CASE REPORT

1. CASE REPORT MODERATOR Asst Professor Dr ASHA BENAKAPPA

2. NAME: B\o Laksmamma • SEX : Male • AGE :NB(6hrs) • IP NO :234620 • DOA :27-1-05 at 9.30pm • DOB :27-1-05 at 3.30pm • DOE :28-1-05 at 8.30am

3. OBSTETRIC HISTORY • MA-27yrs • ML-9yrs 2 degree consanguineous marriage • LMP ? EDD ? • EDDs—23-2-05 • Hb:9gms%

4. G5 P4L1D3 • 1— Hospital delivery male NVx died 1day, 9yrs (resp difficulty) • 2– Home delivery female 7yrs FTND A & H • 3—home delivery male N Vx died 1day ,4yrs (resp difficulty) • 4—Hospital delivery male LSCS extracted with similar abnormal skin lesion ,died 2days(resp difficulty) • 5 present one

5. 1 ANC tumkur Pvt hospital 2ANC VVCH 71\2 mon amennorhea T1 –N\o fever ,Rash T2-N\o PIH ,quickening 5month T3-H\o leaking P\V DOA to VVCH 25-1-05at 11.35am because of leaking P\v 2 doses inj Betnesol given H\o Labour pains 27-1-05 at 6am 2USG scan done

6. USG 11/11/04:Single live fetus 25+/-7 days moderately reduced liqour .Fetus shows narrow thorax & protruberant abdomen ? Asphyxiated thoracic dystrophy. USG 14/12/04 :Single live fetus 27+/-1week with breech in lower pole. Delivered live male baby 27-1-05 at 3.30pm breech BCIAB shifted NICU

7. 2 7yrs

8. Wt-2kg • HC-32cms • CC-28cms • Length –45cms • RR-60 /min HR-130/min Temp-N • CFT <2sec .P.I—2.19 DS-6 SS-5

9. Head :hair loss hyperkeratotic scale • Eyes: Severe ectropion is present. The free edges of the upper and lower eyelids are everted. (ectropion) Conjuctival congestion

10. Ears: Pinna --small and rudimentary. • Nose:Flattened • Lips: Severe traction on the lips ---- eclabium and a fixed, open mouth.

11. Extremities • Limbs are encased in the thick hyperkeratosis, resulting in flexion contractures of the arms, the legs, and the digits. • Limb motility is poor . • Circumferential constriction of a limb, leading to distal swelling . • Hypoplasia of the fingers, the toes, and the fingernails

12. Skin: Severely thickened skin with large, shiny plates of hyperkeratotic scale. • Deep erythematous fissures separate the scales . • TESTES:Undescended

13. Weak cry. • Activity :minimal • NBR reflexes-Sucking-weak Moro—absent Grasp –absent Rooting-absent

14. RS:Grunt tachypneoa SCR+ ICR + B\l air entry+ CVS:S1 S2+ PA: no organomegaly

15. PHOTOS

16. VIDEO

17. PRETERM (32+\-2)WEEKS AGA LBW RDS HARLEQUIN ICHTHYOSIS

18. Skin Biopsy • Marked Hyperkeratosis with follicular plugging evident at places.Dermis is thinned out with minimal inflamation. • RESTRICTIVE DERMOPATHY

19. HARLEQUIN ICHTHYOSIS • SYNONYMS:Ichthyosis congenita, keratosis diffusa fetalis, harlequin fetus . • It was described by OLIVER HART in his diary 1750 ,published in 1896. • It was invariably associated with stillbirth or early neonatal death until Lawlor reported a case that survived in 1985.

20. The term harlequin derives from the newborn's facial expression and the triangular and diamond-shaped pattern of hyperkeratosis .

21. Frequency: • Internationally: More than 100 cases have been reported. • Mortality/Morbidity: The mortality rate is high. With neonatal intensive care and the advent of retinoid therapy, some babies have survived the newborn period. They are still at risk of succumbing to systemic infection, which is the most common cause of death.

