Phenotypic and dermatological manifestations in Down Syndrome
Published Web Locationhttps://doi.org/10.5070/D38jx5f2v2
Phenotypic and dermatological manifestations in Down Syndrome1. Aarupadai Veedu Medical College & Hospital, Vinayaka Missions University, Pondicherry, India. firstname.lastname@example.org
Rengasamy Sureshbabu1 MD, Rashmi Kumari1 MD, Subramaniam Ranugha1 MD, Ramanathan Sathyamoorthy1 DD, Carounanidy Udayashankar2 MD, Paquirissamy Oudeacoumar1 MD
Dermatology Online Journal 17 (2): 3
2. Indira Gandhi Medical College and Research Institute, Pondicherry University, Pondicherry, India
Down syndrome (DS) is associated with various uncommon dermatological disorders and increased frequency of some common dermatoses. This study was conducted over a 2-year period to evaluate the frequency of phenotypic and dermatologic manifestations in patients with Down syndrome in south India. The most common phenotypic manifestations that characterize DS include the epicanthic fold (93.7%), brachicephaly (90.6%), flat nasal bridge (84.2%), upward angle of eyes (83.2%), wide gap between first and second toe (81.1%), clinodactyly (77.9%), small nose (74.7%), short broad neck (72.6%), single palmar crease (61.1%), increased nuchal skin fold (61.1%), and fissured tongue (52.6%). The most common dermatological manifestation seen in patients with DS were lichenification, xerosis, dental anomaly, fine, sparse hair, and delayed dentition. Alopecia areata was seen in 9.4 percent of patients and tended to be severe. Infections were relatively less common in our study. Our study has highlighted many phenotypic features and dermatoses, which may help provide better care for patients and counseling to the families.
Dermatological manifestations of Down syndrome (DS) have not been as well described as the physical and psychosocial aspects of DS . The existing data is mostly in the western literature and that mainly among the hospitalized and institutionalized patients . Data regarding the dermatological conditions occurring in DS from India is scarce.
There have been a few studies in this regard but most have highlighted the features seen in children [3, 4, 5, 6]. The data regarding manifestations of DS in adults is mostly presented as case reports. Hence, we undertook this study to evaluate the frequency of phenotypic and dermatological manifestations in patients with Down syndrome in south India.
II. Materials and methods
This study was conducted over a period of 2 years from September 2007 to August 2009 after approval of our institution review board. The patients were recruited from nearby special schools or special homes in and around Pondicherry by a trained team of 1 dermatologist and 1 pediatrician. All the patients were examined both by the pediatrician and the dermatologist to look for various phenotypic and dermatological manifestations.
All consecutive patients with confirmed diagnosis of Down syndrome (by karyotyping) were included in the study irrespective of the age. Both phenotypic and dermatological manifestations were studied in the two groups, i.e., children (≤ 14 years) and adults (> 14 years). After an informed consent from the parents, a detailed history was taken that included chief complaints related to skin, presence of itching, skin lesions, onset, and associated medical or skin disorders. Complete cutaneous examination was performed on all patients to study all the phenotypic and dermatologic manifestations. If any specific dermatoses were found, the morphology of skin lesions, distribution, and the sites involved were studied. Relevant systemic examination was carried out. Appropriate investigations including skin biopsy were done to confirm diagnosis if required. Results were tabulated and analyzed using the SPSS v-17 software. Chi square test was performed to look for significant differences in the frequencies seen between the children and adult patients.
A total of 95 patients with Down syndrome (DS) were included in this study of which 67 were children and 28 were adult patients. All the patients were residents of Tamilnadu and Pondicherry. Most of the patients seen during this study were between 5 to 10 years of age comprising 34 percent of the total number of patients. The mean age of the study group was 11.97 ± 8.8 with a range of 6 months to 40 years (Table 1). A larger number of males than females were seen in our study with the sex ratio being 1.6:1 (59 males and 36 females).
A. Phenotypic manifestation
The phenotypic manifestations studied are detailed in Table 2. The most common characteristic phenotypic manifestations seen in more than 50 percent of total patients in descending order included the epicanthic fold (93.7%), brachicephaly (90.6%), flat nasal bridge (84.2%), upward angle of eyes (83.2%), wide gap between first and second toe (81.1%), clinodactyly (77.9%), small nose (74.7%), short broad neck (72.6%), single palmar crease (61.1%), increased nuchal skin fold (61.1%), and fissured tongue (52.6%).
