Dermatology: Practical and Conceptual Review | Dermatol Pract Concept 2020;10(4):e2020095 1 Dermatology Practical & Conceptual From Skin to Kidneys: Cutaneous Clues of Renal Disease in Children Mario Diplomatico1, Pierluigi Marzuillo1, Angela La Manna1, Andrea Apicella2, Stefano Guarino1, Vincenzo Piccolo3 1 General and Specialized Surgery for Women and Children, University of Campania Luigi Vanvitelli, Naples, Italy 2 Emergency and ICU Departments, AORN Santobono-Pausilipon, Naples, Italy 3 Dermatology Unit, University of Campania Luigi Vanvitelli, Naples, Italy Key words: pediatrics, dermatology, nephrology, vasculitides, syndromes Citation: Diplomatico M, Marzuillo P, La Manna A, Apicella A, Guarino S, Piccolo V. From skin to kidneys: cutaneous clues of renal disease in children. Dermatol Pract Concept. 2020;10(4):e2020095. DOI: https://doi.org/10.5826/dpc.1004a95 Accepted: June 1, 2020; Published: October 26, 2020 Copyright: ©2020 Diplomatico et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License BY-NC-4.0, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. Authorship: All authors have contributed significantly to this publication. Corresponding author: Mario Diplomatico, MD, General and Specialized Surgery for Women and Children, University of Campania Luigi Vanvitelli, Via Luigi De Crecchio 2, 80138, Napoli, Italy. Email: mario.diplomatico@gmail.com Background: The skin is often seen as a world apart, but not rarely do cutaneous manifestations reveal signs of systemic disease. Objectives: The aim of this review is to include in one paper all the possible correlations between neph- rological and dermatological manifestations of the same disease in pediatric patients while also keeping in mind that in apparent exclusively dermatological diseases there can be nephrological manifestations as part of the same disorder and vice versa. Methods: We searched on PubMed for a possible link between skin and kidney matching the following terms and correlated MeSH terms: dermatology, skin, kidney, renal disease, nephrology, pediatrics, child, childhood, vasculitis, and cancer. We selected only articles reporting a link between nephrology and der- matology in pediatrics, and they are all included in this comprehensive review. Results: Kawasaki disease, Henoch-Schönlein purpura, systemic lupus erythematosus, Dent disease, subcutaneous fat necrosis, Langerhans cell histiocytosis, renal cell carcinoma, non-Hodgkin lymphoma, tuberous sclerosis complex and syndromes with increased risk for Wilms tumor, Fabry disease, nail-pa- tella syndrome, neurofibromatosis type 1, Beckwith-Wiedemann syndrome, Adams-Oliver syndrome 1, Apert syndrome, Fanconi pancytopenia syndrome, Pallister-Hall syndrome, and Fanconi pancytopenia syndrome are all conditions in which there can be both nephrological and dermatological manifestations in children. Conclusions: We could not find any reports that focused attention on the link between nephrological and dermatological manifestations of the same disease in children. It is also important for clinicians to keep in mind that in what may appear to be an exclusively dermatological disease, there can be nephro- logical manifestations as part of the same disorder and vice versa. AbstrACt 2 Review | Dermatol Pract Concept 2020;10(4):e2020095 ated with the risk of cardiac damage. As recently reported by Chuang et al, renal involvement is underestimated, and they found it in 52% of the cases with a significant association between acute kidney injury (AKI) and age and alanine tran- saminase (ALT) level: the younger the age and/or the higher the ALT value, the more important it is to check renal func- tion during both acute and convalescent phases. They also found that sterile pyuria was more prevalent in KD patients with AKI than in the non-AKI group (P < 0.01). Although they did not find a significant correlation at the multivariate logistic regression (P = 0.72), recent studies are frequently