CONGENITAL PERIANAL AND ABDOMINAL NODULES

Laura Cuesta, M.D., Isabel Betlloch, M.D., Fernando Toledo, M.D., Irene Ballester, M.D., Almuenda F. Monteagudo, M.D. and Nuria Latorre, M.D.

Department of Dermatology, Hospital General Universitario, Alicante, Spain

A female infant, born at term after a normalpregnancy and delivery, presented to our institution at28 days of age with disseminated purplish skin lesions.No significant family history existed.

According to the mother, the patient had a smallperianal nodule and another nodule on the abdomen atbirth. Subsequently, these lesions increased in size, andnew lesions appeared on the scalp, trunk, arms, andinguinal area. The infant was in excellent general con-dition,with normal growth parameters. On examina-tion at presentation to our institution at 28 days of age,a hard, painless erythematous nodulewas located in theperianal region (Fig. 1), and several slightly purplishnodules, measuring under 0.5 cm in diameter, werelocated on the scalp, trunk, and extremities (Fig. 2). No

hepatosplenomegaly, adenopathy, or changes in theoral mucosa were found.

A complete blood count showed neutropenia andlymphocytosis, with a normal hemoglobin and platelet

count. TORCH serology, including syphilis serology,and chest radiograph, were normal. A skin biopsy wastaken from the perianal lesion. The result is shown inFigs. 3 and 4.

What is the diagnosis?

LACK OF SCALP AND BODY HAIR ON AN 11-MONTH-OLD GIRL

Kirk A. James, B.S.,* Craig N. Burkhart, M.D., M.S.,� and Dean S. Morrell, M.D.�*University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Corolina, �Department of Dermatology, University of North Carolina at Chapel Hill School ofMedicine, Chapel Hill, North Corolina

Case PresentationAn11-month-oldAfricanAmericangirl presentswith alack of scalp or body hair noted since birth. Thepatient’s mother states that her daughter has never hadany hair except for eyelashes. At birth, the girl wasnoted tohave thick anddiscoloredfingernails, aswell astwo natal teeth which were removed at 3 weeks of age.Her development is normal and she is otherwise heal-thy. The mother is unsure if her daughter sweatsnormally.

Family history reveals that the patient’s sister hasnormal skin, hair, nails, and development. Upon que-rying the girl’s father, however, he notes never havinghad a full head of hair. He had sparse hair on his scalpas a child and has regularly shaved his head since.Additionally, he has thin eyebrows with normal eye-lashes.He has thick nails that he persistently treats withoral terbinafine and thick palms and soles that he fre-quently ‘‘scrapes off.’’ The father sweats normally. Thepatient’s paternal grandfather had a similar history.

Physical examination reveals a scalpwithout hair,but with intact hair follicles (Fig. 1). Very short, fineeyelashes are present. She has no eyebrows, and there isno hair found over the rest of her body. Inspection ofher fingernails reveals micronychia with slight distalthickeningand increased convex curvature laterally.Anunusual punctuate hyperkeratosis is present on thefingertips (Fig. 2).

What is the diagnosis?

GENERALIZED XEROSIS AND HYPERKERATOTIC, INFECTED SCALP

LESIONS IN A 7-YEAR-OLD WITH CONGENITAL HEARING IMPAIRMENT

Meredith E. Miller, B.A.,* Frederick W. Henderson, M.D.,� Craig N. Burkhart, M.D.,� and Dean S. Morrell, M.D.�*University of North Carolina School of Medicine, Chapel Hill, North Carolina, �Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill,North Carolina, �Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Case PresentationA 7-year-old boy presents with a progressive hyper-keratotic inflammatory scalp condition,whichhas beencomplicated by recurrent yeast and bacterial infectionsover the past year. His mother notes that flares of scalpdermatitis often seemed to be precipitated by a viralillness. He also has generalized xerosis, chronic muco-cutaneous candidiasis, and chronic otitis externa. Thepatient’s history is significant for abnormal fingernailsat birth, severe cradle cap, bilateral sensorineuralhearing loss diagnosed at 8 months of age, low basalmetabolic index with poor weight gain, blepharitis, and

repeated episodes of oral candidiasis and otitis media.He has also had increasing episodes of individualcutaneous abscesses on his lower extremities, whichhave been responsive to oral antibiotics.

