Infantile tremor syndrome, often overlooked diagnosis in dermatology

Dimple Chopra; Shayna Aulakh; Archit Garg; Aashi Garg

doi:10.4103/ijpd.ijpd_120_21

CASE REPORT

Year : 2022 | Volume : 23 | Issue : 2 | Page : 156-158

Infantile tremor syndrome, often overlooked diagnosis in dermatology

Dimple Chopra, Shayna Aulakh, Archit Garg, Aashi Garg
Department of Dermatology, Venereology and Leprology, Government Medical College, Patiala, Punjab, India

Date of Submission	02-Aug-2021
Date of Decision	22-Jan-2022
Date of Acceptance	22-Jan-2022
Date of Web Publication	30-Mar-2022

Correspondence Address:
Dr. Dimple Chopra
27, Bank Colony, Patiala - 147 001, Punjab
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijpd.ijpd_120_21

Abstract

Infantile tremor syndrome (ITS) is a clinical condition defined by a tetrad of pallor, development regression, pigmentary changes, and hypotonia which may be accompanied by tremors. The clinical spectrum of ITS may also vary. Not every patient may present with all the symptoms, some of them may show only very subtle features of ITS which may lead to underdiagnosis of this condition in daily clinical practice. We report a case of ITS where the patient had predominantly dermatological features such as hyperpigmentation over the dorsal aspect of hands, knees, feet, axilla, buttocks, brittle nails, thin sparse hairs but without characteristic tremors. This report, with brief review of literature, tends to sensitize dermatologists to keep ITS as a differential diagnosis while dealing with infantile hyperpigmentation and recognizing it in pretremor stage, especially in the exclusive breastfed population of Indian children, where ITS is still widely prevalent.

Keywords: Breastfeeding, hyperpigmentation, infant, infantile tremor syndrome, Vitamin B12 deficiency

How to cite this article:
Chopra D, Aulakh S, Garg A, Garg A. Infantile tremor syndrome, often overlooked diagnosis in dermatology. Indian J Paediatr Dermatol 2022;23:156-8

How to cite this URL:
Chopra D, Aulakh S, Garg A, Garg A. Infantile tremor syndrome, often overlooked diagnosis in dermatology. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 May 20];23:156-8. Available from: https://www.ijpd.in/text.asp?2022/23/2/156/341458

Introduction

Infantile tremor syndrome (ITS) is a clinical state characterized by tremors, anemia, pigmentary changes, regression of mental development, and hypotonia of muscles.^[1] Despite ITS being well-known entity, many dermatologists tend to overlook changes in the skin, hair, and nail and is often not diagnosed as a clinical entity in daily practice.

Case Report

An year old girl was brought by her mother to the skin outpatient department of Rajindra Hospital, Patiala, with the chief complaint of increasing hyperpigmentation of the skin for 2 months, gradual in onset, and slowly progressing to involve bilateral limbs. The child was exclusively breastfed. There was no history of fever or evidence of any recent infection in the child. Immunization of the child was up to date. There was no family history of any pigmentary disorder. On examination, the child was lethargic, irritable, and plump looking. She had evident pallor on mucosae. There was diffuse hyperpigmentation, somewhat in reticular pattern, involving both hands and feet and extending proximally toward both limbs. It was mainly evident on extensors and knuckles. Hairs were brownish, sparse, thin, and lusterless [Figure 1]. Nails were brittle with diffuse leukonychia. Mucosae showed no pigmentary changes. Developmental regression of 3 months was present. No abnormality was detected in the cardiovascular, abdominal, neurological, musculoskeletal, and pulmonary examinations. On investigating, child had macrocytic hypochromic anemia (Hb: 10.9 g/dl) and low serum Vitamin B12 level (85.67 pg/ml), while serum proteins were within normal limit (Total = 6.8 g/dl, albumin = 3.5 g/dl, and globulin = 3.2 g/dl). Based on history, physical examination, and investigations, a provisional diagnosis of atypical variant of ITS was kept, and the child was put on therapeutic trial with injection cyanocobalamin (Vitamin B12) 1000 μg daily intramuscular, injection folic acid 1 mg daily intramuscular, oral nicotinamide 100 mg/day for 2 weeks. Mother of the child was counseled to stop exclusive breastfeeding and to introduce solid foods. On the next follow-up at 2 weeks, hyperpigmentation had started to resolve [Figure 2], and the child had started to regain normal developmental milestones.

