These cases were assessed clinically, when Dr Shruti Bajaj was attached as a Faculty Member as an Asst Professor, in the Dept of Pediatrics, at King Edward Memorial Hospital, Mumbai. With the inputs and analysis from the other contributing authors, the details of the cases were subsequently published by the team in a leading journal- Journal of Postgraduate Medicine (uploaded the pdf version of the articles). A brief summary (abstract) of these cases (part of the publication), are presented herewith for the reader’s interest.
(Dr Shruti Bajaj: maiden name: Dr Shruti Agarwal)
An 18-month-old female child presented to us with clinical features suggestive of nephrotic syndrome. Her physical examination and detailed family history highlighted the familial occurrence of abnormal nails, suggesting a diagnosis of the Nail-Patella syndrome. Nail-Patella syndrome is a rare cause of nephrotic syndrome in children. This case highlights the importance of a detailed history, including pedigree and a thorough examination of the patient.
Our patient presented with congenital heart disease (Tetralogy of Fallot), hypocalcemia, hypoparathyroidism, and facial dysmorphisms. Suspecting DiGeorge syndrome (DGS), a fluorescence in situ hybridization (FISH) analysis for 22q11.2 deletion was made. The child had a hemizygous deletion in the 22q11.2 region, diagnostic of DGS. Unfortunately, the patient succumbed to the heart disease. DGS is the most common microdeletion syndrome, and probably underrecognized due to the varied manifestations. This case stresses the importance of a detailed physical examination and a high index of suspicion for diagnosing this genetic condition. Timely diagnosis can help manage and monitor these patients better and also offer prenatal diagnosis in the next pregnancy. .
(This child was initially seen at King Edward Memorial Hospital, Mumbai. The diagnosis was established while Dr Bajaj was attached to the Genetic Clinic KEMH, Mumbai as an Asst Professor )
A 4.5 year old female child, the only issue of her parents, was referred by an orthopedician in Ahmedabad, Gujarat. The child had approached the orthopedician for recurrent shoulder joint dislocations and buckling of the knee joints while running. Detailed history revealed that the child had looseness of the body since birth and delayed motor milestones. Detailed neurological work-up elsewhere considered the differential of a congenital muscle disorder. Clinical examination showed she had normal growth parameters, with joint and skin laxity and other tell-tale signs suspicious of a connective tissue disorder (rather than a primary muscle disease).
Advanced genetic test i.e. next generation sequencing (clinical exome), revealed that the child had a rare genetic condition, Ehler Danlos type 6. The couple was explained that this is a genetic disorder and that their next child has a 25% risk of having the same disease. The parents were explained the importance of regular follow up of the child for monitoring of known complications and for prenatal diagnosis in the next pregnancy. Proving the diagnosis not just ended a long diagnostic journey of the family; but also avoided the unnecessary muscle biopsy in the child.
The couple followed up some years later when the wife was pregnant again. Successful prenatal counseling was offered to the couple. The fetal cells of the next baby were checked for the same causative mutation (genetic error), seen in the case of the first child (having Ehler Danlos type 6). The expected baby in the womb did not have the causative mutation; assuring the couple that their second baby will not have the given genetic condition. The first child is under close follow-up for known cardiac and ophthalmological complications of Ehler Danlos Syndrome type 6. With active surveillance, we hope to nip any clinical problem in the bud and improve the quality of life of the child.
A four day old male newborn was referred from a tertiary care NICU centre in Mumbai. The baby was born to a young couple who were related to each other by blood (first cousins). The child was born through normal vaginal delivery and weighed 3 kilograms at birth. After an initial uneventful period of two days, the baby suddenly had decreased feeding on the third day of life. This was followed by seizures and altered sensorium. He was comatose and unresponsive since the fourth day of life; necessitating mechanical ventilation and high-level intensive unit care. Inspite of the best medical care, the child succumbed on the fifth day. There was a significant family history. This couple had lost two previous children in an eerily similar fashion. Sensing that there could be a genetic basis to the given recurring disease, the physician had sought timely genetic opinion in this last baby’s case. A detailed and accurate pedigree analysis was outlined. An inborn error of metabolism was suspected. Also, special genetic tests were routed in time, not losing the precious window of opportunity to test the child.
The initial biochemical tests also pointed towards an inborn error of metabolism; proximal urea cycle defect or a mitochondriopathy. However, a biochemical diagnosis is not sufficient to prevent recurrence of the disease in the next child. For prevention of recurrence, one needs to know the error ‘at the level of the gene’ (i.e the mutation).
The child’s DNA was analysed after its death, by highly sophisticated technology, next-generation sequencing. This picked up the causative DNA error (mutation) which had resulted in three newborn deaths in the family. The mystery was unveiled; the cause was a genetic disease, a urea cycle defect. This disorder occurs, when each parent has one healthy copy of a gene and the other copy is a disease-causing one. When present in a single dose, the genetic error is insufficient to cause the disease, thus the parents remain asymptomatic throughout life. However, if the child inherits a disease-causing copy each from both the parents (homozygozity), it leaves no normal gene at the given position in the child. This precipitates the disease in such a child. However, by permutation and combination it is likely that the child may inherit both the healthy copies form both the parents or just one disease-causing gene, and the other one being healthy. In the latter two scenarios the child will remain asymptomatic. Having clinched the diagnosis at the level of the gene, it was possible to inform the couple an accurate risk of recurrence of the same disease in every subsequent pregnancy (25%).
With the genetic error outlined in this family, the couple was informed, that in the next pregnancy, they can select the embryos which do not have the given genetic mutation (preimplantation genetic diagnosis) and ensure the birth of an unaffected child. However, since this technology is relatively expensive, the couple was also counselled about the other option of prenatal diagnosis. In this method, when the mother is around 11-13 weeks pregnant, a small quantity of the fetal DNA is procured through a safe procedure (chorion villous biopsy). This fetal DNA can be checked for the disease-causing mutation in double dose (homozygozity). If present it predicts the same outcome as the previous pregnancies, in this baby too once it is born. In such a case, the parents can opt to discontinue the pregnancy medically and legally, before 20 weeks of pregnancy. On the other hand, if the baby inside is normal or carries just one copy of the disease-causing mutation, then the parents can continue with the pregnancy without stress and anxiety.