Kindler Syndrome in Native Americans from Panama Report of 26 Cases

STUDY Kindler Syndrome in Native Americans From Panama Report of 26 Cases

Homero Penagos, MD; Marta Jaen, MD; Mario T. Sancho, MD; Manuel R. Saborio, MD; Victor G. Fallas, MD; Dawn H. Siegel, MD; Ilona J. Frieden, MD

Objective: To investigate the clinical, genetic, and labo- (92%), severe cutaneous atrophy (89%), hyperkeratosis ratory features of 26 patients with Kindler syndrome. of the palms and soles (81%), congenital acral blisters (81%), severe periodontal disease (81%), and phimosis Design: Case series of patients recruited when they were (80% of male subjects). In 1 large family with 10 pa- seen at outpatient consultations in the Department of Der- tients, inheritance of Kindler syndrome followed that of matology at the Changuinola Hospital in Bocas del Toro, an autosomal recessive disease. Karyotypes in 3 patients Panama, between May 1986 and December 1990. and 1 unaffected father were normal. Findings from ultrastructural studies showed replication of lamina densa Setting: Clinical history, physical examination, and labo- in 10 patients. ratory studies were done at a community hospital in Panama. Twelve of the patients had further studies per- Conclusions: To our knowledge, this study represents formed at a children’s hospital in Costa Rica. the largest series to date of patients with Kindler syndrome. The clinical features confirm previously re- Patients: A total of 26 patients were entered into the ported cases, and segregation analysis confirms its au- study. They were members of the Ngo¨be-Bugle´ tribe and tosomal recessive inheritance. We also report severe resided in isolated villages in rural Panama. phimosis as a complication, which has not been previously described in this syndrome. Results: The major findings were skin fragility with blistering (100%), poikiloderma (96%), photosensitivity Arch Dermatol. 2004;140:939-944

N 1954, THERESA KINDLER DE- this genetically isolated population.12 This scribed progressive poikiloderma genetic locus was also reported by Jobard with marked diffuse cutaneous at- et al13 in a group of North African patients. rophy associated with congenital With the genetic basis now established, the acral bullae and photosensitivity in present study helps define the clinical char- aI 14-year-old girl.1 She hypothesized that acteristics of this disorder. the syndrome might result from the coin- From Chiriqui Regional cidence in 1 patient of 2 rare congenital con- METHODS Hospital, David (Dr Penagos), ditions (dystrophic epidermolysis bullosa and Changuinola Hospital, and congenital poikiloderma) or might be Changuinola (Dr Jaen), Social DEMOGRAPHICS AND Security Bureau of Panama; due to a previously unidentified genetic dis- CULTURAL BACKGROUND National Children Hospital, order. Many subsequent reports have es- San Jose´, Costa Rica tablished this syndrome as a distinct clini- In Panama, 64% of the 194269 Native Americans (Drs Sancho and Saborio), and cal entity.2-11 belong to the Ngo¨be-Bugle´ tribe, 1 of 4 Native Mexico Hospital, Social To our knowledge, we describe herein Americangroups.Thegeneticandgeographiciso- Security Bureau of Costa Rica, lation of these peoples, who live in remote vil- the largest series of patients with Kindler lages in the mountainous and sunny regions of and University of Costa Rica, syndrome (KiS) to date—26 cases in 10 San Jose´ (Dr Fallas); and BocasdelToro,Chiriqui,andVeruguasprovinces, families from the Bocas del Toro province may explain the high rate of this rare, autosomal Departments of Dermatology of Panama. This kindred was used to iden- (Drs Siegel and Frieden) and recessive disorder in this cohort. tify the gene for KiS (KIND1) on chromo- Pediatrics (Dr Frieden), PATIENTS University of California, some 20p12.3. These patients all have an San Francisco. The authors identical homozygous loss of function mu- The 15 male and 11 female patients were Na- have no relevant financial tation (R271X); therefore, it is likely that the tive American members of Panama’s Ngo¨be- interest in this article. high incidence is due to a founder effect in Bugle´ tribe. Age at first diagnosis ranged from

