Nabais Sa-de Vries syndrome (NSDVS) is a rare autosomal dominant disease first time reported in 2020 [1]. The syndrome is caused by heterozygous de novo missense mutations in speckle-type pox virus and zinc finger protein (
Protein homeostasis plays an important function in intracellular biological mechanism. The ubiquitin-protea-some pathway (UPP) works in intracellular protein homeostasis by regulating the breakdown of many proteins. The speckle-type BTB/POZ protein, encoded by the
The
In this study, we report a 4-year-old girl who presents with microcephaly, a wide and thick arched eyebrow, a prominent and wide nasal bridge, a wide and bulbous nasal tip, micrognathia, and pointed chin. She also had microcytic hypochromic anemia without organomegaly. Genetic study was offered, which confirmed the presence of both
The concurrence of the above two genetic mutations and resistant iron deficiency anemia has not been reported previously thus further studies are needed to better understand the mechanisms of the associated clinical manifestations and disease course involved.
Written informed consent was obtained from the parents for the publication of the photographs and clinical information presented in this report.
Our patient, now a 4-year-old girl, was the second live child born at term to nonconsanguineous parents, a 36-year-old father, and a 34-year-old mother with an unremarkable gestational course. The mother had a history of two prior miscarriages due to unknown reasons. None of the family members have NSDVS or other syndromes. Father was diagnosed as beta-thalassemia minor while mother and siblings do not have any hematological dis-eases. Birth weight, length, and head circumference were 2.8 kg (25th percentile), 48.2 cm (25th percentile), and 33 cm (10th percentile) respectively. Perinatal events were significant for hospitalization after birth for 3 days for respiratory issues as well as neonatal jaundice requiring phototherapy then discharged home in stable condition.
On examination, she had microcephaly, a long face, a wide and thick arched eyebrow, widely spaced eyes, a prominent and wide nasal bridge, a wide and bulbous nasal tip, large size ears, and prominent antitragus, micrognathia, and a pointed chin (Fig. 1). Her current growth parameter was, weight 16 kg (50th percentile), height 109 cm (90th percentile), and head circumference 46 cm (<3rd percentile). Abdominal examination was unremark-able including no hepatosplenomegaly. Her neurological assessment identified a hyperactive child with poor interaction and understanding, and speech delay.
At 2 months of age, she developed two seizure-like episodes, however, her neuroimaging and electroencephalogram testing were normal. Her CBC (complete blood count) showed low Hb level (Hb 8.9 g/dL), MCV (69.6 fL), MCH (21.7 pg) and RBC (4.11×106/mL), and high RDW (17.2%) and Mentzer index (16.9) with a corrected reticulocyte count of 3.7%. However, her platelet counts white blood cell, and differential count were normal. Peripheral blood smear findings confirmed the hypochromic microcytic anemia. She was investigated for iron deficiency anemia and initial results showed normal iron stores (iron 8.7 mmol/L, TIBC 42 mmol/L, transferrin saturation 20.7%). Hemoglobin electrophoresis was also done, and beta thalassemia trait was suspected (HB-A 74.5%, HB-F 21.3%, HB-A2 4.2%), however, repeated hemoglobin electrophoresis was advised because of age. Chest x-ray was unremarkable and echocardiography has revealed normal anatomy, size, and good contractility.
At the age of 12 months, laboratory findings showed persistence of hypochromic microcytic anemia (CBC: Hb 8.4 g/dL, MCV 48.1 fL, MCH 15.7 pg, RBC 5.37×106/mL, RDW 23.2% and Mentzer index 9) with normal serum iron (11.2 mmol/L), slightly elevated TIBC (TIBC 86 mmol/L) and low transferrin saturation (13%). At 18 months of age her laboratory showed worsening of anemia (Hb 7.7 g/dL), although her MCV (48.6 fL), MCH (15.8 pg), and RDW (25.4%) remained stable. However, her repeated iron study was suggestive of iron depletion (serum iron 4.4 mmol/L). Peripheral blood smear (Fig. 2A) showed a picture of hypochromic microcytic anemia. Repeated hemoglobin electrophoresis at that time was again suggestive of beta thalassemia trait (HB-A 94.6%, HB-F 1.6%, HB-A2 3.8%).
Whole exome sequencing (WES) was requested and identified the heterozygous variant c.977A>G p. (Asn326Ser) in
Table 1 . Summary of genetic information.
Gene (isoform) | Phenotype/MIM number | Mode of inheritance | Variant | Zygosity | Classification |
---|---|---|---|---|---|
Nabais Sa-de Vries syndrome 618828 618829 | Autosomal dominant | c.977A>G p. (Asn326Ser) chr17:47679230 | Heterozygous | Variant of uncertain significance | |
β-Thalassemia 613985 | Autosomal recessive | c.93-22_59del p.? | Heterozygous | Pathogenic | |
α-Thalassemia | Autosomal recessive | Common deletion (−α3.7/αα) | Heterozygous | Pathogenic |
MIM, Mendelian Inheritance in Man;
At the age of 24 months, CBC showed (Hb 6.4 g/dL, MCV 35.4 fL, MCH 13.7 pg, RBC 5.16×106/mL, RDW 29.6% and Mentzer index 10) with low serum iron and low trans-ferrin saturation (TS) and normal TIBC (iron 2.3 mmol/L, TS 3.5%, TIBC 65 mmol/L). Bone marrow biopsy showed erythroid hyperplasia (Fig. 2B and 2C) and absent iron storage (Fig. 2D). During this period, she received blood transfusions multiple times (Fig. 3), mostly every 1-2 months. Oral iron therapy was initiated but without improvement despite of full dose of ferrous sulphate (6 mg/kg/day) and compliance. Work up for resistant iron deficiency anemia was also initiated, showed no gastrointestinal bleeding or other indefinable causes.
Due to persistent hypochromic microcytic anemia requiring blood transfusion and poor response to oral iron supplement despite of full dose and compliance a trail of parenteral iron (Ferric carboxymaltose 20 mg/kg/dose, weekly, for 4 doses) was initiated with significant improvement in hemoglobin and MCV and drop in RDW as showed in the Fig. 3. Her serial CBC and iron profile results have been summarized in the Fig. 3 and 4.
Our case describes an undiscovered concordance of Nabais Sa-de Vries syndrome and beta thalassemia with refractory microcytic hypochromic anemia as our patient has concurrent
Nabais Sa-de Vries syndrome (NSDVS) is a neurodevelopmental disorder first time described in 2020 [1]. The de novo missense mutations in speckle-type pox virus and zinc finger protein (
The literature review does not report any specific hem-atological association including hemoglobinopathy and refractory iron deficiency anemia in NSDVS1. However, our patient presented with microcytic hypochromic anemia, unresponsive to oral iron supplements while showed significant improvement in hemoglobin level with parenteral iron therapy. Her gastroenterology assessment was also negative for any identifiable cause of her oral iron supplement refractoriness. Her genetic study detected the presence of mutations in the hemoglobin genes including both the α-globin and β-globin genes.
In summary, this report describes an undiscovered concordance of Nabais Sa-de Vries syndrome and thalassemia as our patient has concurrent
The authors have no conflict of interest to declare.