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Prolidase deficiency

Synonym(s) Hyperimidodipeptiduria
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Neonatal
  • E72.8
  • C0268532
  • C1534653
  • D056732
MedDRA -


Prolidase deficiency is an inherited disorder of peptide metabolism (see this term) characterized by severe skin lesions as well as recurrent infections (involving mainly the skin and respiratory system), dysmorphic facial features, variable cognitive impairment and splenomegaly.

The exact prevalence is unknown but prevalence estimates of 1/1,235,000 live births have 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.

The 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 hypertelorism, proptosis, flat nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline. 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. Telangiectasias of the face and hands may precede ulcers. Erythematous, maculopapular lesions or purpuric lesions have also been reported to precede ulcers. Most patients have some degree of intellectual deficiency, but it can range 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. Prolidase deficiency is often associated with systemic lupus erythematosus (SLE; see this term).

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 (a protein essential in maintaining tissue structure and integrity). Mutations in this gene lead to impaired collagen synthesis and wound healing.

Diagnosis is based on clinical and laboratory findings. Urine amino acid analysis reveals massive imidodipeptiduria (10-30mmol/day) in all cases. Patients also usually have elevated liver enzymes, mild anemia, mild thrombocytopenia, hypergammaglobulinemia and hypocomplementemia. Molecular genetic testing can identify a mutation in the PEPD gene, confirming diagnosis.

Differential diagnoses include Werner syndrome, beta-thalassemia, autosomal dominant and recessive forms of hyper-IgE syndrome, vasculitis (see these terms), sickle cell disease, pressure ulcers and arterial and venous insufficiency.

Prenatal diagnosis is possible in families with a known disease-causing mutation.

Prolidase deficiency is inherited in an autosomal recessive manner and genetic counseling can be offered to families with a disease-causing mutation.

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 seen. Antibiotic prophylaxis may be necessary in some cases. In patients with splenomegaly, contact sports should be avoided.

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, chronic pulmonary complications or amputation due to ulcers.

Expert reviewer(s)

  • Dr Heng WANG

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