Banding Pattern on Polarized Hair Microscopic Examination and Unilateral Polymicrogyria in a Patient with Steroid Sulfatase Deficiency

OBSERVATION

ONLINE FIRST Banding Pattern on Polarized Hair Microscopic Examination and Unilateral Polymicrogyria in a Patient With Steroid Sulfatase Deficiency

Puja K. Puri, MD; Deepti M. Reddi, MD; Michele Spencer-Manzon, MD; Kristen Deak, PhD; Sonya U. Steele; Mohamad A. Mikati, MD

Background: Several forms of ichthyosis are lateral ventricle. Constitutional microarray revealed the associated with neurologic manifestations, including typical approximately 1.5-Mb deletion of the steroid sul- Sjo¨gren-Larsson syndrome, Refsum disease, and mental fatase gene. retardation–enteropathy-deafness-neuropathy-ichthyosis- keratoderma (MEDNIK) syndrome. We report a case Conclusions: Steroid sulfatase deficiency is a cause of of X-linked steroid sulfatase deficiency, ichthyosis, sei- X-linked ichthyosis; however, our patient also had reti- zures, abnormal hair banding pattern, and unilateral nitis pigmentosa, seizures, and abnormal hair findings. polymicrogyria. The presence of abnormal hair with a banding pattern on polarized microscopy may be helpful for diagnosis; Observations: A 3-year-old Caucasian male with a his- however, this pattern is not specific to this disease. In tory of ichthyosis since birth presented with general- addition, to our knowledge, the presence of a malforma- ized tonic seizures. Findings from a physical examination of cortical development has not been previously re- tion were remarkable for thin hair, retinitis pigmentosa, ported in patients with steroid sulfatase deficiency. and poor dentition. Polarized light microscopic examination of all the hair samples demonstrated a banding pattern. Magnetic resonance imaging of the brain re- Arch Dermatol. 2012;148(1):73-78. vealed left hemispheric polymicrogyria with decreased Published online September 19, 2011. sulcal pattern and stable asymmetric dilation of the left doi:10.1001/archdermatol.2011.281

