Keratitis-Icthyosis-Deafness Syndrome/KID Syndrome

Are You Confident of the Diagnosis?

What you should be alert for in the history

History for keratitis-ichthyosis-deafness (KID) syndrome includes skin abnormalities since birth: red, thickened, and leathery skin with vernix caseosa-like covering. During childhood, skin becomes dry and thickened with erythrokeratotic plaques. Alopecia may be present at birth.

Characteristic findings on physical examination

– Characteristic universal dry skin with erythroderma and distinctive symmetric plaques

– Demarcated reddish-brown figurate lesions on the face and furrows around mouth giving the patient an aged appearance

– Rippled and hyperkeratotic lesions on the extremities

– Follicular hyperkeratosis on the trunk

Expected results of diagnostic studies

Histopathology of skin is nonspecific, revealing acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis. Often, cone-shaped keratin plugs block follicular orifices and may extend into the mouths of eccrine sweat ducts. A diminished number of eccrine sweat glands have been noted. Hair follicles are absent or atrophic. Elongation of dermal papillae have been described. The superficial dermis may contain a mild to moderate perivascular lymphohistiocytic infiltrate.

After informed consent, blood can be taken from the patient with the purpose of DNA extraction and molecular genetic studies showing mutations in the GJB2 gene or GJB6 gene.

Ocular involvement occurs in up to 95% of patients in childhood or with a delayed onset. Eye lesions start with photophobia, then neovascularizing keratitis occurs and blindness may result. Eye lesions are progressive and may include blepharitis, keratoconjunctivitis sicca, corneal epithelial defects, scarring, and neovascularization, causing progressive decline of visual acuity and eventually leading to blindness (vascularizing keratitis).

Congenital sensorineural hearing loss is generally severe and bilateral.

The noncutaneous features include bilateral neurosensory hearing impairment, which starts at birth; vascularizing keratitis often develops later in the course.

In general, physical growth and intellectual development are not impaired.

Skin involvement of the ear canal with keratosis obturans may complicate hearing-aid fitting.

Diagnosis confirmation

In the newborn period, ichthyosis prematurity syndrome (IPS) constitutes an early differential diagnosis. IPS is characterized by the clinical triad of premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. The diagnosis is supported by electron microscopy showing pathognomonic trilamellar membrane aggregations in the stratum corneum and stratum granulosum.

Clouston syndrome is a hidrotic ectodermal dysplasia with palmoplantar keratoderma, nail dystrophy, and absence of hair.

Vohwinkel syndrome is a mutilating keratoderma, with constrictions of digits leading to autoamputation associated with moderate degrees of deafness.

Bart-Pumphrey syndrome is characterized by congenital deafness, leuconychia, knuckle pads, and variable keratoderma.

Erythrokeratoderma variabilis et progressive diffusa presents with well-demarcated, keratotic, and erythematous plaques, together with migratory erythematous areas, which vary in shape and position over hours or days.

Palmoplantar keratoderma associated with sensorineural hearing loss is another differential diagnosis.

The above disorders may share some common clinical findings but there are several key points that differentiate them, especially the ophthalmological changes characteristic for KID syndrome.

KID syndrome should also be distinguished from the following ichthyosiform dermatoses:

Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is characterized by extensive noninflammatory spiny follicular hyperkeratoses, severe photophobia, and generalized noncicatricial alopecia.

Netherton syndrome, or ichthyosis linearis circumflexa, is a psoriasiform ichthyosis with trichorrhexis invaginata (bamboo hairs) and atopic manifestations. Defective expression of LEKTI in skin sections is another diagnostic feature.

Refsum’s disease is characterized by an ichthyosiform skin rash with neurosensory deafness and retinitis pigmentosa.

Pachyonychia congenita (PC) features hypertrophic nail dystrophy, focal palmoplantar keratoderma and blistering, oral leukokeratosis, and follicular keratoses on the trunk and extremities.

Keratosis follicularis spinulosa decalvans is an uncommon genodermatosis characterized by follicular hyperkeratosis, progressive cicatricial alopecia, and photophobia.

Who is at Risk for Developing this Disease?

Approximately 100 cases of KID syndrome have been reported in the literature to date.

Most classic cases have been sporadic, but autosomal dominant inheritance has been reported in a small number of families.

KID syndrome is extremely rare . Most cases reported have occurred sporadically, but familial cases seem to occur more frequently than anticipated.

There is no ethnic predisposition and the disease has been reported from numerous countries. It is not a typical case of ichthyosis, but rather that of erythrokeratoderma. KID syndrome belongs to the congenital disorders of cornification within the spectrum of ectodermal dysplasia.