On physical examination, he is a thin child who iswearing hearing aids and is appropriately responsivein verbal communication. Examination of the scalpreveals a thickened, adherent, hyperpigmented scaleoverlying focal erythematous papulopustules and ero-sions with serosanguinous and pustular crusts (Fig. 1).He has sparse eyebrows and eyelashes, leukonychiawith subungual thickening, stippled keratoses of the

palms and soles, and diffuse fine ichthyotic scale mostprominent on the extensor upper and lower extremities(Figs. 2 and 3).

Immunological evaluation and genetic studieshave been undertaken.

What is the diagnosis?

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

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Diagnosis: Acute Myeloid Leukemia M5a(monoblastic acute leukemia)

InvestigationsThe biopsy revealed an infiltrate occupying the super-ficial, middle and deep dermis, and extending into thesubcutaneous tissue, with cells of different sizes, somewith scant cytoplasm and a large nucleus, and otherswith a kidney-shaped nucleus. Abundant mitoses wereseen. The immunohistochemical study proved positivefor lysozyme, myeloperoxidase, CD43, CD45, CD3,and CD68 with Ki 67 90%, and negative for S100,CD1a, CD34, and CD20. These findings were charac-teristic of a cutaneous infiltration of acute myeloidleukemia. The peripheral blood study revealed no blastcells.

Although the physical examination had notidentified hepatosplenomegaly, the abdominal ultra-sound in turn showed a slightly enlarged liver withhomogeneous parenchyma. Bone marrow aspirationrevealed 100% large blast cells with a rounded nucleusand cytoplasm without granulation. The immunophe-notype showed most of the cells to be promonocytes.The karyotype was found to be 46XX, t(9,11)(p21;q23),with rearrangementof theMLLgene in 83%of the nuclei analyzed.

Based on these data, type M5a acute myeloidleukemia was diagnosed. Fifteen days after the diag-nosis, the patient showed peripheral blood involve-ment; chemotherapy was therefore started with Ara-C,idarubicin, andVP-16according to theSHOPprotocol.Autologous bone marrow transplantation is currentlypending.

DiscussionAlthough leukemia is a common condition in child-hood, congenital leukemia is very rare. The diseaseaffects oneoutof everyfivemillionnewborn infants andrepresents less than 1% of all pediatric leukemias. Anumber of associated factors have been described (1),such as maternal exposure to radiation, high bodyweight at birth, and high levels of insulin-like growthfactors. It is also more common in children with Downsyndrome and Noonan syndrome; these diseasestherefore should be excluded. Acute myeloid leukemiavery often shows 11q23 translocation and MLL generearrangement (2), observed in 83% of the cells ana-lyzed in our patient.

Skin involvement is seen in approximately 25%to30% of all patients, in the form of firm and usuallymultiple purplish nodules (as in our patient), withoccasional petechiae or ecchymoses. The congenitalperianal lesion in our patient was an unusual presen-tation. Skin lesions are more frequent in acute myeloidleukemia than in acute lymphoblastic leukemia. Inmany cases such lesions may be the first manifestationof the disease and may precede bone marrow andperipheral blood involvement (3), as in our case, wherethe peripheral blood study prior to biopsy revealed noblast cells. The diagnosis is established by histopatho-logical study of the bone marrow, which allowsimmunophenotypingof the cells, and thus classificationof the leukemia. Lysozyme and myeloperoxidase posi-tivity in turn allow differentiation from lymphoblasticleukemia. The prognosis of congenital leukemia is verypoor, but it is usually better in the myeloblastic formsthan in the lymphoblastic presentations. A point ofcontroversy iswhether early skin involvement generally

implies a better or poorer prognosis than the absence ofskin lesions (1).

The presence of red-bluish nodules from birth(blueberry muffin baby and its mimics) poses a differ-ential diagnosis including neonatal hemolysis (4), con-genital infections such as rubella, cytomegalovirus, ortoxoplasma, and tumor processes such as Langerhanscell histiocytosis, neuroblastoma, and rhabdomyosar-coma (4–7). The exclusion of the first two conditions isfundamentally established from the clinical history,complete blood count, and serological findings, whiledifferentiation from tumor processes is established bythe histopathological study.

