypotonia

Lymphedema

Cystic hygroma

Omphalocele

Hydrothorax

Imperforate anus

Short umbilical cord

Short stature

Synonyms and related Syndromes: Cat Eye, Cayler cardiofacial syndrome, charge association, DiGeorge syndrome, Shprintzen syndrome, velocardiofacial syndrome.

Genetics: presence of an additional chromosome 22.

Deletion usually affects chromosome 22q11.

Incidence: 3-5% of all spontaneous abortions.

Clinical description:

1. Craniofacial and neurologic manifestations:

Microcephaly

Long fingers

Hypertelorism

Low set ears

Cleft palate/lip

Flat nasal bridge

Epicanthal folds

Nuchal edema/thickening

Webbed neck

Facial edema

Mental retardation

2. Other manifestations

Growth retardation

Hypotonia

Cardiac abnormalities

Kidney abnormalities

Gastrointestinal abnormalities

Anal stenosis

Seizures

Hearing loss

First descriptions: Giovanni Morgagni, 1768. Henry Turner, 1938.

Synonyms: Monosomy X, Turner-Varny Syndrome; Bonnevie-Ulrich syndrome; Morgagni-Turner-Albright syndrome, chromosome XO syndrome, genital dwarfism, gonadal dysgenesis (45,X); ovarian dwarfism, ovarian aplasia, pterygolymphangiectasia; Schereshevkii-Turner syndrome.

Genetics: absence (total or partial) or alteration of X chromosome (Xp11.2-p22.1).

Possible chromosomal anomalies:

- 45, XO karyotype: 55%.

- 46, XX karyotype: 25% with defective X chromosomes (deletion, duplication etc.).

- Mosaics: 15%.

Incidence: approximately 1 in 2,500 births.

Over 95% of fetuses abort spontaneously.

This syndrome is responsible for about 10% of all spontaneous abortions

Sex ratio: Females only.

Clinical description:

1. Lymphologic manifestations

The etiology of this syndrome is probably anomalies of lymphatic development that lead to lymphatic hypoplasia and valvular dysplasia. The mechanism may involve a deficiency in the gene responsible for activating the protein tyrosine kinase.

The most common manifestations are:

Pterygium colli (webbed neck), 50%

Cystic hygroma, a.k hydrops fetalis

Primary lymphedema of the dorsum of the hands and feet (80%)

Many of the associated lesions typically resolve spontaneously in adulthood.

2. Craniofacial and neurological manifestations

Triangular face

Midfacial hypoplasia

Micrognathia,

Low posterior hairline (80%)

Small lower jaw (70%)

Unusual shape and rotation of ears (80%)

Inner canthal folds (70%)

Eyelid ptosis

Shield chest with widely spaced nipples (78%)

Hearing loss (50%)

High palate (82%)

3. Cardiovascular manifestations

Congenital heart malformations (20-30%)

Coarctation of the aorta (15-30%)

Bicuspid aortic valve (33%)

Aortic aneurysms

Mitral valve prolapse (25%)

Ectopia cordis (malposition of the heart; in the most common form, the heart protrudes out of the chest through a split sternum)

Hypoplastic left heart

Pulmonary stenosis

Vascular malformations: vascular dysplasia, hemangiomata, venous ectasia,

multiple renal arteries (90%)

Hypertension

4. Dermatologic manifestations

Pigmented nevi (50-70%)

Vitiligo

Keloid(s)

Alopecia

Nail hypoplasia, soft upturned nails (70%)

Hirsutism

5. Ophthalmologic manifestations

Blepharoptosis (eyelid ptosis)

Strabismus

Cataracts

Nystagmus

Amblyopia

Myopia

6. Genitourinary manifestations

Double collecting system, absent kidney or abnormalities of the ureters (20%)

Kidney malrotation (15%)

Horseshoe kidneys (10%)

Unilateral aplasia or hypoplasia of the kidneys

7. Endocrinologic manifestations

Short Stature 100%

Gonadal dysgenesis or failure

1. Gonadal dysgenesis usually leads to primary or secondary amenorrhea (95%)

Ovarian failure (90%)

Hypothyroidism (20-30%)

Type II diabetes (5%)

8. Musculoskeletal manifestations

Broad chest (80%)

Cubitus valgus (70%)

Short 4th metacarpals (50%)

Osteoporosis

9. Gastrointestinal manifestations

Protein-losing enteropathy

Hemangiomata

Intestinal bleeding

First descriptions: Giovanni Morgagni in 1768. F. Von Recklinghausen,1882.