Three clinical subsets of KID syndrome have been described. Type 1 is more limited and has a typical facial involvement with bizarre and sharply bordered hyperkeratotic plaques also occurring on elbows, knees, palms, and soles. Type 2 shows more severe and diffuse involvement of the skin with marked scarring alopecia. Type 3 has recently been described and is a lethal form where prenatal diagnosis was made. In this severe form, facial dysmorphy, erythroderma, dystrophic nails, complete atrichia, and absent foreskin has been documented.

What is the Cause of the Disease?

Etiology

In 2002 the first reports showed that KID syndrome is caused by heterozygous missense mutations in the GJB2 gene.

Pathophysiology

KID syndrome is a rare congenital ectodermal disorder caused by mutations of the GJB2 gene encoding the gap junction protein connexin-26 (Cx26). A single patient with KID and atrichia had a mutation in the GJB6 gene encoding connexin-30 (Cx30).

Cx26 and Cx30 are transmembrane proteins that assemble into hexameric hemichannels (connexons) that dock with neighboring hemichannels in adjacent cells, forming gap junctions. These connexins are involved in intercellular communication and control of cellular differentiation in ectoderm-derived stratifying epithelia of the cochlea, cornea, skin, hair follicles, and sweat glands. Pathogenic mutations disturb development and maintenance of ectodermal tissues and disturb epidermal differentiation.

Systemic Implications and Complications

KID syndrome predisposes patients to bacterial, viral, and fungal infections, as well as recurrent scabies. Fatal courses of KID syndrome in the first year of life have been reported, caused by severe infections of the skin and septicemia.

Sometimes hypohidrosis may cause heat intolerance.

Abnormal keratinization leads to plugging of the follicular orifices, cyst formation, and eventual rupture and inflammatory response.

A follicular occlusion triad with dissecting cellulitis of the scalp, cystic acne, and hidradenitis suppurativa are recognized.

Development of pilar cysts and benign or malignant proliferating pilar tumors on the scalp and other sites has been described.

Squamous cell carcinomas of the skin or oral mucosa (tongue) have been observed in at least 10% of patients. Tumors have been diagnosed at a mean age of 25 years (range 6-55 years), and often developed in the setting of chronic folliculitis and recurrent infections.

Growth delay has been described, with short stature and delayed skeletal age. Limited joint mobility has been reported, as well as retraction of the Achilles tendons.

Cerebral malformations have been described, with hydrocephalus, enlarged cisterna magna, and cerebellar hypoplasia/Dandy-Walker malformations. Most patients are intellectually normal.

Treatment Options

Wearing of hearing aids or cochlear implants, together with speech therapy, should be instituted as early as possible, together with ophthalmologic measures (keratolimbal allograft or keratoplasty).

MEDICAL OPTIONS

Topical: Local emmolients, keratolytic agents, rehydrating and antiseptic external therapy
Systemic: retinoids, oral antibiotics, and antifungal medications

SURGICAL OPTIONS

Inflammatory nodules and neoplastic lesions should be excised

PHYSICAL MODALITIES

Phototherapy, heliotherapy, and laser therapy have been used

Optimal Therapeutic Approach for this Disease

Eyes: lubricating treatment with artificial tears. Anti-inflammatory agents (topical corticosteroids and cyclosporin A) may be tried. Subconjunctival bevacizumab has been used to treat corneal neovascularization in a few reports. Different surgical procedures have also been tried to improve visual function.
Ears: cochlear implants have restored hearing in several affected individuals.
Skin: basic treatment with moisturizers (e.g. Zactoline® or Locobase®). Mild soaps should be used on a daily basis. Soothing baths with wheatbran. Potassium permanganate baths can be used when skin is infected or erosive. Vitamin D ointment (calcipotriol) can be used. Keratolytics (e.g. salicylic acid 2%-5%, lactic acid 5%, urea 10%-20%, or topical retinoids such as tazarotene gel 0.05%) may be used to selected keratotic plaques. Potassium permanganate baths can be used when skin is infected and erosive. Antibiotic (e.g. Fucidin® ) and antimycotic (e.g. terbinafine) cream may be needed. Combination products such as Locabase LPL® that contain propylene glycol and lactic acid, or Lac-hydrin® with ammonium lactate can be used. Hydrocolloid dressings may be applied to hyperkeratotic areas.
Low-dose acitretin (10-25mg daily) or isotretinoin (20mg daily) may be needed to improve hyperkeratosis and follicular occlusion. However, low doses are necessary to avoid flare-up and erosive skin lesions. Be aware that systemic retinoids may exacerbate corneal disease. They may decrease the risk of developing skin cancer.
Oral antibiotics (e.g. doxycyline 100mg daily for months or combination of clindamycin 300mg twice daily + rifampicin 300mg twice daily for 8-12 weeks) are necessary when severe infections develop. Oral antifungals (terbinafine or fluconazole) can be used when indicated by fungal cultures.
Prolonged courses of antifungal medications are often needed (e.g. fluconazole 60-100mg daily for months or years) and may result in remarkable clinical improvement.