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Leukokeratosis Patient No./ Poikiloderma Degree of of Labia or Sex/Age, y Blisters Onset Photosensitivity Atrophy Mucosae Keratoderma Ectropion Oral Mucosa Webbing* Phimosis 1/F/27 + Infancy + ++ HBG + + + − NA 2/F/9 + 1 y + + HBG + − − − NA 3/F/28 + Infancy + ++ HBG + + + − NA 4/M/19 + 1 y + ++ HBG/UMS + + − − + 5/F/13 + 6 mo ++ ++ HBG − − − − NA 6/M/10 + 10 mo + + HBG + − − − − 7/M/17 + 1 y + ++ HBG + − − + + 8/M/5 + 6 mo ++ ++ HBG/UMS + − − − + 9/F/1 + 8 mo +++ + − − − − − NA 10/M/0.5 + − + − − − − − − + 11/F/3 + Birth ++ + HBG + − − − NA 12/F/13 + Infancy ++ ++ HBG + − − − NA 13/M/11 + Infancy + + HBG/UMS + − − − + 14/M/5 + 8 mo + + HBG + − − − + 15/M/4 + Infancy + + HBG + − − + − 16/F/2 + 2 d after birth − ± HBG + − − − NA 17/F/1 + Few days ++ − Imperforate −− − +NA after birth anus 18/M/15 + 1 y + ++ HBG + − − − + 19/M/10 + 6 mo + ++ HBG/UMS + − − − + 20/M/1 + 6 mo + − − − − − − − 21/F/8 + 1 y +++ ++ HBG + − − − NA 22/M/19 + Infancy + + HBG/UMS + + + + + 23/F/55 + Infancy + + HBG + − − − NA 24/M/4 + Infancy + + HBG/UMS + − − − + 25/M/2 + Infancy + + HBG + − − − + 26/M/7 + Infancy + + HBG + − − − +

Abbreviations: HBG, hypertrophic bleeding gums; NA, not applicable; UMS, urethral meatal stenosis; −, finding absent; +, finding present; ±, minimal; ++, moderate; +++, severe. *Webbing between the third and fourth and fourth and fifth toes.

0.5 to 28 years (mean, 7.8 years). Of the 26 cases, 17 arose from mation followed cutaneous trauma or exposure to sun- 2 large families and the remainder were individual cases. None light. From the clinical follow-up of younger patients, had parents who were affected by KiS, and pedigree analysis we noted that bullae appeared to diminish in frequency strongly suggested autosomal recessive inheritance. Four karyo- at approximately age 10 to 12 years. Patients who were types (patients 1, 14, and 15, and patient 15’s unaffected fa- first seen as adults also reported a decrease in the num- ther) were normal. ber of blisters at approximately the same age. Neverthe- EXAMINATIONS less, blisters continued to recur in all age groups, and the skin of older patients continued to be fragile and easily Case series of patients were recruited when they were seen at injured by mild trauma. outpatient consults in the Department of Dermatology at the Pyogenic skin infections were common and in 7 Changuinola Hospital in Bocas del Toro, Panama, between May patients (patients 5, 6, 19, 20, 21, 23, and 24) were 1986 and December 1990. Clinical history, physical examina- complicated by cases of acute glomerulonephritis. tion, and laboratory studies were done at a community hospital in Panama. Twelve of the patients had further studies at a Because no skin cultures were obtained, it was not children’s hospital in Costa Rica. known whether the precipitating agent in these cases was a glomerulonephritic strain of group A streptococ- cus or another pathogen. RESULTS

