Prolidase Deficiency

Clinical characteristics.

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.

Diagnosis/testing.

The diagnosis of prolidase deficiency is established by detection of either biallelic PEPD pathogenic variants or reduced prolidase enzyme activity in a proband who has characteristic clinical findings and imidodipeptiduria.

Management.

Treatment of manifestations: No curative treatment is available. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal. Developmental and educational interventions as needed to address motor and cognitive delays.

Prevention of secondary complications: Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection. Antibiotic prophylaxis should also be considered in the appropriate setting.

Surveillance: In the absence of formal surveillance guidelines, the authors recommend annual: skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers, complete blood count, liver function tests, and abdominal ultrasound examination to assess the size of the liver and spleen. Follow up as recommended by a pulmonologist and immunologist. Follow-up assessments of motor and cognitive development as recommended for educational planning.

Agents/circumstances to avoid: In those with splenomegaly: avoid contact sports given the increased risk for splenic rupture.

Genetic counseling.

Prolidase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PEPD pathogenic variants in the family have been identified.

Suggestive Findings

Prolidase deficiency should be suspected in individuals with the following clinical, laboratory, and biochemical findings.

Clinical

• Skin lesions, typically lower extremity ulcers. Other lesions such as telangiectasias of the face and hands are also common [Royce & Steinmann 2002, Dunn et al 2011].
• Recurrent infections, particularly of the skin and respiratory tract [Cleary et al 1994]
• Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype [Luder et al 2007]
• Dysmorphic facial features, including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline [Goodman et al 1968, Falik-Zaccai et al 2010, Dunn et al 2011]
• Developmental delay of variable degree [Hechtman 2001, Lupi et al 2008, Falik-Zaccai et al 2010, Besio et al 2015]
• Splenomegaly [Nasser et al 2015]
• Systemic lupus erythematosus-like phenotype [Falik-Zaccai et al 2010, Klar et al 2010, Butbul Aviel et al 2012]

Laboratory. Frequent, although not universal, laboratory findings include the following:

• Anemia, usually mild (hemoglobin >10 g/dL), but occasionally below that value [Powell et al 1974, Moulonguet et al 1989, Cleary et al 1994]
• Thrombocytopenia, usually mild (>100,000 platelets per μL), although rarely it can be lower [Ogata et al 1981]
• Elevated liver enzymes, with elevation of aspartate aminotransferase in the 100s [Sekiya et al 1985]
• Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM. Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG ~1600 mg/dL, IgA 350 mg/dL, and IgM 280 mg/dL.
  • IgG levels >2,000 mg/dL have been reported numerous times [Ogata et al 1981, Gray et al 1983, Freij et al 1984, Cantatore et al 1993, Shrinath et al 1997, Lopes et al 2002, Kelly et al 2010] and as high as 3,680 mg/dL [Klar et al 2010].
  • IgA levels >500 mg/dL have been reported on several occasions [Gray et al 1983, Freij et al 1984, Lopes et al 2002, Butbul Aviel et al 2012] and as high as 850 mg/dL [Ogata et al 1981].
  • IgM concentrations as high as 568 mg/dL have been described [Shrinath et al 1997].
• Hypocomplementemia. Levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) have been published [Klar et al 2010], with C4 as low as 9 mg/dL (normal: 20-40 mg/dL) [Cleary et al 1994, Shrinath et al 1997].

Biochemical. Prolidase deficiency is characterized by massive imidodipeptiduria* (10-30 mmol/day) on urine amino acid analysis [Hechtman 2001].

• In individuals with prolidase deficiency imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease. (This finding has been used as the basis for urinary newborn screening in Quebec [Lemieux et al 1984].)
• Under normal circumstances the urinary excretion of glycylproline is negligible [Royce & Steinmann 2002]; thus, the absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency [Freij & Der Kaloustian 1986].

Click here (pdf) for information on laboratory methods used to detect imidodipeptiduria.

Other biochemical findings:

• The concentration of imidodipeptides is much lower in serum than urine [Royce & Steinmann 2002].
• Gly-Pro has been reported in the plasma by some investigators [Freij et al 1984], but not others [Hechtman 2001].
• CSF amino acid analysis was normal in the first report of probable prolidase deficiency [Goodman et al 1968].

*Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example glycylproline).

Establishing the Diagnosis

The diagnosis of prolidase deficiency is established in a proband (who has the characteristic clinical findings and imidodipeptiduria) by detection of either biallelic PEPD pathogenic variants (see Table 2) or reduced prolidase enzyme activity.

Molecular genetic testing approaches include single gene testing and targeted analysis for pathogenic variants.

• Single-gene testing. For most individuals, sequence analysis of PEPD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• Targeted analysis for pathogenic variants. For Amish from Geauga County, Ohio and Druze and Arab Muslims from northern Israel, testing for the founder variants p.Arg265Ter and p.Ser202Phe, respectively, may be performed first followed by sequence analysis and gene-targeted deletion/duplication analysis if one or no pathogenic variant is identified.

Measurement of prolidase enzyme activity. In affected individuals, prolidase enzyme activity in erythrocytes, leukocytes, or cultured fibroblasts ranges from none to <10% [Lupi et al 2008].

Click here (pdf) for a short review of laboratory techniques used in the diagnosis of prolidase deficiency; see also Kurien et al [2006] and Viglio et al [2006].

Clinical Description

Skin. The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers. The ulcers are located mainly on the lower extremities, particularly the feet. However, individuals are reported with upper extremity involvement, including one with recurrent upper extremity ulceration beginning at age nine years [Sheffield et al 1977], one with active ulcers on the hands [Cantatore et al 1993], and one with a healed scar from prior ulcers in the dorsum of the hand [El-Darouti 2013]. One had scarring from healed ulcers over most of her body; however, at the time of publication active ulcers were mainly on the legs [Wysocki et al 1988].

Skin ulcers can begin as early as age six months [Mandel et al 2000] or as late as age 30 years [Dyne et al 2001].

Ulceration is recurrent, and individual ulcers can take months to heal.

Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor in at least two individuals [Gray et al 1983, Royce & Steinmann 2002]. See Figure 1.

Figure 1.

Typical skin ulcerations in individuals with prolidase deficiency.

A variety of skin findings can precede the appearance of ulcers by many years [Hechtman 2001]. In the first 20 patients reported [Freij et al 1984], eight had telangiectasias of the face, shoulders, and hands; five had scaly, erythematous, maculopapular lesions; and two had purpuric lesions in the absence of hematologic abnormalities. In addition, five had premature graying of the hair.

Occasional findings:

• Lymphedema [Sheffield et al 1977, Dunn et al 2011]
• Hyperkeratosis of the elbows and knees [Ogata et al 1981]
• Hirsutism [Ogata et al 1981]
• Perioral pitted scars [Dunn et al 2011] or radial scars [Tiller 1977]

As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual [Fimiani et al 1999].

Dysmorphic facial features. Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines [Royce & Steinmann 2002, Falik-Zaccai et al 2010, Besio et al 2015]. See Figure 2.

Figure 2.

Prominent forehead, proptosis, depressed nasal bridge, and thin vermilion of the upper lip can be appreciated.

Neurologic manifestations. Intellectual disability of variable degree has been described in approximately 75% of individuals with prolidase deficiency [Hechtman 2001]. Table 3 summarizes IQ scores reported in the medical literature to date.

• In a review 12 of 30 individuals with molecularly confirmed prolidase deficiency had intellectual disability [Lupi et al 2008].
• In a case series of 12 individuals with prolidase deficiency, one had speech delay, two had mild developmental delay, and six had intellectual disability; three had no delays [Besio et al 2015].
• In a case series of 20 Druze and Arab Muslims with prolidase deficiency living in northern Israel all had some degree of developmental delay, mainly moderate cognitive or speech delay [Falik-Zaccai et al 2010]. More specifically, two had speech delay, eight had mild developmental delay, five had moderate delay, and three had severe delay.

Microcephaly was described in five of 11 individuals [Besio et al 2015].

Seizures have been described in rare cases [De Rijcke et al 1989, Wang et al 2006, Butbul Aviel et al 2012].

