Achondrogenesis is a group of rare and fatal disorders occurring in approximately one in every 40,000-60,000 newborns [1]. It is clinically characterized by short-limbed dwarfism and the affected patients are often lost in
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A 25-year-old pregnant Syrian woman was referred to the perinatology clinic for further screening due to a suspected skeletal anomaly at 27 weeks' gestation. The previous obstetric history was uneventful and the couple was non consanguineous. The first trimester screening was negative, while a detailed sonography scan revealed short long bones (<1st percentile for all long bones, including femur, tibia, fibula, humerus, radius and ulna) with a small thorax and polihydroamnios. The family was provided genetic counseling related to the high suspicion of lethal skeletal dysplasia. After detailed counseling, a cordocentesis was performed. All sonographic findings suggested skeletal dysplasia; a conventional chromosomal analysis confirmed a normal 46,XY karyotype, while an exome sequencing analysis revealed ACG2. After a 10-week follow-up period, a cesarean delivery was carried out at 39 weeks' gestation due to a previous history of cesarean section.
The patient had a 1 and 5 min. APGAR score of 4 and 5 at birth, respectively. The patient was intubated after delivery due to a lack of spontaneous respiration and was admitted to the Level III Neonatal Intensive Care Unit (NICU), Bursa, Turkey. The birth weight was 2780 gr (3-10 percentile), height was 38 cm (below 3 percentile), and head circumference was 37 cm (90-97 percentile). A physical examination revealed extremely short extremities, abdominal distention, a small chest, a prominent forehead and a flat nasal bridge (Figure 1). Ophthalmological examination of the patient was normal. The patient had severe respiratory distress, and follow-up was continued with high frequency oscillation ventilation (HFOV), as conventional mechanical ventilator settings failed to achieve the target saturation level. A peripheral vascular line could not be established due to extensive edema in the body, for which an umbilical catheter was inserted and total parenteral nutrition was initiated.
A cranial and abdominal ultrasound revealed normal findings, while an X-ray examination revealed a short tubular bone structure, metaphyseal widening, short ribs, a small chest and a lack of ossification in the pelvis (Figure 2). A blood sample was obtained for genetic analysis with an antenatal pre diagnosis of ACG2. An echocardiography performed on postnatal day 4 revealed pulmonary hypertension and the patient was administered nitric oxide
therapy for 2 days. Respiratory distress persisted in the follow-up period and the patient was followed with HFOV due to carbon dioxide retention with conventional ventilator settings. The patient died of respiratory insufficiency on postnatal day 25.
Paired-end sequencing was performed on a NextSeq 500 system (Illumina, San Diego, CA, USA) with a read length of 150 x 2, while the base calling and image analysis were conducted using Real-Time Analysis (integrated to the NextSeq 500 system; Illumina) software. The BCL (base calls) binary is converted into FASTQ utilizing the Illumina package bcl2fastq.
All bioinformatic analyses were performed on a Sophia DDM™ platform (Sophia Genetics SA), which includes algorithms for alignment, calling single nucleotide polymorphisms (SNPs) and small insertions/deletions (Pepper™, Sophia Genetics SA patented algorithm) calling copy number variations (Muskat™, Sophia Genetics SA patented algorithm) and functional annotations (Moka™, Sophia Genetics SA patented algorithm). The raw reads were aligned to the human reference genome (GRCh37/ hgl9). Variant filtering and interpretations were performed on the Sophia DDM™ platform (Sophia Genetics SA), and an Integrative Genomics Viewer (IGV) was used to visualize the BAM (binary alignment map) files [5]. In families with consanguineous marriages, homozygosity mapping is carried out with HomSI (
In this report, we present a case with a heterozygous missense variation on the
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Dysostoses are constitutional disorders of the bone that take the form of malformations of single or multiple bones in combination. Based on genetic mutations and variations in blastogenesis, they affect normal bone or cartilage development and cause bone defects and skeletal dysplasias [13]. Achondrogenesis comes in three forms, being ACG1A (Houston-Harris type), ACG1B (Parenti-Fraccaro type) and ACG2 (Langer-Saldino), with differential diagnoses made based on clinical, radiological and molecular findings. The various forms of ACG have identical phenotypic characteristics, such as hydrops fetalis, short neck and trunk, small chest (bell-shaped), prominent abdomen and severe micromyelia, which are typically observed in the all three groups, while there are radiological and molecular differences between the three [13]. The skull is not ossified in ACG1A, whereas there are mildly low ossified areas in ACG1B. Skull ossification is normal in ACG2, alongside decreased ossification in the pelvis and spine. Rib fractures are common in ACG1A, whereas short ribs are often without fractures in ACG2 [2, 4, 13]. The present case of ACG2 had typical phenotypic characteristics, including short trunk, small chest, distinctive abdomen and micromyelia, and a radiologic examination revealed short tubular bones with widened metaphyses and non ossified cervical vertebrae, short unfractured ribs, a narrow bell-shaped chest, lack of ossification in the pelvis and normal ossification of the skull (Figures 1 and 2).
Apart from skeletal anomalies, severe pulmonary hy-poplasia occurs in ACG2 due to the underlying defects in collagen expression, and respiratory distress can occur immediately after birth with severe forms of the disorder [2, 14]. The present case had significant respiratory distress immediately after birth, was followed with HFOV due to persistent respiratory distress during mechanical ventilation using conventional settings and the patient died of respiratory insufficiency on postnatal day 25.
In conclusion, we present a patient with ACG2 and a novel mutation on the