PHYSICAL FINDINGS Photosensitivity Blistering Photosensitivity characterized by erythema, burning, and blister formation after sun exposure was observed in 24 Blistering appeared in all 26 patients, and skin fragility patients (Table). This finding was very marked in some was the most common clinical observation (Table). Blis- patients (patients 5, 8, 9, 11, 12, 17, and 21) and less ters were congenital in 21 patients and appeared during marked in others (patients 1, 2, 19, 23, and 24). It ap- the first days of life in the other 5 patients (patients 5, peared as early as 1 month of age in 1 patient, but the 10, 20, 22, and 23), most frequently on the dorsa of the average age at which photosensitivity developed was 2 hands and feet (Figure 1). In each instance, blister for- years. In some patients, photosensitivity developed af-

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Figure 2. Severe photosensitivity resulting in blisters after sun exposure in ter particularly prolonged sun exposure (Figure 2). The an 8-year-old girl. photosensitivity usually decreased over time, coincid- ing with decreased blister formation by age 10 to 12 years. However, some degree of photosensitivity generally per- tient had sclerodermoid changes on the more proximal sisted (eg, facial erythema after minimal sun exposure). limbs or on the trunk. All patients had type IV-V skin. Hyperkeratosis of the Palms and Soles Poikiloderma Hyperkeratosis of the palms and soles was present in 21 Poikiloderma was present in 25 of 26 patients, and on- patients, accompanied in some by fissuring or wrin- set most frequently occurred between ages 2 to 3 years kling, but it was not associated with acrokeratotic pap- (Table). Poikiloderma developed in patients 9 and 20 ules. The palmar hyperkeratosis often had a glassy ap- on the face at ages 6 and 8 months, respectively, but no pearance, and there was loss of fingerprints. It ended cases of truly congenital poikiloderma were observed. sharply at the volar wrist but extended dorsally onto the Generalized poikiloderma in both sun-exposed and hands, wrists, and as far proximally as the distal one third non–sun-exposed areas eventually developed in all of of the forearms. In addition, some patients had ridged, our patients and persisted throughout adult life. The ribbed hyperkeratosis of the lateral and anterior ankles development of poikiloderma in non–sun-exposed that was reminiscent of epidermolytic hyperkeratosis. areas indicates that it is not solely caused by photodam- Webbing between toes (ie, partial fusion with decreased age. Some patients had axillary freckling. interphalangeal spaces between the third and fourth and fourth and fifth toes) was found in patients 7, 15, and Atrophy 22, but required no surgical treatment. This may have been due to the trauma of repeated blistering and scar- Diffuse cutaneous atrophy was observed in all cases at ring in infancy. the time of first consultation except in patients 10, 17, and 20 (Table). Its main features were thin, wrinkled skin, Mucosal Involvement (cigarette paper skin), most pronounced on the dorsa of the hands and feet (Figure 3). Other affected parts of Mucosal involvement was frequent. Urethral meatal ste- the body included abdomen, thighs, knees, and elbows. nosis was present in patients 4, 8, 13, 19, 22, and 24 and There were frequent sclerodermoid changes distally, with required dilatation in patients 8, 22, and 24 (Table). Pa- loss of the angle of the proximal nail fold and with ta- tient 17 was born with an imperforate anus that re- pering of the fingers. The plate of the nails was thin with quired surgical repair. Severe periodontal disease, in some atrophy and oncolysis in some patients. One patient had cases with premature loss of teeth, was observed in 22 sclerodermoid tightening of the perioral skin, but no pa- patients (Figure 4). Onset of periodontal disease most

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 5. Severe phimosis in a 13-year-old boy. The patient is unable to retract the foreskin. Also note poikiloderma on the non–sun-exposed areas on the upper thigh.

Joint Laxity

Joint laxity was present frequently with variable hypermobility of the thumb and fingers, knees, and elbows. Some patients could easily touch the floor with their palms while standing. However, the skin (eg, at the neck) was not hyperextensible. Joint hypermobility was not seen in family members unaffected by KiS.