supporting the involvement of kidney, bladder, and urethra in its formation [1,2]. Henoch-Schönlein purpura is an IgA vasculitis character- ized by lower extremity purpura that is variably associated with abdominal, joint and renal involvement. In contrast to KD, the risk of renal involvement (hematuria and pro- teinuria within or beyond nephrotic range) in patients af- fected by HSP increases with age: children older than 8 years have a 2.7-fold higher risk of nephritis [3]. The most common primary large vessel vasculitis in childhood is Takayasu arteritis, even though it is predomi- nantly reported in the second and third decades of life, most likely due to its subtle onset that contributes to a delayed diagnosis. It is mainly characterized by constitutional symp- toms, alteration of peripheral pulses, hypertension (due to the narrowing of one or both renal arteries, often overlooked in children), and arthralgias, but it may also present with skin involvement, such as rashes or nodules resembling pyo- derma gangrenosum or erythema nodosum [4]. As a key point, we suggest checking renal involvement in almost every vasculitis. systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting many organs. The manifesta- tions in children are the same as in adults, but children are more often affected by a severe organ involvement as a pre- senting manifestation, primarily nephropathy and hemato- logical involvement [5]. Cutaneous manifestations (some of which are included in the diagnostic criteria) are extremely common in SLE, as they present as the first sign in up to 25% of cases and are classified into specific and non-spe- cific lupus manifestations. Lupus-specific manifestations are acute (malar rash and photosensitive lupus rash), subacute (maculopapular rash), chronic (discoid rash), whereas non- specific ones are mucosal ulcers, non-scarring alopecia, and vascular abnormalities (periungual erythema, livedo reticu- laris, Raynaud phenomenon, vasculitis) [6]. Variable degrees of renal involvement are present in up to 70% of children Introduction The skin is primarily involved in many diseases, and some cutaneous manifestations can also reveal signs of an internal disease. Renal disease is revealed by the changing amount, concentration, elements, and color of the urine, but some- times it can be suspected based on cutaneous manifestations. What about the possibility of recognizing or suspecting re- nal diseases by skin manifestations in pediatric patients? The aim of the present review is to examine cutaneous in- volvement with nephrological diseases, to explore the im- portance of the cutaneous manifestations as a clue to kidney disease, and to put the attention on their possible link. search strategy We searched PubMed for a possible link between skin and kidney using these search strategies: (“Kidney”[MeSH] AND “Dermatology”[MeSH] AND “Pediatrics”[MeSH]), (“Kidney”[MeSH] AND “Dermatology”[MeSH] AND “Child”[MeSH]), (“Kidney”[MeSH] AND “Dermatolo- gy”[MeSH] AND “Childhood”), (“Nephrology”[MeSH] AND “Dermatology”[MeSH] AND “Child”[MeSH]), (“Nephrology”[MeSH] AND “Child”[MeSH] AND “Skin”[MeSH]), (“Kidney Diseases”[MeSH] AND “Der- matology”[MeSH] AND “Child”[MeSH]), (“Kidney Diseases”[MeSH] AND “Dermatology”[MeSH] AND “Pediatrics”[MeSH]), (“Vasculitis”[MeSH] AND “Der- matology”[MeSH] AND “Pediatrics”[MeSH]), (“Vas- culitis”[MeSH] AND “Kidney”[MeSH] AND “Pediat- rics”[MeSH]), (“Neoplasms”[MeSH] AND “Derma- tology”[MeSH] AND “Pediatrics”[MeSH]), (“Neo- plasms”[MeSH] AND “Kidney”[MeSH] AND “Pediat- rics”[MeSH]). We selected only articles that reported a link between nephrology and dermatology in pediatrics, and they are all included in this comprehensive review. Vasculitis Vasculitis is different from systemic lupus erythematosus (SLE) in that inflammation of blood vessels may occur as a primary process, and because of multisystemic involvement, many subspecialties are involved in its diagnosis. In pediatrics, the