PATTERN ICHTHYOSIS IN A NEWBORN

Rachael Cayce, M.D., Andrew P. Word, Nnenna Agim, M.D., and Kim B. Yancey, M.D.

Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas

Case PresentationA newborn boy was evaluated shortly after birth forgeneralized ichthyosis. He was born by spontaneousvaginal delivery to a 39-year-old G5P1A3 carrying amethionine tetrahydrofolate reductase mutation trea-ted with heparin at 38 weeks gestation. Stunted growthof his femurs at 34 weeks noted on sonography com-plicated his prenatal course. The mother had general-ized ‘‘dry skin’’ at birth, which subsequently becamelimited in distribution, and complained of ‘‘scars’’involving her arms and legs that were red, scaly, andhairless. She mentioned having persistent hairless pat-ches on her scalp present since birth and denied havingfocal loss of skin in these areas at birth. She deniedproblemswith vision or hearing. Shewas short (5¢1) buthad no scoliosis. She had given birth to a girl with skinfindings similar to those of the newborn boy; howevershe had given the newborn girl for adoption, so she wasunsure about subsequent changes in her skin or overallhealth.

Physical examination of the baby boy revealedgeneralized faint erythema with overlying fine scale onthe trunk and extremities in a whorled pattern (Fig. 1).There was no ectropion, eclabium, or collodion mem-brane. There were patches of nonscarring alopecia onthe right vertex and temporal scalp, and he had sparseeyebrows and eyelashes. The scrotal sac was wellformed, but no testes were palpated. There was noobvious limb asymmetry, but the right foot showedlimited plantar flexion. There were no gross ophthal-mologic, mucosal, or nail abnormalities. Examinationof the mother revealed linear, whorled erythematouspatches with fine scale on the upper and lower

extremities and areas showing follicular atrophoderma(Fig. 2). She was also noted to have several patches ofnonscarring alopecia on her vertex.

Skeletal radiographs were performed on the baby(Fig. 3).

What is the diagnosis?

A GIRL WITH ECZEMATOUS LESIONS, MULTIPLE RECURRENT SKIN

ABSCESSES AND MUCOCUTANEOUS CANDIDIASIS

Gisela Hebe Petiti Martin, M.D.,* Marıa Villar Buil, M.D.,* Mar Burgues Calderon, M.D.,* Luis M. Allende, M.D.,� and Javier Ortız Frutos, M.D.**Department of Dermatology, Hospital 12 de Octubre, Madrid, Spain, �Department of Immunology, Hospital 12 de Octubre, Madrid, Spain

Case PresentationA 6-year-old girl presented with skin abscesses on thescalp. Her medical history included pustular andeczematous lesions (Figs. 1 and2) that beganwithin thefirst months of her life affecting the face, trunk, andarms and recurrent skin abscesses, oral candidiasis, anddiaper dermatitis. There had also been four episodes ofpneumonia and otitis media that had required hospi-talization. Her father had a history of recurrent skinabscesses, pyogenic pneumonia, eczematous lesions,and scoliosis.

Physical examination revealed an unusual facieswith a broad nose, a prominent forehead, and deep-seteyes; angular cheilitis with fissures; and white plaqueson the oral mucosa (Fig. 3). There were also abscesseson the occipital region and dry white scales over theentire scalp (Fig. 4).

Laboratory data showed eosinophilia (960cells˚mL; normal 180–530 cells˚mL) andhigh serumimmunoglobulin (Ig)E (1900 IU˚mL; normal 2–600 IU˚mL); IgG, IgA, and IgM were all normal.

A skin biopsy was performed for histopathologicanalysis, and samples were taken from the abscess andoral lesions for culture.

What is the diagnosis?

