Prolidase deficiency (ORPHA:742)
Prolidase deficiency is an inherited disorder of peptide metabolism characterized by severe skin lesions, recurrent infections (involving mainly the skin and respiratory system), dysmorphic facial features, variable cognitive impairment, and splenomegaly.
Epidemiology
The exact prevalence is unknown but a prevalence estimate of 1/1,235,000 live births has been suggested. A higher carrier frequency of 1/21 has been reported in the Druze community. Approximately 90 patients from different ethnic groups have been reported in the literature to date, but due to underdiagnosis the exact number is probably higher.
Clinical description
Clinical manifestations and age of onset are quite variable. Prolidase deficiency can present in infancy with splenomegaly. Diarrhea, vomiting, and dehydration may also occur. Dysmorphic facial features include low anterior and posterior hairline, hypertelorism, proptosis, flat nasal bridge, thin vermilion of the upper lip and prognathism. Skin involvement usually appears during childhood (but can appear as early as 6 months and as late as 30 years of age) with severe, chronic, recalcitrant, and painful skin ulcers of the feet, lower legs and, less commonly, the hands. Telangiectasia of the face and hands may precede ulcers as well as erythematous, maculopapular lesions or purpuric lesions. Most patients have some degree of intellectual disability, ranging from mild to severe. Pulmonary (e.g. asthma-like chronic reactive airway disease), immunologic (susceptibility to infections with recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis) and hematologic (e.g. anemia, thrombocytopenia) manifestations have also been reported. Additional, less commonly reported manifestations include short stature, lymphedema, joint laxity, protuberant abdomen, hirsutism, dental dysplasia and keratitis. Some patients, however, remain asymptomatic. An association between prolidase deficiency and systemic lupus erythematosus (SLE; see this term) has been reported.
Etiology
Prolidase deficiency is due to a mutation in the PEPD gene (19q13.11), encoding Xaa-Pro dipeptidase, which plays an important role in the biosynthesis and degradation of collagen. Mutations in this gene lead to impaired collagen synthesis and wound healing.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings. Urine amino acid analysis reveals massive imidodipeptiduria (10-30 mmol/day) in all cases. Patients also usually have elevated liver enzymes, mild anemia, mild thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia. Molecular genetic testing, identifying a mutation in the PEPD gene, confirms diagnosis.
Differential diagnosis
Differential diagnoses include Werner syndrome, beta-thalassemia, vasculitis (see these terms), autosomal dominant and recessive forms of hyper-IgE syndrome, sickle cell disease, pressure ulcers, and arterial and venous insufficiency.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
Prolidase deficiency is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of transmission to future offspring.
Management and treatment
Treatment is symptomatic. Care should be provided by a multidisciplinary team in order to monitor and treat skin, lung, and immunologic manifestations. Topical proline plus glycine ointment, steroids, methylprednisolone, blood transfusions, plasmapheresis, and topical growth hormone ointment have all been used to treat ulcers, with varying degrees of improvement reported. Antibiotic prophylaxis may be necessary in some cases. In patients with splenomegaly, contact sports should be avoided.
Prognosis
Prognosis varies but patients often have a decreased life-expectancy due to severe and sometimes fatal infections. Quality of life is also reduced due to infections and chronic pulmonary complications. When severe, ulcers can lead to amputation.

                            Last update: 
                            April 2016


                            - Expert reviewer(s): 
                            Dr Heng WANG