|Year : 2016 | Volume
| Issue : 2 | Page : 115-118
Severe neonatal thrombocytopenia in a case of Cornelia de Lange syndrome
Priyanka Gupta, Sandeep Kumar, Suman Arora, Veena Devgan
Department of Paediatrics, North Delhi Municipal Corporation Medical College and Hindu Rao Hospital, Malka Ganj, Delhi, India
|Date of Web Publication||8-Apr-2016|
WZ-D/14-15, Dayal Sir Road, Uttam Nagar West, New Delhi - 110 059
Source of Support: None, Conflict of Interest: None
Patients of Cornelia de Lange syndrome (CdLS) may be more susceptible for the development of immune thrombocytopenia than the general population, for which many hypotheses have been generated. However, till date, only a few cases of thrombocytopenia in CdLS have been described; only four reports being from neonates. Here, we describe a case of severe, symptomatic and idiopathic neonatal thrombocytopenia in CdLS from India, which remitted spontaneously without any serious sequel. Diagnostic clinical criteria of CdLS are also discussed.
Keywords: Brachmann de Lange syndrome, Cornelia de Lange syndrome, neonate, thrombocytopenia
|How to cite this article:|
Gupta P, Kumar S, Arora S, Devgan V. Severe neonatal thrombocytopenia in a case of Cornelia de Lange syndrome. J Clin Neonatol 2016;5:115-8
|How to cite this URL:|
Gupta P, Kumar S, Arora S, Devgan V. Severe neonatal thrombocytopenia in a case of Cornelia de Lange syndrome. J Clin Neonatol [serial online] 2016 [cited 2021 Apr 12];5:115-8. Available from: https://www.jcnonweb.com/text.asp?2016/5/2/115/179922
| Introduction|| |
Cornelia de Lange syndrome (CdLS), also called Brachmann de Lange syndrome is a multisystem developmental disorder characterized by a combination of facial dysmorphism, hirsutism, pre- and post-natal growth restriction, limb anomalies, psychomotor delay, behavioral problems and many visceral anomalies. Published estimates for prevalence range from 1:100,000 to as high as 1:10,000. ,
Genetic testing is not mandatory to make a diagnosis of CdLS , and a number of clinical criteria taken together can help in diagnosis, as suggested by CdLS foundation and Scientific Advisory Committee of the World CdLS Federation.  Present case met the facial criteria as well as two major (out of three) and all the three minor criteria.  The important differential diagnoses of CdLS are Fryns syndrome, fetal alcohol syndrome and Coffin-Siris syndrome,  but usually there is no confusion if the clinical criteria are carefully applied.
| Case Report|| |
A dysmorphic baby girl was born vaginally to a 20-year-old primigravid mother at 39 completed weeks of gestation. The antenatal period was uneventful. There was no documented record of fetal anomaly scan. Facies of both the parents were normal, and there was no history of consanguinity, neither any family history of unexplained abortions/stillbirths or dysmorphic births. There was no antenatal risk factor for neonatal sepsis. Amniotic fluid was meconium stained and the baby was born non-vigorous, requiring endotracheal suction followed by positive pressure ventilation for 1 min. Apgar scores at 1, 2, and 5 min of life were 6, 7, and 9 and the cord blood gases and pH were normal. The baby was shifted to Neonatal Intensive Care Unit soon after birth in view of mild respiratory distress (downe's score 3), severe intrauterine growth restriction, dysmorphism and multiple congenital anomalies. Birth weight, length, and head circumference were 1900 g, 44 cm and 30 cm, respectively, all growth parameters being <3 rd percentile when plotted on intrauterine growth charts for healthy newborns.  In view of low birth weight with respiratory distress, empirical IV antibiotics (cefotaxime and amikacin) were started along with supportive care. Complete blood counts, blood sugar, electrolytes, sepsis screen (repeated twice), blood culture and chest X-ray done on day-1 were normal. The platelet count on day-1 was 255 × 10 9 /L. Respiratory distress settled within 8 h of life and, therefore, the antibiotics were stopped after confirming two negative sepsis screens. Enteral feeds were gradually built up with expressed breast milk. On day-4, the baby otherwise well, developed petechiae over her abdomen with platelet counts 22 × 10 9 /L for which a platelets transfusion was given. There was no evidence of any internal bleeding, hepatosplenomegaly or chorioretinitis. Sepsis screen and blood culture were again negative, and the maternal platelet counts were also normal. On day-5, platelet counts spontaneously started rising to 70 × 10 9 /L, becoming 102 × 10 9 /L by day-7 and 180 × 10 9 /L by day-8 of life.
Regarding the syndromic diagnosis of this baby, many features of CdLS were evident from birth itself. These were prenatal growth restriction, microcephaly, arched and confluent eyebrows meeting in the midline, well-defined long eyelashes, short nose, broad and depressed nasal bridge, anteverted nostrils, long and smooth philtrum, thin vermilion border of upper lip, downturned angles of mouth, cleft palate, small chin, low-set protracted and hirsute ears, low anterior and posterior hairline, short neck [Figure 1], bilateral single palmar crease, bilateral small hands, bilateral fifth finger clinodactyly, bilateral hypoplastic first metacarpal [Figure 2] and proximally placed thumb, limited extension up to 120° at both elbows, bilateral webbing of second and third toes, excessive body hair, and small asymptomatic 3.8 mm sized atrial septal defect. Hearing loss was also suspected in view of absence of startle response. Ocular, fundus, and external ear findings were normal. An ultrasound ruled out abdominal and renal anomalies. The phenotype-genotype correlation could not be done; also all the desired criteria  for making a diagnosis of CdLS were not met. Therefore the diagnosis of CdLS was kept provisional at birth.
|Figure 1: Typical facial features of Cornelia de Lange syndrome at birth|
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The baby was discharged on advice about routine care, paladai feeding with expressed breast milk, early stimulation techniques, and physiotherapy. A follow-up schedule for this baby was made with plans to rule out gastroesophageal reflux and detailed hearing evaluation.
