Alopecia areata incognita in Cronkhite-Canada syndrome suggests an autoimmune etiology – and that’s the way it is.
By Warren R. Heymann, MD
Sept. 14, 2017
I was 3 weeks old when Cronkhite and Canada first reported two cases of the syndrome, both of which proved to be fatal, in 42 and 75 year-old women, respectively. The following is quoted from the original manuscript (1):
Physical examination [of the 42 year-old] revealed a well developed woman with striking pigmentary changes in the skin. The backs of the hands and fingers were deeply colored with a diffuse brown pigment, as were most of the body folds. The face and neck were streaked with brown, with ill defined brown patches on the perioral and buccal areas. In the retina were streaks of tan pigment. The scalp hair was scant. Pubic, axillary and facial hair was almost totally absent. The remainder of the physical examination was normal.
Physical examination [of the 75 year-old] revealed a cachectic, elderly woman whose scalp was covered by a few white hairs 1 cm. long. The fingernails and toenails were absent, but at the bases there appeared to be slight regeneration. There was a diffuse brown pigmentation over the arms and hands, with numerous areas of vitiligo.
In their concluding summary, Cronkhite and Canada suggested that these ectodermal changes are part of a generalized deficiency state and that their clinical prominence may be related to the extensive distribution of the lesions in all segments of the digestive tract. Sixty-two years later, the nature of CCS remains an enigma, although there is increasing evidence that it is an autoimmune disorder, as it has been associated with systemic lupus erythematosus, vitiligo, rheumatoid arthritis and hypothyroidism.
CCS is a rare, non-inherited disorder with incidence of one in a million; more than 500 cases have been reported. Although worldwide in distribution, the majority of cases are from Japan. CCS is more prevalent in males than females with 3:2 ratio. The disease commonly occurs in fifth decade of life with a mean age of onset between 50 and 60 years. (2)
CCS is a syndrome of skin hyperpigmentation, polyposis, alopecia, and onychodystrophy, accompanied by abdominal pain and diarrhea. Diffuse GI inflammatory polyposis, sparing the esophagus on endoscopy, is a hallmark of the disease. Colonic polyps are classically hamartomas, although they have been described as inflammatory polyps. The prevalence of GI malignancy in CCS patients is about 10%. (3) Clinicians should consider CCS in patients with unexplained diarrhea and ectodermal abnormalities, especially in those of Japanese descent. No universally agreed-upon therapy for CCS exists, despite studies looking at a variety of agents and diets. Nutritional support and treatment with corticosteroids remain the fundamental therapy. Steroid-sparing immunosuppressive agents can prevent relapse of symptoms. Although some patients with CCS respond to immunomodulatory therapy, the overall mortality of the disease is high, with patients succumbing to cardiac, infectious, or hemorrhagic adverse events. (2,4)
Ong et al reported the case of a 49-year-old Chinese woman diagnosed with CCS following a history of sudden and rapid extensive hair loss over a few weeks. Two weeks prior to developing the alopecia, she experienced an increased appetite with abdominal pain, followed by nausea with severe bloody diarrhea, which resulted in a weight loss of 17 kg within 2 months. On examination, there was diffuse alopecia of the scalp. She also had loss of eyebrows and eyelashes, thinning of pubic hair, subtle macular hyperpigmentation of the nail folds, dorsal fingers, and palms. Transverse ridging of each fingernail was seen at presentation, which later rapidly progressed to onychomadesis involving all fingernails and toenails. There was no mucosal involvement. Most of her routine laboratory studies were normal, with the exception of a minimally elevated ESR, and slightly low levels of vitamin D and zinc. Her autoimmune serologic screen was normal. Biopsies of polyps from the stomach, small and large intestines, demonstrated inflammation without malignancy. She improved with the administration of prednisolone and mesalazine.
Her scalp biopsy revealed a ‘shift out of anagen’, with an increased number of telogen hair follicles, and an anagen-to-telogen ratio of A:T – 60%:40%. There was diffuse hair follicle miniaturization with a terminal-to-vellus ratio of T:V – 1.13:1. Grouping of small telogen hair follicles was present at the isthmus. The subisthmic area showed a peribulbar lymphoid cell infiltrate involving numerous hair bulbs in the subcutaneous tissue and pigment casts.
The authors described this as a variant of alopecia areata (alopecia areata incognita) characterized by acute diffuse hair thinning, which is often difficult to differentiate from telogen effluvium and androgenic alopecia. The concomitant loss of eyelashes and eyebrows with thinning of axillary and pubic hair, as seen in this patient, is more in keeping with alopecia areata, as telogen effluvium affects only the scalp. Moreover, the rapid response to systemic glucocorticoids supported a diagnosis of alopecia areata over telogen effluvium. (5) (In my opinion, I would not be as strident in saying telogen effluvium only affects the scalp — severe cases may affect other sites such as the eyelids and pubic hair.)
Watanabe-Okada E, et al presented detailed histopathological investigations of two female CCS patients with severe hair loss. They observed a marked increase in telogen hair follicles with no sign of minaturization or atrophy of follicular structures. There was no follicular inflammation, despite severe inflammation in the gastrointestinal tract. The authors concluded that anagen-telogen conversion is an early event in CCS and severe alopecia due to an acute telogen effluvium is mostly inevitable. (6) Ong et al speculate that the histopathology reported by Watanabe-Okada et al of diffuse anagen–telogen conversion, more likely represented the ‘shift out of anagen’ observed in the subacute stage of alopecia areata.(4)
Given the acute, potentially severe systemic findings of CCS, I imagine that at least some component of a classical telogen effluvium is at play. The work of Ong et al, however, suggests that it may be more complicated, with autoimmunity contributing to the process. Future studies should clarify this.
Anyone born in the heart of the baby boom looked to Walter Cronkite of the CBS Evening News as “the most trusted man in America” (sounds quaint, no?). I will end this this commentary in typical Cronkite fashion: CCS remains a mystery, although the finding of alopecia areata incognita lends further support to the concept of an autoimmune pathogenesis — and that’s the way it is.
1. Cronkhite LW, Jr, Canada WJ. Generalized gastrointestinal polyposis – an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med 1955; 252: 1011-15
2. Iqbal U, et al. Cronkhite-Canada syndrome: A rare cause of chronic diarrhea. Gastroenterology Res 2017; 10: 196-8.
3. Lipin SP, et al. Case of Cronkhite Canada syndrome shows improvement with enteral supplements. J Assoc Physicians India 2012; 60: 61-4.
4. Vashistha N, et al. Cronkhite-Canada syndrome. Gastrointest Endosc 2017; May 30 [Epub ahead of print]
5. Ong S, et al. Alopecia areata incognita in Cronkhite-Canada syndrome. Br J Dermatol 2017; 177: 531-4.
6. Watanabe-Okada E, et al. Histopathological insights into hair loss in Cronkhite-Canada syndrome: Diffuse anagen-telogen conversion precedes clinical hair loss progression. Australas J Dermatol 2014; 55: 145-8.
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