References1. Hofman I, Zane L, Braun B et al. Congenital leukemia cutis with

subsequent development of leukemia. J Am Acad Dermatol

2006;54:22–27.

2. Gu Y, Nakamura T, Adler H et al. The t(4;11) chromosomal

translocations of human acute leukemias fuses the ALL-1 gene,

related to Drosophilia trithorax, to the AF-4 gene. Cell

1992;71:701–708.

3. Torrelo A, Madero L, Mediero I et al. Aleukemic congenital

leukemia cutis. Pediatr Dermatol 2004;21:458–461.

4. Bacchetta J, Douvillez B, Warin L et al. Leucemie aigu

neonatale et blueberry muffin syndrome: propos dn cas

spontanement regressif. Arch Pediatr 2008;15:1315–1319.

5. Metha V, Balachandran C, Lonikar V. Blueberry muffin baby: a

pictoral differential diagnosis. Dermatol Online J 2008;14:8.

6. Inamadar AC, Palit A, Mankare R et al. Multiple skin nodules in

an infant. Pediatr Dermatol 2009;26:473–474.

7. Sankilampi U, Huikko-Tarvainen S, Krj V et al. Congenital

Langerhans cell histiocytosis mimicking a ‘‘blueberry muffin

baby.’’ J Pediatr Hematol Oncol 2008;30:245–248.

Address correspondence to Laura Cuesta Montero, M.D., Depart-ment of Dermatology, Hospital General Universitario, Pintor Baeza12, 03010 Alicante, Spain, or e-mail: lcuestamontero@hotmail.com.

Diagnosis: Hidrotic ectodermal dysplasia

DiscussionHidrotic ectodermal dysplasia (HED, Clouston’s syn-drome) is a rare autosomal dominant genodermatosischaracterized by hypotrichosis, palmoplantar hyper-keratosis, and nail dystrophy. It is a type of ectodermaldysplasia (ED), which is a group of disorders thataffects tissues derived from embryonic ectoderm. HEDis most common in those of French-Canadian descentbut has been described in other ethnicities (1). It arisesfrom mutations in the human GJB6 gene, whichencodes the protein connexin 30 (2) Connexins formlarger connexons that ultimately create gap junctionsbetween cells, allowing direct cellular communication.Genetic testing was positive in our patient.

Manifestations of HED are variable, but somedegree of hypotrichosis, palmoplantar hyperkeratosis,and nail dystrophy must be present. Sweat glands andteeth are usually normal. Nail dystrophy and pal-moplantar hyperkeratosis begin in infancy or child-hood and worsen with age (3) Hypotrichosis maypresent as early as birth and ranges frompartial to totalalopecia. Any present scalp or body hair is dry, thin,brittle, and scant. Eyebrows and eyelashes are sparse orabsent.The absence of eyelashes increases susceptibilityto conjunctivitis and blepharitis (4). Nail features arethe most pervasive and may be the only obvious find-ings in up to 30% of those with HED (5). Nails aresmall, thick, and discolored with subungual hyper-keratosis often present, resulting in a central bulgeand lateral convexity of the nail plate. Punctate

hyperkeratosis of the distal digits around the nail plate,as seen in our patient, is a characteristic finding. Nailsare prone to bacterial and fungal infections. Severepalmoplantar hyperkeratosis, which is not yet evidentin our patient, can lead to skin fissures and secondaryinfections. Other findings include skin hyperpigmenta-tion over joints, strabismus, and cataracts (6). Eccrinesyringofibroadenomas, which may degenerate intoeccrine syringofibrocarcinoma or squamous cell carci-noma, have been associated with HED (7).

Unlike typical HED descriptions, the patient inthis casehadnatal teeth.The combinationofnatal teethand dystrophic nails should have raised suspicion of anED.Pachyonychia congenita (PC), another typeofED,also manifests as a nail dystrophy. Natal teeth arecommonly seen in PC type 2 (PC-2), but hypotrichosis,alopecia and distal punctuate hyperkeratosis are not(8). Molecular genetic testing will separate the twoconditions.