The baby got lost to follow-up due to migration in another state after which she was brought again at 6 months of age with concerns of not gaining weight well and developmental delay. She had been fed with formula milk since birth. Her weight and length were 3.6 kg and 53.8 cm, respectively, both of which were <3 rd percentile for her age when plotted on the WHO Multicentre Growth Reference Study growth standards.  She had microcephaly; head circumference being 35.2 cm, < −3SD below the median for age.  Mid-upper arm circumference was only 9.8 cm. Even by now, she had no recognition for mother, no social smile, spoke only "Ooo/aah," did not laugh or squeal, did not turn to voice, and could not grasp a rattle. Her head was steady, but she could not bear weight on her legs; nor had she learnt to roll over. Thus, the baby had both growth and development delay, fulfilling the facial criteria along with two major criteria for confirming a diagnosis of CdLS.  Brainstem evoked response audiometry showed a profound sensorineural loss and the High resolution computed tomography of temporal bone found a fusion of dyplastic malleus and incus on both sides [Figure 3]a and b. Echocardiography found spontaneous closure of the atrial septal defect. Gastric scintiscan and upper gastrointestinal contrast imaging revealed gastroesophageal reflex for which oral domperidone and lansoprazole was started. Complete blood counts were re-checked and found to be normal.
|Figure 3: (a and b) Fusion of dysplastic malleus and incus with loss of normal configuration and normal articulations (on both sides)|
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Since both parents had normal facial features, 3-5% recurrence risk in next pregnancy was explained, due to a possibility of germline mosaicism.  Multidisciplinary care was planned in the form of psychological support, parent education, nutritional care, physiotherapy and occupational therapy; and specialist references for auditory rehabilitation, cleft palate, and gastro-esophageal reflux.
| Discussion|| |
There are reports suggesting an increased predisposition for thrombocytopenia and immune thrombocytopenic purpura (ITP) in CdLS.  This becomes much more relevant due to a higher frequency of self-injurious behavior in CdLS.  Still, thrombocytopenia has rarely been reported in CdLS, especially neonates. ,,
The association of thrombocytopenia and CdLS was first reported by Froster and Gortner in 1993.  Subsequently, two other examples were reported.  Lambert et al. retrospectively reviewed a large heterogenous cohort of 1740 clinically diagnosed CdLS patients and came across 15 patients who had at least one episode of moderate to severe thrombocytopenia (platelet count <1 lakh/mm 3 ). Four patients had severe thrombocytopenia <10,000/mm 3 in the setting of severe viral infection, showing spontaneous improvement without bleeding sequelae. Seven patients had ITP (6 chronic ITP cases lasting >1 year and one case of secondary ITP in the setting of systemic lupus erythematosis). This 7/1740 prevalence of ITP in the cohort was striking than the reported prevalence of pediatric ITP in the general population between 5 and 13/100,000 children/year.  The relative risk of ITP in subjects with CdLS was estimated to be 30.95 (CI: 12.36-77.49) even with a conservative estimate of the prevalence of ITP in the general population of 13 per 100,000 children. They also reported four neonates who had transient thrombocytopenia.
The mechanism of thrombocytopenia in CdLS is still unclear. Inheritance of CdLS may be autosomal dominant (NIPBL, SMC3 or RAD21 gene; chromosome 5, 10 and 8, respectively) or X linked dominant (SMC1A or HDAC8 gene), leading to dysfunction of the cohesin complex. ,, There may be three possible mechanisms for thrombocytopenia in CdLS. Several genetic disorders with immune dysregulation (like 22q deletion and primary immunodeficiency) have been associated with ITP. Thus, the gene dysregulation resulting in dysfunction of cohesin complex may alter gene expression in both B and T cells lineages causing immune thrombocytopenia. Several disorders (such as Fanconi anemia, some subtypes of VACTERL associations, thrombocytopenia with absent radii, and amegakaryocytic thrombocytopenia with radioulnar synostosis) that have been linked to DNA damage repair can present with both skeletal limb anomalies and thrombocytopenia. Members of the cohesin complex have also been shown to play multiple roles in DNA damage repair. Based on these observations, another hypothesis can be generated that one of the underlying mechanism for thrombocytopenia in CdLS is altered DNA repair. Cohesin and its regulatory proteins regulate sister chromatid cohesion, and the megakaryocytes that do not reach sufficient ploidy are markedly less efficient at platelet production, which may be the third possible mechanism of thrombocytopenia in CdLS. 
The present case re-emphasizes the rare but potentially fatal occurrence of neonatal thrombocytopenia in CdLS. Thrombocytopenia (defined as platelet count <150 × 10 9 /L) is very common in neonatal care units, reported in up to 35% admissions and up to 50% of those under intensive care; around 20% of these episodes being severe (i.e., platelet count <50 × 10 9 /L). , If the thrombocytopenia is severe (<50 × 10 9 /L), immune-mediated thrombocytopenia, infections, and genetic disorders should always be considered.  This observation of thrombocytopenia in a baby with complex medical issues might be thought of uncertain significance. However, due to the severity of thrombocytopenia (requiring platelet transfusion) and its correlation with baby's medical condition, the possibility of some underlying predisposition strongly exists. Based on these rare reports but a measured susceptibility for thrombocytopenia, we re-emphasize the recommendations for screening for thrombocytopenia at the time of diagnosis, as well as at five-yearly-intervals thereafter. 
Declaration of Patient Consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3]