LABORATORY FINDINGS

Figure 3. Diffuse cutaneous atrophy with wrinkling and webbing between Microcytic anemia was found in 23 patients (87%). The fingers, with features of premature aging, in a 10-year-old child. microcytic anemia is likely unrelated to KiS, since it is also common in the general population. The most likely causes are malnutrition and parasites. No other hema- tologic disorders were identified. Other studies performed were entirely within normal limits including serum urea nitrogen, glucose, serum calcium, phosphorus, cholesterol, alkaline phosphatase, total bilirubin, VDRL test for syphilis, immunoglobulins, and aspartate ami- notransferase. Urinary uroporphyrin study findings were normal. When performed, endocrine evaluations (thy- rotropin, follicle-stimulating hormone, luteinizing hormone, and cortisol) were within normal limits.

RADIOLOGICAL STUDIES

Renal and abdominal ultrasound findings were normal in 12 cases. Two intravenous pyelograms were per- Figure 4. Severe periodontal disease in a 26-year-old man. formed (patients 2 and 8); the results from both were normal except for an anatomically normal kidney present commonly began in early adolescence. Ectropion of the in the pelvis in patient 8. Five patients had delayed os- lower eyelid was present in 10 patients. sification of the epiphyses in the hand and wrist. This finding also was common in the general population and Phimosis likely is due to malnutrition.

Phimosis was found in 12 (80%) of 15 male patients, re- PHOTOSENSITIVITY TESTING quiring circumcision in 10 (Figure 5). Histopathologi- cal studies of the preputial samples were those of poiki- We performed photopatch testing in 13 patients at Na- loderma: epidermal atrophy, vascular ectasia, and tional Children’s Hospital, San Jose´, Costa Rica (pa- lichenoid tissue reaction. No genital changes were seen tients 1, 2, 5, 6, 8, 9, 11, 12, 17, 19, 21, 23, and 24); the in female patients. other 14 patients were classified by clinical history and

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 physical examination. In patients 11 and 12, the mini- nosis, ectropion, and in 12 cases, severe phimosis re- mal erythema dose for UV-B was abnormal, and 2 pa- quiring surgical correction. tients also had an abnormal minimal erythema dose for Our histopathological studies showed a lichenoid UV-A. Patients 5 and 6 developed hyperpigmentation 48 tissue reaction and splitting at the lamina densa level. hours after the test. Our youngest patients appeared to We were not able to determine the level of bullae on be the most sensitive in their response to UV-B light in electron microscopic studies, and, similar to other re- the photosensitivity tests, which may correlate with the ports to date, we found no definitive ultrastructural fea- clinical observation that the photosensitivity was great- ture.6 However, several articles report a pattern regard- est in children. ing KiS and ultrastructural findings such as marked duplication of the lamina densa,5,17 basal layer separa- HISTOPATHOLOGY tion,18 and blistering with trauma above the level of the lamina densa.16 Light Microscopy Several conditions can cause blistering, cutaneous atrophy, and/or poikilodermalike skin changes. Weary Histologic features of the poikilodermic skin from all 10 et al19 described a similar syndrome with an autosomal KiS patients who underwent biopsy showed orthokera- dominant pattern of transmission named “hereditary ac- totic hyperkeratosis, epidermal atrophy, and focal vacu- rokeratotic poikiloderma,” and a subsequent report by olization of the basal layer. In the papillary dermis, nu- Larregue et al20 proposed the name “Weary-Kindler merous melanophages and rare colloid bodies were seen. syndrome” to describe patients with this constellation There was also vascular ectasia and lymphohistiocytic in- of findings. However, our findings suggest that both the filtrate. In 8 patients with bullous lesions, vacuolization clinical features and inheritance patterns of these syn- of the basal layer with intraepidermal cleft formation was dromes are distinctive enough to warrant separation. In present. Subepidermal clefts were not seen. KiS, blisters are often congenital, photosensitivity is frequent, and the poikiloderma typically has its onset after Electron Microscopy age 1 year and involves both sun-exposed and non–sun- exposed skin. In addition, marked diffuse skin atrophy In the 10 patients who underwent biopsy, nontrauma- in areas of skin not exposed to the sun and mucosal in- tized poikilodermic skin and bullous lesions showed involvement is also present. In contrast, the blisters in terruption and reduplication of the basal lamina. Col- Weary syndrome are not usually congenital, photosen- loid bodies were present in the upper dermis. The sitivity is generally absent, keratotic papules develop on epidermis and the keratinocytes of the basal layer were the dorsal hands, elbows, and knees, and there is no normal. We were not able to determine the level of the mucosal involvement. blister split on electron microscopic studies. The group of patients described in the present study were used for linkage studies and molecular OTHER STUDIES analysis, which were crucial to the identification of the gene KIND1 for KiS.12 This gene appears to function as Additional tests included audiometric, ophthalmo- actin-extracellular matrix linker protein, and is a homo- scopic, and psychiatric evaluations in the 12 patients logue of the Caenorhabditis elegans protein UNC-112.21 evaluated at the National Children’s Hospital. Findings The discovery of the gene will aid in the confirmation of from all audiometric tests were normal except for pa- the diagnosis in new cases and may eventually lead to tients 19 and 24, who both had mild conductive hearing the development of new treatments. Our findings dem- loss at the time of testing. Findings from all eye exami- onstrate that KiS is a distinctive entity that can be dif- nations were normal except for patient 8, who was found ferentiated from similar conditions such as Weary syn- to have a posterior subcapsular cataract. Psychometric drome, on the basis of clinical and histologic features test results were normal in all instances. and genetics.

