Clouston Syndrome

AUTHORS:
Alexander K. C. Leung, MD^1,2 • Kin Fon Leong, MD³ • Joseph M. Lam, MD⁴

AFFILIATIONS:
¹Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
²Alberta Children’s Hospital, Calgary, Alberta, Canada
³Pediatric Institute, Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia
⁴Department of Pediatrics and Department of Dermatology and Skin Sciences, University of British Columbia, Vancouver, British Columbia, Canada

CITATION:
Leung AKC, Leong KF, Lam JM. Clouston syndrome. Consultant. 2021;61(1):29-31. doi:10.25270/con.2020.06.00019

Received May 12, 2020. Accepted June 9, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Alexander K. C. Leung, MD, #200, 233 16th Ave NW, Calgary, AB T2M 0H5, Canada (aleung@ucalgary.ca)

An 8-year-old boy presented with a history of sparse hair on the scalp, eyebrows, and eyelashes, and milky white and deformed fingernails and toenails that had developed gradually since early infancy. With time, the nails had become discolored, triangular, more thickened, hyperconvex, and hypoplastic. Excessively thickened skin of the palms and soles was noted at 2 years of age, and the thickening had worsened with age.

The child’s developmental milestones, physical development, and mental development were normal. Findings of a review of systems were normal. In particular, there was no history of fever of unknown origin, hypohidrosis, or hearing problems. The parents were nonconsanguineous and healthy. His maternal grandfather, mother, and two of his four younger sisters also had childhood-onset progressive hair loss, nail dystrophy, and palmoplantar keratoderma, with variable clinical severity. The other two younger sisters were phenotypically normal.

On physical examination, the child was cheerful and talkative, with normal intelligence. His weight and height were normal. There was diffuse thinning of scalp hair with extensive alopecia (Figure 1). His scalp hair was brittle. His eyebrows and eyelashes were sparse and short. His fingernails and toenails were short, thickened, discolored, and with a triangular configuration (Figure 2). Markedly hyperkeratotic plaques were noted on the palms and soles (Figure 3). Dentition was normal, and there were no other abnormal features.

Figure 1. An 8-year-old boy with diffuse thinning of scalp hair with extensive alopecia.

Figure 2. The boy’s fingernails and toenails were short, thickened, discolored, and with a triangular configuration.

Figure 3. The boy’s feet had bilateral plantar keratoderma.

A diagnosis of Clouston syndrome (also referred to as hidrotic ectodermal dysplasia) was made based on the triad of alopecia, nail dystrophy, and palmoplantar hyperkeratosis, as well as a positive family history. The boy’s normal sweating and normal dentition ruled out hypohidrotic ectodermal dysplasia.

Genetic counseling was offered to the child and family, who were informed that chance of another sibling or future offspring having Clouston syndrome would be 50%. Regarding the alopecia, wearing wigs was discussed as an option, should there be significant cosmetic concern in the future. His palmoplantar keratoderma was treated with an emollient ad libitum and a topical keratolytic agent consisting of urea in combination with hydrocortisone twice a day, which led to significant improvement of the skin condition. Ablation of the nail matrix was suggested to improve the appearance of the nail dystrophy but was refused by the parents.

DISCUSSION

Clouston syndrome is an autosomal dominant disorder characterized by a triad of alopecia, nail dystrophy, and palmoplantar hyperkeratosis, with varying degrees of severity.¹ The condition was first described by Nicolle in 1895 and later by Clouston in 1939.²

Clinically, sparse hair and nail dystrophy are present in early infancy.^1,3 In affected individuals, the scalp hair is sparse, brittle, and fine and grows slowly.¹ Extensive or total alopecia may occur.¹ The eyelashes and eyebrows are sparse and short and may be absent. Hair loss is usually gradual and may involve other body areas such as the axillae and pubic area.

Nail abnormalities include thickening, shortening, and ridging, as well as hypoplastic, hyperconvex, discolored, and triangular nail plates.³ Nails are milky white during early childhood and gradually become discolored.³ Distal tapering of the nail plates results in a triangular configuration. Distal onycholysis may occur. Nail growth is typically slow.

Palmoplantar keratoderma is often noted in childhood and increases in severity with age.^1,3 Additional clinical features include hyperpigmentation of the skin over large joints and the periorbital region, tufting of terminal phalanges, clubbing of fingers, polydactyly, syndactyly, thickening of the skull bone, sensorineural deafness, strabismus, cataracts, epidermoid cysts, and eccrine syringofibroadenomas.^1,3-5 Teeth and sweating are characteristically normal. Facial dysmorphism is absent. Physical growth and intelligence are usually normal.

