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Hereditary lymphedema type I(LMPHM1)

MedGen UID:
309963
Concept ID:
C1704423
Disease or Syndrome
Synonyms: Congenital hereditary lymphedema; Early onset lymphedema; Hereditary lymphedema 1; LMPHM1; LYMPHATIC MALFORMATION 1; Meige's disease; Milroy Disease; Milroy's disease; Nonne's syndrome; Nonne-Milroy disease; Nonne-Milroy syndrome; Nonne-Milroy-Meige syndrome; Primary congenital lymphedema
SNOMED CT: Hereditary lymphedema type I (399889006); Nonne-Milroy lymphedema (399889006); Milroy lymphedema (399889006); Primary congenital lymphedema (399889006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): FLT4 (5q35.3)
 
Monarch Initiative: MONDO:0007919
OMIM®: 153100
Orphanet: ORPHA79452

Definition

Primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014). Genetic Heterogeneity of Lymphatic Malformation Primary lymphedema is genetically heterogeneous: see also LMPHM2 (611944), which maps to chromosome 6q16.2-q22.1; LMPHM3 (613480), caused by mutation in the GJC2 gene (608803) on chromosome 1q42; LMPHM4 (615907), caused by mutation in the VEGFC gene (601528) on chromosome 4q34; LMPHM5 (153200); LMPHM6 (616843), caused by mutation in the PIEZO1 gene (611184) on chromosome 16q24; LMPHM7 (617300), caused by mutation in the EPHB4 gene (600011) on chromosome 7q22; LMPHM8 (618773), caused by mutation in the CALCRL gene (114190) on chromosome 2q31; LMPHM9 (619319), caused by mutation in the CELSR1 gene (604523) on chromosome 22q13; LMPHM10 (610369), caused by mutation in the ANGPT2 gene (601922) on chromosome 8p23; LMPHM11 (619401), caused by mutation in the TIE1 gene (600222) on chromosome 1p34; LMPHM12 (620014), caused by mutation in the MDFIC gene (614511) on chromosome 7q31; LMPHM13 (620244), caused by mutation in the THSD1 gene (616821) on chromosome 13q14; and LMPHM14 (620602), caused by mutation in the ERG gene (165080) on chromosome 21q22. Lymphedema can also be a feature of syndromic disorders such as lymphedema-distichiasis syndrome (153400), which is caused by mutation in the FOXC2 gene (602402), and various forms of nonimmune hydrops fetalis (NIHF; see 236750). [from OMIM]

Additional description

From MedlinePlus Genetics
Milroy disease is a condition that affects the normal function of the lymphatic system. The lymphatic system produces and transports fluids and immune cells throughout the body. Impaired transport with accumulation of lymph fluid can cause swelling (lymphedema). Individuals with Milroy disease typically have lymphedema in their lower legs and feet at birth or develop it in infancy. The lymphedema typically occurs on both sides of the body and may worsen over time.

Milroy disease is associated with other features in addition to lymphedema. Males with Milroy disease are sometimes born with an accumulation of fluid in the scrotum (hydrocele). Males and females may have upslanting toenails, deep creases in the toes, wart-like growths (papillomas), and prominent leg veins. Some individuals develop non-contagious skin infections called cellulitis that can damage the thin tubes that carry lymph fluid (lymphatic vessels). Episodes of cellulitis can cause further swelling in the lower limbs.  https://medlineplus.gov/genetics/condition/milroy-disease