most common primary medium to small vessel vasculitides in childhood are Kawasaki disease (KD) and Henoch-Schönlein purpura (HSP). KD is a febrile disease associated with polymorphous exanthema, changes in extremities (erythema of the palms and soles, indurative edema of the hands and feet, swelling, and fissuring between the nails and the tips of the fingers), bilateral bulbar con- junctivitis without exudate, lip and oral cavity involvement, and cervical lymphadenopathy. Notably, it is always associ- Review | Dermatol Pract Concept 2020;10(4):e2020095 3 Fabry Disease Fabry disease is an X-linked metabolic disorder due to a de- ficiency of lysosomal α-galactosidase A. This deficiency leads to accumulation of glycosphingolipids in the whole body, including the heart and peripheral and autonomic nervous systems later in life. Onset of symptoms seems to occur ear- lier in males than in females (mean age 10.9 vs 22.6 years). Children diagnosed with Fabry disease can develop pro- teinuria, anhidrosis, and angiokeratoma. Early recognition is important because increasing evidence suggests that enzyme replacement treatment is most beneficial in terms of clinical outcome when initiated early in the disease process [16]. subcutaneous Fat Necrosis Until the establishment of protocols for therapeutic neonatal hypothermia, a documented complication was subcutaneous fat necrosis (SFN). SFN is a granulomatous disorder associ- ated with perinatal asphyxia, trauma, or prolonged exposure to cold, that presents with subcutaneous indurated purple- colored nodules associated with hypercalcemia (probably because of the damage to the fat tissue). Although not clearly understood, the mechanism of hypercalcemia in SFN may be due to the damage to fat tissue that causes necrosis, in- creased production of 1.25-dihydroxyvitamin D by macro- phages, increased calcium absorption from the gastrointesti- nal tract, and osteoclast activation by prostaglandins. Severe hypercalcemia (calcium level >3 mmol/L) is a life-threatening condition at any age, has a mortality rate of up to 15% in SFN, and it is associated with kidney injury, with or without nephrocalcinosis, as well as with cardiac complications [17]. In the case of severe hypercalcemia a urinalysis and kidney ultrasounds are suggested. Langerhans Cell Histiocytosis Langerhans cell histiocytosis (LCH) is a rare disease char- acterized with various presentations. The most commonly involved sites are bones, skin, lymph nodes, pituitary gland, liver, lung, and spleen, and the dissemination affects the prognosis and treatment. Histopathology shows monoclo- nal Langerhans cells together with lymphocytes, eosinophilic granulocytes and non-dendritic histiocytes. This disease usu- ally presents on the skin with brown or purplish papules and an eczematous rash (often misdiagnosed as “cradle cap” on the scalp). Renal involvement is rarely reported in the liter- ature but is characterized by a variable infiltration of glo- meruli or interstitium, and presents as nephrotic syndrome or interstitial nephritis [18]. More frequently, polyuria and polydipsia can be the nephrological signs of pituitary gland involvement causing central diabetes insipidus [19]. affected by SLE. Lupus nephritis is defined by kidney biopsy in 6 classes and can be present without any other sign of SLE [7]. Lupus nephritis is not the only way in which SLE can involve the kidney. Other forms of renal involvement are: tubulointerstitial nephritis (strong correlation with the prognosis for hypertension, elevation of plasma creatinine concentration, and progressive clinical course); vascular dis- ease (with deposition of immune deposits in the glomeruli, thrombotic microangiopathy, and atherosclerosis); glomeru- lar podocytopathy (independent of immune complex depo- sition); and collapsing glomerulosclerosis (similar to HIV-as- sociated nephropathy) [8–11]. If SLE is suspected, screening for renal involvement is