A case of lamellar ichthyosis with rickets and carcinoma of the hypopharynx.

Lamellar ichthyosis (LI) is an autosomal recessive disorder rarely associated with systemic organ involvement and development of carcinoma. Rickets has occasionally been described with LI owing to impaired vitamin D synthesis following altered keratinization. There has also been a high association of cutaneous cancers in patients of LI. We as Dermatologists should therefore be very meticulous while doing a full work up of these patients. We report here a case of LI associated with rickets and carcinoma of the hypopharynx.

What was known?

LI is an inherited disorder of keratinization associated with rickets and cutaneous cancers. Dysregulated vitamin D metabolism and excessive calcium loss through the skin is associated with rickets and later cancer development.

Introduction

Ichthyosis is a heterogeneous group of skin disorders characterized by generalized scaling. Lamellar ichthyosis (LI) is an autosomal recessive disorder and has been known by several terms including non-bullous congenital icthyosiform erythroderma, non-erythrodermic autosomal recessive LI, ichthyosis congenital and classic LI.[1] LI is known to be associated with rickets owing to the dysregulated vitamin D metabolism in the skin because of the abnormal keratinization, and later development of carcinoma.[2] An association of LI with hypopharngeal carcinoma and rickets together has not been reported until date. Whether there is an association of the same with vitamin D deficiency per se is still uncertain. We hereby present this case report as the first ever reported case of having the three clinical conditions together.

Case Report

A 45 year old man presented to the Department of Dermatology, with the complaints of scaly lesions over the body since birth with dysphagia for the past 1 month [Figure 1]. A history of collodion membrane at birth, which peeled off 40 days after birth was noted, which was followed by scaly lesions over the body with winter exacerbation. There was a history of seizures since birth for which the patient was on phenobarbitone. Recently, watering of eyes and dysphagia for solids observed with no other significant co-morbidities. General examination revealed a poorly nourished individual with bowing of both legs [Figure 2]. Cardiovascular examination showed a pre-systolic murmur in the aortic region, and occasional rhonchi in respiratory examination.

Figure 1

Well-defined ichthyotic scales over the face and the trunk with mild ectropion both the eyes

Figure 2

Both lower limbs showing bowing of the tibia with the characteristic ichthyotic scales over the shins

Dermatologic examination revealed diffuse thickening of skin with visible ichthyotic scales predominantly over the face, extremities, and lateral aspect of the abdomen. Mild hyperpigmentation of the palms and soles, dystrophic changes in nails, with ectropion of lower eyelids were observed. Radiography of both lower limbs showed the characteristic bowing of both tibia [Figure 3]. Histopathologic examination of the skin showed epidermal hyperkeratosis and mild parakeratosis with extension and blunting of the rete ridges [Figure 4]. Upon suggestions from otorhinolaryngology regarding hoarseness of voice, we conducted a laryngoscopic examination, which showed a proliferative growth involving the right pyriform fossa and extending to the postcricoid region. An endoscopic biopsy from the growth revealed a moderate to well differentiated squamous cell carcinoma [Figure 5].

Figure 3

Radiographic findings showing the characteristic bowing of the tibia

Figure 4

H and E section of the skin showing compact orthohyperkeratosis, variable mild focal parakeratosis with extension and blunting of the rete ridges in the epidermis. Minimal changes in the dermis

Figure 5

Squamous cell carcinoma of the hypopharynx showing increased mitotic figures and nuclear atypia

Hematologic investigations showed reduced serum calcium levels (6.3 mg/dL), reduced vitamin D3 levels (9 ng/mL) and an increased level of alkaline phosphatase (291 International Units [IU]). Bone scan revealed increased tracer uptake in the right femur and the left tibia, otherwise normal. Electrocardiography showed sinus rhythm with premature atrial complexes, aberrant conduction, low voltage QRS complex (Q-wave, R-wave and S-wave), nonspecific T-wave abnormality and prolonged QT interval. Echocardigraphy showed high frequency ectopics, mild mitral and tricuspid regurgitation.

Diagnosis of LI with rickets and carcinoma hypopharynx was made based on the clinical findings, biochemical and histopathology and radiography reports. Patient was started on Cap Acitretin 25 mg once at night, Vitamin D 2000 IU daily as advised by the endocrinologist and white soft paraffin as an emollient prescribed. Patient was referred to the Department of Otorhinolaryngology for the management of the growth in the hypopharynx. Within a month our patient succumbed to the laryngeal malignancy and expired.

Discussion

LI is a congenital autosomal recessive disorder.[3] Infants with LI are often born preterm and maybe encased in a taut membrane that resembles a collodion and hence the term collodion baby. However, the collodion membrane is not specific for LI and can also be seen as a manifestation of congenital ichthyosiform erythroderma.[3]

It is caused by transglutaminase (TGM1) gene mutation that encodes the transglutaminase1 (TGase1) enzyme which is critical for the assembly of the cornified cell envelope in the terminally differentiating keratinocytes. TGase1 is a complex enzyme existing as both cytosolic and membrane bound forms. Moreover TGase1 is proteolytically processed and the major functionally active form consists of three polypeptides forming a 67/33/10 kDa complex.[345678] Other genetic defects included higher filaggrin expression in scales.

Clinically patients with LI present as large dark brown firmly adherent scales over the scalp, limbs and abdomen mainly, but may involve other sites also. In severely affected patients, the thick rigid scales are intermittently shed causing deep painful fissures especially around the flexures and on the digits, palms and soles. Other features include limitation of joint movements, flexion contractures, digital sclerodactyly, palmoplantar keratoderma, scarring alopecia and persistent ectropion, congenital hypoplasia of nasal and aural cartilage and impaired sweating. The child has a normal growth and intellect. Severe forms of LI seldom improve with age and psychological problems resulting from cosmetic effects and limited mobility can lead to isolation, depression and poor school performance.[9]

Treatment includes emollients, keratolytics, topical calcipotriol, 10% urea, topical N-acetyl cysteine and topical tazarotene 0.05% gel. In severe cases Acitretin 0.5-0.75 mg/kg/day.

LI is known to be associated rarely with systemic organ involvement. Few case reports with LI associated with either rickets[1011] or carcinoma[1214] have been observed. This is the first report presenting with both rickets and carcinoma in one patient. Sethuraman et al.,[10] have shown an association of LI with rickets. Similarly Thacher et al.,[11] reported the association of LI with nutritional rickets. Elbaum et al.,[12] reported two cases of LI who later developed squamous cell carcinoma. The development of squamous cell carcinoma has also been reported in a patient of non-bullous congenital ichthyosiform erythroderma by Arita et al.,[13]. Kampp et al.,[14] have reported a case of basal cell carcinoma masquerading as chronic ectropion in a patient of LI. We present our case wherein the patient had rickets as well as cancer of the hypopharynx with LI. Such a case of LI with rickets and carcinoma has not been reported before and we present it to you for its rarity. Cutaneous malignancies have been well associated with LI. A recently published meta-analysis study on serum 25-hydroxyvitamin D in colorectal cancer, revealed intake of vitamin D could minimize the risk of colorectal cancer.[15] Thus an association of mucosal malignancies with decreased levels of vitamin D3 has been seen too. Similar studies have shown deficiency of vitamin D in association with prostate and ovarian cancer risk.[161718] However, hypopharyngeal carcinoma in association with LI and rickets is being reported for the first time. Whether there is an underlying gene mutation responsible or due to vitamin D deficiency per se for the underlying malignancy is still uncertain and at present literature too is unavailable for the same. Further molecular studies may help in this particular scenario. We as dermatologists tend to overlook systemic involvement in LI, which must be given due importance.