TEROID SULFATASE (STS) DE- the defect is associated with short stat- ficiency is an X-linked ich- ure, chondrodysplasia punctate, mental re- thyosis condition, classi- tardation, X-linked ichthyosis, Kallmann cally thought of as being syndrome,3,4 and ocular albinism.4 The size primarily a dermatologic con- of the deletion and the subsequent num- dition. A broader phenotype is beginning ber of disrupted genes affect the final phe- S 5 to emerge, and this disorder has been notype. Other conditions involving ich- shown to increase the risk for attention- thyosis with prominent neurologic signs deficient/hyperactivity disorder, autism, include Sjo¨gren-Larsson syndrome, Ref- and social communication deficits.1 The sum syndrome, and mental retardation– steroid sulfatase (STS) gene is located in enteropathy-deafness-neuropathy- Author Affiliations: Divisions chromosome Xp22.31 and codes for the ichthyosis-keratoderma (MEDNIK) of Dermatopathology (Drs Puri syndrome.6,7 and Reddi), Medical Genetics STS enzyme, which is present in a ubiq- (Dr Spencer-Manzon), uitous distribution. Deficiency of placen- Cytogenetics (Dr Deak), and tal sulfatase can lead to marked decrease REPORT OF A CASE Child Neurology (Ms Steele and in estrogens and dehydroepiandros- Dr Mikati), and Departments of terone during the last weeks of preg- HISTORY Pathology (Drs Puri, Reddi, and nancy, leading to birth complications.2 Af- Deak) and Pediatrics (Drs Spencer-Manzon and ter birth, this gene defect gives rise to The patient was born via cesarean deliv- 2 Mikati and Ms Steele), Duke X-linked ichthyosis. Approximately 10% ery owing to fetal distress at 38 weeks with University Medical Center, of cases are part of a more complex con- nuchal cord and meconium. He weighed Durham, North Carolina. tiguous deletion of the X chromosome, and 6 pounds and 2 ounces, was born with ich-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 thyosis, and had an otherwise unremarkable hospital stay. sis. Findings from additional studies included normal lev- Pyloric stenosis was diagnosed at 2 weeks, and the pa- els of plasma amino acids, acylcarnitine profile, and plasma tient underwent a pyloromyotomy at the age of 3 weeks. carnitine, L-carnitine, ammonia, lactate, peroxisomal Findings from computed tomographic (CT) scans and panel, and urine organic acids, and normal results from magnetic resonance imaging (MRI) performed at that time electrocardiography. showed an enlarged left lateral ventricle, thought to likely Chromosome analysis showed a normal male karyo- be within normal variation. At 3 years and 3 months of type, which ruled out a large genomic rearrangement such age, he presented with a 1-year history of atypical ab- as an X to Y translocation. Single-nucleotide polymor- sence seizures that usually lasted a few seconds, al- phism (SNP) microarray analysis was performed using though some episodes lasted several minutes, and con- the Affymetrix human genome-wide SNP 6.0 array (Santa sisted of staring, eye fluttering, unresponsiveness, head Clara, California). The microarray revealed a genomic loss drops, generalized limpness, and falling down. Once per of approximately 1.6 Mb in size involving chromosome week he had tonic seizures lasting about 2 minutes. In Xp22.31, with estimated genomic boundaries begin- addition, he had pallid breath-holding spells occurring ning at linear positions 6,477,902 and ending at 8,095,645 3 times per week when he got upset, and these occasion- (National Center for Biotechnology Information Build 36, ally progressed into his usual tonic seizures, with the hg18) (Figure 1). This deletion was consistent with the whole episode and seizure activity lasting about 2 min- known microdeletion syndrome, STS deficiency or X- utes. The patient received levetiracetam, which seemed linked ichthyosis (OMIM 308100). The KAL1 gene was to increase his seizures. not in the deleted interval. Fluorescence in situ hybridization (FISH) analysis of FAMILY HISTORY metaphase and interphase cells was performed using a probe specific for the STS region, RP11-269D06. It An older brother was noted to have ichthyosis and had showed signal patterns consistent with a deletion at had 1 febrile seizure. He was subsequently found to also chromosome Xp22.31, confirming the microarray find- have the STS deficiency due to Xp22.3 deletion. The pa- ings. Subsequent FISH analysis of the maternal blood tient’s mother had no abnormal skin findings and was sample also showed deletion of RP11-269D06 at healthy. She was found to be a carrier of the Xp22.3 de- Xp22.31, indicating maternal inheritance of STS defi- letion found in her sons. The remainder of the maternal ciency. The brother of the proband, also with abnormal family history was unremarkable. The patient’s father de- skin findings, showed deletion of RP11-269D06. Four scribed difficulties in school. The paternal grandmother protein-encoding genes (HDHD1, STS, VCX, PNPLA4) had neonatal losses in 2 pregnancies and a stillborn twin and 1 microRNA gene (MIR651) were located within gestation. There was a history of autism in a paternal sec- the common deletion. Of these, the only OMIM dis- ond cousin. The family was of French and mixed Cau- ease–associated gene was STS. casian descent. Consanguinity was denied. Electroencephalography (EEG) showed (1) intermit- tent runs of high-amplitude generalized spike and slow PHYSICAL EXAMINATION wave pattern with the lead in the left hemisphere; (2) bilateral spikes and slow waves, more prominent over the The patient was seen at age 3 years and 3 months. He left hemisphere with increased synchronization during had normal facies without notable dysmorphic features. wakefulness; and (3) focal slowing in the left frontocen- He had very poor dentition, xerosis, with dry scaling on tral region. During his seizures there was a diffuse spike his flanks, bilateral shins, and shoulders. His hair was short and slow wave pattern in the EEG that was consistent and sparse. His head circumference was 49.3 cm, which with atypical absence seizures, which manifested as rhyth- was at the 50th percentile. The patient’s height was at mic eye blinking, behavioral arrest, and occasional head the 20th percentile and weight at the 5th percentile. He dropping during wakefulness. There was an overall de- had a tendency to flex his right wrist and had a tight heel crease in the frequency of epileptiform activity follow- cord in his right foot. A motor strength examination re- ing the introduction of clonazepam and lamotrigine. vealed a strength score of 4 on a scale of 0 to 5 on the Findings from an MRI scan of the brain demon- right with increased tone. He did not have pincer func- strated polymicrogyria throughout the left hemisphere, tion in the right hand and could grasp large objects for which was smaller in size with decreased sulcal pattern less than a minute. Examination of the deep tendon re- and stable asymmetric dilation of the left lateral ven- flexes revealed 3ϩ on the right and 2ϩ on the left. Plan- tricle (Figure 2). Despite the cortical abnormality and tar responses were extensor on the right foot and flexor the decreased volume of white matter on the affected side, on the left. The patient revealed a wide-based gait with a the white matter appeared normal. To further evaluate right lower extremity weakness. Findings from an oph- the integrity of the white matter, we determined the ap- thalmologic examination demonstrated retinitis pigmen- parent diffusion coefficient (ADC) of white matter re- tosa (RP) and no glistening white dots on the retina. gions of interest on the diffusion-weighted imaging performed at ages 3 years and 3 months. The ADC values ANCILLARY TESTS (reported in ϫ10−5 cm2/s) were similar to values described in the literature and ranged from 0.83 to 0.94.8,9 Full sequencing analysis of the ALDH3A2 gene was com- Region of interest analyses of white matter areas re- pleted and did not show a mutation, thereby excluding vealed no apparent diffusivity differences between the 2 Sjo¨gren-Larsson syndrome from the differential diagno- hemispheres. The means (SDs) for the left hemisphere

