We have previously described a kindred with hereditary medullary thyroid carcinoma and pheochromocytoma (multiple endocrine neoplasia type 2 A [MEN 2A]) with localized pruritic cutaneous manifestations present only in affected members. Although the initial skin biopsies reported did not show amyloidosis, subsequent skin biopsy results reported here have demonstrated amyloid which stained for keratin but not for calcitonin and established that this family represents an association of a rare autosomal dominant form of lichen amyloidosis with MEN 2A

D\u27Armiento, M.

di Giovanni, G.

Lettera, A. M.

Mancini, M.

Nunziata, V.

Henry Ford Health System Scholarly Commons

Henry Ford Hospital Medical Journal Volume 37 Number 3 Article 17 9-1989 Cutaneous Lichen Amyloidosis Associated with Multiple Endocrine Neoplasia Type 2A V. Nunziata G. di Giovanni A. M. Lettera M. D'Armiento M. Mancini Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal  Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Nunziata, V.; di Giovanni, G.; Lettera, A. M.; D'Armiento, M.; and Mancini, M. (1989) "Cutaneous Lichen Amyloidosis Associated with Multiple Endocrine Neoplasia Type 2A," Henry Ford Hospital Medical Journal : Vol. 37 : No. 3 , 144-146. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol37/iss3/17 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Cutaneous Lichen Amyloidosis Associated with Multiple Endocrine Neoplasia lype 2 A V. Nunziata,* G. di Giovanni,* A.M. Lettera,* M. D'Armiento,* and M. Mancini* We have previously described a kindred wilh hereditary medullary thyroid carcinoma and pheochromocytoma (mulliple endocrine neoplasia type 2 A [MEN 2AJ) with localized pruritic cutaneous manifestations presenl only in affected members. Although the inilial skin biopsies reporled did nol show amyloidosis, subsequeni skin biopsy results reporled here have demonstrated amyloid which stained for keratin bul nol for calcitonin and established that this family represents an associalion ofa rare autosomal dominant form of lichen amyloidosis wdh MEN 2 A. (Henry Ford Hosp MedJ 1989:37:144-6) S ince no phenotypic characteristics have been described in multiple endocrine neoplasia type 2A (MEN 2A), the ex-pected occunence of thyroid tumors in this syndrome requires affected members to be identified by periodic evaluation of basal and stimulated calcitonin (CT) levels begun at an early age. However, we have reported a kindred with MEN 2A in which a cutaneous manifestafion was noted only in affected adult mem-bers (1). The skin manifestations appeared early in life and may have preceded the biochemical presentation of thyroid tumor. Initial histologic study disclosed no characteristic abnormalities and the condition was considered to be hereditary localized pra-ritus. However, after becoming aware of another family in whom MEN 2A appeared to cosegregate with lichen amyloidosis (2,3), we performed further studies which also demonstrated amyloidosis of the skin in our family. Patients and Methods The pedigree of the M family was shown in our initial pub-lication (1). After the propositus was diagnosed as having medullary thyroid carcinoma (MTC), 40 members in five gener-ations were identified (1). Twenty-nine members were examined at our clinic, and data on three additional members were ob-tained from clinical records supplied by other hospitals. All the relatives examined had analyses as described in our earlier de-scription of the family (I). Chnical and Biochemical Data A retrospective diagnosis of MEN 2A can be made for two relatives, both deceased, and a total of ten members were diag-nosed as being affected on the basis of clinical and biochemical data. These ten members, five men and five women, were be-tween 18 and 66 years old (mean age 36 years) at the time of diagnosis. MTC was surgically proven in each with histology showing the typical MTC pattem with amyloid in all cases. Gen-erally, the cervical lymph nodes were involved in the older pa-tients, and the main symptom was dianhea in the presence of liver metastases. Flushing of the face and neck after even a mod-erate emotion was observed in two members. CT levets were very high in atl but four patients who showed an excessive re-sponse only after pentagastrin stimulation ( I ) . Car-cinoembryonic antigen levels were very high in four patients (more than 50 p.g/L) but did not correlate with CT levels. Three patients have died from MTC and one from an undiagnosed pheochromocytoma. The remaining six patients have had sur-gery, and all but two now have normal CT levels. Pheochromocytomas were identified in three members. A 46-year-old man had a history of sustained hypertension during the three years prior to being hospitalized for a severe hypertensive attack. He died two days later; a right adrenal pheo-chromocytoma and an unsuspected MTC were found at au-topsy. In two patients, computed tomography showed adrenal masses that were surgically proven to be typical pheo-chromocytomas. Those patients who had increased urinary va-nillylmandelic acid excretion and epinephrine/norepinephrine ratios were found to be normotensive, and the youngest had a one-year history of ortho.static hypotension. Serum calcium and parathyroid hormone levels were normal in all patients, and parathyroid histology performed in seven cases did not show hyperplasia. Submitted for publication: October 24. 