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Prolidase deficiency

MedGen UID:
120647
Concept ID:
C0268532
Disease or Syndrome
Synonyms: Deficiencies, Imidodipeptidase; Deficiencies, Prolidase; Deficiency, Imidodipeptidase; Deficiency, Prolidase; Hyperimidodipeptiduria; Hyperimidodipeptidurias; Imidodipeptidase Deficiencies; Imidodipeptidase Deficiency; Prolidase Deficiencies; Prolidase Deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Hyperimidodipeptiduria (410055005); Hyperimidodipeptiduria due to proline dipeptidase deficiency (410055005); Iminodipeptiduria (410055005); Deficiency of imidodipeptidase (360969006); Deficiency of prolidase (360994007); Deficiency of proline dipeptidase (361010007)
 
Gene (location): PEPD (19q13.11)
OMIM®: 170100

Definition

Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described. [from GTR]

Additional descriptions

From GeneReviews
Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described.  https://www.ncbi.nlm.nih.gov/books/NBK299584
From NCBI curation
Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described.
From OMIM
Prolidase deficiency is a rare autosomal recessive multisystem disorder associated with massive imidodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. The disorder is clinically heterogeneous and severity varies widely. Features include chronic, slowly healing ulcerations, mainly on the legs and feet. The ulcers are often preceded by other dermatologic manifestations that may occur anywhere and include erythematous papular eruptions, telangiectasias with pruritus and photosensitivity, impetigo-like eruptions, pruritic eczematous lesions, and necrotic papules. Mild to severe mental retardation is often a feature, and recurrent respiratory tract infections, sometimes fatal, are common. Facial dysmorphism may include low hairline and hirsutism, saddle nose, ocular hypertelorism, micrognathia, a high-arched palate, mandibular protrusion, and exophthalmos. Clinical manifestations are usually detectable after birth or in early childhood, but late-onset cases have been reported (summary by Lupi et al., 2008).  http://www.omim.org/entry/170100
From GHR
Prolidase deficiency is a disorder that causes a wide variety of symptoms. The disorder typically becomes apparent during infancy. Affected individuals may have enlargement of the spleen (splenomegaly); in some cases, both the spleen and liver are enlarged (hepatosplenomegaly). Diarrhea, vomiting, and dehydration may also occur. People with prolidase deficiency are susceptible to severe infections of the skin or ears, or potentially life-threatening respiratory tract infections. Some individuals with prolidase deficiency have chronic lung disease.Characteristic facial features in people with prolidase deficiency include prominent eyes that are widely spaced (hypertelorism), a high forehead, a flat bridge of the nose, and a very small lower jaw and chin (micrognathia). Affected children may experience delayed development, and about 75 percent of people with prolidase deficiency have intellectual disability that may range from mild to severe.People with prolidase deficiency often develop skin lesions, especially on their hands, feet, lower legs, and face. The severity of the skin involvement, which usually begins during childhood, may range from a mild rash to severe skin ulcers. Skin ulcers, especially on the legs, may not heal completely, resulting in complications including infection and amputation.The severity of symptoms in prolidase deficiency varies greatly among affected individuals. Some people with this disorder do not have any symptoms. In these individuals the condition can be detected by laboratory tests such as newborn screening tests or tests offered to relatives of affected individuals.  https://ghr.nlm.nih.gov/condition/prolidase-deficiency