suggested, ie, a urinalysis to rule out the presence of hema- turia and proteinuria. Dent Disease Dent disease is a heterogeneous X-linked recessive disorder that, similarly to Fanconi syndrome, presents with low mo- lecular weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, and progressive renal failure. Up until now, due to its heterogeneity, only 2 genes have been identified: CLCN5 (Dent disease type 1-60% of cases) and OCRL1 (Dent disease type 2-15% of cases). The remaining percentage of disease remains genetically unexplained, as there have been reported cases of patients with Dent disease phenotype without mutations in these 2 genes [12,13]. No association between skin and Dent disease type 2 (DD-2) be- fore 2018 was reported, although it has been reported with Lowe syndrome, namely, oculocerebrorenal syndrome; sec- ondary to a mutation in the same OCRL1 gene; and some- times presents with eruptive hair vellus hair cysts, tricho- epithelioma, and excessive skin folds [14]. Marzuillo et al re- ported the possible association between DD-2 and hidraden- itis suppurativa. Hidradenitis suppurativa has a prevalence of 1% in the general population with an average age onset in the second to third decade of life but a prevalence of 80% in patients affected by DD-2: all males, with mean age of onset of 13 years. As postulated, a possible explanation could be an increased susceptibility to staphylococcal cutaneous in- fections and a stimulation of cutaneous inflammation asso- ciated with impairment of the junctional components due to mutations in OCRL1 gene that drastically reduce (<10%) inositol polyphosphate 5-phosphatase (OCRL1) activity [15]. Therefore, Dent disease should be taken into consid- eration when evaluating a male child or a young boy with hidradenitis suppurativa and proximal tubule dysfunction with low molecular weight proteinuria and hypercalciuria, nephrolithiasis, nephrocalcinosis, progressive renal failure, and intellectual disability. 4 Review | Dermatol Pract Concept 2020;10(4):e2020095 Neurofibromatosis type I (NF1) is a genetic disorder due to a mutation in or deletion of the NF1 gene that produces neurofibromin, a tumor suppressor protein. NF1 is usually recognized by axillary freckling, café-au-lait spots, and neu- rofibromas, but the kidney may also be involved in develop- ing WT or angiomyolipomas. This disease also affects the bones, eyes, and nervous system [25]. Beckwith-Wiedemann syndrome is an overgrowth disor- der due to abnormalities involving genes on chromosome 11. Beckwith-Widemann syndrome is characterized by large kid- neys with medullary dysplasia, renal cysts, and urinary tract anomalies, neuroblastoma or WT (approximately 7.5% of cases), hemihypertrophy, and facial nevus flammeus in skin [26]. Adams-Oliver syndrome 1 is a genetic disorder that manifests with occasional urinary tract anomalies associated with a more common aplasia cutis congenita of the parietal region, trunk or limbs, cutis marmorata, telangiectasia con- genita, and hypopigmented skin [26]. Apert syndrome is an autosomal dominant disease, with onset in infancy, that presents with craniofacial anomalies, syndactyly, hyperhidrosis, and pronounced acne at adoles- cence. In 10% of cases, it is associated with polycystic kid- neys and hydronephrosis [26]. Fanconi pancytopenia syndrome commonly affects the skin, producing brownish pigmentation, and the kidneys by developing different renal anomalies such as hypoplasia or malformation [26]. Pallister-Hall syndrome usually affects both kidneys with renal ectopia or dysplasia and the skin with midline facial hemangioma [26]. Conclusions We could not find any reports that focused attention on the link between nephrological and dermatological manifesta- tions of the same disease in children. It is also important for clinicians to keep in mind that in what may appear to be an exclusively dermatological disease, there can be nephro- logical manifestations as part