Clouston syndrome occurs in approximately 1 per 500,000 live births.⁶ The condition is seen most often in individuals with French Canadian ancestry, but all ethnic and racial groups can be affected. Clouston syndrome results from mutation in GJB6, which encodes the gap junction protein connexin 30 and is located on 13q11-12.^6-8

The diagnosis is mainly clinical, based on typical features and a positive family history. A negative family history, on the other hand, does not rule out Clouston syndrome, since sporadic cases may occur due to de novo mutation of GJB6.⁹ The diagnosis can be confirmed by molecular studies, which may reveal a mutation in GJB6.⁸

The differential diagnosis includes hypohidrotic ectodermal dysplasias, Schopf-Schulz-Passarge syndrome, and pachyonychia congenita. Hypohidrotic ectodermal dysplasia is characterized by fine, sparse, or absent hair, conoid or absent teeth, markedly decreased sweating, and normal nails. The normal dentition and ability to sweat distinguish Clouston syndrome from hypohidrotic ectodermal dysplasia.

Schopf-Schulz-Passarge syndrome, caused by mutation in WNT10A, is usually inherited as an autosomal recessive fashion. The syndrome is characterized by eccrine syringofibroadenomas, multiple cysts on along the palpebral margins (apocrine hidrocystomas), variable oligodontia, hypotrichosis, nail dystrophy, and palmoplantar hyperkeratosis. Eccrine syringofibroadenomas and eyelid apocrine hidrocystomas are hallmark features of Schopf-Schulz-Passarge syndrome, which help to differentiate it from other ectodermal dysplasias. Eyelid apocrine hidrocystomas typically develop at a mean age of 50 years.

Pachyonychia congenita is characterized by hypertrophic nail dystrophy (prominent distal hyperkeratosis), painful palmoplantar keratoderma with blistering, palmoplantar hyperhidrosis, oral leukoplakia, pilosebaceous cysts, pili torti, and follicular keratosis on the extremities and trunk.¹⁰ The disorder is inherited in an autosomal dominant trait and associated with a heterozygous pathogenic variant in one of the following keratins genes: KRT6A, KRT6B, KRT6C, KRT16, and KRT17. The absence of alopecia and/or hypotrichosis help differentiate pachyonychia congenita from Clouston syndrome.¹⁰

Individuals with Clouston syndrome are prone to immune system disturbances (reduced phagocytic activities of granulocytes and monocytes) and paronychia.¹¹ Alopecia and dystrophic nails can be cosmetically unsightly and socially embarrassing. Affected patients usually have a normal life span.

REFERENCES:

1. Khatter S, Puri RD, Mahay SB, Bhai P, Saxena R, Verma IC. Mutation-proved Clouston syndrome in a large Indian family with a variant phenotype. Indian J Dermatol. 2019;64(2):143-145. doi:10.4103/ijd.IJD_510_17
2. Clouston HR. The major forms of hereditary ectodermal dysplasia (with an autopsy and biopsies on the anhydrotic type). Can Med Assoc J. 1939;40(1):1-7. Accessed June 10, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC536929/
3. Cammarata-Scalisi F, Rinelli M, Pisaneschi E, et al. Novel clinical features associated with Clouston syndrome. Int J Dermatol. 2019;58(8):e143-e146. doi:10.1111/ijd.14507
4. Odell ID, Lilly E, Reeve K, Bosenberg MW, Milstone LM. Well-differentiated syringofibrocarcinoma in a patient with Clouston syndrome. JAMA Dermatol. 2016;152(4):484-486. doi:10.1001/jamadermatol.2015.4496
5. Sukakul T, Yang H-S, Onoufriadis A, Hsu C-K, McGrath JA. Pterygium and thinning of nails as an unusual manifestation in Clouston syndrome. J Dermatol. 2019;46(9):e329-e330. doi:10.1111/1346-8138.14867
6. Trídico LA, Antonio JR, Pozetti EMO, Rosa AM, Antonio CR. Clouston syndrome: 25-year follow-up of a patient. An Bras Dermatol. 2015;90(6):897-899. doi:10.1590/abd1806-4841.20153990
7. Agarwal N, Singh PK, Gupta K, Gupta N, Kabra M. Identification of GJB6 gene mutation in an Indian man with Clouston syndrome. Indian J Dermatol Venereol Leprol. 2016;82(6):697-700. doi:10.4103/0378-6323.190855
8. Fraser FC, Der Kaloustian VM. A man, a syndrome, a gene: Clouston’s hidrotic ectodermal dysplasia (HED). Am J Med Genet. 2001;100(2):164-168. doi:10.1002/1096-8628(20010422)100:2<164::aid-ajmg1244>3.0.co;2-w
9. Sanches S, Rebellato PRO, Fabre AB, Campos GLM. Do you know this syndrome? Clouston syndrome. An Bras Dermatol. 2017;92(3):417-418. doi:10.1590/abd1806-4841.20175716
10. van Steensel MAM, Jonkman MF, van Geel M, Steijlen PM, McLean WHI, Smith FJD. Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol. 2003;121(5):1035-1038. doi:10.1046/j.1523-1747.2003.12527.x
11. Pietrzak A, Grywalska E, Gerkowicz A, et al. Immune system disturbances in Clouston syndrome. Int J Dermatol. 2016;55(5):e241-e249. doi:10.1111/ijd.13152