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 Figure 1. Results of the microarray analysis showing a microdeletion of approximately 1.5 Mb at chromosome Xp22.31. The proximal breakpoint maps to 6,477,902 and the distal breakpoint to 8,095,645 (Build 36). Numbers on the vertical axis show the smooth signal, log2 ratio, and overall copy number state for all probes in the deleted interval (top to bottom). The position of the genes is represented along the bottom and shows that only 4 genes (HDHD1, STS, VCX, and PNPLA4 ) are included in the deleted interval.

frontal, parietal, temporal, and occipital, respectively, are COMMENT as follows: 0.89 (0.04), 0. 87 (0.06), 0.94 (0.06), and 0.83 (0.05); and for the right hemisphere: 0.86 (0.05), 0.93 (0.05), 0.93 (0.05), and 0.83 (0.06). The patient described herein has a deletion at chromo- The patient’s hair was clipped for microscopic exami- some Xp22.31 that is consistent with STS deficiency. He nation. The light microscopic examination showed nor- has congenital ichthyosis, developmental delay, RP, atypi- mal cortical fibers (Figure 3A) with no evidence of trich- cal seizures, malformation of cortical development (MCD) orrexhis nodosa, trichoschisis, or ribboning. All the hair with polymicrogyria and unilateral ventricular dilation, samples demonstrated a banding pattern under polar- and a hair banding pattern that can be seen under po- ized light microscopy. The microscope stage was ro- larized microscopy. In addition, he had pyloric stenosis tated on a horizontal plane; therefore, the hairs were ro- soon after birth, which has been previously described in tated relative to the polarizing lens. The light and dark patients with STS deficiency.10 To our knowledge, this intervals were not regular and were reversible based on is the first case that associates MCD, seizures, and hair the rotation of the microscope stage, allowing the dark banding pattern with STS deficiency. regions in the first position to become bright and vice Lennox-Gastaut syndrome is composed of a triad of versa on rotation (Figure 3B and C). multiple seizure types (atonic, tonic, atypical absence, myoclonic, and generalized tonic-clonic), cognitive FOLLOW-UP dysfunction, and slow spike-and-wave activity (slower than 2.5 Hz) on EEG.11 However, this syndrome is usu- After the initial presentation to us at 3 years and 3 months ally generalized and as a rule does not show lateraliza- of age, the patient continued to have atypical absence sei- tion of EEG activity.11 Our patient demonstrates a zures twice daily and tonic seizures once a week. Fur- pseudo–Lennox-Gastaut syndrome with localization to ther use of zonisamide failed to control his seizures. He the left hemisphere shown on EEG. The seizures possi- is currently taking 50 mg of zonisamide twice a day and bly result from secondary generalization from the dys- half a tablet of clonazepam twice a day (the tablet is 0.25 genetic hemisphere. Unilateral hemispheric MCD, such mg). The patient has dysarthria with delays in expres- as hemimegalencephaly, has been associated with epi- sive language skills. dermal nevus syndrome, hypomelanosis of Ito, Proteus