RECURRENT STERILE PUSTULES AND PAPULES IN A 7-MONTH-OLD

INFANT

Xiaoran Zhang, M.S., Nicolas Hunzelmann, M.D., and Iliana Tantcheva-Poor, M.D.Department of Dermatology, University of Cologne, Germany

Case PresentationA 7-month-old healthy white girl presented with a 3-month history of recurrent papules and pustules thatinitially began on her arms and abdomen. The cropsoccurred once monthly and lasted for approximately5–7 days. Topical treatment with fusidic acid creamand Octenisept Solution (Schuelke and Mayr,Norderstedt, Germany) and systemic therapy withclarithromycin, cefaclor, erythromycin, and amoxicil-lin˚ clavulanic acid had been unsuccessful. Clinicalexamination revealed confluent pustules with yellowcrusting on the patient’s scalp and scattered pin-point-sized papulopustules on the extensor aspects of herlower arms and abdomen (Fig. 1A, B). With theexception of a single methicillin-resistant Staphylococ-cus aureus–positive smear, the child’s cultures for bac-teria and fungi were repeatedly negative. Prick tests forcommon airborne and food allergens were negative.The patient’s family history was positive for atopy.

What is the diagnosis?

PEDIATRIC DERMATOLOGY PHOTOQUIZEditor: Maureen Rogers, M.D., F.A.C.D.

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Diagnosis: Conradi-Hunermann-Happlesyndrome (X-linked dominantchondrodysplasia punctata) in amale infant.

InvestigationsSkeletal radiographs showed multiple punctate calcifi-cations throughout the thoracic and lumbar spine,acetabula, proximal femurs, anddistal tibias.Therewasno asymmetric limb shortening noted (Fig. 3). Meta-bolic analysis with gas chromatography—mass spec-trometry sterol quantification was performed anddemonstrated high levels of 8(9)-cholesterol, consistentwith a diagnosis of Conradi-Hunermann-Happle syn-drome.

DiscussionChondrodysplasia punctata (CDP) is a heterogeneousgroup of disorders characterized by transient cartilag-inous stippling of growing bones observed radio-graphically. Only some of the described associateddisorders demonstrate cutaneous manifestations (1,2).Most of these conditions are inherited, but CDP mayalso result from vitamin K deficiency in the form ofwarfarin embryopathy, although this entity is notassociated with skin findings, and the patient’s motherdenied use of warfarin for her coagulopathy (2).

The X-linked recessive form of CDP may mani-fest an X-linked pattern of ichthyosis through a con-tiguous gene deletion involving steroid sulfatase, whichis associatedwith cryptorchidism. There are three typesof autosomal-recessive rhizomelic CDP, all due toperixosomal mutations, which present with character-istic proximal limb shortening (rhizomelia) and ich-

thyosis in an estimated 50% of cases without acharacteristic pattern (1,3).

X-linkeddominantCDP, also knownasConradi-Hunermann-Happle syndrome (CHH), presents withasymmetric findings given the mosaic distribution ofthe disrupted gene. These include a blaschkoid patternof fine scaling at birth that quickly resolves and is re-placedbyblaschkoidpatchesof erythemaand follicularatrophoderma (2). Other features include patches ofscalp alopecia and unilateral cataracts. Skeletalabnormalities may include facial asymmetry, asym-metric limb reduction, scoliosis, and short stature (4).

The blaschkoid presentation of skin findings inour patient, in combination with his mother’s exami-nation findings, was suggestive of a diagnosis of CHHfor mother and son. Because most individuals withCHH are female because of the lethal nature of themutation in a hemizygous male (XY), genetic evalua-tion for other forms of chondrodysplasia punctatawithcryptorchidism (such as X-linked recessive) wereundertaken.

CHH results from mutations in the emopamilbinding protein (EBP) gene, which encodes a 8-7 sterolisomerase (1,3). Deficiency of this enzyme interruptscholesterol biosynthesis, resulting in accumulation of 8-dehydrocholesterol and 8(9) cholesterol, which is dif-ferent from other forms of CDP (3). By demonstratinghigh levels of 8(9)-cholesterol, the diagnosis of CHHcan be confirmed. Cutaneous histology may demon-strate characteristic transient dystrophic calcification offollicular keratotic plugs (2).

Most males diagnosed with CHH have beendemonstrated to have a 47, XXY karyotype withresulting lyonization. Other males have carried post-zygotic mutations or less-severe mutations in EBP (4).