1989. Accepted lor publication: Novembers. 1989. •Institute of Intemal Medicine and Metabolic Diseases. University of Naples. Naples, Italy. tPathology Department, University of Naples, Naples, Italy. Address correspondence to Dr Nunziata, Instituto di Medicina Intema e Malattie Meta-btiliche, II Clinica Medica, 11 Facolta di Medicina e Chirurgia, via Sergio Pansini 5, 80I3I Naples, Italy. 144 Henry Ford Hosp Med J—Vol 37, Nos 3 & 4, 1989 Cutaneous Lichen Amyloidosis in MEN 2A—Nunziata et al Fig 1—Histology ofa punch biopsy ofthe skin in a family mem-ber with clinical features of lichen amyloidosis; typical deposi-tion of amyloid (Congo red stain, X270). % ' I » Fig 2—Histology ofa punch biopsy ofthe skin in a family mem-ber whh clinical features of lichen amyloidosis; fine granularity in the amyloid indicating positive immunohistochemical stain-ing for low molecular weight keratin (X106). Cutaneous Manifestations All affected members examined showed cutaneous man-ifestations (1) consisting of intermittent itching in a roughly cir-cular area, 5 to 10 cm in diameter, located on the back at the level of the first thoracic vertebrae extending from the midline to the right or left scapular region. This symptom generally began at age 4 or 5 years, and in adults hyperkeratosis was evident as a darkened, raised area. Family members reported that such man-ifestafions were present in two ancestors in whom the diagnosis of MEN 2A has been formulated either by clinical records or retrospectively. None of the relatives who were unaffected and older than 30 years have this peculiarity of the skin. In genera-fion IV, three children between ages 4 and 11 years have this cutaneous praritus. They have been considered to be unaffected because of nonnal basal and stimulated CT levels. However, an abnormal CT response was recentty demonstrated in one pafient (peak 1.2 ixg/L) by acombined pentagastrin plus calcium test (2 mg/kg body weight) (4). Cutaneous biopsy performed on one affected member re-vealed deposifion of an amorphous material at the interface be-tween the dermis and epidermis which stained with hematox-ylin-eosin and Congo red stain (Fig 1) as typical amyloid. For immunoperoxidase staining, paraffin sections were incubated with two monoclonal antibodies which recognize 57-66 and 48, 51, 52, and 54 kilodalton forms of keratin (DAKO Corporation, Santa Barbara, CA) as previously described (5). The immu-nohistochemical stains for CT were performed utilizing a poly-clonal rabbit antiserum against human CT (DAKO Corporation, Santa Barbara, CA). Immunohistochemical stains of the amyloid for keratin were positive particularly for low molecular weight keratins (Fig 2) but were negafive for CT. MTCs from all affected members stained positive for CT. Discussion The only cutaneous abnormalities described in the MEN 2 syndromes are masses of myelinated and nonmyelinated nerves observed in the dermis of clinically normal skin of patients with MEN 2B who otherwise do not complain of itching (6). Skin histology of our patient has shown cutaneous lichen amyloidosis, a rare skin manifestation occurring in both spo-radic and hereditary forms. The hereditary form ofthis disease is transmitted as an autosomal dominant trait, and 65 cases have been reported since 1960 (7-17). The skin lesions usually appear as prarific papular and pigmented lesions tocated either on the back as in our family (8,10,17) or on the extensor surfaces of the thighs, legs, or arms (7,8,11,13,14,18). Amyloid deposition is noted in the skin, as in our family, with no amyloid elsewhere in the body. The chemical nature of the amyloid (19,20) has not been definitely characterized, but it is believed to be derived from keratin. tn the previous study (1) we described two affected members of the same MEN 2A kindred who complained of intermittent itching but had no evident hyperkeratosis. Cutaneous biopsy performed on both had failed to demonstrate amyloid (1). Such negafive results could have come from sampling enor, or, alter-natively, perhaps dermal amyloid can be demonstrated onty after tong-term scratching when the skin appears clearly hyper-keratotic and pigmented. If so, dermal amyloid may occur onty secondary to the chronic scratching trauma. After becoming aware of