Brain MRI findings include:

• Multiple microthromboses bilaterally in the cerebral white matter [Arata et al 1991]
• Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [Butbul Aviel et al 2012]
• Findings compatible with vasculitis [Falik-Zaccai et al 2010]
• Normal (one affected individual) [Cantatore et al 1993]

On nerve conduction studies one affected individual had decreased amplitude of motor action potentials and sensory action potentials [Cantatore et al 1993].

Organomegaly. Hepatomegaly and splenomegaly are common [Royce & Steinmann 2002] and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) has been reported [Nasser et al 2015].

Liver enzymes may be mildly elevated [Wang et al 2006, Butbul Aviel et al 2012].

Hematologic manifestations. Anemia can be either mild microcytic hypochromic anemia [Powell et al 1974, Powell et al 1977, Pedersen et al 1983, Milligan et al 1989] or normocytic normochromic anemia [Dunn et al 2011].

Hemolysis has been described [Lapiere & Nusgens 1969], with reticulocytosis varying from 5.9% [Powell et al 1977] to 8.6% [Powell et al 1974].

Thrombocytopenia is fairly common [Powell et al 1974, Ogata et al 1981, Kavala et al 2006, Wang et al 2006, Butbul Aviel et al 2012].

Immunologic manifestations. Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common [Royce & Steinmann 2002].

Elevated levels of IgG, IgA and IgM, and hypocomplementemia have been reported [Cleary et al 1994], as has decreased neutrophil chemotaxis [Cleary et al 1994, Shrinath et al 1997, Lopes et al 2002]. Serum levels of C1q have been normal [Gray et al 1983, Kurien et al 2013].

Increased serum IgE levels have been reported [Di Rocco et al 2007, Kelly et al 2010, Klar et al 2010]:

• Martins et al [2000] reported a patient with an IgE level of 20,000 IU/mL, which was as high as 77,600 IU/mL on follow up, with a Grimbacher score of 34 [Lopes et al 2002].
• Fukumura et al [2009] reported an individual with a level of 23,000 IU/mL.
• Hershkovitz et al [2006] reported a patient with levels of 1,000-2,000 IU/mL with a Grimbacher score of 41, suggestive of autosomal dominant hyper IgE syndrome.

Pulmonary manifestations. Asthma-like chronic reactive airway disease was described in three of four Amish individuals with prolidase deficiency [Wang et al 2006].

Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis phenotype including elevated sweat chloride and transepithelial potential difference has been described [Luder et al 2007].

One male developed severe progressive restrictive lung disease at age 45 years [Luder et al 2007].

A Druze woman age 24 years had progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity [Butbul Aviel et al 2012]. She experienced further deterioration in her pulmonary function and secondary pulmonary hypertension, and became oxygen dependent.

An Amish boy age six years with pulmonary hypertension required supplemental oxygen [Kelly et al 2010].

Systemic lupus erythematosus-like findings. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described in at least ten individuals, including three of 23 individuals from northern Israel [Butbul Aviel et al 2012].

This association, first described by Bissonnette et al [1993] in a female age 16 years, included Raynaud's phenomenon, photosensitivity, arthritis, nephritis (with segmental mesangial deposits of IgA, IgM, and C3), antinuclear antibodies 1:650, and a positive rheumatoid factor.

Shrinath et al [1997] reported two cousins with prolidase deficiency and SLE:

• One had a malar facial rash, joint swellings, thrombocytopenia, neutropenia, proteinuria, pericarditis, hypocomplementemia, positive antinuclear antibody test (ANA), and strongly positive anti-dsDNA;
• The other had recurrent mouth ulcers, a malar rash, thrombocytopenia, neutropenia, positive ANA, positive anti-dsDNA, and positive pANCA.

A boy age 11 years had photosensitivity, malar erythema, and a positive ANA of 1:40 [Cabrera et al 2004].

A boy age six years diagnosed with SLE was treated for two years with steroids and azathioprine, with amelioration of the immunologic abnormalities but worsening of the skin lesions [Lupi et al 2004].