Clinical features

From HPO
Hemangioma
MedGen UID:
5477
Concept ID:
C0018916
Neoplastic Process
A hemangioma is a benign tumor characterized by blood-filled spaces lined by benign endothelial cells. A hemangioma characterized by large endothelial spaces (caverns) is called a cavernous hemangioma (in contrast to a hemangioma with small endothelial spaces, which is called capillary hemangioma).
Papilloma
MedGen UID:
10566
Concept ID:
C0030354
Neoplastic Process
A tumor of the skin or mucous membrane with finger-like projections.
Hydrocele testis
MedGen UID:
318568
Concept ID:
C1720771
Congenital Abnormality
Accumulation of clear fluid in the between the layers of membrane (tunica vaginalis) surrounding the testis.
Urethral stricture
MedGen UID:
1641821
Concept ID:
C4551691
Pathologic Function
Narrowing of the urethra associated with inflammation or scar tissue.
Cellulitis
MedGen UID:
40174
Concept ID:
C0007642
Disease or Syndrome
A bacterial infection and inflammation of the skin und subcutaneous tissues.
Hypoplasia of lymphatic vessels
MedGen UID:
871105
Concept ID:
C4025570
Congenital Abnormality
Congenital underdevelopment of lymph vessels.
Predominantly lower limb lymphedema
MedGen UID:
320552
Concept ID:
C1835228
Finding
Localized fluid retention and tissue swelling caused by a compromised lymphatic system, affecting mainly the legs.
Hyperkeratosis over edematous areas
MedGen UID:
320555
Concept ID:
C1835253
Finding
Upslanting toenail
MedGen UID:
331939
Concept ID:
C1835255
Finding
Upturned concavity of toenails.
Prominent superficial veins
MedGen UID:
324870
Concept ID:
C1837785
Finding
A condition in which superficial veins (i.e., veins just under the skin) are more conspicuous or noticable than normal.
Non-immune hydrops fetalis
MedGen UID:
105327
Concept ID:
C0455988
Disease or Syndrome
Hydrops fetalis is a descriptive term for generalized edema of the fetus, with fluid accumulation in extravascular components and body cavities. It is not a diagnosis in itself, but a symptom and end-stage result of a wide variety of disorders. In the case of immune hydrops fetalis, a frequent cause is maternofetal incompatibility as in that related to a number of genetic anemias and metabolic disorders expressed in the fetus; in other instances, it remains idiopathic and likely multifactorial (summary by Bellini et al., 2009). Nonimmune hydrops fetalis accounts for 76 to 87% of all described cases of hydrops fetalis (Bellini et al., 2009). Genetic Heterogeneity of Hydrops Fetalis In southeast Asia, alpha-thalassemia (604131) is the most common cause of hydrops fetalis, accounting for 60 to 90% of cases. Almost all of these cases result from homozygous deletion of the HBA1 (141800) and HBA2 (141850) genes. A few cases have been reported that had 1 apparently normal alpha-globin gene, termed the hemoglobin H (613978) hydrops fetalis syndrome (summary by Chui and Waye, 1998). Other genetic disorders predisposing to NIHF include other congenital anemias, such as erythropoietic porphyria (e.g., 606938.0013), and many metabolic disorders, such as one form of Gaucher disease (e.g., 606463.0009), infantile sialic acid storage disease (269920), mucopolysaccharidosis type VII (253220), glycogen storage disease IV (232500), congenital disorder of glycosylation type Ia (212065), and disorders of lymphatic malformation (see, e.g., LMPHM1, 153100).

Professional guidelines

PubMed

Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, Zucker DS, Matthews CE, Ligibel JA, Gerber LH, Morris GS, Patel AV, Hue TF, Perna FM, Schmitz KH
Med Sci Sports Exerc 2019 Nov;51(11):2375-2390. doi: 10.1249/MSS.0000000000002116. PMID: 31626055Free PMC Article
Greenlee H, DuPont-Reyes MJ, Balneaves LG, Carlson LE, Cohen MR, Deng G, Johnson JA, Mumber M, Seely D, Zick SM, Boyce LM, Tripathy D
CA Cancer J Clin 2017 May 6;67(3):194-232. Epub 2017 Apr 24 doi: 10.3322/caac.21397. PMID: 28436999Free PMC Article
Trayes KP, Studdiford JS, Pickle S, Tully AS
Am Fam Physician 2013 Jul 15;88(2):102-10. PMID: 23939641

Recent clinical studies

Etiology

Ghalamkarpour A, Morlot S, Raas-Rothschild A, Utkus A, Mulliken JB, Boon LM, Vikkula M
Clin Genet 2006 Oct;70(4):330-5. doi: 10.1111/j.1399-0004.2006.00687.x. PMID: 16965327

Diagnosis

Boudon E, Levy Y, Abossolo T, Cartault F, Brouillard P, Vikkula M, Kieffer-Traversier M, Ramful D, Alessandri JL
Eur J Med Genet 2015 Jun-Jul;58(6-7):329-31. Epub 2015 Apr 18 doi: 10.1016/j.ejmg.2015.03.006. PMID: 25896638
Yu Z, Wang J, Peng S, Dong B, Li Y
J Genet Genomics 2007 Oct;34(10):861-7. doi: 10.1016/S1673-8527(07)60097-6. PMID: 17945164
Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, A Shalev S
J Hum Genet 2006;51(10):846-850. Epub 2006 Aug 19 doi: 10.1007/s10038-006-0031-3. PMID: 16924388
Makhoul IR, Sujov P, Ghanem N, Bronshtein M
Prenat Diagn 2002 Sep;22(9):823-6. doi: 10.1002/pd.418. PMID: 12224079

Clinical prediction guides

Evans AL, Brice G, Sotirova V, Mortimer P, Beninson J, Burnand K, Rosbotham J, Child A, Sarfarazi M
Am J Hum Genet 1999 Feb;64(2):547-55. doi: 10.1086/302248. PMID: 9973292Free PMC Article

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