COMMENT Accepted for publication September 29, 2003. In a socially and geographically isolated population of We would like to thank the Biblioteca Nacional de Native Americans in Panama characterized by a high de- Salud y Seguridad Social (The National Library of Health gree of consanguinity,14 we have identified 26 cases of and Social Security), the Lodging Center, Hospital Nacio- KiS. In this case series—the largest reported to date to nal de Nin˜os–National Children’s Hospital, and the our knowledge—the principal clinical features were skin National Amusement Park, San Jose´, Costa Rica; Ervin fragility and acral blister formation beginning at birth or Epstein, Jr, MD, for his invaluable support and revision of in early infancy, photosensitivity (which is most promi- the manuscript; and Colin Weibe, BSc, DDS (Alberta), nent during childhood), diffuse cutaneous atrophy, poi- GPR (Saskatchewan), DiplPerio, MSc (British Columbia), kiloderma, and palmoplantar hyperkeratosis without FRCD(C), for his support and for donating Figure 4; and punctate lesions. Mucosal manifestations were also very Christina Walker, JD, for her assistance in preparation of common and included hemorrhagic mucositis, hemor- the manuscript. rhagic gingivitis, periodontal disease, and premature loss Correspondence: Homero Penagos, MD, Chiriqui Re- of teeth, similar to other recent reports.7,15,16 Other mu- gional Hospital Apartado 855 David, Chiriqui, Panama cosal findings included labial leukokeratosis, urethral ste- [email protected]).

