Clinical Profile of Indian Children with Down Syndrome

Abstract

This retrospective study was performed on 208 patients with Down syndrome (DS) from heterogeneous ethnic population and admitted under Genetics Metabolic Unit. The aim of the study was to look for phenotypic variability and associated complications in children and adolescents with DS. The average age of the evaluated DS patients was 34 months. Cardiac anomalies were found in 128 (62%) of the 208 cases. Among the cardiac disorders, atrial septal defects accounted for 30% of cases. Other complications observed were hypothyroidism and developmental delay in around 31% cases and neonatal cholestasis in 14% cases. Also, we report two cases with Moya-Moya disease and one case with atlanto-axial dislocation.

Introduction

Down syndrome (DS) is the most common chromosomal disorder leading to intellectual disability. ^{1 2 3 4} About 95% of DS cases are caused by full chromosome 21 trisomy resulting from meiotic nondisjunction, 2 to 3% are caused by Robertsonian translocation between acrocentric chromosomes such as 13, 14, 15, 21, and 22, while the remaining 2 to 3% are due to mosaicism. The risk of having a child with trisomy 21 increases with maternal age, especially after 30 years of age.

Approximately, 1 child in 850 live births is born with DS. ² The clinical phenotype seen in DS includes flat facies, upslanting palpebral fissures, epicanthic folds, brachycephaly with a flat occiput, hypotonia, short stature and a short neck, flat nasal bridge, single palmar crease, protruding tongue, sandal gap, clinodactyly, brachydactyly, microcephaly, small ears, open mouth, and squint and umbilical hernia. ³ Postnatal diagnosis can be made by karyotyping or sometimes by fluorescent in-situ hybridization. A thorough knowledge of the associated problems and issues helps in better management of DS patients. The management of DS include holistic approach with nutritional rehabilitation, physiotherapy, speech therapy, and occupational therapy as well as treatment of associated complications like cardiac disease, hypothyroidism, celiac disease, and infections. ⁵ In present article, we describe the comorbidities observed in patients with DS presenting to a tertiary care center in a developing country.

Materials and Methods

This is a retrospective observational analysis performed on DS patients diagnosed, evaluated, managed, and followed up in genetic and metabolic unit of a tertiary care center. The center caters to at least six northern territories in India namely Punjab, Haryana, Himachal Pradesh, Chandigarh, Uttar Pradesh, and Jammu and Kashmir. The analysis was performed on 208 DS patients admitted between January 2018 and September 2020 after taking clearance from the Departmental Review Board (DRB, no. 02–21). Informed consent was taken from legal guardians of the patients, mostly parents.

The demographic details name, age, sex, and dysmorphic features were noted on a predesigned data collection form. The clinical presentation, complaints at admission and complications in form of failure to thrive, cardiac, endocrinological, gastrointestinal complications, hearing, and speech and vision abnormalities were recorded for each case.

Head circumference, weight, and height were evaluated and recorded. This anthropometric data were used to assess the nutritional values of the children and was expressed in Z-score terms.

Results

Out of a total of 208 patients, 134 were males (64.4%) and 74 females (35.5%; Fig. 1 ). Most of the DS patients were in the 0 to 5 years of age group (i.e., 179, including males and females). Average maternal age was 29 years in the cohort. Analysis of head circumference, weight, and height was performed for the children. In relation to weight and height, 114 children (58.8%) presented with low weight and 48 children (23.07%) with low height while 74 cases (35.57%) with microcephalic. All cases included in the study were diagnosed postnatally. Hypotonia was found to be the common clinical feature with cases 137 (65.86%) followed by other features as summed in Table 1 . Karyotyping was performed in all cases and trisomy 21 was found in 203 cases (97.6%), while translocation and mosaic were identified in five (2.4%) cases. In associated complications, cardiac defects were found in 62% of cases, hypothyroidism in 30.28%, central nervous system (CNS) problems in form of developmental delay in 31%, and seizures in 2.4%. Additionally, we report two cases with Moya-Moya disease and 1 case with atlanto-axial dislocation ( Table 1 ). Among the cardiac complications, atrial septal defects were found to be the most common with the associated heart conditions are summarized in Fig. 2 .