22. Race: No racial predilection is known. • Sex: No increased risk based on sex is known.

23. Genetics: This disorder occurs in consanguineous relationships; multiple siblings within a family can be affected. • This has led to the supposition of autosomal recessive inheritance. • A new mutation inherited as an autosomal dominant trait has also been suggested

24. History: This condition presents at birth. It may or may not have been diagnosed prenatally in a high-risk family. The history should carefully explore the following questions: • Is the couple consanguineous? • Does the couple have another child with ichthyosis? • Is there a family history of severe skin disorders?

25. Is there a history of intrauterine or neonatal deaths in the couple or their families? • What was the expected date of delivery? • Were decreased fetal movements or intrauterine growth retardation noted during the pregnancy? • Did the mother have a prenatal ultrasound? • Were any prenatal procedures (eg, amniocentesis, fetal skin biopsy) performed?

26. CLINICAL FEATURES • Skin: Severely thickened skin with large, shiny plates of hyperkeratotic scale is present at birth. Deep erythematous fissures separate the scales. • Eyes: Severe ectropion is present. The free edges of the upper and lower eyelids are everted, leaving the conjunctivae at risk for desiccation and trauma. • Ears: Pinnae may be small and rudimentary or absent.

27. Lips: Severe traction on the lips causes eclabium and a fixed, open mouth. • Nose: Nasal hypoplasia and eroded nasal alae may occur. • Extremities • Limbs are encased in the thick hyperkeratosis, resulting in flexion contractures of the arms, the legs, and the digits.

28. Limb motility is poor to absent. Circumferential constriction of a limb can occur, leading to distal swelling or even gangrene. • Hypoplasia of the fingers, the toes, and the fingernails has been reported. Polydactyly has been described.

29. Temperature dysregulation • Thickened skin prevents normal sweat gland function and heat loss. • The infants are heat intolerant and can become hyperthermic.

30. Respiratory status: Restriction of chest-wall expansion can result in respiratory distress, hypoventilation, and respiratory failure. • Hydration status: Dehydration from excess water loss can cause tachycardia and poor urine output.

31. Central nervous system Metabolic abnormalities can cause seizures. CNS depression can be a sign of sepsis or hypoxia. Spontaneous movements may be restricted by hyperkeratosis, making neurologic assessment difficult.

33. Histologic, ultrastructural, and biochemical studies have identified several characteristic abnormalities in the skin of patients. The 2 main abnormalities involve lamellar granules and the structural proteins of the cell cytoskeleton. • The interrelationship between these 2 abnormalities and the mechanism by which they alter desquamation of the skin is poorly understood

34. Abnormal lamellar granule structure and function • Lamellar granules are intracellular granules that originate from the Golgi apparatus of keratinocytes in the stratum corneum. • These granules are responsible for secreting lipids that maintain the skin barrier at the interface between the granular cell layer and the cornified layer. • The extruded lipids are arranged into lamellae in the intercellular space with the help of concomitantly released hydrolytic enzymes. The lamellae form the skin’s hydrophobic sphingolipid seal. • .

35. All patients with harlequin ichthyosis have absent or defective lamellar granules and no intercellular lipidlamellae. • The lipid abnormality is believed to allow excessive transepidermal water loss; lack of released hydrolases prevents desquamation, resulting in a severe retention hyperkeratosis

36. Abnormal conversion of profilaggrin to filaggrin • Profilaggrin is a phosphorylated polyprotein residing in keratohyalin granules in granular cell layer keratinocytes. • During the evolution to the corneal layer, profilaggrin converts to filaggrin via dephosphorylation. • Filaggrin allows dense packing of keratin filaments. Its subsequent breakdown into amino acids occurs prior to desquamation of the stratum corneum.

