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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
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)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PEPD (19q13.11)
 
Monarch Initiative: MONDO:0008221
OMIM®: 170100
Orphanet: ORPHA742

Disease characteristics

Excerpted from the GeneReview: Prolidase Deficiency
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 organomegaly (typically splenomegaly but occasionally associated with hepatomegaly) with elevated liver enzymes. Skeletal anomalies, chronic pulmonary disease, anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are observed in a minority of affected individuals. An association between prolidase deficiency and autoimmune conditions – particularly systemic lupus erythematosus (SLE) – has been described. [from GeneReviews]
Authors:
Francis Rossignol  |  Heng Wang  |  Carlos Ferreira   view full author information

Additional descriptions

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, telangiectases 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 MedlinePlus Genetics
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://medlineplus.gov/genetics/condition/prolidase-deficiency

Clinical features

From HPO
Hyperimidodipeptiduria
MedGen UID:
1730346
Concept ID:
C5399950
Finding
Elevated levels of proline-containing dipeptides in urine.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
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.
Febrile seizure (within the age range of 3 months to 6 years)
MedGen UID:
3232
Concept ID:
C0009952
Disease or Syndrome
A febrile seizure is any type of seizure (most often a generalized tonic-clonic seizure) occurring with fever (at least 38 degrees Celsius) but in the absence of central nervous system infection, severe metabolic disturbance or other alternative precipitant in children between the ages of 3 months and 6 years.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
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.
Mild global developmental delay
MedGen UID:
861405
Concept ID:
C4012968
Finding
A mild delay in the achievement of motor or mental milestones in the domains of development of a child.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Chronic lung disease
MedGen UID:
196656
Concept ID:
C0746102
Disease or Syndrome
According to the definitions of the American and British Thoracic Societies, including pulmonary functional tests, X-rays, and CT scans for items such as fibrosis, bronchiectasis, bullae, emphysema, nodular or lymphomatous abnormalities.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
Asthma is characterized by increased responsiveness of the tracheobronchial tree to multiple stimuli, leading to narrowing of the air passages with resultant dyspnea, cough, and wheezing.
Eczema
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
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. An X-linked dominant form of SLE (SLEB17; 301080) is caused by heterozygous mutation in the TLR7 gene (300365) on chromosome Xp22. 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 increased size of the spleen.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Crusting erythematous dermatitis
MedGen UID:
358224
Concept ID:
C1868496
Disease or Syndrome
Increased circulating antibody level
MedGen UID:
1713383
Concept ID:
C5397581
Finding
An increased level of gamma globulin (immunoglobulin) in the blood.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Concave nasal ridge
MedGen UID:
78105
Concept ID:
C0264169
Finding
Nasal ridge curving posteriorly to an imaginary line that connects the nasal root and tip.
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.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
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.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
Petechiae are pinpoint-sized reddish/purple spots, resembling a rash, that appear just under the skin or a mucous membrane when capillaries have ruptured and some superficial bleeding into the skin has happened. This term refers to an abnormally increased susceptibility to developing petechiae.
Skin ulcer
MedGen UID:
52369
Concept ID:
C0037299
Disease or Syndrome
A discontinuity of the skin exhibiting complete loss of the epidermis and often portions of the dermis and even subcutaneous fat.
Diffuse telangiectasia
MedGen UID:
224748
Concept ID:
C1265776
Finding
Telangiectases (small dilated blood vessels) with a diffuse localization.
Facial hirsutism
MedGen UID:
337950
Concept ID:
C1850041
Finding
Excess facial hair.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
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 (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Term Hierarchy

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

Professional guidelines

PubMed

Arjona Aguilera C, Albarrán Planelles C, Tercedor Sánchez J
Actas Dermosifiliogr 2016 Mar;107(2):116-24. Epub 2015 Dec 1 doi: 10.1016/j.ad.2015.09.013. PMID: 26593686
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Recent clinical studies