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Figure 2. Magnetic resonance image of the brain in transverse view. A, Asymmetric dilation of the left lateral ventricle. RH indicates right hemisphere. B, Polymicrogyria throughout the left cerebral hemisphere.

possibility that the observed association in this patient A B C may be coincidental. The finding of RP in this patient is a novel clinical mani- festation in someone with STS deficiency. X-linked RP is associated with multiple loci. There is 1 report13 of link- age of RP to Xp22, between markers DXS1223 and DXS7161. The interval between markers DXS1223 and DXS7161 (chromosome X: 8,353,912-18,864,466), is close to, but does not contain, the STS critical region. How a downstream deletion may affect development of RP in this patient is unclear but warrants further investigation. The deletion interval that is common to both the un- affected carrier mother and brother with only the VCX3A gene, part of a family of genes containing 4 nearly iden- tical paralogs on Xp22.3, has been proposed as the caus- ative gene deleted in patients with X-linked nonspecific 14 Figure 3. Microscopic examination of hair. A, Cortical fibers within hair shaft mental retardation. Several other studies, however, have (original magnification ϫ400). B and C, Hair under polarized light shown that deletion of the VCX3A gene, as well as the demonstrating a banding pattern (original magnification ϫ400). Arrows other VCX paralogs in this region, are not sufficient to indicate a fixed position at 90° rotation and 180° rotation, respectively. cause mental retardation.15-17 The SNP microarray analysis indicates that the region deleted in this individual, as syndrome, and Klippel-Trenaunay-Weber syndrome.12 well as his normally developing older brother, contains Findings from this patient’s dysmorphologic examina- only the VCX gene and not the VCX3A or VCX2 genes. tion did not support a diagnosis of any of these syn- This finding gives further support to the idea that the VCX dromes. genes alone do not play a major role in cognitive devel- To our knowledge, STS deficiency has not been pre- opment and/or that additional modifier loci are impor- viously recognized as a neurocutaneous syndrome, and tant in the development of mental retardation in indi- our observation of the association of its skin and hair mani- viduals with STS deficiency. festations with polymicrogyria suggests that it may be. A case report18 was made of a female patient with ich- The finding that patients with STS deficiency are at higher thyosis, epilepsy, mental retardation, hypergonadotro- risk for attention deficient disorder than the general popu- phic hypogonadism, polyneuropathy, and cranial dys- lation does further support the idea that this deletion could morphisms. This patient also showed a similar cause central nervous system dysfunction.1 However, constellation of features, including focal cortical dyspla- pending further similar observations confirming or ne- sia, which is another form of MCD, ichthyosis, and sei- gating this association, we still need to acknowledge the zures. The patient was described as having Rud syn-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 drome in the report. Rud syndrome is a term that has thology, Duke University Medical Center, DUMC 3712, previously been used to classify a neurocutaneous dis- Durham, NC 27710 ([email protected]). order characterized by congenital ichthyosis, hypogo- Author Contributions: Drs Puri, Reddi, and Mikati had nadism, and mental retardation. In most cases, epilepsy full access to all of the data in the study and take respon- has also been present. In addition, there may be delayed sibility for the integrity of the data and the accuracy of growth or short stature.5 Retinitis pigmentosa, neuro- the data analysis. Study concept and design: Puri, Spencer- sensory deafness, and polyneuritis have also been de- Mazon, and Mikati. Acquisition of data: Puri, Reddi, Spen- scribed in these patients.6 Although STS may be defi- cer-Mazon, Deak, and Mikati. Analysis and interpreta- cient in some of these patients, normal STS activity has tion of data: Puri, Reddi, Spencer-Mazon, Deak, Steele, also been described in patients previously reported un- and Mikati. Drafting of the manuscript: Puri, Reddi, Steele, der the classification of Rud syndrome.19 Traupe20 sug- and Mikati. Critical revision of the manuscript for impor- gested that the term Rud syndrome be abandoned owing tant intellectual content: Puri, Reddi, Spencer-Mazon, Deak, to the different symptoms and genetic profiles of these and Mikati. Statistical analysis: Deak. Administrative, tech- patients. Alternatively, these syndromes should be re- nical, and material support: Puri, Reddi, Deak, Steele, and classified according to the syndromes with better char- Mikati. Study supervision: Puri and Mikati. acterization. Financial Disclosure: None reported. This patient demonstrates a possible expanded clini- Additional Contributions: Steven D. Chen provided valu- cal spectrum of STS deficiency that is the result of a de- able contribution analyzing the neuroimaging data, and letion of the Xp22.3 locus with the presence of atypical Steven Conlon and Susan Reeves provided technical as- seizures, MCD, unusual hair findings, and RP. What ad- sistance with the photographs. ditional factors are contributing to his phenotype, which is different from others with STS deficiency, is un- REFERENCES known. It is possible that other genes modify the phenotype the way that filaggrin modifies the severity of ich- 1. Kent L, Emerton J, Bhadravathi V, et al. X-linked ichthyosis (steroid sulfatase 21 thyosis in this syndrome. Many neurocutaneous deficiency) is associated with increased risk of attention deficit hyperactivity dis- syndromes, such as neurofibromatosis, have a highly vari- order, autism and social communication deficits. J Med Genet. 