Medicine® CLINICAL CASE REPORT Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type Eight Case Reports Vito Pavone, MD, Salvatore Santo Signorelli, MD, Andrea Domenico Pratico`, MD, Giovanni Corsello, MD, Salvatore Savasta, MD, Raffaele Falsaperla, MD, PhD, Piero Pavone, MD, PhD, Giuseppe Sessa, MD, and Martino Ruggieri, BA, MD, PhD Abstract: Pigmentary mosaicism of the (hypomelanosis of) Ito type is (extracutaneous) syndromic manifestations, apart from the HOG (ie, an umbrella term, which includes phenotypes characterized by mosaic with a clinical phenotype of hypomelanosis of Ito). hypopigmentation in the form of streaks, whorls, patchy, or more bizarre The present study, which includes children and adults with the skin configurations (running along the lines of Blaschko): these longest follow-up so far recorded, confirms the association between cutaneous patterns can manifest as an isolated skin disorder ( pigmen- pigmentary mosaicism of the Ito type and HOG lowering previous tary mosaicism of the Ito type) or as a complex malformation syndrome estimates (7% vs 16%) for HOG in the context of mosaic hypopig- in association with extracutaneous anomalies (most often of the mus- mentation. A careful examination, looking at subtle to moderate asym- culoskeletal and/or nervous systems) (hypomelanosis of Ito). Affected metries and associated complications within the spectrum of these individuals are anecdotally reported to have also partial or total body mosaic pigmentary disorders, is recommended. hemi-overgrowth (HOG), which often causes moderate to severe com- (Medicine 95(10):e2705) plications. We studied the occurrence and features of HOG in the 114 children Abbreviations: HI = hypomelanosis of Ito, HOG = hemi- and adults with mosaic pigmentary disorders of the Ito type diagnosed overgrowth, IP = incontinentia pigmenti, ND = nevus and followed up (from 2 to 22 years; average follow-up 16 years) at our depigmentosus. Institutions. Eight patients (5 M, 3 F; aged 4 to 25 years; median age 16 years) out of the 114 analyzed (7%) fulfilled the criteria for unilateral HOG, with INTRODUCTION differences in diameter ranging from 0.4 to 4.0 cm (upper limbs) and 1.0 igmentary mosaicism of the (hypomelanosis of) Ito type to 9.0 cm (lower limbs). Moreover, among these 8 patients, 5/8 filled in P (still known as incontinentia pigmenti achromians; MIM # the 75th to 90th percentile for height; 6/8 had associated kyphoscoliosis; 300337) is a not uncommon mosaic cutaneous disorder.1–8The and 5/8 showed cognitive delays. No tumour complications were abnormal skin patterning is characterized by hypopigmentation recorded. Overall, 6/8 HOG patients presented with additional in the form of whorls, streaks, or patches that may be unilateral or bilateral.5–8 The hypopigmented streaks and whorls are irregularly shaped and of variable size, following the lines of Blaschko (arranged in narrow bands, according to the arche- Editor: Giovanni Li Volti. typical patterns of cutaneous mosaicism),7,9,10 and running Received: September 23, 2015; revised: January 7, 2016; accepted: January parallel to one another. The body areas, which tend to be 14, 2016. From the Department of Orthopaedics, AOU ‘‘Policlinico-Vittorio affected by hypopigmentation, are the trunk and the limbs; in Emanuele,’’ (VP, GS); Department of Clinical and Experimental Medicine, the latter sites, such manifestations tend to assume a linear shape University of Catania, (SSS); Department of Biomedical and Biotechno- (for this reason the condition is also known as ‘‘linear hypo- logical Sciences (ADP); Department of Clinical and Experimental melanosis in narrow bands’’).9,10 Scalp, palms, soles, or Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania (ADP, MR); Department of Sciences for Health mucous membranes are usually spared. The disorder affects Promotion and Mother and Child Health Care, Pediatric Unit, University both the sexes, occurs in all races, and is (so far regarded as) of Palermo, Palermo, (GC); Department of Pediatrics, IRCCS Hospital San sporadic.5,7,8 Matteo, University of Pavia, Pavia (SS); and Unit of Paediatrics and The skin patterns may appear as an isolated skin disorder (a Emergency Paediatrics, AOU ‘‘Policlinico-Vittorio Emanuele,’’ (RF, PP) pure cutaneous trait) ( pigmentary mosaicism or linear hypo- Catania, Italy. 