Etiology

Say M, Tella E, Boccara O, Sauvage M, Bourrat E, Tian Y, Monfort JB, Lok C, Desierier F, Beneton N, Abasq-Thomas C, Kupfer-Bessaguet I, Mallet S, Lacour JP, Plantin P, Sigal ML, Mazereeuw-Hautier J, Mahé E; on behalf the Angio-Dermatology Group of the French Society of Dermatology, the Research Group of the French Society of Pediatric Dermatology
Ann Dermatol Venereol 2022 Mar;149(1):51-55. Epub 2021 Jul 1 doi: 10.1016/j.annder.2021.05.004. PMID: 34218940
Chasset F, Richez C, Martin T, Belot A, Korganow AS, Arnaud L
Joint Bone Spine 2019 Mar;86(2):165-171. Epub 2018 Oct 26 doi: 10.1016/j.jbspin.2018.10.007. PMID: 30837156
Wilk P, Uehlein M, Piwowarczyk R, Dobbek H, Mueller U, Weiss MS
FEBS J 2018 Sep;285(18):3422-3441. Epub 2018 Aug 14 doi: 10.1111/febs.14620. PMID: 30066404
Nir V, Ilivitky A, Hakim F, Yoseph RB, Gur M, Mandel H, Bentur L
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Bone 2015 Mar;72:53-64. Epub 2014 Nov 20 doi: 10.1016/j.bone.2014.11.009. PMID: 25460580

Diagnosis

Chasset F, Richez C, Martin T, Belot A, Korganow AS, Arnaud L
Joint Bone Spine 2019 Mar;86(2):165-171. Epub 2018 Oct 26 doi: 10.1016/j.jbspin.2018.10.007. PMID: 30837156
Namiduru ES
Bratisl Lek Listy 2016;117(8):480-5. doi: 10.4149/bll_2016_093. PMID: 27546702
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Therapy

Karthikeyan K, Polly D, Asmathulla S, Balamurugan R, Kaviraj M
Clin Exp Dermatol 2019 Apr;44(3):344-346. Epub 2018 Jun 25 doi: 10.1111/ced.13702. PMID: 29943458
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Prognosis

Say M, Tella E, Boccara O, Sauvage M, Bourrat E, Tian Y, Monfort JB, Lok C, Desierier F, Beneton N, Abasq-Thomas C, Kupfer-Bessaguet I, Mallet S, Lacour JP, Plantin P, Sigal ML, Mazereeuw-Hautier J, Mahé E; on behalf the Angio-Dermatology Group of the French Society of Dermatology, the Research Group of the French Society of Pediatric Dermatology
Ann Dermatol Venereol 2022 Mar;149(1):51-55. Epub 2021 Jul 1 doi: 10.1016/j.annder.2021.05.004. PMID: 34218940
Chasset F, Richez C, Martin T, Belot A, Korganow AS, Arnaud L
Joint Bone Spine 2019 Mar;86(2):165-171. Epub 2018 Oct 26 doi: 10.1016/j.jbspin.2018.10.007. PMID: 30837156
Besio R, Gioia R, Cossu F, Monzani E, Nicolis S, Cucca L, Profumo A, Casella L, Tenni R, Bolognesi M, Rossi A, Forlino A
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Arch Dis Child 1997 May;76(5):441-4. doi: 10.1136/adc.76.5.441. PMID: 9196362Free PMC Article

Clinical prediction guides

Wilk P, Uehlein M, Piwowarczyk R, Dobbek H, Mueller U, Weiss MS
FEBS J 2018 Sep;285(18):3422-3441. Epub 2018 Aug 14 doi: 10.1111/febs.14620. PMID: 30066404
Surazynski A, Donald SP, Cooper SK, Whiteside MA, Salnikow K, Liu Y, Phang JM
Int J Cancer 2008 Mar 15;122(6):1435-40. doi: 10.1002/ijc.23263. PMID: 17999410
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Recent systematic reviews

Rossignol F, Duarte Moreno MS, Benoist JF, Boehm M, Bourrat E, Cano A, Chabrol B, Cosson C, Díaz JLD, D'Harlingue A, Dimmock D, Freeman AF, García MT, Garganta C, Goerge T, Halbach SS, de Laffolie J, Lam CT, Martin L, Martins E, Meinhardt A, Melki I, Ombrello AK, Pérez N, Quelhas D, Scott A, Slavotinek AM, Soares AR, Stein SL, Süßmuth K, Thies J, Ferreira CR, Schiff M
Genet Med 2021 Sep;23(9):1604-1615. Epub 2021 May 26 doi: 10.1038/s41436-021-01200-2. PMID: 34040193Free PMC Article

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