Autosomal recessive anhidrotic ectodermal dysplasia: a rare entity.

We describe a case of anhidrotic ectodermal dysplasia (AED) with an autosomal recessive mode of inheritance, a very rare entity, in a 2-year-old female child of two asymptomatic, consanguineous parents. Their previous child also had a similar condition. Autosomal recessive AED (AR-AED) can have its full expression both in males and females and it is clinically indistinguishable from the x-linked recessive AED (XL-AED), which is the most common type of ectodermal dysplasia. Unlike the partially symptomatic carriers of XL-AED, the heterozygotes of AR-AED are phenotypically asymptomatic.

What was known?

Most cases of anhidrotic ectodermal dysplasia are X-linked recessive type, accounting for 80% of cases. However there is a rare autosomal recessive variant of anhidrotic ectodermal dysplasia which can be clinically indistinguishable from XL-AED.

Introduction

Ectodermal dysplasias (ED) are a heterogeneous group of disorders characterized by developmental dystrophies of ectodermal structures such as hair, teeth, nail and sweat glands. EDs are usually categorized into anhidrotic and hidrotic based on the absence or presence of sweating, respectively.[1] Another classification of EDs was provided by Pinheiro and Freire-Maia in 1994. In this classification system, the basic affected structures were designated by numerals such as 1, 2, 3, 4, and 5, representing hair, nail, teeth, sweat-glands, and other ectodermal defects, respectively.[2] X-linked recessive anhidrotic ED (XL-AED) is the most common type accounting for 80% of cases. A clinically indistinguishable autosomal recessive variant of AED (AR-AED) has been described very rarely.[1]

Case Report

A 2-year-old female child, third of the sibship, born out of second degree consanguinity (parents are first cousins), by a normal vaginal delivery at term without any complications, presented to us with complaints of sparse scalp hair growth with absent body hair, eyebrows, and eyelashes and delayed dentition. Mother reports absence of sweating in her child with history of recurrent pyrexia since neonatal age. Her psychomotor development was normal. There was no family history of similar symptoms, except that her previous female sibling had same complaints with a dysmorphic appearance, whose neonatal period was complicated with recurrent fever and chest infection leading to her death at 6 m of age. The parents’ first pregnancy resulted in an abortion at 2 months, due to an unknown cause.

Cutaneous examination revealed a normal-looking smooth skin with normal palmoplantar skin and dermatoglyphics. The child had a typical old-man appearance with finely wrinkled periorbital skin, everted lower lip and low-lying ears. Scalp hair was sparse, light colored, thin with complete absence of eyelashes and eyebrows and body hair. Oral examination showed eruption of only two conical, wide spaced maxillary teeth and a low-arched, flat palate [Figure 1a and b]. There were no nail abnormalities. Systemic examination was unremarkable with no evidence of mental retardation. Orthopantomogram and lateral view of mandible showed oligodontia with only two maxillary teeth and a left mandibular tooth bud [Figure 2a and b]. Biochemical investigations revealed no abnormalities. Histopathology of palmer skin from hypothenar area showed inconspicuous sweat glands. Genetic study was not done due to resource-limited set up. Parents were determined to be unaffected after careful physical examination [Figure 3].

Figure 1

Clinical phenotype. (a) A female child with sparse scalp hair and absent eyebrows and eyelashes with an old man appearance. (b) Same girl with two widely spaced conical anterior maxillary teeth

Figure 2

Radiographs. (a) Lateral view mandible. (b) Orthopantomogram showing oligodontia with only two anterior maxillary teeth and a right side mandibular tooth bud

Figure 3

Pedigree chart of the family showing both heterozygote parents with first pregnancy resulting in abortion, second child was a female who was affected and now deceased and the third child is also a female, affected and the proposita here

Discussion

According to Freire-Maia and Pinhero classification, our patient fits in 1-2-4 subgroup.[2] Full blown expression of AED in a female can either be an autosomal recessive, dominant, or sporadic AED due to autosomal translocation of X chromosome.[34] Disease expression in more than one sibling and the presence of consanguinity and asymptomatic parents supports an autosomal recessive form. Mutations in the ectodermal dysplasia autosomal recessive (EDARADD) gene, or in the ectodysplasin anhidrotic receptor (EDAR) gene appear to be responsible for the AR-AED.[5] The autosomal recessive type of inheritance of AED is extremely rare and clinically it is indistinguishable from the X-linked type and clinically presents with triad of signs comprising sparse hair (atrichosis or hypotrichosis), abnormal or missing teeth (anodontia or hypodontia) and inability to sweat due to lack of sweat glands (anhidrosis or hypohidrosis).[1] About half of the affected individuals exhibit mild nail dystrophy, but nail beds are more susceptible to progressive injury with age; therefore, nail dystrophies are seen more commonly in older individuals.[6] Complications like hyperthermia, due to lack of sweating, and recurrent chest infections and diarrhea, due to poor development of mucous glands in the respiratory and gastro-intestinal tract, are seen in these neonates.[17] Unlike the XL-AED type, where only the males have full expression of the syndrome, in AR-AED, both male and female can be severely affected and the heterozygotes of AR-AED are phenotypically asymptomatic in contrast with the carriers of XL-AED who can have partial expression of the syndrome.[6]

Diagnostic tool is the typical clinical physiognomy. First clue to the diagnosis is the premature “old man” look at birth with a typical facies comprising frontal bossing, a depressed nasal bridge and everted lips and large ears. The skin is smooth, soft, dry, and finely wrinkled around the eyes with lack of eyebrows and eyelashes. Due to the absence of sweat glands, they suffer from recurrent episodes of hyperthermia and sometimes febrile seizures.[13] Histopathology of palmar skin from the hypothenar area shows total the absence or sparse and partially developed sweat glands in the dermis.[14] The standard methods of demonstration of reduced sweating and sweat pore counts are available. These are silicon rubber plastic imprints for sweat pore counts, starch–iodine test and quantitative pilocarpine iontophoresis to determine the sweating ability. These tests are not essential for diagnosis but help in quantitative assessment of disease severity.[8]

Children with ectodermal dysplasia need life-long maintenance care and revisions. Hyperthermic episodes, recurrent chest infections and tooth agenesis needs attention from treatment point of view. Maintenance of a cool, ambient temperature is vital for the management of these patients. An air-conditioned environment reduces the chances of sudden hyperpyrexia. Light clothing, repeated cool water sprays and avoidance of exertion help the patients combat hyperthermic tendencies. Chest infections and diarrhea episodes should be treated promptly.[146]

Tooth agenesis and its secondary effects on the growth and development of jaw, is often the most significant clinical problem. Early placement of partial or full dentures is commonly recommended from the age of 2 or 3 years onwards and the denture must be periodically modified as alveolar growth, erupting teeth, and rotational jaw growth change the alveolar dimensions with the growing age of the child.[17]

Intelligence and life expectancy of these patients are usually normal, but hyperthermia in neonatal age can result in brain damage and early neonatal death in some.[1] Therefore, they deserve an early diagnosis and genetic counselling is important to recognize AR-AED. Prenatal diagnosis of AED has occasionally been reported, with fetal skin biopsy, obtained by fetoscopy by 20 weeks. But this procedure is complicated and implies a considerable risk to the pregnancy.[9]

What is new?

In AR-AED, both male and female can be severely affected and the heterozygotes of AR-AED are phenotypically asymptomatic in contrast with the carriers of XL-AED who can have partial expression of the syndrome.