2008;45(8): able clinical phenotype, even within families. To our 519-524. knowledge, the presence of hair banding under polar- 2. Traupe H, Happle R. Clinical spectrum of steroid sulfatase deficiency: X-linked recessive ichthyosis, birth complications and cryptorchidism. Eur J Pediatr. 1983; ized microscopy is a novel finding in STS deficiency. How- 140(1):19-21. ever, cysteine and methionine levels in the hair have not 3. Ballabio A, Andria G. Deletions and translocations involving the distal short arm been measured, and concomitant trichothiodystrophy can- of the human X chromosome: review and hypotheses. Hum Mol Genet. 1992; not be entirely excluded. Tiger-tail banding with polar- 1(4):221-227. 4. Schaefer L, Ferrero GB, Grillo A, et al. A high resolution deletion map of human ized microscopy is classically described in the hair of pa- chromosome Xp22. Nat Genet. 1993;4(3):272-279. tients with trichothiodystrophy, some of whom have a 5. Gohlke BC, Haug K, Fukami M, et al. Interstitial deletion in Xp22.3 is associated deficiency in cystine or methionine with affect sulfur con- with X linked ichthyosis, mental retardation, and epilepsy. J Med Genet. 2000; tent.22 However, banding may occur in other deficiency 37(8):600-602. states, such as arginiosuccinic aciduria23 and acroder- 6. Larbrisseau A, Carpenter St. Rud syndrome: congenital ichthyosis, hypogonad- 24 ism, mental retardation, retinitis pigmentosa and hypertrophic polyneuropathy. matitis enteropathica. Banding has also been de- Neuropediatrics. 1982;13(2):95-98. 25 scribed in keratitis ichthyosis deafness syndrome and 7. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of in- in pseudopili annulati.26 In addition, it has been de- herited ichthyoses: results of the first ichthyosis consensus conference in Sorèze, scribed in healthy infants.27 Sperling and Di Giovanna28 2009 J Am Acad Dermatol. 2010;63(4):607-641. 8. Lo¨bel U, Sedlacik J, Gu¨llmar D, Kaiser WA, Reichenbach JR, Mentzel HJ. Diffu- proposed that banding occurs because there is undula- sion tensor imaging: the normal evolution of ADC, RA, FA, and eigenvalues stud- tion of cortical hair fibers within the hair shaft. We did ied in multiple anatomical regions of the brain. Neuroradiology. 2009;51(4): not observe this finding in our patient. 253-263. In summary, STS deficiency may have a more com- 9. Oksuzler YF, Cakmakci H, Kurul S, Oksuzler M, Dirik E. Diagnostic value of diffusion- plex clinical phenotype than has previously been re- weighted magnetic resonance imaging in pediatric cerebral diseases. Pediatr Neurol. 2005;32(5):325-333. ported. It is possible that this may account for a portion 10. Garcia Perez A, Crespo M. X-linked ichthyosis associated with hypertrophic py- of patients who were previously described as having Rud loric stenosis in three brothers. Clin Exp Dermatol. 1981;6(2):159-161. syndrome. Steroid sulfatase deficiency is seen in pa- 11. Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide tients with X-linked ichthyosis; however, our patient also for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70(21):1950-1958. has RP, atypical seizures, MCD, and abnormal hair find- 12. Flores-Sarnat L, Sarnat HB, Da´vila-Gutie´rrez G, Alvarez A. Hemimegalen- ings. The presence of abnormal hair with a banding pat- cephaly: part 2: neuropathology suggests a disorder of cellular lineage. J Child tern on polarized microscopy may be helpful in making Neurol. 2003;18(11):776-785. a diagnosis; however, this pattern is not specific to this 13. Hardcastle AJ, Thiselton DL, Zito I, et al. Evidence for a new locus for X-linked disease. To our knowledge, the presence of an MCD and retinitis pigmentosa (RP23). Invest Ophthalmol Vis Sci. 2000;41(8):2080-2086. 14. Fukami M, Kirsch S, Schiller S, et al. A member of a gene family on Xp22.3, VCX-A, hair-banding pattern has not been reported previously is deleted in patients with X-linked nonspecific mental retardation. Am J Hum in patients with STS deficiency. Genet. 2000;67(3):563-573. 15. Macarov M, Zeigler M, Newman JP, et al. Deletions of VCX-A and NLGN4: a vari- Accepted for Publication: July 19, 2011. able phenotype including normal intellect. J Intellect Disabil Res. 2007;51(pt 5): 329-333. Published Online: September 19, 2011. doi:10.1001 16. Cuevas-Covarrubias SA, Gonza´lez-Huerta LM. Analysis of the VCX3A, VCX2 and /archdermatol.2011.281 VCX3B genes shows that VCX3A gene deletion is not sufficient to result in men- Correspondence: Puja K. Puri, MD, Department of Pa- tal retardation in X-linked ichthyosis. Br J Dermatol. 2008;158(3):483-486.