of the same disorder and vice versa. Whenever a kidney disease is suspected, the following tests must always be performed: urinalysis and quantifica- tion of proteinuria, serum creatinine, and urea and an ultra- sound of kidneys. Acknowledgments The authors thank Anna Carella for reviewing the English language of this manuscript. renal Cell Carcinoma Renal cell carcinoma is extremely rare in children, but is more common in adolescents older than 15 years of age. The classic triad of hematuria, flank pain, and palpable ab- dominal mass is present in less than 10% of adult cases; the diagnosis is often incidental. The skin may be involved by flushing because of prostaglandins production [20]. Non-Hodgkin Lymphoma Non-Hodgkin lymphoma is a tumor originating from lym- phoid tissues, mainly lymph nodes, that in about 30% of cases presents with extranodal involvement at the diagnosis. The most commonly involved sites are skin, bone marrow, central nervous system, gastrointestinal and genitourinary tract, thyroid, and sinuses. The skin is the second most com- mon extranodal localization of disease presenting with rashes or lesions that should always be biopsied. The possible renal involvement (up to 14% of cases) includes enlarged kidneys, ureteral obstruction (due to retroperitoneal disease), tubular dysfunction (due to acute uric acid nephropathy), and renal failure [21]. Other syndromes, Malformations and Genetic Disorders Wilms tumor (WT) is rarely diagnosed in the neonate, but it is the most common renal cancer in childhood (95% of cases). In approximately 10% of cases, it is part of syndromes such as WAGR, Beckwith-Weidemann, and Denys-Drash. Certain overgrowth conditions associated with capillary malforma- tion and hemihypertrophy or macrocephaly-capillary mal- formation also have an increased risk for WT; in these cases, a ultrasonographic screening for WT is necessary [22]. Tuberous sclerosis complex is an autosomal dominant genetic disorder (TSC1 or TSC2 genes) with an incidence of 1:5000-10000 that involves many organ systems. Re- ported skin lesions are hypopigmented macules, angiofibro- mas, shagreen patches, fibrous plaque, and ungual fibro- mas, whereas renal lesions include angiomyolipomas, cysts, lymphangiomas, and renal cell carcinoma that can interfere with renal function causing hypertension and hemorrhage. Since the prevalence of renal manifestations increases with age, ultrasonographic follow-up is required every 1-3 years [23]. Nail-patella syndrome is an autosomal dominant condi- tion affecting the nails, skeletal system, kidneys, and eyes, and while renal failure can appear later in life, the most com- mon sign is having missing or underdeveloped fingernails and toenails [24]. Review | Dermatol Pract Concept 2020;10(4):e2020095 5 ture. 1996;379(6564):445-449. DOI: 10.1038/379445a0. PMID:8559248. 14. Erdoğan F, Ismailoğullari S, Soyuer I, Ferahbaş A, Poyrazoğlu H. Different Seizure Types and Skin Lesions in Oculocerebrore- nal Syndrome of Lowe. J Child Neurol. 2007;22(4):427-431. DOI: 10.1177/0883073807301928. PMID:17621522. 15. Marzuillo P, Piccolo V, Mascolo M, et al. Patients affected by dent disease 2 could be predisposed to hidradenitis suppurativa. J Eur Acad Dermatology Venereol. 2018;32(8):e309-e311. DOI: 10.1111/jdv.14860. PMID:29430722. 16. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539-548. DOI: 10.1097/01.gim.0000237866.70357.c6. PMID:16980809. 17. Arango ML, Shah AN. Visual diagnosis: an infant with rash and hypercalcemia. Pediatr Rev. 2019;40(3):e11-e13. DOI: 10.1542/pir.2017-0058. PMID:30824504. 18. Materne C, Porubsky S, Gerth J, Grone H-J, Wolf G. His- tiocytosis X and renal insufficiency. Nephrol Dial Trans- plant. 2007;22(12):3664-3667. DOI: 10.1093/ndt/gfm299. PMID:17890248. 19. Marzuillo P, Grandone A, Guarino S, et al. A 23-month-old girl with chronic ‘seborrhoeic’ dermatitis, dehydration and fail- ure to thrive. Arch Dis Child Educ Pract Ed. April 2018:ed- pract-2018-314828. DOI: 10.1136/archdischild-2018-314828. PMID:29703813. 