prolidase deficiency

1. PID forum-
Hyper IgE overlap syndrome - Prolidase
deficiency
Ritasman Baisya
6.1.2021

2. Patient information
• 5 year old male child
• Born out of third degree consanguineous marriage
• First OPD visit in Oct ,2020
• Referred from Medical Genetics

3. Chief complaints
• H/O recurrent ear discharge from 4 months of age
• H/O recurrent skin lesions with purulent discharge from 1 yr of age

4. History of present illness
• Recurrent ear discharge from 4 months of age – both ear , occasionally
purulent , with pain , most of time treated with topical antibiotic .
• Recurrent skin lesions from 1 year of age - Most of the lesions are papular
associated with itching, occasional pustules with purulent discharge
present over lower and upper limb
• At 1 year of age , he had two pneumonia episodes for which
hospitalization required , later subsided .

5. History continues
• No H/O of fever ,
• No H/O loose stool , pain abdomen , neurological complaints
• No H/O blood transfusion
• No H/O delayed separation of umbilical cord
• No H/O TB or TB contact .
• No H/O repeated fall or fracture

6. History in elder sister
• Her elder sister had on and off eczematous rash over both lower limb
since 1 year age
• At 7 yr age - She was admitted outside with multiple eczematous rash
, cervical lymphadenopathy and abdominal distension
• She had also right lower zone pneumonia
• She succumbed to pneumonia
• Her reports showed IgE – 2500 mg /dL , NIH score 40

7. Pedigree analysis

8. Examination
Ht- 107 cm
Wt -20 Kg
HC – 48 cm
Multiple healed papular lesions over extensor surface of hands and legs
Small cervical lymph nodes
MSK – hyperextension of the joints , no deformity
P/A – spleen palpable -3 cm below costal margin
Chest /CVS – normal

9. Facial dysmorphology
• Broad and depressed nasal bridge
• Smooth philtrum
• Low set ears
• Thin upper lip
• Maxillary hypoplasia
• High arched palate

10. Investigation
• CBP- 10/11800/2 lakh , AEC-
354
• IgE > 3000 IU /ml
• IgG -1060 mg/dL
• IgM -86 mg/dL
• IgA-241 mg /dL
Lymphocyte
subset
Absolute
count
Percentage Mean
CD3 T cell 2990 81 56-75
CD4 T cell 1642 44 28-47
CD8 T cell 1220 33 16-30
CD4/CD8 1.3
CD19 B cell 342 13 14-33
CD16,CD56
NK cell
94 3.6 4-18

11. NIH scoring system

12. NIH scoring – 41
• Higher serum IgE > 2000 – 10
• Skin abscess – 8
• Pneumonia ( episodes over lifetime ) – 4
• Parenchymal lung anomalies – 0
• Retained primary teeth – 2
• Scoliosis , maximum curvature – 0
• Fracture with minor trauma – 0
• Highest eosinophil count – 0 (354 )
• Characteristic facies – 5
• Midline anomaly – 0
• Eczema – 4
• URTI / yr – 0
• Candida -0
• Fatal infection – 0
• Hyperextensibility – 5
• Lymphoma – 0
• Increased nasal width – 1
• High arch palate – 2
• New born rash – 0
• Other serious infection – 0
• Age – 6 yr – 0

13. Genetic Result

14. Final diagnosis
This is a case of Hyper IgE overlap syndrome associated with prolidase
enzyme deficiency

15. Hyper IgE syndrome
• The Hyper-immunoglobulin E syndromes (HIES) are rare primary
immune deficiencies characterized by elevated serum IgE, dermatitis
and recurrent skin and lung infections
• Job’s syndrome: described in 1966
• Reference to the Biblical Job who was “ smote with sore boils”
• Incidence in western countries - 1/ 1 million
• Male: female 1:1

16. Types of HIES
• AD-Hyper-IgE Syndrome ( STAT3 Deficient) /Job syndrome
• AR-Hyper-IgE Syndrome ( DOCK8 Deficient)
• AR-Hyper-IgE Syndrome ( Tyk2 Deficient)
• Hyper IgE overlap syndrome – Dubowitz , Saethre-chotzen , Prolidase
deficiency