1. Head and neck features
|Figure 1||Figure 2|
|Figure 1. Brachicephaly|
Figure 2. Flat nasal bridge and small nose
|Figure 3. Small and dysplastic ear with overfolded helix|
Head and neck features of Down syndrome included brachicephaly (Figure 1), flat nasal bridge, small nose, short broad neck, increased nuchal skin fold, and small and dysplastic ear. The transverse diameter of the head was greater in most of the children (brachicephaly). The most common features were brachicephaly, flat nasal bridge and small nose (Figure 2), and short broad neck.
Depressed nasal bridge was seen in 80 patients of which 60 were children and 20 were adults. This feature was seen in significantly more children than in adults (p value=0.027). Forty-five patients with small ear and 7 patients with dysplastic ear with over folded helix were seen (Figure 3).
2. Eye manifestations
The most common eye manifestation included epicanthic fold (Figure 4) and upward angle of eyes (Figure 4) seen in all the age groups, but was less prominently seen in adults as compared to children (p value=0.039). Epicanthic fold is an extra skin fold over the upper eyelid covering the inner corner (medial canthus) of the eye.
This epicanthic fold was seen in 89 patients of which 65 were children. But refractory errors were seen more in adult (7 patients) than children and this difference was statistically significant (p value=0.008).
|Figure 4||Figure 5|
|Figure 4. Epicanthic fold and upward angle of eyes|
Figure 5. Fissured (scrotal) tongue with chelitis
3. Oral manifestations
An open mouth with a tendency of tongue protrusion, a fissured and furrowed tongue (Figure 5), and mouth breathing with drooling were commonly noted in our patients. Fissured tongue, small mouth, and protruding macroglossia were seen in almost 50 percent of patients, but macroglossia was significantly more evident in children as compared to adults (p value=0.044).
4. Chest and abdomen
Protruding abdomen was seen in 45 patients. Divarication of rectus abdominus muscles in 35 patients, flat nipple in 34 patients and umbilical hernia in 4 patients were observed in our study. Flat nipples were seen in 30 children as compared to 4 adults and this difference is statistically significant (P=0.005).
5. Hands and Feet manifestations
|Figure 6||Figure 7|
|Figure 6. Wide gap between first and second toes|
Figure 7. Single palmar crease, clinodactyly and single flexion crease of the 5th finger
Wide gap between the first and second toes (Figure 6), single palmar crease (Figure 7) (this was seen as single crease that extends across the palm of the hand, formed by the fusion of the two palmar creases), and clinodactyly, which is the bend of the fifth finger (“little finger”) toward the adjacent four fingers (Figure 7), were seen commonly in our study. Clinodactyly is more prominently seen in children as compared to adults with p value=0.023. Single flexion crease of 5th finger was not commonly seen but was present in all patients who had single transverse palmar crease.
Hyperlinearity of the palms was seen in a 10-year-old girl without any other features suggestive of atopic dermatitis. Polydactyly was seen in one patient.
B. Dermatological manifestations in Down syndrome
The most common dermatological manifestations seen in more than 25 percent of total patients in descending order included lichenification (52.6%), xerosis (43.2%), dental anomaly (35.8%), fine, sparse hair (27.4%) and delayed dentition (25.3%). The dermatological manifestations are detailed in both the pediatric and adult groups in Table 3.
1. Scalp and hair
|Figure 8||Figure 9|
|Figure 8. Alopecia totalis|
Figure 9. Alopecia universalis
Fine, sparse hair was most commonly seen in 26 patients (27.4%). Eight patients with alopecia areata were seen, of which 5 were children and 3 were adults. Of the eight patients with alopecia areata 5 had patchy alopecia areata, 2 had alopecia totalis (Figure 8), and one had alopecia universalis (Figure 9). Premature graying was seen only in adults (4 out of 28). Seborrheic dermatitis was seen in 4 children, the youngest of them was 6 months old.