Patient Management

Overall, treatment of patients with KID syndrome is difficult and often disappointing.

Along with ophthalmologic and otolaryngologic measures, simple topical therapies with bland emollients and topical keratolytics such as tazarotene or calcipotriol twice daily may improve skin condition in KID syndrome, precluding the possible hazards of systemic therapy.

Systemic retinoids reduce the hyperkeratosis but do not affect the underlying disease mechanism. They may, however, be a good choice to prevent skin cancer.

Meticulous skin care is necessary in order to avoid the formation of cracks, fissures, erosions, and subsequent microbial colonization.

Routine follow-up and blood work is needed for those on systemic retinoid therapy. This therapy should be not used in females of child-bearing age.

Topical and systemic antibiotics may be needed when skin lesions become erosive and oozing. Antifungals are needed when yeasts or dermatophytes complicate skin lesions.

KID patients should undergo regular surveillance for skin and mucosal carcinomas (e.g. two to three times yearly). In case of markedly irregular or nodular/ulcerating areas, multiple deep biopsies should be taken. Pilar cysts and proliferative pilar tumors should be included in the cancer surveillance of KID syndrome. Early excision is recommended to prevent malignant transformation and metastatic disease.

Careful ophthalmological and otological follow-up should be recommended, and patients should be included in developmental programs for combined hearing and vision loss, and provided speech therapy.

Prenatal diagnosis is possible in some cases, and it should be discussed with patients who plan to start a family. The possibility of germline mosaicism in the parents has to be taken into account.

Unusual Clinical Scenarios to Consider in Patient Management

Somatic mosaicism , with subtle clinical features along Blaschko lines, has been reported in a mother of a Portuguese boy with KID syndrome.

Apparently healthy patients have had more than one child with KID syndrome, indicating germline mosaicism.

Genetic counseling should be offered to affected families, as the risk of transmission from an affected parent is 50%. Segmental skin lesions (somatic mosaicism) and germline mosaicism should be considered as a risk factor for transmission of a generalized form.

Prenatal diagnosis may be offered to families where the disease-causing mutation has been identified.

Alitretinoin is a member of a new generation of systemic retinoids that have the capacity to influence disorders of cornification and inflammation. It might be that alitretinoin is more effective than acitretin, although no data are available.

What is the Evidence?

Burns, FS. “A case of generalized congenital erythroderma”. J Cutan Dis. vol. 33. 1915. pp. 255-60. (The first recognized description of a patient with congenital keratoderma in combination with deafness and corneal inflammatory disease was reported in 1915.)

Senter, TP, Jones, KL, Sakati, N, Nyhan, WL. “Atypical ichthyosiform erythroderma and congenital neurosensory deafness—a distinct syndrome”. J Pediatr. vol. 92. 1978. pp. 68-72. (Report of a 13-year-old boy with ichthyosiform erythroderma, sensorineural deafness, and progressive corneal vascularisation, together with twelve patients previously described in the literature.)

Skinner, BA, Greist, MC, Norins, AL. “The keratitis, ichthyosis and deafness (KID) syndrome”. Arch Dermatol. vol. 117. 1981. pp. 285-9. (Skinner summarized the literature and proposed the denomination KID to describe the triad of keratitis, ichthyosis, and deafness. The acronym is generally accepted, although the name is not entirely accurate, given that the skin lesions are not true ichthyosis. Deafness may be only partial and keratitis is usually of later onset and not mandatory.)