Fig. 1.

Age distribution of the patients of Down syndrome in present study (total n  = 208, male = 134, female = 74).

Table 1. Clinical features and complications in children with Down syndrome in present study ( n  = 208) .

Clinical manifestations	n	%	Clinical manifestations	n	%
Hypotonia	137	65.9	Failure to thrive	114	54.8
Poor feeding	7	3.36	Stunting	48	23
Constipation	35	16.8	Global developmental delay	66	31.7
Clinodactyly	34	16.3	Cardiac	128	61.5
Microcephaly	74	35.57	Celiac disease	3	1.44
Brachycephaly	22	10.57	Gastrointestinal anomalies (Hirschsprung/malrotation/ duodenal atresia)	6	2.9
Brachydactyly	18	8.65	Pneumonia	37	17.78
Umbilical hernia	6	2.9	Atlantoaxial dislocation	1	0.5
Thrombocytopenia	8	3.84	Vision abnormalities	4	1.9
Meningitis	6	2.9	Hearing abnormalities	2	0.96
Hypothyroidism	63	30.3	Seizures	5	2.4
Hydronephrosis	1	0.5	Celiac disease	3	1.44
Neonatal cholestasis	29	13.9	Moya-Moya	2	0.96

Fig. 2.

The spectrum of cardiac anomalies in 145 children with Down syndrome.

We present here four illustrative cases admitted in the genetic ward of the center:

• Case 1: A 1-month-old male born at term was admitted to our ward with complaints of respiratory distress since birth. His birth weight was 2.8 kg. On examination, the child had systolic murmur, suspicion of heart disease with cardiac failure, and pneumonia. His respiratory rate was 72/min and he had features of DS including the typical eyes and low set ears. His Hb was 17 g/dL and white blood cell was 15,170/mm ³ . The renal function tests revealed blood urea (13 mg/dL) and normal serum creatinine. On day 3 of ward stay, the child developed worsening tachypnea, with chest X- ray revealing bilateral infiltrates. Echocardiography (ECHO) revealed complete AV canal defect (AVCD), large VSD with OS ASD, right-sided AV valve regurgitation, and a tiny PDA. Ultrasonography (USG) of cranium-cerebral hemispheres were normal. USG KUB showed mild prominence of left renal pelvis with anteroposterior diameter (APD) of 6 mm. There was also minimal splitting of bilateral pelvicalyceal system, and on follow-up USG, the right APD was 2.5 mm and the left APD was 3.4 mm.

• Case 2: An 18-month-old female child born to a nonconsanguineous couple, with developmental delay presented with sudden onset of nonprogressive weakness of the left upper and lower limb with facial deviation toward the right side since 4 days. Her birth weight was 1.5 kg. On examination, the child had wide open anterior fontanelle, facial features including the slanting eyes, saddle toes, protruded tongue, simian crease, and left facial nerve upper motor neuron palsy. In addition, she had hypotonia, and decreased power in left upper and lower limbs. Head circumference was 41.4 cm, consistent with microcephaly. The possibility of DS phenotype with acute ischemic stroke, possibly Moya-Moya disease versus embolic stroke was considered.

On routine investigations, Hb was 7.8 g/dL, WBC of 9530/mm ³ , and normal renal function tests. The child had one episode of generalized tonic-clonic seizures on day 2 of her hospital stay which lasted for <1 minute. Magnetic resonance imaging (MRI) of the brain showed multiple patchy subacute infarcts in bilateral parietal lobes (R > L) in deep watershed zone and right gangliocapsular region. Gyral altered signal intensity in right frontotemporal lobe and insula was observed, which as due to ischemia. MR angiography was suggestive of Moya-Moya pattern. Physiotherapy was initiated. There was gradual improvement in power of both upper and lower limb. Other causes for the stroke were evaluated. ECHO showed structurally normal heart with normal biventricular function. The antinuclear antibody, C3/C4, lipid profile, and coagulation tests were normal, except for elevated triglycerides. Ophthalmological evaluation was normal. Hearing assessment could not be done due to presence of ear wax. At discharge, power of both upper and lower left limbs was three-fifths.