2. Oral manifestations
Chapped lip (chelitis) was seen 11 children and 2 adults (Figure 5). It was more commonly seen in children between 5-10 years of age, and it was totally absent in children less than 5 years of age. Angular stomatitis was noted in 6 patients, 5 children and one adult. Dental anomaly, delayed dentition, and dental caries were commonly seen in our study. Dental anomaly was more frequently encountered (35.8%) than others. Twenty-four patients had delayed dentition and 16 patients had dental caries.
3. Keratinization disorders
|Figure 10. Lichenification|
Amongst all the keratinizing disorders, the most commonly seen disorder was lichenification in 50 patients (52.6%) with a peak incidence in the 5-10 year age group (Figure 10). It was commonly seen over frictional areas such as knees, elbows, and ankles. The next most common was xerosis in 41 patients (43.2%), seen commonly over the legs, forearms, and trunk. Xerosis was more frequently seen between 5-10 years of age. Ichthyosis vulgaris was present in 9 patients (9.5%), commonly appreciated over the legs. There was no positive family history in these patients. All patients with ichthyosis were more than 5 years old. One case each of conditions keratosis pilaris, callus, phrynoderma and palmoplantar keratoderma was also seen.
Infections were relatively less common in our study. Bacterial infection was seen in 11 patients, of which 6 were folliculitis, 4 were furuncles, and one was impetigo. Folliculitis was commonly seen over the limbs. Fungal infection was seen in only two patients in the form of chronic paronychia of thumbs in an adult and a child. Three patients with pediculosis capitis were seen. One case of molluscum contagiosum was seen over the face in a 13-year-old child as a single umblicated papule over the chin. A single verruca vulgaris lesion was seen in a 14-year-old boy over the left thumb. There was no evidence of any underlying immuosuppression in either of these patients.
5. Pigmentary disorders
Pigmentary changes were observed in 15 (15.7%) patients. Post inflammatory hyperpigmentation following impetigo was seen in 5 patients, café-au-lait macules (CALM) in 4 patients, and nevus depigmentosus was seen in 2 patients. Even though CALM macules were seen in four patients, none of them had more than 3 macules. One case each of freckles and dermal melanocytosis were found in our study. Pigmented purpuric dermatosis was seen in an obese 24-year-old patient over the ankle joints on both sides. Mucosal vitiligo was seen in a 10-year-old boy as a single patch over the glans penis.
|Figure 11||Figure 12|
|Figure 11. Anetoderma|
Figure 12. Lateral view of anetoderma
Other dermatological conditions such as miliaria rubra (4 patients), hypertrichosis (1 patient), and lichen nitidus (1 patient) were seen. Anetoderma was found in 3 children in the 5-10 year old group (Figures 11 and 12). Histopathology of anetoderma revealed normal epidermis with a decrease in the number of elastic fibers with irregular arrangement in the papillary and reticular dermis. Acanthosis nigricans (AN) was seen in 3 children and 5 adults. Acne vulgaris (3 patients) and striae (one patient) were seen in adults.
Our study has included both children and adults with a confirmed diagnosis of Down syndrome. Very few studies in the literature have highlighted both phenotypic and dermatological manifestations of Down syndrome. Newer reports are mostly in the form of case reports highlighting the rare dermatological findings .
DS has been studied in 4 major surveys but the results are not concordant, probably because of different criteria of sampling and methodology (Table 4) [3, 4, 5, 6]. These studies differ in two major aspects, i.e., age range and living conditions of the study group. A recent study published by Daneshpazhooh et al had studied 100 children with DS with a mean age of 11.2 years . Carter and Jegasothy studied 213 institutionalized patients with ages between 12 and 48 years for features of DS . Ercis et al examined 71 children, all of whom were living with their families . Polenghi et al studied adults, 14-53 years old . Schepis et al studied 203 patients from infancy till adulthood with a mean age of 11.7 years .
Our study was comprised of 95 patients with Down syndrome including 67 children and 28 adults (ratio 2.5:1). The mean age of the study group was 11.9 years, ranging from 6 months to 40 years, which is the same as seen by Schepis et al . The male prevalence (sex ratio 1.6:1 with 59 males and 36 females) is the same as seen by Schepis et al .
