GRAND ROUND By DR.Mohamed ALshaikh (Immunologist) and DR.Minosh ALnasef (senior resident)

1. GRAND ROUNDByDR.Mohamed ALshaikh(Immunologist)andDR.Minosh ALnasef(senior resident)

2. Case presentation: History: • Khadija is a 3 month old term pakistani baby girl of birth weight 3.5 Kg presented to SMC with : • History of poor feeding & activity for 5 days • History of fever for 3 days • No history of recent travel • No history of similar condition in other siblings

3. Past history: • Skin rash ( hyper pigmented) at 1 week of age. • History of 1 miscarriage • History of death of 1 sibling at age of 3 month due to sepsis & FTT. • Did not have any medical problems before presenting at 3 month of age to SMC.

4. Physical examination: • Child was hypoactive, lethargic, pale, febrile ( 38.9 ), CFT 3 sec. maintaining all other vitals. • Wt was 4.5 kg ( below centile of growth charts) • Skin: hyperpigmented lesion all over the body • Hair: woolly, sparse hair • Chest, CVS, abdomen, CNS: NAD

5. Patient was admitted with clinical impression of : • To R/O sepsis • FTT for investigation

6. Patient stay in hospital: • From day of admission: full septic workup done & was covered with antibiotics (ampicillin & claforan) • During her stay: pt. had 2 acute episodes • Developed 2 attacks of convulsions • Developed pneumonia, needed intubation & ventilation for 1 week. Baby was covered with broad spectrum antibiotic, IVIG daily for 1 week. She recovered from this acute event.

7. Investigations: • C/S (blood, urine, CSF ): STERILE • CBC: normal WBC , severe lymphopenia, mild eosnophillia, normal peripheral smear • TORSCH: Normal • MRI: slight volume loss at the periventicular white matter • In view of lymphopenia & +ve family history of death of one sibling at 3 month of age with sepsis and FTT, immune workup was done

8. Immunoglobulin level: all immunoglobulin isotypes A, G, M, E : very low. • Lymphocyte subset: no T, B, cells in flowcytometry Therefore immunologist was consulted. In view of the characterstic skin lesions, family history, immune deficieny: skin Biopsy was requested for susspesion of:

9. Incontinential pigmentosa Skin Biopsy showed: normal epidermis with numerous melanophages suggestive of hyperpigmented stage of Incontinential pigmentosa

10. Condition was explained to the parents BMT is needed as soon as possible. • Baby condition improved and was discharged on septrin prophylaxis and IVIG once per week. • HLA typing was done for mother and sister and were awaiting the results.

11. 2 weeks later: baby presented to A/E septic with mouth ulcers and difficulty of breathing. • Baby was intubated, NS boluses given, broad coverage antibiotics started. • However baby arrested, CPR was done but unfortunatily baby passed away

12. What is INCONTINETIA PIGMENTI ???

13. It is an x-linked dominant neurocutenous syndrome characterized by abnormalities of tissues and organs derived from ectoderm and neuro ectoderm. • It represent a type of ectodermal dysplasia associated with: • Cutenous • Neurological • Opthalmological • Dental manifestation

14. Epidimiology • Race: more common in whites but also reported in black and asians • Sex: 95%of reported cases are in female inhereting the mutant IKPKG mutation from their mother or as denovo mutation Rarely occurs in male as it is a( male lethal syndrome) however can occur in:- • Klinfelter syndrome xxy • Somatic mosacium for IKPKG deletion • Hypomorphic mutation in NEMO gene

15. Age : skin lesions appear from birth and develops in 1st few weeks of life. while neurological and ophthalmological sequelle present during early infancy • Mortality & morbidity:- depends on presence & severity of associated extra cutaneous manifestation. • Frequency:- 700 cases are reported in literature only!! Because many mild and uncomplicated cases are likely unrecognized

16. Clinical diagnosis • No strict diagnostic criteria for IP exist • Establishing the diagnosis relies on presence of at least 1 major criteria • Presence of minor criteria supports the clinical diagnosis. Complete absence of minor criteria raises doubt against the diagnosis • Family history:- consistent with x-linked inheritance or multiple miscariages also support the diagnosis

17. Major criteria • Erythema followed by blisters( vesicles) anywhere in the body except the face usually in a linear distribution. the blisters clears within weeks and may be replaced by new crop. This is stage 1 (1st few weeks of life to age of 4 month) • Hyperpigmented streaksand whorls:- that respect Blaschko’s lines occurring mainly on the trunk and fading in adolescence.This is stage 3 ( 4 month to 16 years) • Pale / hairless atrophic linear streaks or patches this is stage 4 ( adolescence upto adulthood)

18. Minor criteria • Teeth:- hypodontia or anodontia abnormally shaped teeth • Hair:- vertex alopecia, woolly hair • Nail :-mild ridging, pitting or curved nails • Retina :- peripheral neurovascularization.