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 17. Mochel F, Missirian C, Reynaud R, Moncla A. Normal intelligence and social in- cystine content caused by methionine deficiency? Acta Derm Venereol. 1996; teractions in a male patient despite the deletion of NLGN4X and the VCX genes. 76(1):62-64. Eur J Med Genet. 2008;51(1):68-73. 23. Kvedar JC, Baden HP, Baden LA, Shih VE, Kolodny EH. Dietary management re- 18. Marconi S, Cantalupo G, Marliani F, et al. Rud syndrome with focal cortical dys- verses grooving and abnormal polarization of hair shafts in argininosuccinase plasia: a case report [published online November 11, 2010]. Brain Dev. 2010. deficiency. Am J Med Genet. 1991;40(2):211-213. 19. Mu¨nke M, Kruse K, Goos M, Ropers HH, Tolksdorf M. Genetic heterogeneity of 24. Traupe H, Happle R, Gro¨be H, Bertram HP. Polarization microscopy of hair in the ichthyosis, hypogonadism, mental retardation, and epilepsy syndrome: clini- acrodermatitis enteropathica. Pediatr Dermatol. 1986;3(4):300-303. cal and biochemical investigations on two patients with Rud syndrome and re- 25. De Raeve L, Bonduelle M, Deconinck H, Roseeuw D, Stene JJ. Trichothiodystrophy- view of the literature. Eur J Pediatr. 1983;141(1):8-13. like hair abnormalities in a child with keratitis ichthyosis deafness syndrome. Pe- 20. Traupe H. Ichthyosis and hypogonadism: reflections on the so-called Rud’s diatr Dermatol. 2008;25(4):466-469. syndrome. In: Traupe H, Melnik B, eds. The Ichthyoses: A Guide to Clinical Di- 26. Lee SS, Lee YS, Giam YC. Pseudopili annulati in a dark-haired individual: a light agnosis, Genetic Counseling, and Therapy. New York, NY: Springer-Verlag; 1989: and electron microscopic study. Pediatr Dermatol. 2001;18(1):27-30. 91-97. 27. de Berker D. ‘Tiger tail’ pattern on polarized hair microscopic examination is found 21. Liao H, Waters AJ, Goudie DR, et al. Filaggrin mutations are genetic modifying in healthy infants. Arch Dermatol. 1997;133(10):1313-1314. factors exacerbating X-linked ichthyosis. J Invest Dermatol. 2007;127(12): 28. Sperling LC, DiGiovanna JJ. “Curly” wood and tiger tails: an explanation for light 2795-2798. and dark banding with polarization in trichothiodystrophy. Arch Dermatol. 2003; 22. Goerz G, Behrens W, Megahed M, et al. Brittle and sparse hair with normal 139(9):1189-1192.