another unrelated famity in whom MEN 2A and cutaneous lichen amyloidosis appear to cosegre-gate (2,3), we performed the additionat skin biopsy which showed amyloidosis even though previous biopsy on that indi-viduat and another affected member had failed to demonstrate amyloidosis (1). Gagel et at (2) and Donovan et al (3) described three members having the same typical skin lesions and MEN 2A and two additional members with MEN 2A but no observ-able skin changes. Those who were positive for both diseases had noted local itching since age 18. The age of onset of praritus in their family was different from that in the kindred in which the localized itching appeared before the age of 10. The cosegregation of MEN 2A and cutaneous lichen amyloidosis in two unrelated families is unlikely to have oc-Henry Ford Hosp Med J—Vol 37. Nos 3 & 4. 1989 Cutaneous Lichen Amyloidosis in MEN 2A—Nunziata et al 145 cuned by chance atone. It is highly probable that the cutaneous lichen amyloidosis/MEN 2A syndrome represents an overlap-ping of contiguous gene syndromes in which a microdeletion or mutation has caused both diseases (21,22). In these famUies cutaneous lichen amyloidosis may be considered as a phe-notypic marker for screening in future generations. In patients with hereditary cutaneous lichen amyloidosis, we suggest an ap-propriate screening for MEN 2A tumors to determine the preva-lence of this newty described syndrome. References 1. Nunziata V, Giannattasio R, di Giovanni G, D'Armiento MR, Mancini M. Hereditary localized pruritus in affected members of a kindred with multiple en-docrine neoplasia lype 2a (Sipple's syndrome). Clin Endocrinol 1989;30:57-63. 2. Gagel RE Levy ML, Donovan DT, Aiford BR, Wheeler T, Tschen JA. Mulliple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Inlem Med 1989;111:802-6. 3. Donovan DT, Levy ML, Furst EJ, et al. Familial cutaneous lichen amyloidosis in association with mulliple endocrine neoplasia type 2A: A new variant. Henry Ford HospMedJ 1989;37:147-50. 4. Wells SA Jr, Baylin SB, Linehan WM, Farrell RE, Cox EB, Cooper CW, Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. AnnSurg 1978;188:139-41. 5. Tschen JA, McGavran MH, Kettler AH. Pagetoid dyskeratosis: A selective keratinocytic response. J Am Acad Dermatol 1988;19:891-4. 6. Pages A, Marty H, Baldet P, Paroldi R. Neurofibromatosis—thyroid medullary carcinoma—pheochromocytoma syndrome. Arch Anal Pathol (Paris) 1970;18:137-42. 7. Isaak L. Localized amyloidosis cutis associated with psoriasis in siblings. Arch Derm Syph 1950;61:859-62. 8. Vastly DB, Bhatia SG, Uhlin SR. Familial primary cutaneous amyloidosis: Clinical, genetic, and immunofluorescent studies. Arch Dermatol 1978;114:1173-6. 9. Tay CH. Genodermatosis in Singapore. Asian J Med 1971;7:413-22. 10. Sagher F, Shanon J. Amyloidosis cutis: Familial occurrence in three gen-erations. Arch Denn 1963;87:171-5. 11. Rajagopalan K, Tay CH. Familial lichen amyloidosis: Report of 19 cases in 4 generations of a Chinese family in Malaysia. Br J Dermatol 1972;87:123-9. 12. Porto J, Posse FA, Filho AM, Amiloidose cutanea familial: Case presen-tation in the meeting of the Society for the Brasilian Dermatology and Syph-ilology, October 29, 1958. 13. OzakiM. Familial lichen amyloidosis. Int J Dermatol 1984;23:190-3. 14. Newton JA, Jagjivan A, Bhogal B, McKee PH, McGibbon DH. Familial primary cutaneous amyloidosis. BrJDermatol 1985;112:201-8. 15. LeBoit PE, Greene I . Primary cutaneous amyloidosis: Identically dis-tributed lesions in identical twins. Pediatr Dermatol 1986;3:244-6. 16. DeSouza AR. Amiloidose cutanea bulbosa familial: Observacao de 4 cases. Revta Hosp Clin Eac Med Univ S Paulo 1963;18:413-7. 17. DePietro WP. Primary familial cutaneous amyloidosis: A study of HLA antigens in a Puerto Rican family. Arch Dermatol 1981:117:639-43. 18. Tay CH, Dacosta JL. Lichen amyloidosis: Clinical study of 40 cases. Br J Dennatol 1970;82:129-36. 19. Kobayashi H, Hashimoto K. Amyloidogenesis in organ-limited cuta-neous amyloidosis: An antigenic identity between epidermal keratin and skin amyloid. J Invest Dermatol 1983;80:66-72. 20. Maeda H, Ohta S, Saito Y, Nameki H, Ishikawa H. Epidermal origin of the amyloid in localized cutaneous amyloidosis. Br J Dermatol 1982; 106:345-51. 21. Jackson CE, Van Dyke DL, Talpos GB, Norum RA, Tashjian AH Jr. MEN-2 tumor associations suggest a linear order of specific endocrine tumor genes. Horm Metab Res 1989;21(suppl):9-12. 22. Schmickel RD. Contiguous gene syndromes: A component of recogniz-able syndromes. J Pediatr 1986:109:231-41. 146 Henry Ford Hosp Med J—Vol 37, Nos 3 & 4. 1989 Cutaneous Lichen Amyloidosis in MEN 2A—Nunziata et al 

Cutaneous Lichen Amyloidosis Associated with Multiple Endocrine Neoplasia Type 2A

Abstract

Similar works

Full text

Available Versions

Henry Ford Health System Scholarly Commons