Bloom Syndrome in Two Siblings

Sheikh Javeed Sultan, M.D.,* and Sheikh Tariq Sultan, M.B.B.S.�

*SKIMS Medical College, Srinagar, �Government Medical College, Srinagar, Kashmir, India

Abstract: Bloom syndrome (congenital telangiectatic erythema) is arare autosomal recessive disorder characterized by telangiectasias andphotosensitivity, growth deficiency of prenatal onset, variable degrees ofimmunodeficiency, and increased susceptibility to neoplasms of many sitesand types. We are reporting Bloom syndrome in two brothers from Kashmir(India), 8 and 6 years of age, who presented with erythematous rashes on theface, photosensitivity, and growth retardation.

Bloom syndrome is an autosomal recessive disordercharacterized by proportionate pre- and postnatalgrowth deficiency; sun-sensitive, telangiectatic, hypo-and hyperpigmented skin; predisposition to malignancy;and chromosomal instability. First described by DavidBloom in 1954 (1), Bloom syndrome was for quite sometime thought to be confined solely to the AshkenaziJewish population (2). It has since been described innumerous other ethnicities, including Indian, Ethiopian,Latin American, French-Canadian, Japanese, andTurkish populations (3,4). We report two boys fromKashmir (India) with Bloom syndrome.

CASE REPORTS

Sibling 1

An 8-year-old boy, a native Kashmiri, born of non-consanguinous parentage and uneventful pregnancywas brought with complaints of redness and scarringover the face. The child was apparently normal untilthe age of 2 months when his mother noticed an ery-thematous eruption with small blisters over both cheeksthat was exacerbated on exposure to sunlight. Gradu-ally, the eruption became more progressive and severe,extending to the forehead, nose, and ears with the

development of oozing, crusting, atrophy, and telangi-ectasias over the face, despite treatment. The patienthad no history suggestive of constitutional symptoms,bowel and bladder complaints, Raynaud phenomenon,alopecia, discoloration of urine on standing, andchronic systemic or cutaneous infections. The patienthad a history of recurrent upper respiratory tractinfections since infancy. The patient’s father (aged32 yrs) and mother (aged 29 yrs) were apparentlynormal. The patient had a history of low birthweight(1.60 kg; <2 SD mean) and delayed developmentalmilestones, with standing and speech at 3 years of age(normal 18–24 mos) and failure of shedding of primarydentition. Examination revealed an agile child with acharacteristic facies (Fig. 1); short stature (height100 cm vs 125 cm mean height for 8 yrs; <2 SD mean)and short stubby fingers. The skull was dolichocephalicwhile the head circumference was 46 cm (<2 SDmean). Genitalia showed poor development and boththe testes were not palpable. The rest of the generalphysical examination was normal. Cutaneous exami-nation revealed erythema with areas of hyperpigmen-tation, telangiectasias, crusting and atrophy involvingboth sides of the face, nose, forehead and external earsbut predominantly in a butterfly distribution. Mucosalexamination revealed cheilitis of both lips. Teeth and

Address correspondence to Dr. Sheikh Javeed Sultan, M.D.,Shalimar-Srinagar, Kashmir, India 191121, e-mail: sjsultan@gmail.com

DOI: 10.1111/j.1525-1470.2010.01101.x

174 � 2010 Wiley Periodicals, Inc.

Pediatric Dermatology Vol. 27 No. 2 174–177, 2010

nails were normal. Hemogram, liver function tests,kidney function tests, collagen vascular profile, chestradiograph and ECG were within normal limits. SerumIgM and IgA levels were decreased. Ultrasonographyrevealed undescended testes with the right testis at thedeep inguinal ring and the left testis in the inguinalcanal. Blood, urinary and stool porphyrin analyseswere within normal limits. Direct immunofluorescenceexamination of the skin was negative. Lymphocyteculture followed by differential staining for chromo-somes revealed manifold increase in sister chromatidexchanges (Fig. 2).

Sibling 2

This 6-year-old younger brother of the above child hadsimilar complaints of redness and scarring over the facethat started at the age of 7 months. The patient had nohistory suggestive of constitutional symptoms, blistering,Raynaud phenomenon, alopecia, or discoloration ofurine on standing. The patient was a full-term normaldelivery of uneventful pregnancy with history of lowbirthweight (1.50 kg; <2 SD mean). Developmentalmilestones were delayed with speech at 3.5 years of age(normal 18–24 mos). The child was agile with a charac-teristic facies (Fig. 3) similar to that of his brother. Thechild was of short stature (75 cm vs 114 cmmean heightfor 6 yrs; <2 SD mean); the skull was dolichocephalicand head circumference was 44 cm (<2 SD mean).His genitalia showed poor development but both testeswere palpable in the scrotum. The rest of the systemicexamination was normal. Cutaneous examinationrevealed erythema with telangiectasias, atrophy andhyperpigmentation involving the face in butterfly distri-bution (Fig. 3). Mucosal examination revealed cheilitisof both lips. Teeth and nails were normal. Hemogram,liver function tests, kidney function tests, collagenvascular profile, porphyrin profile, chest radiograph, andECGwere within normal limits. Serum immunoglobulinlevels were within normal range. Direct immunofluo-rescence examination of the skin was negative.

Figure 1. Erythema with areas of hyperpigmentation, telan-giectases, crusting and atrophy on the face of the eldersibling.

Figure 2. Manifold increase in sister chromatid exchanges(giemsa stain, magnification 2000·).