Notable Notes

Mikhail Bulgakov: The Master and Syphilis

Immediately after Mikhail Afanasievich Bulgakov (1891- outpatient surgery records: “I had sat up the whole lonely night 1940) finished his medical studies in 1916, he was ordered poring over the hospital records and the splendid German text- to run a rural hospital near Smolensk, Russia. His experi- books with their colourful illustrations.” In the records, he ence with more than 15 000 patients, seen within 1 year, is traces only cases of secondary and tertiary syphilis, not a single described in A Country Doctor’s Notebook.1 In the story “The case of primary chancre. “[T]his means that the people here Speckled Rash,” he masterly portrays his confrontation with have no conception of syphilis and the lesions don’t frighten syphilis. Prompted by intuition, he investigates the skin of a them....Ibecame convinced that syphilis was so fearful here man who is about 40 years old: precisely because it was not feared.” Finally, a young mother with 2 children, all 3 of whom were infected, motivates Bul- [T]he light of the kerosene pressure-lamp shone on his gakov to set up an inpatient section for syphilitics, where he yellow-tinged skin. A white, speckled rash showed starts treatment with arsphenamine. through the yellow colouring of his flanks and bulging Bulgakov was born in Kiev, then part of the Russian chest. “Like stars in the sky,” I thought to myself with a Empire.2 As a soldier in World War II, he was wounded chill of fear....“This is it—syphilis,” I repeated grimly twice, which might explain his morphine addiction some to myself. This was my first professional encounter with years later. His interest in venereal diseases, at that time it, as I had been flung straight from university into a re- signifying almost exclusively syphilis, prompted him to mote village....Imade my patient take off more clothes practice as a venerologist in his home town of Kiev between and found a primary lesion which was already healing. 1918 and 1920. However, his statement “and I later devoted 1 To Bulgakov’s own surprise, he is not able to convince the the best years of my life to venereal diseases” fits more his patient to carry out the then standard treatment with mer- feelings than the facts. In the Stalin era, most of his stories cury ointment, despite giving a vivid account of grave and plays were considered counterrevolutionary and conse- 3 consequences of the disease. “It was, in fact, less of a conver- quently forbidden, spoiling the last decade of his life. It was sation than a monologue—a brilliant monologue by me,....” his widow, Jelena, fighting tirelessly for his rehabilitation, Among the large number of patients with syphilis he encoun- who succeeded in getting his finest work The Master and tered, only 1 young woman is scared because of suspected Margarita published, only 25 years after his death. infection. He starts studying the disease, first by screening the Friedrich A. Bahmer, MD Contact Dr Bahmer at Derma am Diako, Groepelinger Heerstrasse 406, 28239 Bremen, Germany ([email protected]).

1. Bulgakov M. A Country Doctor’s Notebook. London, England: Collins Harvill; 1990:63-78. 2. Mikhail Bulgakov. Wikipedia Web site. http://en.wikipedia.org/wiki/Mikhail_Bulgakov. Accessed June 16, 2011. 3. Belozenskaya-Bulgakova J. My life With Mikhail Bulgakov. New York, NY: Ardis Publisher; 1983.

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