A male age 25 years had bilateral and symmetric synovitis affecting hands, elbows, and knees, a positive rheumatoid factor (516 IU/mL) and homogeneous ANA (1:640), and low C4 and CH50 (0.07 g/L and 61%) [Marotte et al 2010]. He fulfilled the American College of Rheumatology (ACR) criteria for rheumatoid arthritis and SLE (rhupus). Although he was diagnosed with prolidase deficiency based on increased imidodipeptiduria, prolidase enzymatic activity was not measured and PEPD sequencing was not performed. This patient did have increased bone turnover, a known cause of imidodipeptiduria in the absence of prolidase deficiency.

An Amish boy age 2.5 years with fever of unknown etiology had urinalysis with 2+ proteinuria and hypoalbuminemia, ANA of 1:1080 with speckled pattern, and a positive anti-dsDNA [D'Souza et al 2006].

Of two sibs reported by Klar et al [2010]:

• A girl age eight years had Raynaud's phenomenon, a positive ANA (1:1280; homogenous pattern), a positive anti ds-DNA >1:160, positive anti-ENA, anti-RNP and anti-Smith;
• Her brother, age 12 years, had Raynaud's phenomenon, a positive ANA (1:40; homogeneous) and anti ds-DNA (1.6 μg/mL), and low C3 (30-74 mg/dL).

An individual with positive ANA and anti-dsDNA titers, as well as low complement levels had no hematologic, renal, or articular problems; although he was given a diagnosis of SLE, he did not fulfill ACR diagnostic criteria [Di Rocco et al 2007].

Falik-Zaccai et al [2010] reported two individuals:

• One with Coombs-positive hemolytic anemia, severe medication-resistant thrombocytopenia which required splenectomy, high levels of ANA and anti-cardiolipin antibodies, and a strongly positive anti-dsDNA;
• One with aphthous stomatitis, macroscopic hematuria and proteinuria eventually leading to renal failure (with a renal biopsy compatible with lupus nephritis), seizures, pancytopenia, Coombs-positive hemolytic anemia, hypocomplementemia, and elevated ANA and anti-dsDNA antibodies).

Butbul Aviel et al [2012] reported three individuals with the SLE/prolidase deficiency association:

• A boy age 4.5 years with a rash consistent with hypertrophic discoid lupus on biopsy, proteinuria and mild hematuria with a renal biopsy consistent with WHO Class IV lupus nephritis, low C3 and C4 levels, positive ANA (1:640; homogeneous pattern), anti ds-DNA, anti-RNP, anti-SM, anti Ro (SS-A) and anti La (SS-B)
• A girl age 16 years with macroscopic hematuria and proteinuria, with a renal biopsy demonstrating WHO Class IV lupus nephritis; she had low C3 and C4, as well as a highly positive ANA and positive anti ds-DNA titer
• A woman age 24 years with thrombocytopenia, a positive Coombs test, low C3 and C3 levels, and positive ANA and anti ds-DNA titers

Positive ANA, anti-dsDNA, anti-ENA (anti-Ro), anti-Sm and anti-chromatin have been found in individuals with prolidase deficiency even in the absence of clinical findings of SLE [Kurien et al 2013].

Bone manifestations. Among 12 affected individuals reported by Besio et al [2015], short stature was described in seven, osteopenia in six, and genu valgum in four.

Other bone findings include spina bifida of C3 and 13 thoracic vertebrae [Freij et al 1984]; fusion of C2 and C3 [Lacarbonara et al 2014]; and delayed bone age [Pedersen at al 1983, Lacarbonara et al 2014].

Digital clubbing, in the presence and in the absence of pulmonary abnormalities, has also been reported [Luder et al 2007, Kelly et al 2010].

Other manifestations

• Joint laxity [Pasquali Ronchetti et al 1991, Lombeck et al 1986, Kavala et al 2006], including hip dislocation [Arata et al 1979, Ogata et al 1981]
• Protuberant abdomen in five of the first 17 cases reported [Freij et al 1984]
• Obesity [Andry et al 1992]
• Optic and chorioretinal atrophy [Ogata et al 1981], keratitis [Ogata et al 1981, Freij et al 1984] and pathologic myopia [Kiratli & Satilmiş 1998]
• Erosive cystitis (one individual) [Milligan et al 1989]
• Dental dysplasia [Moulonguet et al 1989]
• Autoimmune adrenal failure (one individual) [Luder et al 2007]

Prognosis. The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one [Lupi et al 2006] or all toes [Sekiya et al 1985], whereas others remain entirely asymptomatic.