The most common characteristic phenotypic manifestation seen in our study includes in descending order of frequency, epicanthic fold, brachicephaly, flat nasal bridge, upward angle of eyes, wide gap between first and second toe, clinodactyly, small nose, short broad neck, single palmar crease, increased nuchal skin fold, and fissured tongue. Schepis et al reported single transverse palmar crease as the most frequent finding seen in 33 percent of patients . Daneshpazhooh et al reported fissured tongue seen in 28 percent , whereas palmoplantar hyperkeratosis was the most frequent dermatologic manifestation seen by Ercis et al .
Examination of the head and neck region show the most common features of DS were brachicephaly (90.6%), flat nasal bridge (84.2%), small nose (74.7%), and short broad neck (72.6%). Brachicephaly has been reported in DS in 63-98 percent of patients . Flat nasal bridge was seen both in adults and children but it appeared to be more prominent during childhood. The ears are usually small and sometimes dysplastic with over folded helix. These features are commonly reported with Down syndrome (28-91%) .
Among the phenotypic features in the eyes the most common was epicanthic fold (93.7%); this also was the single most common phenotypic finding seen. These folds have been noted in 60-100 percent of individuals with Down syndrome by Liyanage et al and usually regress with age . The percentage of patients showing upward angle of eyes (83.2% of patients) in our study is similar to other studies, although it may vary anywhere between 70-98 percent .
The incidence of refractive errors, nystagmus, and strasbismus was comparatively lower in our study than that by Liyanage et al, with higher frequencies reported of refractive errors (50%), strabismus (43%), and nystagmus (30%) .
A wide gap between the first and second toes, single palmar crease, and clinodactyly were seen in more than 60 percent of patients. This feature is typically seen in 44-97 percent of DS patients and may give an early clue to the DS diagnosis apart from the facial features . Single flexion crease of the 5th finger was seen in around 18 percent of patients. This finding has been reported in a previous study in around 20 percent of patients with DS .
The incidence of single palmar crease (61.1% of patients) in our study is definitely higher than in the study of Schepis et al (31.5%) . Single transverse palmar crease has been seen in 42-64 percent of patients with DS and is an important diagnostic feature along with clinodactyly and single flexion crease of the fifth finger . Single palmar crease, considered as a minor variant, is seen unilaterally in about 4 percent of the normal population and bilaterally in about 1 percent .
The neck is usually short and broad in DS and the skin and subcutaneous tissue may be loose and abundant, especially during infancy . Loose skin on the nape of the neck was seen in around 60 percent patients. Flat nipples were seen in 35 percent of patients and are the most important feature seen in the chest among children. This feature was not prominent among adults. In our study protruding abdomen was seen in 45 patients. The exact frequency of divarification of rectus abdominus muscles and umbilical hernia in DS although, mentioned as a common association, is not known .
Fissured tongue was seen with a frequency of 52.6 percent, being the most common feature seen in the oral cavity. This incidence ranges between 20 percent by Ercis et al  to 95 percent by Zeligman and Scalia in 1954 . However, it is definitely higher than the incidence found in general population (2-5%) , probably a feature of nutritional deficiency.
A review of dermatological manifestations of DS showed a high incidence of alopecia areata, vitiligo, atopic dermatitis, and infection. This may be related to the immunological deficiency in T-cell function, which exists in DS [4, 14, 15, 16].
Amongst all the dermatological disorders lichenification was found to be the most common disorder, seen in 50 patients (52.6%), with a peak incidence in the 5-10 year age group. This finding was not noted in other studies. In DS, the skin in infancy is usually soft, but soon becomes dry, thick, and rough, with patchy lichenification . The reported frequency of xerosis differs from 9.8 percent  to 85 percent  in various studies. Our study also supports this finding with xerosis noted in 43.2 percent of our patients.
None of our subjects fulfilled the criteria of Hanifin and Rajka for atopic dermatitis . This is in contrast to the high incidence reported by Carter et al (56.5%) and cited in major review articles [4, 18]. In two recent well-designed studies, Schepis et al found figures of 3 percent and 4.9 percent for the prevalence of atopic dermatitis in Down syndrome using the criteria of Rajka and Hanifin [6, 19]. Our results are in favor of the opinion put forward by Schepis et al that atopic dermatitis is not as common as previously thought when using the acknowledged diagnostic criteria of Rajka and Hanifin. However, those patients with DS who had lichenification, xerosis or palmoplantar keratoderma may represent patients with an atopic diathesis without actually having atopic dermatitis at the time of examination.