• Case 3: A 3-year-old female child admitted to our ward with chief complaints of fall on ground 3 days back while playing. She had paucity of movements in the left upper and lower limb for 2 days, and was not able to sit or stand for 2 days. She was third born to a nonconsanguineous couple with birth weight of 3 kg. On examination, respiratory rate was 26/min and the child had microcephaly with head circumference of 37 cm (−6.65z) and also had inward-downward slant of the eyes, prominent epicanthal fold, depressed nasal bridge, sandal gap, brachycephaly, flat occiput, short neck, open mouth, and decreased tone in all four limbs. On routine, investigations Hb was 13.3 g/dL, and WBC was 6,600/mm ³ ; renal function tests showed blood urea/serum creatinine of 16/0.29 units. Thyroid function tests and transglutaminase antibody were normal. An initial possibility of atlanto-axial dislocation was kept. At the time of admission, the child was neurologically stable with improving left hemiparesis. X-ray of craniovertebral junction (CVJ) and computed tomography scan of the head were grossly normal. MRI brain with spine shows atlanto-axial subluxation with fracture or unfused odontoid process, displacement with associated ligamentous injury with spinal canal stenosis. Repeat X-ray of CVJ lateral view showed persistence of atlanto-axial subluxation with fracture odontoid process with displacement, and she was referred to surgical management.

• Case 4: A 7-month-old male child presented with fever and cough for 5 days. The child was put on oxygen therapy, IV antibiotics, and furosemide. After 5 days, the oxygen requirement decreased, and antibiotics were also stopped. He had undergone PDA ligation earlier and he had the typical facial features of DS; his hands showed brachydactyly, short second phalanges of digits, and extra creases over the thumb. Karyotype done showed 48, XXY, + 21 ( Fig. 3 ).

Fig. 3.

The karyotype in child with double aneuploidy showing three copies of chromosome 21 and extra copy of X chromosome.

Discussion

Three types of chromosomal aberrations may result in DS. These include full chromosome 21 trisomy (free trisomy), Robertsonian translocation, and mosaicism. In case of free trisomy which is present in majority (>97%) of DS cases is due to improper segregation of chromosomes during meiosis, and advanced maternal age is an important risk factor. In our study, most mothers were below 35 years of age at birth of their DS child. Several studies observed advanced maternal age as an increased risk factor. In a study conducted in Brazil >90% cases were of free trisomy. We found 98% cases with free trisomy 21. According to a study from Mumbai, 83.87% cases were detected with free trisomy.

During the 2 years of the study period, 208 DS cases in which more than one major structural anomalies were evaluated and documented. In present study, we have observed a higher percentage of associated anomalies. Therefore, patients with DS need to be evaluated carefully for all possible associated major congenital anomalies. The most common findings of this study in patients with DS is hypotonia found in 137 cases (65.9%), poor weight gain/failure to thrive in 114 cases (54.8%), and microcephaly in 74 cases (35.57%).

