Pediatric Dermatology Vol. 24 No. 3 267–271, 2007
Hypohidrotic Ectodermal Dysplasia and Intrathoracic Neuroblastoma Sabrina Buoni, M.D., Ph.D.,* Raffaella Zannolli, M.D., Ph.D.,* Francesca Macucci, M.D.,* Massimo Molinelli, Ph.D.,* Massimo Viviano, M.D., Aldo Cuccia, M.D.,à Joseph Hayek, M.D.,– Luca Volterrani, M.D.,# Maria M. de Santi, Ph.D.,** Clelia Miracco, M.D.,** and Alberto Fois, M.D., *Department of Pediatrics, Section of Pediatric Neurology, Policlinico Le Scotte, University of Siena, Siena, Department of Odontostomatological Sciences, Policlinico Le Scotte, University of Siena, Siena, àDepartment of Internal Medicine and Immunological Sciences, Section of Dermatological Sciences, University of Siena, Siena, –Pediatrics Neuropsychiatric Unit, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, #Department of Human Pathology and Oncology, Section of Radiology and Radiotherapy, Policlinico Le Scotte, University of Siena, Siena, **Department of Human Pathology and Oncology, Section of Pathological Anatomy and Istology, Policlinico Le Scotte, University of Siena, Siena, Depatment of Pediatrics, University of Siena, Siena, Italy
Abstract: We report a 6-year-old girl with a subtle form of hypohidrotic ectodermal dysplasia and a phenotype consisting of curly hair, a round face, a stocky build, and obesity, which was associated with intrathoracic neuroblastoma. Although this new association could be a chance occurrence, its description may alert physicians to look for similar combinations and report these, as it may lead to better syndrome delineation, and patient care.
Constitutional molecular defects are known to play a role in oncogenesis. Recently, Merks et al (1), after studying 1000 children with cancer, reported that 4% of these patients had associated syndromes, half of which were undiagnosed before the study. New syndrome—tumor associations were suggested for several entities: cleidocranial dysostosis (Wilms tumor), Bardet– Biedl syndrome (acute lymphoblastic leukemia), Kabuki syndrome (neuroblastoma), LEOPARD syndrome (neuroblastoma), Poland anomaly (osteosarcoma; Hodgkin disease), and blepharophimosis epicanthus inversus syndrome (Burkitt lymphoma). They concluded that all children with malignancies should be examined to determine if they have malformation syndromes. We report a subtle form of hypohidrotic ectodermal dys-
plasia (HED) in a young girl with a phenotype consisting of curly hair, a round face, stocky build and obesity, who developed a sporadic intrathoracic ganglioneuroblastoma. CASE REPORT A 6-year-old girl (Fig. 1) was referred to us because of intermittent fever of unknown origin that had persisted since early infancy. Fever episodes occurred mainly during the summer and seldom occurred during winter, except during the hospitalization periods. She was the youngest of three apparently healthy, lean, and relatively tall siblings. The child was born at term after an uneventful pregnancy, and her parents were apparently
Address correspondence to Raffaella Zannolli, M.D., Ph.D., Department of Pediatrics, Section of Pediatric Neurology, Policlinico Le Scotte, University of Siena, Siena, Italy, or e-mail:
[email protected].
2007 The Authors. Journal compilation 2007 Blackwell Publishing, Inc.
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Figure 1. Note the curly hair, round face, stocky build, obesity (A). Diastema of the upper central incisor (B). Patient’s photographs as a younger child (C–F), when she was 2 (C,D), 3 (E) and (F) 4 years old, respectively. Note the substantially unchanged phenotype.
healthy, lean, relatively tall and nonconsanguineous. Besides from blisters caused by these fevers, for which she was referred to us, and a sporadic intrathoracic neuroblastoma (ganglioneuroblastoma—stage 1) (2), which was incidentally diagnosed when she was 4 years old and treated with surgery with no relapses, she apparently had no other severe health problems. Her karyotype was 46,XX. Her fevers of unknown origin had been studied intensely elsewhere. All routine, hormonal, metabolic, and instrumental examinations, including high field (1.5 T) brain magnetic resonance imaging, ultrasounds, and roentgenograph were normal. There were no elements to indicate the presence of any known immunodeficiency. Ophthalmologic examination showed normal fundus oculi and visual evoked potentials. Physical and instrumental ear, nose, and throat examinations (tonal audiometric examination and impedentiometry) were
normal. Echocardiography showed normal cardiac performance. Ultrasound examination revealed that the genitourinary system was normal. At 6 years of age, her weight was 55 kg (>97th centile), her height 148 cm (75th–90th centile), her body mass index 25 kg/m2 (+4 SD), and her head circumference 54 cm (75th centile). She had no apparent severe dysmorphism. She presented with obesity, a stocky build, and a round face. Her hands and feet were small, and appeared ill proportioned in comparison with her body size. Her arms and legs were normally proportioned with no rhizomelic shortening. A neurologic examination revealed normal intelligence with an IQ (Wechsler intelligence scale for children, revised; WISC-R) of 125. She also had curly hair, a feature not present in her relatives. Her teeth showed diastema of the upper central incisor; nails were apparently normal. Microscopy of the hair showed several abnormalities in
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Figure 2. Optic microscopy of the hair shows irregular local forms, longitudinal grooving, and hair shaft discontinuities (A–D), and pili torti (E). Original magnification: A 4·, B 2·, C 10·, D and E 30·.