37. Some patients with harlequin ichthyosis have shown persistence of profilaggrin and absence of filaggrin in the stratum corneum. • A defect in protein phosphatase activity and subsequent lack of conversion of profilaggrin to filaggrin has been implicated in the disorder's pathogenesis. • Abnormal expression of keratin • Abnormal keratohyalin granules

38. Based on the immunohistocytochemical features, harlequin ichthyosis has been classified into 3 types. • Type 1 has a normal expression of keratins. Profilaggrin is present, but filaggrin is absent. Large, stellate keratohyalin granules that look almost normal are present. • In type 2, the hyperproliferative keratins (K6/K16) are present,. Profilaggrin is present, but filaggrin is absent. Keratohyalin granules are abnormally small and rounded.

39. Type 3 has normal expression of keratins. Profilaggrin is expressed in intraepidermal sweat ducts and is barely present in the interfollicular epidermis. Filaggrin is absent. No interfollicular keratohyalin granules are present; but like profilaggrin, keratohyalin can be seen in the keratinizing cells around the sweat ducts.

40. SKIN BIOPSY • The stratum corneum is thick and compact. • Hyperkeratosis may be more marked around hair follicles compared with the interfollicular epidermis. • Cells within the stratum corneum are abnormally keratinized. • Granular, spinous, and basal cell layers appear unremarkable. Inflammatory cells may infiltrate the papillary dermis.

41. Electron microscopy reveals absent or abnormal lamellar granules within the granular layer keratinocytes. • Lamellae are absent in the intercellular spaces between the granular cell layer and the cornified cell layer. • Densely packed lipid droplets and vacuoles are seen within the cytoplasm of the aberrantly cornified cells of the stratum corneum.

42. . Keratohyalin granules may be absent, normal, or abnormally small and globular. • Keratin intermediate filaments within granular cells may have reduced density.

43. TREATMENT • Ensure airway, breathing, and circulation are stable after delivery. • Babies require intravenous access. Peripheral access may be difficult. Umbilical cannulation may be necessary. • Place infants in a humidified incubator. Monitor temperature, respiratory rate, heart rate, and oxygen saturation. Avoid hyperthermia.

44. Once stabilized, transfer newborns with harlequin ichthyosis to a level 3 neonatal nursery. • Apply ophthalmic lubricants to protect the conjunctivae. Bathe infants twice daily. Use frequent applications of wet sodium chloride compresses followed by bland lubricants to soften hard skin and to facilitate desquamation

45. Intravenous fluids are almost always required; neonates initially do not feed well. • Consider excess cutaneous water losses in daily fluid requirement calculations. • Monitor serum electrolyte levels. A risk of hypernatremic dehydration exists. • Maintain a sterile environment to avoid infection

46. Retinoids-- These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes. They modulate keratinocyte differentiation. • Isotretinoin • 0.5 mg/kg/d PO

47. Complications: • Gram-positive and gram-negative sepsis has been reported outside the newborn period. • Children who survive have symptoms that resemble nonbullous congenital ichthyosiform erythroderma, with chronic erythroderma and a fine scale over the whole body. • Relapses of severe ichthyosis with eclabium and ectropion occur. Contractures and painful fissuring of the hands and the feet may occur without adequate topical or systemic therapy.

48. PROGNOSIS • Fulminant sepsis remains the most common cause of death in these infants. • Life expectancy is unknown. A report of survival to 9 years of age has been published. • Both normal intellect and developmental delay have been described. In general, intellectual development is thought to be normal.

49. Prenatal diagnosis • Amniotic fluid samples obtained as early as 17 weeks’ gestation have demonstrated hyperkeratosis and abnormal lipid droplets within the cornified cells. • Fetal skin biopsy can detect harlequin ichthyosis as early as 20 weeks’ gestation; this information is valuable to parents who may be considering aborting the pregnancy because the fetus is affected.

50. Biopsy samples from a number of sites in the fetus reveal the presence of characteristic changes on all skin surfaces, except the mucous membranes. • Prenatal ultrasonography can be used to identify characteristic physical features of harlequin ichthyosis but not until late in the second trimester when enough keratin buildup is present to be sonographically detectable.