DS children have higher risk of cardiac defect, Hirschsprung disease, and duodenal atresia. ^{5 6} The incidences of cardiac abnormalities in DS patients is approximately 60%, according to a study in Brazil and 56.5% of DS children were presented with cardiac abnormalities in another. Many studies to assess the anomalies associated with DS have reported varied results. In previous studies, the anomalies which are most common in DS cases were congenital heart defect (CHD), the percentage varied from 44.6, 26, and 56.5%. ^{7 8 9} In the present study, a high proportion (62%) of DS children presented with cardiac anomalies. This is because our center is a tertiary care facility, and hence, more severe cases are referred for evaluation and management. Among the cases with cardiac anomalies, the most common defects observed were ASD (30%), followed by PDA (23%), VSD in 20% AVCD in 10%, TOF in 4%, and pericardial effusion and other cyanotic heart disease accounted for 3 and 2%, respectively. The high incidence of cardiac disease is not unique finding of our study. High incidence of ASD as the most common CHD was also found in a Korean study by Kim et al. In the study done on 394 DS infants, they found 56.9% had a CHD. ¹⁰ ASD was the most common defect accounting for 30.5% of DS followed by ventricular septal defect (19.3%), patent duct arteriosus (17.5%), and atrioventricular septal defect (9.4%). In a recent study from Egypt, the authors reported heart defects in 36.9% of DS patients. ¹¹ In the Egyptian study, however, VSD was the commonest of the cardiac defects, seen in around 17%; either isolated or with additional cardiac anomalies like PDA or ASD.

DS patients are found to have additional anomalies or problems which can lead to morbidity and mortality. ^{12 13 14 15} Earlier studies from India have showed that methylene tetrahydrofolate reductase (MTHFR) hypermethylation and CRELD1 gene mutations may contribute to cardiac defects and AVCD respectively in DS patients. ^{12 13} The primary caregivers of DS children can have social and psychological issues, which should also be considered and attended to while managing DS children. ¹⁶

Additional clinical findings in the DS cases in the present study included 31% with developmental delay, 30% with hypothyroidism, 23% with stunting, and 16.8% with constipation. Anthropometric indices in the present study revealed significant proportion of cases with low weight (58.8%) and low height (23.07%) while 74 cases (35.57%) had microcephaly. According to a study in Brazil, low weight was noted in 12.3% cases and low height in 16.4% cases. ⁹ Pneumonia/upper respiratory tract infections were seen in 77.4% in a Brazilian study, while in present study 37 cases (7.78%) children presented with pneumonia. Recurrent respiratory problems including pneumonia are more prevalent in DS patients due to underlying cardiac defect, additional feeding problems due to hypotonia, and gastrointestinal reflux disease. Interestingly, we found neonatal cholestasis in 13.9% (29/208) cases. In a previous report compiling the published literature had found neonatal cholestasis in 3.9% of cases. ¹⁷ The other problems affecting liver function include nonalcoholic liver disease, autoimmune hepatitis, and biliary lithiasis.

Earlier Moya-Moya disease has been reported from our center in DS cases. ¹⁸ The case 2 described here also had Moya-Moya disease. Some disorders with increased prevalence of this problem leading to stroke include DS and microcephalic osteodysplastic primordial dwarfism. Other reasons for predisposition to stroke on DS include cardiac defect, hypothyroidism, and hypercholesterolemia. Earlier five cases have been reported with DS and in addition Graves' disease and Moya–Moya disease, with mean of 15.6 years age. ¹⁹

One of the patients with DS in present study also had another chromosomal abnormality revealed by karyotyping. He had double aneuploidy, DS and Klinefelter syndrome, which is quite rare. Previously, a child with this form of double aneuploidy has been described from Brazil, who had AVCD and hydrocele, and died at 11 months of age. ²⁰

Around 50% of patients will develop thyroid disease by adulthood which includes hypothyroidism and hyperthyroidism. Hypothyroidism is common in infants with congenital hypothyroidism, unrelated to autoimmune disease. ²¹ Those with higher TSH levels and low T4 may be worked up for autoimmune cause of hypothyroidism. Management involves levothyroxine in these cases with periodic monitoring.

Since significant proportion of patients in the present study showed failure to thrive or stunting, the management has to be focused on better nutritional support for DS patients, especially in developing countries. Also, appropriate periodic monitoring, and symptomatic treatment for the additional complications especially cardiac defect; that are more likely to occur in children with DS can improve ultimate outcomes and survival in DS.