Clinical features

Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
Drooping of the upper lid due to deficient development or paralysis of the levator palpebrae muscle.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Proptosis
MedGen UID:
350667
Concept ID:
C1862425
Finding
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Diffuse telangiectasia
MedGen UID:
224748
Concept ID:
C1265776
Finding
Telangiectases (small dilated blood vessels) with a diffuse localization.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement of the spleen.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A laboratory test result indicating that there is an abnormally small number of platelets in the circulating blood.
Anemia
MedGen UID:
56401
Concept ID:
C0162119
Finding
A laboratory test result demonstrating decreased levels of hemoglobin in a biological specimen.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
A chronic respiratory disease manifested as difficulty breathing due to the narrowing of bronchial passageways.
Chronic lung disease
MedGen UID:
196656
Concept ID:
C0746102
Disease or Syndrome
A persistent non-neoplastic disorder of the lungs. Representative examples include: chronic obstructive pulmonary disease, chronic bronchitis, emphysema, pulmonary fibrosis, pneumoconiosis, asbestosis, atelectasis, radiation induced pneumonitis, and radiation fibrosis.
Recurrent pulmonary infections
MedGen UID:
349099
Concept ID:
C1859117
Finding
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
A chronic respiratory disease manifested as difficulty breathing due to the narrowing of bronchial passageways.
Systemic lupus erythematosus
MedGen UID:
6146
Concept ID:
C0024141
Disease or Syndrome
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008). Genetic Heterogeneity of Systemic Lupus Erythematosus An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3. See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement of the spleen.
Recurrent pulmonary infections
MedGen UID:
349099
Concept ID:
C1859117
Finding
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Crusting erythematous dermatitis
MedGen UID:
358224
Concept ID:
C1868496
Disease or Syndrome
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Convex nasal ridge
MedGen UID:
66809
Concept ID:
C0240538
Finding
Nasal ridge curving anteriorly to an imaginary line that connects the nasal root and tip. The nose appears often also prominent, and the columella low.
Abnormal facial shape
MedGen UID:
91281
Concept ID:
C0376634
Congenital Abnormality
An abnormal morphology (form) of the face or its components.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
Proptosis
MedGen UID:
350667
Concept ID:
C1862425
Finding
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
Prominent forehead
MedGen UID:
401234
Concept ID:
C1867446
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Diffuse telangiectasia
MedGen UID:
224748
Concept ID:
C1265776
Finding
Telangiectases (small dilated blood vessels) with a diffuse localization.
Low posterior hairline
MedGen UID:
383755
Concept ID:
C1855728
Finding
Hair on the neck extends more inferiorly than usual.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Crusting erythematous dermatitis
MedGen UID:
358224
Concept ID:
C1868496
Disease or Syndrome

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVProlidase deficiency

Recent clinical studies

Etiology

Nir V, Ilivitky A, Hakim F, Yoseph RB, Gur M, Mandel H, Bentur L
Pediatr Pulmonol 2016 Nov;51(11):1229-1233. Epub 2016 May 1 doi: 10.1002/ppul.23435. PMID: 27132891
Besio R, Maruelli S, Gioia R, Villa I, Grabowski P, Gallagher O, Bishop NJ, Foster S, De Lorenzi E, Colombo R, Diaz JL, Moore-Barton H, Deshpande C, Aydin HI, Tokatli A, Kwiek B, Kasapkara CS, Adisen EO, Gurer MA, Di Rocco M, Phang JM, Gunn TM, Tenni R, Rossi A, Forlino A
Bone 2015 Mar;72:53-64. Epub 2014 Nov 20 doi: 10.1016/j.bone.2014.11.009. PMID: 25460580
Falik-Zaccai TC, Khayat M, Luder A, Frenkel P, Magen D, Brik R, Gershoni-Baruch R, Mandel H
Am J Med Genet B Neuropsychiatr Genet 2010 Jan 5;153B(1):46-56. doi: 10.1002/ajmg.b.30945. PMID: 19308961
Wang H, Kurien BT, Lundgren D, Patel NC, Kaufman KM, Miller DL, Porter AC, D'Souza A, Nye L, Tumbush J, Hupertz V, Kerr DS, Kurono S, Matsumoto H, Scofield RH
Am J Med Genet A 2006 Mar 15;140(6):580-5. doi: 10.1002/ajmg.a.31134. PMID: 16470701
Viglio S, Annovazzi L, Conti B, Genta I, Perugini P, Zanone C, Casado B, Cetta G, Iadarola P
J Chromatogr B Analyt Technol Biomed Life Sci 2006 Feb 17;832(1):1-8. Epub 2006 Jan 24 doi: 10.1016/j.jchromb.2005.12.049. PMID: 16434239