The DNA repair theory offers one explanation for accelerated aging in DS . A positive correlation has been postulated between maximum life span and the capacity to repair UV-induced DNA damage. In addition, the incidence of premature graying is definitely higher in adults (4.2%) in our study, as expected. The figure reported by Carter and Jegasothy was 1.4 percent .
Cheilitis and angular stomatitis showed an overall frequency of 20 percent, but this feature was not seen in children below the age of 4 years. Ercis et al had attributed the increased incidence of angular stomatitis (5.6%) to the presence of a depressed nasal bridge and muscular hypotonia, causing an open mouth and protruding tongue that produced an increase in salivation and maceration of the angles of mouth . Butterworth et al in their study had found cheilitis in 6 percent and Schepis et al in 2.5 percent of their patients [6, 21].
Dental anomaly (35.8%), delayed dentition (25.3%) and dental caries (16.8% cases) were commonly seen in our study. The DS infant usually has normal lips, but with time there is whitening and thickening of the mucous membrane . Later, vertical fissures occur followed by enlargement of the lips, scaling, and crusting. Although the fissures are deep, they heal at times, leaving prominent vertical lines . The hypertrophy, scaling, crusting, and fissuring noted in the lips of DS patients are thought to be the result of trauma or chronic low-grade infection, but the true cause remains unknown .
In our study, alopecia areata was seen in 9.4 percent of patients (6 boys and 2 girls) without any female predilection as observed by Carter and Jegasothy . Alopecia areata was seen in 3 percent of patients in the study of Schepis et al, with the usual age of onset in middle childhood (5-10 years) . Alopecia areata, when present in people with DS, is usually severe and refractory to the standard treatments . The incidence of vitiligo is not significantly higher in our study.
Fine, sparse hair was seen in 27.4 percent of our patients. Although this finding has not been reported in other studies it may be related to poor nutrition or poor scalp hygiene.
Seborrheic dermatitis was seen in four patients (4.2%), of which 3 patients were less than 4 years of age. Ercis et al reported a figure of 31 percent (mostly during the first year of life)  and Carter and Jegasothy observed this finding in 36 percent of adult patients . Seborrhoeic dermatitis is commonly seen in patients with immunodeficiency .
A low incidence of infection was seen in our study in contrast to Carter et al who reported a high prevalence of fungal infections . Schepis et al also reported a relatively low figure for onychomycosis and tinea corporis . Fungal infections may have been over diagnosed in the past or may be caused by poor hygienic conditions. Norwegian scabies can appear as isolated or epidemic conditions  but no cases were recorded in our study.
In our study we have seen anetoderma in three patients (3.2%). Schepis et al reported 3.9 percent of patients having anetoderma in their study . It has been hypothesized that a congenital malformation of elastic fibers in this population may be responsible for anetoderma secondary to chronic folliculitis . Anetoderma is due to elastolysis probably induced by leukocytes or bacteria during the recurrent inflammatory events .
Acanthosis nigricans was seen in 3 children and 5 adults. The increased incidence of AN in adults is more than in children, but this fact may be attributed to the fact that all these patients were obese with a high BMI (> 30).
Other miscellaneous cutaneous lesions were probably coincidentally seen in our study, concordant with that seen in the general population. In our study no patients with syringoma, milia-like calcinosis cutis, leukemia cutis, elastosis perforans serpiginosa, carotenemia, or vascular instability were seen; this may relate to the fact that our study was not hospital based, unlike other previous studies.
A higher prevalence of certain dermatological disorders such as alopecia areata indicate an underlying immunological disturbance. DS is associated with premature aging and with decreased life expectancy of DS patients. In our series, atopic dermatitis did not seem to occur with an increased prevalence in DS patients, contrary to other studies. DS patients do not seem to have a high incidence of bacterial or fungal skin infections, although these patients are at increased risk of development of anetoderma secondary to folliculitis. Improved hygiene and good patient care at home may underlie the absence of infections among our children. Xerosis, lichenification (atopic diathesis) with increased dental anomalies, cheilitis, and fine sparse hair are the dermatological manifestations seen with increased frequency in our population of DS patients.
In conclusion, our study has highlighted many phenotypic features and dermatologic conditions which may help in the early detection of DS and hence help provide better care for the patients with DS by the parents, teachers, and physicians.
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