20. Sadeghian A, Rouhana H, Oswald-Stumpf B, Boh E. Etiolo- gies and management of cutaneous flushing. J Am Acad Der- matol. 2017;77(3):405-414. DOI: 10.1016/j.jaad.2016.12.032. PMID:28807108. 21. Hunter S, Samir A, Eisner B, et al. Diagnosis of renal lymphoma by percutaneous image guided biopsy: experience with 11 cases. J Urol. 2006;176(5):1952-1956; discussion 1956. DOI: 10.1016/j.juro.2006.07.032. PMID:17070216. 22. Peterman CM, Vadeboncoeur S, Mulliken JB, Fishman SJ, Liang MG. Wilms tumor screening in diffuse capillary malformation with overgrowth and macrocephaly–capillary malformation: A retrospective study. J Am Acad Dermatol. 2017;77(5):874-878. DOI: 10.1016/j.jaad.2017.06.014. PMID:28822558. 23. Curatolo P, Bombardieri R, Jozwiak S. Tuberouse sclerosis. Lan- cet. 2008;372:657-668. DOI: 10.1016/S0140-6736(08)61279- 9. 24. Sweeney E, Hoover-Fong JE, McIntosh I. Nail-Patella Syn- drome. In: Gene Reviews. University of Washington, Seattle; 1993-2020. http://www.ncbi.nlm.nih.gov/pubmed/20301311. 25. Has C, He Y. Renal-skin syndromes. Cell Tissue Res. 2017;369(1):63-73. DOI: 10.1007/s00441-017-2623-y. PMID: 28432467. 26. Reimer A, He Y, Has C. Update on genetic conditions affecting the skin and the kidneys. Front Pediatr. 2018;6(March). DOI: 10.3389/fped.2018.00043. PMID:29552546. references 1. Chuang GT, Tsai IJ, Lin MT, Chang LY. Acute kidney injury in patients with Kawasaki disease. Pediatr Res. 2016;80(2):224- 227. DOI: 10.1038/pr.2016.81. PMID:27064240. 2. Watanabe T. Pyuria in patients with Kawasaki disease. World J Clin Pediatr. 2015;4(2):25-29. DOI: 10.5409/wjcp.v4.i2.25. PMID:26015877. 3. Jauhola O, Ronkainen J, Koskimies O, et al. Renal manifesta- tions of Henoch-Schonlein purpura in a 6-month prospective study of 223 children. Arch Dis Child. 2010;95(11):877-882. DOI: 10.1136/adc.2009.182394. PMID:20852275. 4. Forsey J, Dhandayuthapani G, Hamilton M, Martin R, Tizard E, Ramanan A. Takayasu arteritis: key clinical factors for early diagnosis. Arch Dis Child Educ Pract. 2011;96(5):176-182. DOI: 10.1136/adc.2010.196774. PMID:21406449. 5. Cervera R, Khamashta M, Hughes G. The Euro-lupus proj- ect: epidemiology of systemic lupus erythematosus in Europe. Cervera R, Tincani A, eds. Lupus. 2009;18(10):869-874. DOI: 10.1177/0961203309106831. PMID:19671784. 6. Chiewchengchol D, Murphy R, Morgan T, et al. Mucocuta- neous manifestations in a UK national cohort of juvenile-on- set systemic lupus erythematosus patients. Rheumatology. 2014;53(8):1504-1512. DOI: 10.1093/rheumatology/keu137. PMID:24692572. 7. Weening JJ, D’agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revis- ited. Kidney Int. 2004;65(2):521-530. DOI: 10.1111/j.1523- 1755.2004.00443.x. PMID:14717922. 8. Yu F, Wu L-H, Tan Y, et al. Tubulointerstitial lesions of pa- tients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int. 2010;77(9):820-829. DOI: 10.1038/ki.2010.13. PMID:20182417. 9. Park MH, D’Agati V, Appel GB, Pirani CL. Tubulointersti- tial disease in lupus nephritis: relationship to immune depos- its, interstitial inflammation, glomerular changes, renal func- tion, and prognosis. Nephron. 1986;44(4):309-319. DOI: 10.1159/000184012. PMID:3540691. 10. Shea-Simonds P, Cairns TD, Roufosse C, Cook T, Vyse TJ. Lupus podocytopathy. Rheumatology (Oxford). 2009;48(12):1616- 1618. DOI: 10.1093/rheumatology/kep256. PMID:19713441. 11. Salvatore SP, Barisoni LMC, Herzenberg AM, Chander PN, Nickeleit V, Seshan S V. Collapsing glomerulopathy in 19 pa- tients with systemic lupus erythematosus or lupus-like disease. Clin J Am Soc Nephrol. 2012;7(6):914-925. DOI: 10.2215/ CJN.11751111. PMID:22461531. 12. Hoopes RR, Shrimpton AE, Knohl SJ, et al. Dent disease with mutations in OCRL1. Am J Hum Genet. 2005;76(2):260-267. DOI: 10.1086/427887. PMID:15627218. 13. Lloyd SE, Pearce SH, Fisher SE, et al. A common molec- ular basis for three inherited kidney stone diseases. Na-