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 12. Siegel DH, Ashton GH, Penagos HG, et al. Loss of Kindlin-1, a human homolog REFERENCES of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet. 2003;73:174-187. 1. Kindler T. Congenital poikiloderma with traumatic bulla formation and progres- 13. Jobard F, Bouadjar B, Caux F, et al. Identification of mutations in a new gene sive cutaneous atrophy. Br J Dermatol. 1954;66:104-111. encoding a FERM family protein with a pleckstrin homology domain in Kindler 2. Bordas X, Palou J, Capdevila JM, Mascaro JM. Kindler’s syndrome: report of a syndrome. Hum Mol Genet. 2003;12:925-935. case. J Am Acad Dermatol. 1982;6:263-265. 14. Sinclair F. Enfermidad genetica y poblacion amerindia en Panama. Hombre y Cul- 3. Forman AB, Prendiville JS, Esterly NB, et al. Kindler syndrome: report of two cases tura. 1991;1:173-192. and review of the literature. Pediatr Dermatol. 1989;6:91-101. 15. Ricketts DN, Morgan CL, McGregor JM, Morgan PR. Kindler syndrome: a rare 4. Hacham-Zadeh S, Garfunkel AA. Kindler syndrome in two related Kurdish fami- cause of desquamative lesions of the gingiva. Oral Surg Oral Med Oral Pathol lies. Am J Med Genet. 1985;20:43-48. Oral Radiol Endod. 1997;84:488-491. 5. Senturk N, Usubutun A, Sahin S, et al. Kindler syndrome: absence of definite 16. Wiebe CB, Larjava HS. Abnormal deposition of type VII collagen in Kindler syn- ultrastructural feature. J Am Acad Dermatol. 1999;40:335-337. drome. Arch Dermatol Res. 1999;291:6-13. 6. Suga Y, Tsuboi R, Hashimoto Y, Yaguchi H, Ogawa H. A Japanese case of Kin- 17. Shimizu H, Sato M, Ban M, et al. Immunohistochemical, ultrastructural, and mo- dler syndrome. Int J Dermatol. 2000;39:284-286. lecular features of Kindler syndrome distinguish it from dystrophic epidermoly- 7. Wiebe CB, Silver JG, Larjava HS. Early-onset periodontitis associated with Weary- sis bullosa. Arch Dermatol. 1997;133:1111-1117. Kindler syndrome: a case report. J Periodontol. 1996;67:1004-1010. 18. Haber RM, Hanna WM. Kindler syndrome: clinical and ultrastructural findings. 8. Hovnanian A, Blanchet-Bardon C, de Prost Y. Poikiloderma of Theresa Kindler: Arch Dermatol. 1996;132:1487-1490. report of a case with ultrastructural study, and review of the literature. Pediatr 19. Weary PE, Manley WF Jr, Graham GF. Hereditary acrokeratotic poikiloderma. Arch Dermatol. 1989;6:82-90. Dermatol. 1971;103:409-422. 9. De Mattos RA, Sittart JA, Valente NY. Poikiloderma congenitale of the Kindler 20. Larregue M, Prigent F, Lorette G, Canuel C, Ramdenee P. Bullous and hereditary type associated with multiple seborrheic warts. Med Cutan Ibero Lat Am. 1990; Weary-Kindler’s acrokeratotic poikiloderma. Ann Dermatol Venereol. 1981;108: 18:232-237. 69-76. 10. Kapasi AY, Khopkar U, Raj S, Wadhwa SL. Weary-Kindler syndrome with mul- 21. Rogalski TM, Mullen GP, Gilbert MM, Williams BD, Moerman DG. The UNC-112 tiple seborrheic keratoses. Int J Dermatol. 1993;32:444-445. gene in Caenorhabditis elegans encodes a novel component of cell-matrix ad- 11. Al Aboud K, Al Hawsawi K, Al Aboud D, Al Githami A. Kindler syndrome in a Saudi hesion structures required for integrin localization in the muscle cell mem- kindred. Clin Exp Dermatol. 2002;27:673-676. brane. J Cell Biol. 2000;150:253-264.

News and Notes

Board Certification in Dermatopathology he International Board of Dermatopathology will T organize under the auspices of the International Committee for Dermatopathology (www.icdpath.org) the Second Certifying Examination in Dermatopathology (Di- ploma in Dermatopathology) in Frankurt/Main, Ger- many, on December 11, 2004. Participating societies are the International Society of Dermatopathology, the Eu- rpoean Society for Dermatopathology, and the Ibero- Latin American Society of Dermatopathology. For further information about this examination contact Helmut Kerl, MD, Department of Dermatology, Medical Univer- sity of Graz, Auenbruggerplatz 8, 8036 Graz, Austria; phone: +43-316-385-2538; fax: +43-316-385-3424; e-mail: [email protected] or Guenter Burg, MD, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland; phone: +41-1-255-2550; fax: +41-1-255-4403; e-mail: [email protected].

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