19. History 1) H/O cutenous manifestation occuring since birth in a characterstic chronological sequence: Stage 1:vesicular stage (blister like bullous eruption) Stage 2:verrucious stage(hypertrophic wart like rash) Stage 3:Hyperpigmented stage Stage 4 :Atrophic /Hypopigmented stage 2)H/O of multiple miscarriges

23. Physical: 1)Ectodermal changes • Skin • Hair : (28- 38%) vertex alopecia (scaring alopecia): hair is sparsce in early childhood later it has a woolly, wiry, coarse • Nail : (7 – 40%) Nail dystrophy (pitting / ridging) • Dental : ( 50- 80%)Delayed eruption,Partial anodontia,Hypodontia Conical or pegged shaped teeth Most common associated oral manifestation are cleft palate and high arched palate

24. 2)Ophthalmological findings: occurs in 20- 35%, usually assymetrical involvment including • Retinal manifestations:- Retinal detachment, proliferative retinopathy, viterous hemmorhage, atrophy of ciliary body • Non retinal manifestations:- Strabismus, optic nerve atrophy Conjunctival pigmentation Cataract, strabismus, nystagmus, uveitis

25. 3)Neurological :- occurs in 30% of cases • Seizures: it is the most common neurological complication which develops within first few weeks of life. It can be present before cutenous manifestation • Ataxia, spatic paralysis, microcephally • Porencephally, periventicular hemmorhagic infarcts which result from micro vascular vaso occlusive ischemic events, inflammation and apoptosis affecting mainly small and medium sized arteries • Developmental delay, intellectual disabilities.

26. Other abnormalities:- • Breast: aplasia of breast, supernumerary nipples. • Skeleton : hemivertebrae, scoliosis, skull deformities • Spina bifida • Ear anomalies. • CVS: cardiopulmonary failure primary pul. HTN

27. Can patients with incontinentia pigmentosa a skin disease present as immune defficient disease ?

28. Pathophysiology:- • IP is caused by deletion of exon 4-10 of IKPKG present on xq28 • What is IKPKG: (inhibitor of kappa light polypeptide gene enhancer in B-cell kinase gamma) It is 10 exon gene which encodes the regulatory subunit of the inhibitor of kappa B complex, (IKK) complex which activates NF-Kappa B resulting in activation of gene involved in Inflammation Immunity Cell survival, apoptosis

29. NF-KB :( nuclear factor kappa-light chain enhancer of activated B cell) • Previously called NEMO • It is a protein complex that controls the description of DNA; its activation promotes the expression of 100 target genes which include: • Cytokines • Chemokines • Adhesion receptors • Protein involved in antigen presentation • Receptors for immune recognition

30. So NF-KB or previously called NEMO is considered as: the central mediator of immune response • Impaired but not total abolishment of NF-KB results in immunological defect. while total abolishment is not compatible with life that explains why IP is lethal for male fetus

31. Incontinentia pigmentosa is the first genetic disorder to be ascribed to NF-Kappa (NEMO) dysfunction.

32. Patients with NEMO mutation or NF-Kappa B dysfunction usually suffers from: • Severe life threatening bacterial infection • Recurrent bacterial infection of lower Resp. tract, skin, soft tissue, bones, GIT, meningitis, septicemia in early childhood. Causitive organism:- • Gram +ve bacteria ( s.pneumonia, st. aureus) followed b • Gram –ve bacteria ( pseudomonas species, H. influenza) • Mycobacteria As a comparison ,SCID does not cause enviroment mycobacteriosis so early in life.

33. Immunologically :- • Hypogammaglobulinemia with low serum IgG, IgE • IgM may be elevated resembling ( hyper IgM syndrome) • Normal to high W.B.C • Lymphopenia • Eosinophilia

34. Take home message: Neonatal examination: skin hypo or hyperpigmentation is more to take for further investigations. Don’t forget NEMO

35. Thank u