Diagnosis

Nir V, Ilivitky A, Hakim F, Yoseph RB, Gur M, Mandel H, Bentur L
Pediatr Pulmonol 2016 Nov;51(11):1229-1233. Epub 2016 May 1 doi: 10.1002/ppul.23435. PMID: 27132891
Adışen E, Erduran FB, Ezgü FS, Kasapkara ÇS, Besio R, Forlino A, Gürer MA
Int J Low Extrem Wounds 2016 Mar;15(1):86-91. Epub 2015 Dec 4 doi: 10.1177/1534734615619550. PMID: 26637345
Kuloglu Z, Kansu A, Serwas N, Demir A, Yaman A, Ensari A, Boztug K
Genet Couns 2015;26(2):205-11. PMID: 26349190
Solak B, Kara RO, Erdem T, Muftuoglu T
Int J Low Extrem Wounds 2015 Mar;14(1):92-4. Epub 2015 Feb 17 doi: 10.1177/1534734615570360. PMID: 25691319
Lacarbonara M, Cazzolla AP, Lacarbonara VA, Di Venere D, Capogreco M, Marzo G
Eur J Paediatr Dent 2014 Jul;15(2 Suppl):224-8. PMID: 25101509

Therapy

Vestita M, Giudice G, Bonamonte D
BMJ Case Rep 2017 Jan 6;2017 doi: 10.1136/bcr-2016-217329. PMID: 28062424
Dunn R, Dolianitis C
Australas J Dermatol 2008 Nov;49(4):237-8. doi: 10.1111/j.1440-0960.2008.00485.x. PMID: 18855790
Lupi A, Tenni R, Rossi A, Cetta G, Forlino A
Amino Acids 2008 Nov;35(4):739-52. Epub 2008 Mar 14 doi: 10.1007/s00726-008-0055-4. PMID: 18340504
Trent JT, Kirsner RS
Adv Skin Wound Care 2004 Nov-Dec;17(9):468-72. PMID: 15632738
Zhang J, Sugahara K, Yasuda K, Kodama H, Sagara Y, Kodama H
Free Radic Biol Med 1998 Mar 15;24(5):689-98. PMID: 9586797

Prognosis

Besio R, Gioia R, Cossu F, Monzani E, Nicolis S, Cucca L, Profumo A, Casella L, Tenni R, Bolognesi M, Rossi A, Forlino A
PLoS One 2013;8(3):e58792. Epub 2013 Mar 13 doi: 10.1371/journal.pone.0058792. PMID: 23516557Free PMC Article
Klar A, Navon-Elkan P, Rubinow A, Branski D, Hurvitz H, Christensen E, Khayat M, Falik-Zaccai TC
Eur J Pediatr 2010 Jun;169(6):727-32. Epub 2009 Nov 24 doi: 10.1007/s00431-009-1102-1. PMID: 19937054
Lupi A, Casado B, Soli M, Bertazzoni M, Annovazzi L, Viglio S, Cetta G, Iadarola P
Br J Dermatol 2002 Dec;147(6):1237-40. PMID: 12452876
Mandel H, Abeling N, Gutman A, Berant M, Scholten EG, Sheiman C, Luder A, van Gennip AH
Prenat Diagn 2000 Nov;20(11):927-9. PMID: 11113899
Shrinath M, Walter JH, Haeney M, Couriel JM, Lewis MA, Herrick AL
Arch Dis Child 1997 May;76(5):441-4. PMID: 9196362Free PMC Article

Clinical prediction guides

Besio R, Gioia R, Cossu F, Monzani E, Nicolis S, Cucca L, Profumo A, Casella L, Tenni R, Bolognesi M, Rossi A, Forlino A
PLoS One 2013;8(3):e58792. Epub 2013 Mar 13 doi: 10.1371/journal.pone.0058792. PMID: 23516557Free PMC Article
Mandel H, Abeling N, Gutman A, Berant M, Scholten EG, Sheiman C, Luder A, van Gennip AH
Prenat Diagn 2000 Nov;20(11):927-9. PMID: 11113899
Sugahara K, Jianying Z, Yamamoto Y, Yasuda K, Kodama H, Kodama H
Eur J Clin Chem Clin Biochem 1994 Mar;32(3):113-7. PMID: 8031960
Kodama H, Nakamura H, Sugahara K, Numajiri Y
J Chromatogr 1990 May 18;527(2):279-88. PMID: 2387877
Endo F, Matsuda I, Ogata A, Tanaka S
Pediatr Res 1982 Mar;16(3):227-31. PMID: 7063276

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