the shape of the shaft, with irregular local forms, hair shaft discontinuities, excessive longitudinal grooving, and pili torti (Fig. 2). Sudomotor function was subtly impaired. A pilocarpine iontophoresis sweat test with continuous monitoring of body temperature showed that she was sweating poorly (20 lL; normal values 100 lL) and had an increased body temperature (39.5C, axillary) at the end of the test (3). A skin biopsy specimen taken from the left hand, hypotenar side (4) documented a low density of sweat glands (10/cm2; normal value 600–700/ cm2). The glands were small and their ductal components were more prominent than the secretory components (Fig. 3). The corneum and granular layers were noticeably thickened. Based on the clinical (tooth and hair abnormalities as well as impaired thermoregulation because of poor sweating) and the histologic findings, a diagnosis of HED was made. DISCUSSION Hypohidrotic ectodermal dysplasia is a syndrome defined by maldevelopment of one or more ectodermally derived tissues, including the epidermis and cutaneous appendices, teeth, and exocrine glands. Currently, there are at least four known types of HED with known molecular bases: (1) the autosomal dominant form
(MIM 129490) for which the molecular basis is a mutation in the ectodysplasin anhidrotic receptor gene, EDAR (GeneID 10913), located on chromosome 2 (2q11-q13); (2) the autosomal recessive form (MIM 224900) for which two molecular bases are recognized: (i) mutation in the EDAR gene, (GeneID 10913) and (ii) mutation in the EDAR-associated death domain gene, EDARADD (GeneID 128178), located on chromosome 1 (1q42.3q43); (3) the X-linked recessive form (MIM 305100) for which the molecular basis is a mutation in the ectodysplasin A gene, EDA (GeneID 1896), located at Xq12q13.1; (4) and the X-linked recessive form associated with immunodeficiency (MIM 300291, HED immune deficiency) for which the molecular basis is a mutation in the nuclear factor j B gene essential modulator (NEMO), NLK (or nemo-like kinase, GeneID 51701), located on chromosome 17 (17q11.2). All of these phenotypes share the characteristics of congenital disorders of the teeth, hair, and eccrine sweat glands because of loss of function of the ectodysplasin pathway, a new TNF pathway that has an important function in embryonic development, especially in the formation of ectodermal structures (5). The fourth form also presents with severe infectious disease. Here, we report an occurrence of subtle HED in a young girl associated with a phenotype consisting of curly hair, a round face, a stocky build, and obesity.
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Figure 3. Optic microscopy of the skin specimen (left hand, hypotenar side). Sweat eccrine glands are small (A, overview; B, detail). Corneum and granular layers are noticeably thickened (C). (A) Hematoxylin & eosin; original magnification 50·. (B) Hematoxylin & eosin; original magnification 200·. (C) Immunohistochemistry: streptavidin–biotin, substrate: diaminobenzidine; original magnification 100·.
Mutational analysis was not performed, but the most likely form of HED in this patient is the autosomal dominant type (type 1 in the preceding list), although the recessive form (type 2 in the preceding list) could not be excluded. The two X-linked forms could be ruled out on the basis of sex and the absence of infectious disease. However, fully affected girls with balanced translocations affecting the EDA loci have occasionally been reported (6). In the dominant form (MIM 129490), hypohidrosis was variable and some individuals sweated normally when hot. Scanning electron microscopy showed longitudinal grooves along the hair shafts. The nails were normal. Boys and girls were equally affected. Our patient also developed sporadic intrathoracic ganglioneuroblastoma, which has an incidence rate of 12.5 per million in the population of white people aged from birth to 14 years (2). Although it is not possible to exclude chance association, it is noteworthy. Possible associations with tumors have been found in two other syndromes, the Kabuki syndrome (MIM#147920) and the LEOPARD syndrome (MIM#151100), but neuroblastoma in association with HED has never been
described. In conclusion, although this new association could be a chance occurrence, its description may alert physicians to look for similar combinations. ELECTRONIC DATABASE INFORMATION URLs for data in this article are as follows. Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm..nih.gov./Omim/Center for Medical Genetics, Johns Hopkins University, Baltimore, MD, and the national Center for Biotechnology Information, National Library of Medicine, Bethesda, MD: • MIM #129490 ECTODERMAL DYSPLASIA 3, ANHIDROTIC; ED3 • MIM #224900 ECTODERMAL DYSPLASIA, ANHIDROTIC • MIM #305100 ECTODERMAL DYSPLASIA 1, ANHIDROTIC; ED1 • MIM #300291 ECTODERMAL DYSPLASIA, HYPOHIDROTIC, WITH IMMUNE DEFICIENCY
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• MIM %147920 KABUKI SYNDROME • MIM #151100 LEOPARD SYNDROME
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guideline, 2nd ed. Waynes: US National Committee for Clinical Laboratory Standards Document C34-A2 (ISBN 1-556238-40704), 2000. 4. Berg D, Weingold DH, Abson KG et al. Sweating in ectodermal dysplasia syndromes. A review. Arch Dermatol 1990;126:1075–1079. 5. Itin PH, Fistarol SK. Ectodermal dysplasias. Am J Med Genet C Semin Med Genet 2004;131C:45–51. 6. Zankl A, Addor MC, Cousin P et al. Fatal outcome in a female monozygotic twin with X-linked hypohidrotic ectodermal dysplasia (XLHED) due to a de novo t(X;9) translocation with probable disruption of the EDA gene. Eur J Pediatr 2001;160:296–299.
