Scaly§ Skin A Fishy Story

Workshop: Common Allergic Skin Disorders ALLSA Congress Dr Candice Royal Baby S

• First-born to married non-consanguineous parents • Uncomplicated antenatal and birth history • Birth weight 3330g, no abnormalities detected • Discharged after 6 hours • Exclusively breast-fed • Thrived during first month of life Age One Month

• Developed a red and scaly predominantly of the face and scalp • GP visit: • Rx: emollients, topical steroids • Both parents had eczema in childhood- not severe, no other atopic disorders • No family history of any other skin disorder Age Three Months

• significantly deteriorated • No longer growing • Referred to Red Cross Services • Noted to have erythroderma, extensive dry and scaly skin, hair loss • ? Ichthyosiform disorder • Skin biopsy Admission to Red Cross

• Unwell, febrile and losing weight • Missed 10 and 14 week vaccinations • Skin worsened despite emollient wraps • WFA < -3 Z score • WFL < -2 Z score • Referred to general paediatrics for further management ? Serious bacterial infection

Investigations

HIV Rapid Negative

FBC: WCC 28 (N) Hb 9.8 Plts 825

CRP: 94

Renal function and elecs: Normal

TP 51 Albumin 22 Investigations

Blood culture: No growth

Urine dipstix NAD, Micro Neg, Culture Neg

CSF: P 56 L 26 E 16640 Prot 0.29 Gluc 6.2

Skin Biopsy: “favours an ichthyosiform ” Differential Diagnosis

Skin Rash Serious Failure Infection to thrive ? Differential Diagnosis

Inflammatory Skin Disorder

Congenital

Infection

Metabolic: Zinc, CF, Biotinidase deficiency

Primary Immune Deficiency Inflammatory Skin Disorder Inflammatory Skin Disorder

Infection Inflammatory Skin Disorder

Infection

Congenital Ichthyosis Inflammatory Skin Disorder

Infection

Congenital Ichthyosis

Metabolic: Zinc, CF, Biotinidase deficiency Inflammatory Skin Disorder

Congenital Ichthyosis

Infection

Metabolic: Zinc, CF, Biotinidase deficiency

Primary Immune Deficiency Course of Admission

• Rigorous skin care • Nutritional Support • IV Ceftriaxone • Extensive work-up Course of Admission

• Continued Deterioration

• D10 developed rapidly progressive conjunctivitis - Bilateral Perforated Corneal Ulcers - Cultured Pseudomonas

• New sepsis - fever, raised WCC and CRP - Blood Culture: Acinetobacter, Enterococcus Faecalis

Investigations

Congenital Syphillis Excluded

Metabolic: Normal Zinc Faecal Elastase 189ug/g, CF genetics Neg

Immune profile: Normal lymphocyte subsets, IgE 246

Immunocaps Investigations

• Fx5: - IgE to paediatric foods 6.38 - IgE Cow’s milk 1.00 - IgE Wheat 0.15 - IgE Peanuts 24.3 - IgE Soya 0.13 - IgE Fish <0.1 - IgE Egg White 9.62 Diagnosis Progress

• D15 given IVIG • Continued weight loss • Repeated infections incl fungal sepsis • Skin refractory to emollients, topical steroids • Difficulties with IV access and sampling • Feed changed to alimentum • D34 profound hypernatremic dehydration complicated by AKI and neurologic sequelae ICU admission

• Difficulties managing electrolytes and renal function - Peak Na+ 197 - Peak Creatinine 267 • Ongoing episodes of sepsis • MDT decision not for escalation of care • Demise on D 48 of admission Cutaneous Manifestations of PIDD

• Early diagnosis of a PID is critical

• Skin manifestations are present in 40-70%

• Skin manifestations were the presenting features in 39% of total PID Al-Herz et al, Pediatric Dermatology, 2011. • Although not pathognomic skin manifestations should trigger consideration of a PID Skin Primary Immune Deficiency Manifestation

Telangiectasia Ataxia Telangiectasia

Partial Albinism Griscelli syndrome type 2, Chediak-Higashi syndrome and Hermansky– Pudlak syndrome type 2

Eczematous skin rash Hyperimmunoglobulin-E syndrome Autosomal dominant (STAT3 mutation) Autosomal recessive (DOCK8 mutation) IPEX, Wiskott–Aldrich syndrome, Omenn syndrome , Erythroderma Netherton’s syndrome, Omenn syndrome and SCID with graft vs host disease

Epidermal Dysplasia NEMO deficiency, , Papillon–Lefèvre syndrome Eczematous in PIDD

• Eczema affects between 13 % and 22 % of PIDD cohorts studied

• Non-specific eczema in children with humoral immunodeficiencies

• Severe eczema presenting shortly after birth especially with eosinophilia and high IgE levels is suggestive of immunodysregulation Autosomal Dominant HIES

• Caused by STAT 3 mutation

• Characteristic facial, dental, and skeletal abnormalities

• Recurrent infections - Mucocutaneous esp cold staphylococcal - Pulmonary infections with resultant bronchiectasis and/ or pneumatoceles

• Eczema 80-100%

Autosomal Recessive HIES • Caused by DOCK8 or Tyk2 mutations

• Present primarily with immunodeficiency: viral infections (herpes zoster, , varicella)

• Lack the skeletal and facial characteristics of the AD form

• Neurological sequelae

• Eczema in DOCK8 is more severe and occurs in the newborn period in 24%

• High prevalence of other atopic disorders including food allergy

Wiskott-Aldrich Syndrome • X-linked recessive

• Triad thrombocytopenia, eczema and immune deficiency.