Treatment is based on symptom severity. Foralopecia, wigs can improve aesthetic appearance.Combination therapy with topical tretinoin andminoxidil deserves consideration—a recent case reportnoted that 6 months of therapy increased the density ofscalp hair threefold in a 6-year-old boy with HED (9).First-line agents for symptomatic palmoplantarhyperkeratosis include topical keratolytics and reti-noids (10). Systemic retinoid therapy has been suc-cessfully used to treat more severe symptoms, albeitwith a risk of adverse effects (4). Palliative nail matrixablation may be used in those with persistent parony-chia (4).

References1. Kibar Z, Dube MP, Powell J et al. Clouston hidrotic ectodermal

dysplasia (HED): genetic homogeneity, presence of a founder

effect in the French Canadian population and fine genetic

mapping. Eur J Hum Genet 2000;8:372–380.

2. Essenfelder GM, Bruzzone R, Lamartine J et al. Connexin 30

mutations responsible for hidrotic ectodermal dysplasia cause

abnormal hemichannel activity. Hum Mol Genet 2004;13:

1703–1714.

3. McNaughton PZ, Pierson DL, Rodman OG. Hidrotic ectoder-

mal dysplasia in a black mother and daughter. Arch Dermatol

1976;112:1448–1450.

4. Stein A, Goldsmith LA. Genetic epidermal diseases. Principles

of molecular medicine. Totowa, NJ: Humana Press Inc, 2006.

5. Der Kaloustian VM. Hidrotic Ectodermal Dysplasia 2. Gene-

Reviews 2007. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?

book=gene&part=ed2. Accessed on January 19, 2010.

6. Clouston HR. The major forms of hereditary ectodermal

dysplasia (with an autopsy and biopsies on the anhydrotic

type). Can Med Assoc J 1939;40:1–7.

7. Poonawalla T, Xia L, Patten S et al. Clouston syndrome and

eccrine syringofibroadenomas. Am J Dermatopathol 2009;31:

157–161.

8. van Steensel MA, Jonkman MF, van Geel M et al. Clouston

syndrome can mimic pachyonychia congenita. J Invest

Dermatol 2003;121:1035–1038.

9. Melkote S, Dhurat RS, Palav A et al. Alopecia in congenital

hidrotic ectodermal dysplasia responding to treatment with a

combination of topical minoxidil and tretinoin. Int J Dermatol

2009;48:184–185.

10. Lee RA, Yassaee M, Bowe WP et al. Keratosis Palmaris et

Plantaris. eMedicine Dermatology 2008. http://emedicine.

medscape.com/article/1108406-overview. Accessed on Janu-

ary 27, 2010.

Address correspondence to Kirk A. James, B.S., 312A McCauleyStreet, Chapel Hill, NC 27516, or e-mail: kirk_james@med.unc.edu.

Diagnosis: KID (keratosis, ichthyosis, and

deafness) syndrome

DiscussionNo specific immunodeficiency was found; however,genetic studies conducted at 8 months of age due tohearing loss revealed a connexin-26 gene mutation.

Keratosis, ichthyosis, and deafness syndrome is arare congenital disorder of the ectoderm characterizedby vascularizing keratitis, icthyosis, and sensorineuraldeafness. Less than 100 cases have been documentedsince it was first reported in 1915 by Burns (1). A spo-radic autosomal dominant mis-sense mutation in theGJB2 gene on chromosome 13 leading to defects inconnexin-26 is typically identified. Connexins aretransmembrane gap junction proteins expressed in skinthat regulate epidermal growth and differentiation (2).Defects in connexins result in impaired epithelialhomeostasis and differentiation, leading to increasedsusceptibility to cutaneous infections and epidermalcarcinogenesis (3).

Connexin 26 is found in ectoderm-derived strati-fying epithelia of the cochlea, cornea, palmoplantarepidermis, sweat glands, and hair follicle root sheath(4). Various heterozygous mutations of the gene havebeen identified and are associated with a range of dis-orders and sensorineural hearing impairment (5).