In our patient, the blaschkoid ichthyosiform erythema(characteristic of mosaicism) suggested an underlyingXXY karyotype and gave an explanation for the pa-tient’s cryptorchidism. Use of fluorescence in situhybridization analysis allowed diagnosis of the pa-tient’s 47, XXY karyotype. These results hold signifi-cant implications for genetic counseling because it islikely that the mother carries a mutation lethal to 46,XY male offspring.

The stippling noted at birthmay lead to abnormalgrowth of bones and is the most common cause ofmorbidity as the child develops. Abnormal skeletalshortening and facial asymmetry may arise. Since pre-sentation, the patient has developed bilateral cataractsand torticollis but has not manifested skeletal abnor-malities.

References1. Irving MD, Chitty LS, Mansour S et al. Chondrodysplasia

punctata: a clinical diagnostic and radiological review. Clin

Dysmorphol 2008;17:229–241.

2. Hoang MP, Carder KR, Pandya AG et al. Ichthyosis and

keratotic follicular plugs containing dystrophic calcification in

newborns: distinctive histopathologic features of x-linked dom-

inant chondrodysplasia punctata (Conradi-Hunermann-Happle

syndrome). Am J Dermatopathol 2004;26:53–58.

3. White AL, Modaff P, Holland-Morris F et al. Natural history of

rhizomelic chondrodysplasia punctata. Am J Med Genet A

2003;118A:332–342.

4. Furtado LV, Bayrak-Toydemir P, Hulinsky B et al. A novel X-

linked multiple congenital anomaly syndrome associated with an

EBP mutation. Am J Med Genet A 2010;152A:2838–2844.

Address correspondence to Rachael Cayce, Department of Derma-tology, University of Texas Southwestern Medical Center, 5939Harry Hines Blvd, Dallas, TX 75390, or e-mail: rachaelcayce@gmail.com.

Diagnosis: Autosomal-dominanthyperimmunoglobulin E syndrome(AD-HIES).

Laboratory Findings and Clinical CourseThe skin biopsy showed a normal epidermis. In thedermis, there was a superficial, perivascular, and peri-adnexal infiltrate of lymphocytes and scattered eosin-ophils.

A culture of the samples from theoccipital abscessand the oral lesion were positive for Staphylococcusaureus and for Candida albicans, respectively.

The National Institutes of Health (NIH) scoringsystem (1)wasused todiagnoseAD-HIESand revealeda total score of 37.

We conducted a mutational search in all exons ofthe signal transducer and activator of transcription 3(STAT3) gene. Direct sequencing analysis was per-formed with genomic DNA isolated from peripheralblood leukocytes. As a result, we identified a hetero-zygous A-to-G change leading to substitution of thre-onine at the amino acid position 714 to alanine(p.T714A) affecting the transactivation domain of theprotein. The patient’s father was also heterozygous forthe mutation described.

These findings are consistent with a diagnosis ofAD-HIES. She was treated with trimethoprim-sulfa-methoxazole, nystatin, topical steroids, emollients, andintravenous immunoglobulins (500 mg˚kg permonth). She continues having recurrent skin abscessesbut had had no new episodes of pneumonia.

DiscussionHIES is a rare primary immune deficiency character-ized by high serum IgE, dermatitis, and recurrent skin

and lung infections. Davis and colleagues (2) firstdescribed it as Job’s syndrome in 1966. The term‘‘hyper-IgE syndrome’’ was introduced when high ser-um IgE levels were reported in the condition (3).

HIES can be inherited in an autosomal-dominant(AD) or autosomal-recessive (AR) manner or, in somecases, occur sporadically. Individuals with AD-HIESoften present with pustular and eczematous rasheswithin the firstmonth of life (typically affecting the faceand scalp), recurrent pulmonary infections, pneumato-celes, staphylococcal skin infections, mucocutaneouscandidiasis, and abnormalities of bone and connectivetissue (including the characteristic facies, retained pri-mary teeth, high arched palate, scoliosis, fractures withminor trauma, and hyperextensibility of joints).

In 2007, Minegishi and colleagues and Hollandand colleagues independently identified the causativemutations in AD-HIES, which are heterozygousmutations in the gene encoding the STAT3 gene (4,5).