Figure 1: Pretreatment (a) Thin sparse hair on the scalp of plump-looking child, (b) reticular hyperpigmentation present on the dorsum of feet, extending over to limbs, (c and d) prominent knuckle hyperpigmentation

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Figure 2: Posttreatment (a) Regrowing scalp hair, (b) resolving pigmentation on feet and lower limbs, (c and d) resolving pigmentation on the dorsum of hands and disappearing knuckle hyperpigmentation

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Discussion

ITS is characterized by the presence of tremors, anemia, pigmentary skin changes, and regression of mental development along with muscle hypotonia.^[1] In the Indian subcontinent, ITS accounts for 0.2%–2% of all pediatric hospital admissions.^[2] It usually affects children between 6 to 24 months of age.^[3]

A number of etiologies such as metabolic, nutritional, and infectious (like upper respiratory tract, gastrointestinal, and urinary tract infections with Escherichia coli and Pseudomonas aeruginosa) have been linked to ITS, but there is no clear-cut evidence.^[4] Many studies have shown the deficiency of macro and micronutrients such as zinc, magnesium, and Vitamin B12 to be associated with ITS.^[5] Exclusive breastfeeding, weaning failure, refusal of solid food, and inadequate introduction of animal-origin food rich in Vitamin B12 have also been implicated.^[6]

Skin and hair changes come in the spectrum of clinical signs of ITS along with tremors and developmental regression.^[3] The skin shows hyperpigmentation on the dorsal surfaces of both hands and feet with the hyperpigmentation more pronounced on the knuckles, hence the name knuckle hyperpigmentation. Hyperpigmentation can also be present on the trunk and extremities in a reticular or honeycomb fashion. However, hyperpigmentation in oral cavity and nail has not been reported much. This pattern of skin pigmentation may mimic Addisonian pigmentation, but the lack of other characteristic features such as fatigue, myalgias along with laboratory tests (ITS shows low Vitamin B12 levels, rather than low cortisol), and gradual resolution of pigmentation with Vitamin B12 supplementation helps to distinguish it well from that of Addison's disease.^[7] Scalp hair also becomes sparse, rough, easily pluckable, lusterless, and gets a brownish tinge, as was the case with our patient as well.

Although it is said that ITS is characterized by a tetrad of pallor, developmental regression, hyperpigmentation of the skin, and sparse brown hair, it is not necessary that the patient has all the features of ITS making the diagnosis of atypical variant of ITS even more difficult. One of the studies conducted by Goraya et al. showed that out of the 21 cases of ITS that attended their institute, all of them had brown scaly hair, skin hyperpigmentation, pallor, developmental regression, and lethargy. However, not all of them had tremors (27%), hypotonia (25%), and growth retardation (22%).^[8] Moreover, tremors are absent in the pretremor stage of ITS. To verify this, another study was done by Chaudhary et al. among two groups of pre-ITS and ITS to study the role of Vitamin B12 in causation and treatment of ITS and found that tremors were present in only 21.7% of all the patients, but all of them had hyperpigmentation and pallor.^[9] The absence of tremors may prevent the doctors from considering ITS as a differential in a child with only neuro-regression and cutaneous symptoms or even just cutaneous symptoms along with Vitamin B12 deficiency.^[10] The reason for hyperpigmentation due to Vitamin B12 deficiency is suggested to be due to decreased intracellular redox potential, resulting in oxidation of reduced glutathione. It subsequently lowers the levels of reduced glutathione which is no longer available to inhibit tyrosinase and results in increased melanin production by melanocytes.^[11] Vitamin B12 deficiency also causes a defect in melanin transfer between melanocytes and keratinocytes which may lead to pigmentary incontinence and resultant hyperpigmentation.^[12]

Since the exact etiology of ITS is not known, its treatment has also been controversial. Usually, it is treated by a combination of dietary modification, especially stopping exclusive breastfeeding and initiating weaning with nutritious food, multivitamins, and mineral supplementation.^[6] Successful treatment of Vitamin B12 deficiency has also resulted in the complete resolution of symptoms of ITS, including tremors and neurological regression, if present.^[6],[8],[9] Hematological recovery is usually observed within 5–7 days, and skin hyperpigmentation is corrected within 2–4 weeks. Hair changes are slow to occur. In severe cases, intravenous fluids to treat dehydration, antibiotics to treat infection, propranolol, carbamazepine, sedatives, or emetine to treat tremors have been used but none of them have been totally effective and their exact role in the treatment of ITS is still not conclusive.^[13]

Conclusion

Diagnosing ITS has always been difficult considering the fact that no clear etiology and no specific diagnostic findings can be attributed to it. It is thus challenging and of course quintessential for dermatologists to diagnose it in pretremor stage and prevent progression to tremor and neurodevelopmental regression stages. Hence, ITS should be kept as a differential diagnosis for all the infants coming with pigmentary changes and seeking dermatological consult rather than pediatric, and should be supplemented accordingly.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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