• Variable expression but the immunodeficiency is usually characterized by low IgM and IgE high IgA.

• Eczema is present in 81% of patients

• Presentation is usually with petechiae or bleeding Wiskott-Aldrich Syndrome IPEX Syndrome

• Immunodysregulation polyendocrinopathy enteropathy X- linked syndrome

• Linked to the dysfunction of the transcription factor FOXP3- regulator of the regulatory T cell lineage

• Leads to autoimmunity

• Features incl: intractable diarrhoea, endocrinopathies (type 1 diabetes, thyroiditis), eczema, infections Erythroderma

• Involvement of >90 % of the total body surface area with and/or scaling

• A survey of erythroderma in infancy found 48 % of cases to be due to primary immunodeficiency Al-Dhalimi et al, J Derm, 2007

• Specific disorders: Omenn, Netherton’s, SCID Omenn Syndrome

• Autosomal recessive form of SCID • Mutation in RAG1, RAG2

• Clinical features: - Exfoliative erythroderma with diffuse alopecia, - Lymphadenopathy, hepatosplenomegaly - Failure to thrive.

• Leucocytosis with eosinophilia, raised IgE, increased numbers of clonal T cells and decreased B cells with hypogammaglobulinaemia. Omenn Syndrome Netherton’s Syndrome

Classic Triad • Congenital ichthyosiform erythroderma

• Hair shaft defect: trichorrhexis invaginata

• Atopic manifestations Epidemiology

• Inheritance is AR

• Incidence is estimated at 1/200,000 births

• Thought to be the cause of up to 18% cases of congenital erythroderma

• 20% Fatality rate in the first year of life Aetiology

• Mutation on chromosome 5q32, gene SPINK5 (serine protease inhibitor, Kazal type-5)

• Encodes an inhibitor of serine proteases called LEKTI (lympho- epithelial Kazal-type 5 related inhibitor)

• Increase in trypsin-like hydrolytic activity in the stratum corneum causing premature desquamation and a severe skin barrier defect Clinical Features

• Presents at or shortly after birth with non-bullous ichthyosiform erythroderma, may be eczematous

• Erythroderma may be more pronounced with infection

• Pruritus is an inconsistent feature, no white dermatographism

• Palms and soles are normal

• Nails and teeth are unaffected

• Later many develop and/or ichthyosis linearis circumflexa Ichthyosis Linearis Circumflexa Clinical Features

• Severe cases: Failure to thrive Hypernatremic dehydration Recurrent infections Intestinal malabsorption

• 44 Case Reports Hypernatraemic Dehydration in 7% Wasting in 16% Recurrent Infections 30% Smith et al, JACI, 1995. Clinical Features

• Hair is characteristically sparse and easily broken

• Pathognomonic feature: trichorrhexis invaginata “ball and socket defect”

• Pili torti and trichorrhexis nodosa are also seen Tricorrhexis Invaginata

Hair shaft abnormality in which the shaft ‘telescopes’ in on itself at several points along the shaft Tricorrhexis Invaginata Pili torti

Hair shaft defect characterized by short and brittle hairs that appear flattened and twisted when viewed through a microscope (Menke’s) Trichorrhexis Nodosa

Minute nodes are formed in the hair shafts, weakening the hair and causing splitting and breaking Clinical Features

• Other features: delayed growth short stature intermittent aminoaciduria intellectual deficit

• 75% of patients develop atopic manifestations: asthma, atopic dermatitis, food allergies, urticaria, angioedema

• Nut and fish allergy is the most frequently reported food allergy Diagnosis

• Suggestive: eosinophilia, elevated IgE, positive skin prick tests or Immunocaps to food and aeroallergens

• Skin biopsy specimens are generally nonspecific and largely noncontributory in the diagnosis of NS

• Immunostaining of a skin biopsy with a specific monoclonal antibody against LEKTI

• Examination of hairs for the trichorrhexis invaginata

• Molecular diagnosis through identification of the genetic mutation Treatment

• Topical corticosteroids are largely ineffective and may be absorbed in greatly increased amounts rendering these patients particularly susceptible to AE.

• Therapy includes emollients, etretinate, PUVA, topical tacrolimus, and pimecrolimus 1% with moderate and temporary effects

• Ammonium lactate lotion Smith et al, JACI, 199 Wehr et al, J Am Acad Derm, 1988

• Systemic drugs like methotrexate and cyclosporine have been found ineffective Braun et al. Dermatology 1997

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