The generation of a nonfunctional STAT3 alleleaffects the development of interleukin-17, producingTH17 effector T cells, which are thought to play aprominent role in controlling infectious agents, such asextracellular bacteria and fungi (6).

In contrast, AR-HIES is characterized by recur-rent viral infections (molluscum contagiosum and her-pes simplex) and involvement of the central nervoussystem without connective tissue and bone abnormali-ties.AR-HIEShas nowbeen associatedwithmutationsin the dedicator of cytokinesis 8 gene and the tyrosine-kinase 2 gene (7,8).

In 1999, the NIH clinical HIES scoring systembased on 19 clinical and laboratory findings wasintroduced (1). A score of 40 or greater suggest HIES,whereas a score less than 20 makes the diagnosis un-likely. For intermediate values, no firm conclusion can

be reached. Therapy for AD-HIES remains largelysupportive. Antimicrobial prophylaxis may be used toprevent Staphylococcus aureus skin and lung infection.Pneumonia should be treated aggressively with the aimof preventing permanent parenchymal damage.

AcknowledgmentsLuis I. Granado, M.D., Department of Pediatrics,Hospital 12 de Octubre, Madrid, Spain.

References1. Grimbacher B, Schffer AA, Holland SM et al. Genetic linkage of

hyper-IgE syndrome to chromosome 4. Am J Hum Genet

1999;65:735–744.

2. Davis SD, Scaller SJ, Wedgwood RJ. Job’s syndrome: recur-

rent, ‘‘cold,’’ staphylococcal abscesses. Lancet 1966;1:1013–

1015.

3. Buckley RH, Wray BB, Belmaker EZ et al. Extreme hyperim-

munoglobulinemia E and undue susceptibility to infection.

Pediatrics 1972;49:59–70.

4. Holland SM, DeLeo FR, Elloumi HZ et al. STAT3 mutations in

they hyper-IgE syndrome. N Engl J Med 2007;357:1608–1619.

5. Minegishi Y, Saito M, Tsuchiya S. Dominant-negative mutations

in the DNA-binding domain of STAT3 cause hyper-IgE syn-

drome. Nature 2007;448:1058–1062.

6. Renner ED, Rylaarsdam S, Anover-Sombke S et al. Novel

signal transducer and activator of transcription 3 (STAT3)

mutations, reduced T(H)17 cell numbers, and variably defective

STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin

Immunol 2008;122:181–187.

7. Engelhardt KR, McGhee S, Winkler S et al. Large deletions and

point mutations involving the dedicator of cytokinesis 8 (DOCK8)

in the autosomal-recessive form of hyper-IgE syndrome. J

Allergy Clin Immunol 2009;124:1289–1302.

8. Minegishi Y, Saito M, Morio T et al. Human tyrosine kinase 2

deficiency reveals its requisite roles in multiple cytokine signals

involved in innate and acquired immunity. Immunity 2006;

25:745–755.

Address correspondence toGiselaHebePetitiMartin,M.D.,AvdadeCordoba S/N, 28041 Madrid, Spain, or e-mail: gisepetiti@hotmail.com.

Diagnosis: Infantile eosinophilic pustularfolliculitis (I-EPF).

Microscopic and Laboratory FindingsA biopsy from lesions on the scalp and abdomen re-vealed a dense perifollicular and follicular infiltratecomposed chiefly of eosinophils (Fig. 2). Completeblood count during the crops repeatedly showedeosinophilia of up to 26.8%. Serum immunoglobulin(Ig)E level was normal.

DiscussionI-EPF is a rare sterile pustulosis of childhood first de-scribed by Lucky et al (1). It typically presents in thefirst 3–10 months of life with recurrent pruritic crops ofpustules and papulopustules on an erythematous base.As in our case, the lesions are most prominent on thescalp but may also be found on other body parts. Thecrops usually occur every 3–4 weeks, and last forapproximately 1 week; the condition usually resolvescompletely by the age of 3–5 years. Negative cultures

for bacteria, fungi, and viruses are also characteristic.Active disease is associated with systemic eosinophiliain 70% of patients. In our patient, the pustules andblood eosinophilia responded to topical methylpred-nisolone and cetirizine.