2–4,7 Correspondence: Piero Pavone, Unit of Pediatrics, Unit of Paediatrics and melanosis [of the Ito type]) or as a complex malformation Emergency Paediatrics, AOU ‘‘Policlinico-Vittorio Emanuele,’’ Via syndrome in association with extracutaneous manifes- Plebiscito, 626, 95124 Catania, Italy (E-mail: [email protected]). tations,5,6,8 including central nervous system or musculoskeletal Authors’ contribution: VP and ADP wrote the first and subsequent drafts of alterations (hypomelanosis of Ito [HI]).5,6,8,11–16 More rarely, manuscript: they followed up the HOG patients; SSS performed the 5,11–13,15 angiographic evaluations; PP, RF, SS, and MR followed up the patients the eyes, heart, and genital organs can also be involved. with pigmentary mosaicism and reviewed the literature; and GC and MR With regards to body asymmetry, the term ‘‘hemi-hyper- revised the paper. plasia’’ is applied when a pathological growth is linked to an The authors have no funding and conflicts of interest to disclose. Copyright # 2016 Wolters Kluwer Health, Inc. All rights reserved. abnormal proliferation of cells, and the term ‘‘hemi-hypertrophy’’ This is an open access article distributed under the Creative Commons is used when an abnormal growth is caused by an increase in the Attribution- NonCommercial License, where it is permissible to download, size of existing cells.17 In the absence of histologic evaluation, the share and reproduce the work in any medium, provided it is properly cited. terms ‘‘overgrowth’’ or ‘‘abnormal growth’’ are the most suit- The work cannot be used commercially. ISSN: 0025-7974 able. The association between pigmentary mosaicism of the Ito DOI: 10.1097/MD.0000000000002705 type and asymmetric overgrowth (hemi-overgrowth [HOG]) has Medicine Volume 95, Number 10, March 2016 www.md-journal.com | 1 Pavone et al Medicine Volume 95, Number 10, March 2016 been previously anecdotally reported, but no systematic studies stable patterns at or around puberty, with later (postpubertal) were undertaken. decrease of hypopigmentation. The patterns were, however, The aim of this retrospective study is to report the personal visible in all adult patients and over the entire follow-up period experience in individuals with a combination of pigmentary in children. mosaicism of the Ito type and HOG seen at our Institutions, and to review the existing literature on this topic. The updated Extracutaneous Patterns treatment recommendation and the risk of tumour compli- The mosaic skin phenotypes, in the forms and patterns cations in these HOG patients are also discussed. reported above, were associated with extracutaneous abnorm- alities, including musculoskeletal (n ¼ 55), neurological METHODS (n ¼ 30), and combined musculoskeletal and neurological (n ¼ 29) abnormalities; 32/114 had, in addition, minor eye Population Studied abnormalities and major or minor dysmorphic features (mostly Between April 1992 and December 2014, 114 individuals [ie, 87%] falling in the group of combined extracutaneous with pigmentary mosaic skin manifestations of the Ito type (ie, abnormalities). with hypopigmented skin patterns running along the lines of 7,9,10 Blaschko) were referred to the Section of Pediatrics and Diagnostic Workup Child Neuropsychiatry (formerly, Department of Pediatrics and The patients’ follow-up spanned from 2 to 22 years; Child Neurology) of the University of Catania, Italy, which average follow-up was 16 years. The initial (or early middle) caters to children/adolescents with neurological disorders. This diagnostic work-up included in all the 114 probands’ general University Section also holds a longstanding tradition (ie, since dermatological, and general and neurological examination, the 90s) of adult referrals affected or suspected of having routine laboratory tests, full ophthalmologic evaluation and neurocutaneous disorders, and for these reasons it caters to heart, and abdominal and pelvic ultrasound examination. When adults with mosaic pigmentary patterns associated or not to dictated by the clinical findings, we obtained radiographs and systemic abnormalities. other additional laboratory studies; magnetic resonance ima- The local ethics committee of the University Hospital ging (MRI) studies of the brain were obtained in all the 114 ‘‘Policlinico Vittorio-Emanuele’’ of Catania, approved the patients at different ages. study. An informed consent on the present study was given to 8 of the selected patients affected by HI and HOG. Hemi-overgrowth Demographic Data Among these 114 patients, HOG was recognized as a clinical discrepancy in length (>0.5 cm) and diameter At the time of the present study, the 114 included patients (>1 cm) of the lower and (>0.4 cm) upper limbs. From an were children (n ¼ 80) or adults (n ¼ 34). Of the 80 children, 49 epidemiological viewpoint, we compared findings in the HOG were boys (aged 2–18 years, average age 12 years) and 31 were subgroup versus findings in the overall group of 114 patients girls (aged 18 months to 17 years, average age 11 6/12 years). Of with pigmentary mosaicism and in the syndromic group of HI the 34 adults, 20 were males (aged 18–65 years:, average