17. Clinical features of AD-HIES
• Newborn rash on face & scalp ( pustular) –
Worsen by S.aureus
• After NB period- cutaneous abscess, mucocutaneous candidiasis, infected dermatitis
of axilla & groin etc.
• Recurrent pneumonia in early childhood –
S. aureus is the commonest followed by Strep. pneumoniae, H. influenzae .
lack of fever & systemic signs of inflammation .
• Pneumatocele & bronchiectasis that accumulate aspergillosis & gram negative
bacteria .
• Molds invade blood vessels & resulting to hemoptysis & disseminated infection –
• Other opportunistic infections; Pneumocystis jiroveci, histoplasmosis, muco-
cutaneous candidiasis
Clin Rev Allergy Immunology ,2001

18. Somatic features
• Face - asymmetry, broad fleshy nose & porous skin
• Neurological- Arnold-Chiari I malformation(20% of cases), cranio-synostosis
• Bone- minimal trauma fractures, osteopenia, hyper-extensibility, scoliosis & joint
degeneration
• Failure of primary teeth extraction
• Vascular abnormalities- aneurysm, lacunar infarction
• Malignancy- non-Hodgkin, Hodgkin & leukaemia
• Esophageal dysfunction

20. Common organisms causing skin infection
Medicine , Baltimore 2012

21. Clinical Characteristics of AR-HIES
• Eczema
• Boils
• Recurrent pneumonia without pneumatoceles
• Sepsis
• Mucocutaneous candidiasis
• Skin viral infections
• Neurologic symptoms
• Vasculitis
• Increased serum IgE Eosinophilia

22. Treatment
• Aggressive skin care and treatment of infection
• Anti bacterial , anti fungal
• Immunomodulator- Levamisole , Immunoglobulin in AD variant
• Curative – Bone marrow transplantation
• Surgical treatment

23. Prolidase enzyme
• Prolidase or proline dipeptidase- unique enzyme capable of degrading dipeptides,
in which a proline or hydroxyproline residue is located at the C-terminal position.
• It is of great importance during collagen turnover, inflammation, tissue fibrosis
and skeletal abnormalities
• Prolidase activity in individuals with PD is either knocked out or severely reduced.
• The gene for prolidase (PEPD gene) localized on chromosome 19

24. Prolidase deficiency
• A rare autosomal recessive disorder with numerous skin manifestations.
• Accompanied by mental retardation, facial dysmorphism and susceptibility to
pyogenic infections
• Skin fragility and ulcerations, characteristically involving the lower extremities and
the anogenital area
• Recurrent infections, particularly otitis media, sinusitis and upper respiratory tract
infections, and splenomegaly are also common clinical occurrences
• Patients eliminate excessive amounts of iminopeptides in their urine

25. HIES- PD association
• PD associated with typical features of HIES
• Linkage to the proximal region of chromosome 4q has been reported
in some but not all cases of HIES
• mutations in PEPD may also underlie some cases of HIES, which
present in association with PD
• HIES may be part of PD clinical spectrum of manifestations.

26. A patient presenting a peculiar phenotype combining manifestations of prolidase
deficiency with features typical of hyper-IgE syndrome
Prolidase deficiency associated with hyper-IgE syndrome, a rare disorder, can be
caused by mutations in PEPD.

27. This is a 23 year old man
Diagnosed as HIES at 10 year of age
At age 23 y the diagnosis of PD has been made by the detection of dipeptiduria

28. Take home points
• Hyper IgE syndrome can be dominant ( Job syndrome ) or recessive
• AD HIES – STAT mutation with Pneumonia, pneumatocele, facial features,bone
abnormalities
• AR HIES – Tyk2 /DOCK8 mutation with viral skin infections, sepsis, neurological,
malignancy, food allergy, decreased IgM
• Prolidase enzyme deficiency is an autosomal recessive disease with cutaneous
and somatic manifestations
• Hyper IgE syndrome can be associated with Prolidase deficiency

29. Thank
you