I-EPF, infantile acropustulosis, and eosinophilicpustulosis of the scalp are most probably differentmanifestations of the same disease. The pathogenesis isstill unknown. In some cases of I-EPF, hypersensitivityto the house dust miteDermatophagoides pteronyssinushas been suggested as a possible cause (2).

Histology reveals dense folliculocentric infiltratesof eosinophils with epidermotropism and spongiosis ofthe infundibular epithelium. Because of the more pro-nounced interfollicular involvement in some patients,‘‘eosinophilic pustulosis’’ has been proposed as amore-accurate name (3). In contrast to the adult formofEPF,known as Ofuji’s disease, there is no association withthe human immunodeficiency virus, and pustules donot form circinate plaques with central cleaning.

The differential diagnosis of I-EPF includes scalppyoderma, scabies, herpetic and fungal folliculitis, andLangerhans cell histocytosis. Erythema toxicum neo-natorum, transient pustular melanosis, miliaria, con-genital syphilis, candidosis, and listeriosis should beadditionally considered inneonates (4).Aneosinophilicpustular eruption with leukocytosis and markedeosinophilia was described in a preterm neonate whowas the donor in twin–twin transfusion syndrome andwas given intravenous immunoglobulin and granulo-cyte colony-stimulating factor (5). Chamlin et al (6)described eight infants with eosinophilic papulopus-tules on the scalp and cheeks who were diagnosed withhyper-IgE syndrome an average of 18 months later. Inretrospect, all of these children had also had earlyrecurrent infections, unexplained fever, or signs ofosteopenia.

We considered papular urticaria (PU) as a possi-ble cause of the lesions on our patient’s trunk andextremities. PU is a hypersensitivity reaction toarthropod bites and usually occurs as itchy papulove-sicles during summer and early fall. In our patient, thecrops on the trunk persisted in the winter months andcoincided with extensive pustules on the scalp. Thecrops persisted when the child wasmoved to a differentenvironment.

In conclusion, I-EPF is a rare disease that shouldbe included in the differential diagnosis of recurrentinfantile pustulosis. It is a benign condition, and accu-rate diagnosis will prevent inappropriate antibiotictreatments, as in our patient. Patients should be fol-lowed for systemic symptoms such as infections, fever,and fractures because very rarely I-EPF could be thepresenting manifestation of hyper-IgE syndrome.

References1. Lucky AW, Esterly NB, Heskel N et al. Eosinophilic pustular

folliculitis in infancy. Pediatr Dermatol 1984;1:202–206.

2. Boone M, Dangorsse C, Andre J et al. Eosinophilic pustular

folliculitis in three atopic children with hypersensitivity to

Dermatophagoides pteronyssinus. Dermatology 1995;190:164.

3. Taieb A, Bassan-Andrieu L, Maleville J. Eosinophilic pustulosis

of the scalp in childhood. J Am Acad Dermatol 1992;27:55–60.

4. Van Praag MCG, Van Rooij RWG, Folkers E et al. Diagnosis

and treatment of pustular disorders in the neonate. Pediatric

Dermatol 1997;14:131–143.

5. Ladrigan MK, LeBoit PE, Frieden IJ. Neonatal eosinophilic

pustulosis in a 2-month old. Pediatr Dermatol 2008;25:52–55.

6. Chamlin SL, McCalmont T, Cunningham BB et al. Cutaneous

manifestations of hyper-IgE syndrome in infants and children.

J Pediatr 2002;141:572–575.

Address correspondence to Xiaoran Zhang, Medical ScientistTraining Program, University of Pittsburgh, 3550 Terrace Street,Room 526, Pittsburgh, PA, 15261, or e-mail: zhang.xiaoran@medstudent.pitt.edu.

Figure 2.

RECURRENT STERILE PUSTULES AND PAPULES IN A 7-MONTH-OLD

INFANT

PATTERN ICHTHYOSIS IN A NEWBORN

A GIRL WITH ECZEMATOUS LESIONS, MULTIPLE RECURRENT SKIN

ABSCESSES AND MUCOCUTANEOUS CANDIDIASIS

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