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 ul- trastructural 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 syn- drome. 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 previ- ously described in this syndrome. Results: The major findings were skin fragility with blis- tering (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- Ia 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 (REPRINTED) ARCH DERMATOL / VOL 140, AUG 2004 WWW.ARCHDERMATOL.COM 939 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Clinical Features of Kindler Syndrome in Panama 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 hospi- tal 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- (REPRINTED) ARCH DERMATOL / VOL 140, AUG 2004 WWW.ARCHDERMATOL.COM 940 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 1. Acral blistering in an affected 1-month-old infant (patient 10). 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.