Synonyms: Recklinghausen's phakomatosis, Recklinhausen neurofibromatosis, von Recklinghausen neuropathy, neurinofibrolipomatosis, neurinomatosis centralis et peripherica, neurofibromatosis generalisata, Elephant Man’s syndrome.

Genetics: autosomal dominant disorder with complete penetrance and highly variable expression, probably of neural crest origin. About 50% of all cases are in fact mutations.

Incidence: 1 per 3,000-3,500 births.

Clinical description:

1- Dermatologic manifestations

Café au lait spots spots(90-100%), made of increased or brownish skin pigmentation, commonly present in the trunk, axillae (axillary freckles), and inguinal area (inguinal freckles).

2- Neurobehavioral manifestations

Schwannomas or neurofibromata: multiple, often soft, sessile peripheral nerve tumors. These two types of tumor can become malignant over time.

Seizures

Hydrocephalus

Macroencephaly

Learning disabilities (25-60%).

Speech impediments

Mental retardation

3. Ophthalmologic manifestations

Lisch nodules (iris hamartomas or iris nevi) are clear, yellow or brown dome-shaped elevations on the surface of the iris (50% of adults).

They usually do not produce any ophthalmologic complications.

Optic nerve gliomas (15%) commonly located on the chiasm or pre-chiasm area.

They may provoke visual disturbances which do not usually progress to visual loss.

Proptosis (droopy eyelid)

Phakoma

Glaucoma

Corneal opacity

4. Endocrinologic manifestations

Short stature (43%)

Early or delayed puberty

Thyroid problems

5. Musculoskeletal manifestations

Scoliosis (10-20%)

Pseudoarthrosis (1-2%)

Kyphosis

Spinal dislocation

6. Other manifestations:

Lymphodysplasia

Hearing loss

Hypertension

Headaches

Malignancies: malignant myeloid disorders, neurofibrosarcomas, astrocytomas, meningiomas, medulloblastomas,

First description: P.D Samman and W.F.White, 1964.

OMIM (Online Mendelian Inheritance in Man database) reference number: 153300

Genetics: Autosomal dominant disorder. Mutation of the gene FOXC2 (MFH1).

Incidence: Rare – about 100 cases throughout the world have been described in the literature.

Approximately 10% of the cases are congenital.

Median age of onset: 40 year old.

Sex ratio: Twice as many female as males.

Clinical description:

The probable etiology of this syndrome is anomalies of lymphangiogenesis leading to lymphatic hypoplasia

The yellow nail syndrome is characterized by a triad of manifestations:

- Yellow nails (89%)

- Lymphedema (80%)

Pleuropulmonary symptoms (63%)

Chronic sinusitis or bronchiectasis.

1. Dermatologic manifestations

Thick, slow growing and dystrophic yellow or greenish nails

Onycholysis (a common nail disorder characterized by a spontaneous separation of the nail plate starting at the distal margin and progressing proximally)

Loss of the nail cuticle

2. Lymphologic manifestations

Symmetrical hypoplastic lymphedema, usually of the lower extremities; less frequently it can involve the upper extremities, face or genitalia.

Chylothorax

3. Pneumologic manifestations

Recurrent unilateral or bilateral pleuropulmonary effusion, bronchiectasia (usually the latest symptom to develop in the triad)

Chronic maxillary sinusitis

(short stature, hypertelorism, and abnormal scrotum). Probably X-linked recessive disorder.