Skin changes associated with KID syndromeapparent in neonates include generalized erythema,sometimes with diffuse scaling and leathery skin.During early infancy, features of erythrokerato-derma develop, appearing as sharply demarcated

erythematous hyperkeratotic plaques particularly onthe knees, elbows, scalp, forehead, cheeks, and perioralarea in addition to scattered follicular hyperkeratosison the trunk (6,7). Sparse hair of the scalp, eyebrows,and eyelashes, leukonychia, thickened nailplates, anddental abnormalities are additional findings associatedwith KID syndrome (8). Chronic skin infections,particularly candidiasis, are seen in about half of cases(7). No consistent immunodeficiency has been demon-strated, supporting the hypothesis that it is the chronicdermatologic disorder that predisposes the patient tofungal and bacterial infections.

Severe or total sensorineural deafness is anessential component of KID syndrome; it is typicallycongenital and nonprogressive. As in this patient,genetic studies conducted upon discovery of hearingimpairment often reveal the diagnosis. Three-fourths ofpatients develop a vascularizing keratitis of the cornea(1); it is typically progressive, preceded by photopho-bia, and first appears in childhood or early adolescence(9).

Long-term complications of KID syndromeinclude blindness due to progressive corneal opacifi-cation and delayed speech development due to hear-ing impairment. Keratosis, ichthyosis, and deafnesssyndromeassociated connexin 26 defects are reportedlythe only connexin defect associated with an increasedsusceptibility for squamous cell carcinoma, particularlyarising from hyperkeratotic skin lesions, and casereports of malignant proliferative pilar tumors of thescalp also exist (3,4).

Treatment is largely empirical, with topical kera-tolytics and emollients being standard and antifungals

or antibacterials as needed for acute infections. Patientsshould be regularly assessed by an ophthalmologist.Cochlear implants and corneal transplants may beconsidered. Fortunately for our patient, weeklyitraconazole has been effective in controlling chronicfungal infections.

References1. Burns FS. A case of generalized congenital erythroderma.

J Cutan Dis 1915;33:255–260.

2. de Zwart-Storm EA, Hamm H, Stoevesandt J et al. A novel

missense mutation in GJB2 disturbs gap junction protein

transport and causes focal palmoplantar keratoderma with

deafness. J Med Genet 2008;45:161–166.

3. Wenghoefer M, Allam JP, Novak N et al. Surgical therapy in a

patient with Keratosis-Ichthyosis-Deafness (KID) syndrome

associated with follicular occlusion triad. Eur J Dermatol

2007;17:449–450.

4. Nyquist GG, Mumm C, Grau R et al. Malignant proliferating pilar

tumors arising in KID syndrome: a report of two patients. Am J

Med Genet 2007;143:734–741.

5. Binder B, Hennies HC, Kraschl R et al. Connexin 26 mutation

and keratitis-ichthyosis-deafness (KID) syndrome. J Dtsch

Dermatol Ges 2005;3:105–108.

6. Caceres-Rios H, Tamayo-Sanchez L, Ruiz-Maldonado R.

Keratitis, ichthyosis and deafness (KID syndrome): review of the

literature and proposal of new terminology. Pediatr Dermatol

1996;13:105–113.

7. Miteva L. Keratitis, ichthyosis, and deafness (KID) syndrome.

Pediatr Dermatol 2002;19:513–516.

8. Singh K. Keratitis, ichthyosis and deafness (KID) syndrome.

Aust J Dermatol 1987;28:38–41.

9. Ahmadi S, McKenna K. Keratitis-ichthyosis-deafness syndrome

and carotenaemia. Clin Exp Dermatol 2003;28:394–396.

Address correspondence to Meredith E. Miller, B.A., 342 Summer-walk Circle, Chapel Hill, NC 27517, or e-mail: Meredith_Miller@med.unc.edu.

GENERALIZED XEROSIS AND HYPERKERATOTIC, INFECTED SCALP

LESIONS IN A 7-YEAR-OLD WITH CONGENITAL HEARING IMPAIRMENT

CONGENITAL PERIANAL AND ABDOMINAL NODULES

LACK OF SCALP AND BODY HAIR ON AN 11-MONTH-OLD GIRL

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