Grob, JJ, Breton, A, Bonafe, JL, Sauvan-Ferdani, M, Bonerandi, JJ. “Keratitis, ichthyosis and deafness (KID) syndrome: vertical transmission and death from multiple squamous cell carcinomas”. Arch Dermatol. vol. 123. 1987. pp. 777-82. (Description of vertical transmission of KID from father to daughter, with complicating multiple squamous cell carcinomas and fatal skin cancer)

Caceres-Rios, H, Tamayo-Sanchez, L, Duran-Mckinster, C, de la Luz Orozco, M, Ruiz-Maldonado, R. “Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology”. Pediatr Dermatol. vol. 13. 1996. pp. 105-13. (Careful observation and exhaustive review of sixty-one patients in the literature. Only eighteen patients developed eye symptoms before the age of 15, and it appears that some patients will never develop keratitis)

Richard, G, Rounan, F, Willoughby, CE, Brown, N, Chung, P, Ryynänen, M. “Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome”. Am J Hum Genet. vol. 70. 2002. pp. 1341-8. (Richard and coworkers provided evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2, and established the autosomal dominant nature. Decreased host defense and increased carcinogenic potential in KID illustrate that gap junction communication plays not only a crucial role in epithelial homeostatis and differentiation, but also in immune response and epidermal carcinogenesis.)

Van Steensel, MA, van Geel, M, Nahuys, M, Smitt, JH, Steijlen, PM. “A novel connexin 26 mutation in a patient with keratitis-ichthyosis-deafness syndrome”. J Invest Dermatol. vol. 118. 2002. pp. 724-7. (Van Steensel detected a connexin-26 mutation in a patient with sporadic KID syndrome by sequencing connexin genes known or expected to be involved in skin disorders sometimes accompanied by deafness.)

Jan, AY, Amin, S, Ratajczak, P, Richard, G, Sybert, VP. “Genetic heterogeneity of KID syndrome: Identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia”. J Invest Dermatol. vol. 122. 2004. pp. 1108-13. (A case report indicating that KID syndrome can also be associated with a mutation involving GJB6)

Mazereeuw-Hautier, J, Bitoun, E, Chevrant-Breton, J, Man, SY, Bodemer, C, Prins, C. “Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients”. Br J Dermatol. vol. 156. 2007. pp. 1015-9. (This study tried to establish a possible genotype-phenotype correlation in KID syndrome by performing a clinical examination and molecular analysis of GJB2 in fourteen patients originating from eleven families, together with a review of twenty-three cases previously reported in the literature. Twelve patients (86%) were heterozygous for the p.Asp50Asn mutation and two patients (14%) were heterozygous for the p.Ser17Phe mutation. The study suggests that patients with the p.Se

Barker, EJ, Briggs, RJ. “Cochlear implantation in children with keratitis-ichthyosis-deafness (KID) syndrome: outcomes in three cases”. Cochlear Implants Int. vol. 10. 2009. pp. 166-73. (Three children with KID syndrome received cochlear implants, showing that cochlear implants can be effective in these patients.)

Mazereeuw-Hautier, J, Bitoun, E, Chevrant-Breton, J, Man, SYK, Bodemer, C, Prins, C. “Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients”. Br J Dermatol. vol. 156. 2007. pp. 1015-9.

Nyquist, GG, Mumm, C, Grau, R, Crowson, AN, Shurman, DL, Benedetto, P. “Malignant proliferating pilar tumors arising in KID syndrome. A report of two patients”. Am J Med Genet A. vol. 143. 2007. pp. 734-41.

Lazic, T, Horii, KA, Richard, G, Wassermann, DI, Antaya, RJ. “A report of GJB2 (N14K) connexin 26 mutation in two patients – a new subtype of KID syndrome”. Pediatr Dermatol. vol. 25. 2008. pp. 535-40.

De Raeve, L, Bonduelle, M, Deconinck, H, Roseeuw, D, Stene, JJ. “Trichothiodystrophy-like hair abnormalities in a child with keratitis ichthyosis deafness syndrome”. Pediatr Dermatol. vol. 25. 2008. pp. 466-9.

Neoh, CY, Chen, H, Ng, SK, Lane, EB, Common, JEA. “A rare connexin 26 mutation in a patient with a forme fruste of keratitis-ichthyosis-deafness (KID) syndrome”. Int J Dermatol. vol. 48. 2009. pp. 1078-81.

Sbidian, E, Feldmann, D, Bengoa, J, Fraitag, S, Abadie, V, de Prost, Y. “Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form”. Clin Genet. vol. 77. 2010. pp. 587-92.

Arndt, S, Aschendorff, A, Schild, C, Beck, R, Maier, W, Laszig, R. “A novel dominant and a de novo mutation in the GJB2 gene (connexin 26) cause keratitis-ichthyosis-deafness syndrome: implication for cochlear implantation”. Otol Neurotol. vol. 31. 2010. pp. 210-5.

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