See: Aarskog syndrome

or N-Acetyl-Alpha-D-Galactosaminidase deficiency (NAGA).

These syndromes may lead to progressive neurologic abnormalities (psychomotor retardation). Gene location: 22q11.

See: Alpha-Galactosidase B deficiency

(Carbohydrate-Deficient Glycoprotein syndrome Type Ib; Gastrointestinal type Mannosephosphate Isomerase deficiency). The clinical features include: severe psychomotor retardation and blood coagulation abnormalities (Jaeken et al. 1980)

Gene location: 15q22-qter.

See: Congenital disorder of Glycosylation, Type Ib

German syndrome: arthrologic disorders, hypotonia-hypokinesia, and lymphedema (German J. et al., 1975).

Gene location: 20q13.33

See: Hypotrichosis-Lymphedema-Telangiectasia Syndrome

(generalized edema of the fetus of non immunologic origin)

See: Idiopathic Hydrops Fetalis

Also called “familial idiopathic dysproteinemia” (Homburger and Petermann, 1949). Patients with intestinal lymphangiectasia may have lower extremities lymphedema, vascular changes, hypogammaglobulinemia, lymphocytopenia, and skin anergy

(lissencephaly is characterized by microcephaly and a thickened cortex), Norman-Roberts Type. Gene location: 7q22.

Facial Changes

See: Lymphedema-Atrial Septal Defect

(Cumming, W. A.; 1986).

Campomelia is characterized by an abnormal curvature of the long bones, especially from lower extremities.

See: Lymphedema-Microcephaly-Chorioretinopathy

Gene location: 16q24.3.

See: Lymphedema-Ptosis

See: Lymphedema-Osteopetrosis-Ectodermal

See: Dysplasia-Anhidrotic-Immunodeficiency or OL-EDA-ID syndrome (Duffinger et al. 2001).

Gene location: Xq28.

(Franck J., Pipper P.G., 1959)

See: Pulmonary Cystic Lymphangiectasis

The patients affected by Nevo syndrome may have kyphosis, increased growth, volar edema, spindle-shaped fingers, hyperbilirubinemia, and generalized hypotonia (Nevo S. et al., 1974)

Peho Syndrome is progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (Salonen R. et al, 1991)

Include: Prolidase deficiency, prolidase, imidodipeptidase, proline peptidase d deficiencies, dipeptidase and aminoacyl-l-proline hydrolase,.

Patient with PEPD may have dermatologic manifestations (particularly leg ulcers) and mental retardation.

Gene location: 19cen-q13.11

Pateints are female that do not develop secondary sexual characteristics at puberty and present streak gonads.

Gene location: Xp22.11-p21.2.

see also: Swyer syndrome

(Published with permission from the author of Silent Waves Theory And Practice Of Lymph Drainage Therapy (Ldt) With Applications For Lymphedema, Chronic Pain And Inflammation Author: Bruno Chikly, M.D.2000 Publisher: I.H.H. Publishing, Arizona. Isbn Hard Cover = 0-9700530-5-3

Dec 2010

Morcaldi G, Boccardo F, Campisi C, Bellini T, Massocco D, Bonioli E.

Source

Department of Pediatrics, University of Genoa, Gaslini Children's Hospital, Italy. gmorcaldi@fastwebnet.it

Abstract

Kabuki syndrome was first described in Japan in 1981 as a rare disorder of unknown cause. Its main features include characteristic facies, postnatal growth retardation, and mental delay. To date, there is no molecular marker for Kabuki syndrome, which is considered genetically heterogeneous and still is a clinically-based diagnosis. Here we describe the first case of a patient affected by Kabuki syndrome associated with lymphatic dysplasia. We suggest accurate evaluation of all Kabuki patients as early as possible in order to diagnose lymphedema or other clinical manifestations of lymphatic system involvement. Early identification of lymphatic system maldevelopment provides the best chance for reducing the risk of developing progressive lymphedema with associated tissue changes (fibrosis, sclerosis, and fat deposition).

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Updated Jan. 21, 2012