Figure 3. Erythema with telangiectases, atrophy andhyperpigmentation involving the face in butterfly distribution ofthe younger sibling.

Sultan and Sultan: Bloom Syndrome in Two Siblings 175

DISCUSSION

Bloom syndrome is a rare, autosomal recessive diseasecharacterized by short stature, immunodeficiency, and apredisposition for malignancies. It is a ‘‘chromosomebreakage syndrome’’ in which the recessively inheritedmutation in the BLM gene leads to an inordinate fre-quency of chromosomal breaks and rearrangements.The mutation responsible for Bloom syndrome has beenmapped to chromosome 15q26.1 (5); the BLM geneencodes a RecQ DNA helicase that is important forDNA repair, defects of which give rise the characteristicchromosomal changes (6). Although most commonlyseen among Ashkenazi Jews, it has been reported to beprevalent in other ethnicities as well. Male patients areslightly more frequently affected than female patients(1.3:1) (7,8).

Genomic instability seen in Bloom syndrome canaffect virtually all genetic loci, cell types, and tissues;thus clinical features arise from multiple organ systems.Patients have a characteristic narrow facies with promi-nent nose and ears, dolichocephalic skull, and often apersistent telangiectatic facial erythema that begins inthe first few months of life and which is exacerbated bysunlight. Blisters, erythematous macules, cheilitis, cafe-au-lait macules, and axillary acanthosis nigricans mayalso occur (7–9).

Patients with Bloom syndrome display deficiency ofproportional growth, which begins in utero resulting inlow birthweights. Although mental retardation occa-sionally occurs, normal intelligence is the rule. Patientshave a typical high-pitched voice and hypogonadism(primary) with infertility, especially in male patients.Malar hypoplasia with small mandibles and lack ofsubcutaneous fat may also occur. Other associatedabnormalities include clinodactyly, syndactyly, congen-ital heart disease, annular pancreas, and highly archedpalate (7,8,10).

Many ophthalmologic abnormalities have beenobserved in Bloom syndrome. Themost common ocularfinding is the presence of retinal drusen at an early agethat have been termed ‘‘colloid body-like spots.’’ Otherreported ocular findings include conjunctivitis, conjunc-tival telangiectasias, narrow anterior chamber angles,madarosis, iris pigment alteration and bilateral opticnerve hypoplasia (11,12).

Diabetes mellitus develops in about 10% of patientswith Bloom syndrome and usually occurs in its noninsulin-dependent form (12). Recurrent respiratory andgastrointestinal infections, beginning in early childhood,may occur as a result of immunologic abnormalities thatinclude deficiencies of immunoglobulins (IgM and IgAeither alone or in combinationwith IgG),malfunction of

helper T cells and delayed hypersensitivity reactions(13,14).

As a result of excessive chromosomal rearrangementsin all cell types, somatic mutations occur at a high fre-quency throughout the patient’s life; the hypermutabilityof Bloom syndrome cells is responsible for the benignand malignant neoplasms that arise at unusually earlyages, usually after second decade and in excessive num-bers. Tissues with high mitotic indices—bone marrow(leukemias), lymphoid tissues (lymphomas), and gas-trointestinal mucosa (adenocarcinoma)—are most fre-quently involved but skin, breast, oral cavity, and lungcancers are also seen. Most of these malignancies inpatients with Bloom syndrome are highly sensitive tochemotherapy and radiotherapy (15–18).

The fundamental derangement in Bloom syndromeresults from abnormalities of DNA repair and chromo-some structure.Among these aberrations are a decreasedrate of DNA replication, chromosome breaks and rear-rangements, chromatid and isochromatid gaps, acentricsegments and a markedly increased (6- to 12-fold)frequency of sister chromatid exchanges with increasedtriradial and quadriradial configurations (19–23).

The sister chromatids of a metaphase chromosomestained differentially (Giemsa) demonstrate the strikingand specific increase in the frequency with which sisterchromatids exchange segments. Whereas phytohemag-glutinin-stimulated lymphocytes from normal controlsusually show 1–14 sister chromatid exchanges permetaphase, those from persons with Bloom syndromerange from 45 to 162. Normal frequencies of sisterchromatid exchanges are found in other disorderscharacterized by chromosome instability like ataxiatelangiectasia and Fanconi anemia (22,23).

As there is no cure for Bloom syndrome, regularmonitoring has to be carried out to identify any malig-nancies as early as possible. Radiographs and otherenvironmental exposure to compounds that cause DNAdamage should be avoided, to the maximum extentpossible. Sun exposure should be minimized using effec-tive sunscreens and other measures of sun protection.Infections require prompt treatment with antibiotics.Resistance to infections, erythema, and photosensitivitygradually improve with age. Gene therapy may offer acure in future. Prenatal diagnosis is possible by cyto-genetic analysis of fetal cells obtained by either amnio-centesis or chorionic villus sampling (24).

In both of our patients, characteristic facies, shortstature, telangiectatic facial erythema, along with theincrease in sister chromatid exchanges in cultured lym-phocytes, enabledpromptdiagnosis ofBloomsyndrome.In addition, the older patient had history of recurrentupper respiratory tract infections, low IgM and IgA

176 Pediatric Dermatology Vol. 27 No. 2 March ⁄April 2010

levels, and bilateral undescended testes. As cutaneoussigns of excessive ultraviolet radiation were present inboth patients, both patients were advised to use topicalsun-screens and oral antioxidants and were counseledabout avoiding exposure to sunlight and to report tohospital every 3 months. The older patient, in addition,required orchidopexy.

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