Two individuals diagnosed through systematic urinary newborn screening in Quebec [Lemieux et al 1984] remained asymptomatic 14 years later [Hechtman 2001].

A man age 26 years, whose younger sister was affected, had imidodipeptiduria and prolidase deficiency in erythrocytes but no clinical manifestations [Isemura et al 1979].

A woman age 29 years, the sister of an affected individual, had absence of prolidase activity in serum or erythrocytes, but no skin ulcers or other clinical manifestations of prolidase deficiency [Lupi et al 2006].

In most instances, individuals with prolidase deficiency experience severe morbidity and early death, usually due to infection.

The individual with probable prolidase deficiency reported by Goodman et al [1968] had died of influenza by the time of a follow-up biochemical report four years later [Buist et al 1972]. He was about age 50 years at the time of death [Royce & Steinmann 2002].

The female reported by Lapiere & Nusgens [1969] died at age 36 years [Endo et al 1990]; she had superinfection of skin ulcers with Pseudomonas aeruginosa, which lead to septic shock and disseminated intravascular coagulation [Royce & Steinmann 2002].

A female died of a fungal infection and disseminated intravascular coagulation [Sekiya et al 1985].

A girl age 16 years with prolidase deficiency and SLE developed cellulitis of the leg, followed by adult respiratory distress syndrome and death [Bissonnette et al 1993].

A male died at 15 years of age of unknown reasons [Endo et al 1990].

A patient age 15 years died of terminal liver failure and cardiac failure [Royce & Steinmann 2002].

A patent age 11 years died of unknown causes [Besio et al [2015].

A boy age eight years with prolidase deficiency and SLE died after developing a facial abscess and septicemia [Shrinath et al 1997].

The youngest reported death was at age four years [Mandel et al 2000].

Genotype-Phenotype Correlations

There are no known genotype-phenotype correlations. Marked phenotypic variability has been found among affected individuals from the same family (who have the same pathogenic variants) [Falik-Zaccai et al 2010].

Nomenclature

Prolidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency.

Prevalence

Approximately 90 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of under-recognition by physicians.

The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal Urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, for an incidence of 1:1,235,000 [Renaud & Dagenais 2009]. Thus, a few thousand cases would be predicted to exist worldwide, as opposed to only 90 cases reported to date.

Prolidase deficiency has been diagnosed throughout the world [Lupi et al 2008].

A founder variant has been described in the Geauga County settlement in Ohio [Wang et al 2006], as well as in the Druze population in northern Israel, the latter with a carrier frequency of 1:21 [Falik-Zaccai et al 2008].

Disorders with Imidodipeptiduria

Imidodipeptiduria has been described in bone disorders, presumably originating from collagen under conditions of high bone turnover.

Glycylproline has been found in the urine of:

• A child with severe bone disease and hyperphosphatasia [Seakins 1963];
• Two sisters with multiple fractures and striking bone deformities of unknown etiology [Alderman et al 1969];
• A woman age 28 years with osteomalacia and severe hyperparathyroidism who excreted large amounts of glycylproline, equivalent to ~1 g/day [Cahill et al 1970];
• Three individuals with rickets [Scriver 1964] who excreted decreasing amounts of glycylproline concomitant with clinical improvement, until the imidodipeptiduria disappeared with recovery from the disease.

Disorders with Skin Ulcers

Werner syndrome is characterized by cancer predisposition and the premature appearance of features associated with normal aging. Findings shared by prolidase deficiency and Werner syndrome are chronic lower extremity ulcers [Sternberg et al 1982, Yeong & Yang 2004, Noda et al 2011], premature graying of the hair, and a "bird-like" facial appearance [Milligan et al 1989, Pasquali Ronchetti et al 1991, Zanaboni et al 1994]. Imidodipeptiduria has not been reported in Werner syndrome. Werner syndrome is caused by biallelic pathogenic variants in WRN and inherited in an autosomal recessive manner.

Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Leg ulcers which are relatively common in SCD were found in 2.5% of patients from the Cooperative Study of Sickle Cell Disease in the US [Koshy et al 1989], in 43% in the Jamaican Cohort Study [Clare et al 2002], and in 1.7% [Akinyanju & Akinsete 1979] to 13.2% [Knox-Macaulay 1983] of Africans.

Although urinary excretion of hydroxyproline has been shown to be significantly increased in persons with sickle cell disease compared to controls [Mohammed et al 1991] (presumably due to bone involvement), glycylprolinuria has not been reported in SCD. More importantly, although individuals with prolidase deficiency can have mild findings of hemolysis, they do not have veno-occlusive episodes. SCD is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.

Beta-thalassemia is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in reduced amounts of hemoglobin A, microcytic hypochromic anemia, and an abnormal peripheral blood smear with nucleated red blood cells. Affected individuals with other hemoglobinopathies such as β-thalassemia can also have chronic leg ulcers [Stevens et al 1977, Gimmon et al 1982, Levin & Koren 2011, Taher et al 2013], but again no imidopeptiduria is known to occur. Persons with prolidase deficiency should have a normal hemoglobin electrophoretic pattern. β-thalassemia is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.

Acquired causes of lower-extremity ulcers include arterial insufficiency, venous insufficiency, pressure ulcers, vasculitis, systemic lupus erythematosus, and infectious etiologies, among others. Although glycineprolinuria could be anticipated in cases of secondary skin ulcers given the high content of collagen in the dermis, a number of patients with extensive skin ulceration have been tested, and imidodipeptiduria was only found when accompanied by severe concurrent bone disease (e.g., multiple fractures) [Sheffield et al 1977].

Disorders with Hyper IgE

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency syndrome characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several connective tissue and skeletal abnormalities like osteopenia, minimal trauma fractures, and scoliosis. AD-HIES is caused by mutation of STAT3. A Grimbacher score of >40 is suggestive of AD-HIES.

Autosomal recessive hyper IgE syndrome (AR-HIES) (OMIM 243700) is a distinct clinical disorder, characterized by elevated serum concentration of IgE, severe eczema, and recurrent skin and lung infections [Renner et al 2004], all of which can also be seen in prolidase deficiency. Prolidase deficiency differs from AD-HIES by an increased incidence of neurologic abnormalities, an increased occurrence of viral infections of the skin (e.g., Molluscum contagiosum, warts) and virus-driven malignancies, as well as absence of the non-immunologic findings of AD-HIES (e.g., connective tissue, skeletal and dental involvement) [Renner et al 2004]. AR-HIES is caused by biallelic pathogenic variants in DOCK8.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the following evaluations are recommended:

• Review of systems to assess for the possibility of pulmonary complications. In those with a history of pulmonary complications, consider chest imaging, pulmonary function tests, an echocardiogram to assess for pulmonary hypertension, and consultation with a pulmonologist.
• Physical examination to evaluate for splenomegaly. If present, perform an abdominal ultrasound examination to evaluate the extent of splenomegaly.
• Complete blood count to evaluate for anemia and thrombocytopenia
• Liver function tests to assess for the possibility of elevated liver enzymes
• Developmental assessment
• Consultation with a wound care specialist
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No curative treatment is available.

Care is preferably provided by a multidisciplinary team. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal.

Click here (pdf) for further details, including treatments in which only partial or short-term benefit was reported.

Prevention of Secondary Complications

Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection.

Antibiotic prophylaxis should also be considered in the appropriate setting.

Surveillance

In the absence of formal surveillance guidelines, the authors recommend:

• Annual:
  • Skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers
  • Complete blood count
  • Liver function tests
  • Abdominal ultrasound examination to assess liver and spleen size
• Follow up as recommended by a pulmonologist and immunologist;
• Follow-up assessments of motor and cognitive development as recommended for educational planning.

Agents/Circumstances to Avoid

Individuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Adenovirus-mediated gene transfer. Ikeda et al [1997] performed transfer of the human prolidase cDNA into fibroblasts from patients with prolidase deficiency. This increased the fibroblast prolidase activity up to 75 times normal.

Intracellular delivery of liposome-encapsulated prolidase. Perugini et al [2005] showed that active prolidase encapsulated in liposomes was completely transported via endocytosis into fibroblasts six days after incubation.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.