Prenatal Diagnosis of a Lethal Skeletal Dysplasia.

A 20-year-old gravida 1, para 0 pregnant woman with a diagnosis of severe fetal skeletal dysplasia presented to our multidisciplinary fetal therapy clinic for a second opinion and counseling at 36 weeks’ gestation. Her medical history was uncomplicated; she had no prior surgeries. She was taking a daily prenatal vitamin. The patient’s partner was of advanced paternal age (50 years old) and their respective family histories were notable for no congenital anomalies, intellectual disability, or known genetic conditions. Her prenatal laboratory test results were unremarkable, and her pregnancy was dated based on ultrasonography at 5 weeks, 6 days. She underwent initial aneuploidy screening with cell-free DNA with “no result” at approximately 11 weeks of gestation and repeat testing at 16 weeks’ gestation showed low risk for trisomies 13, 18, and 21, and was consistent with a male fetus.Her prior ultrasound reports were reviewed at the time of her consultation at our center. Her 22-week anatomic ultrasound scan was notable for a 3-week lag in both humerus and femur length (FL) measurements and possible clubbed feet. After this ultrasound imaging, she was referred to a local maternal-fetal medicine specialist for further evaluation and consultation at 25 weeks’ gestation. Ultrasonography at that time noted all extremity long bones lagging by 4 to 5 weeks; the femur and humerus lengths measured lower than the 1st percentile. Morphologically, bone ossification appeared normal without bowing, stippling, or fractures. The feet appeared clubbed, and the chest appeared bell-shaped. The FL/abdominal circumference (AC) (0.162) and heart/thoracic ratios (0.5) were at the cusp of concern for a lethal skeletal dysplasia. Fetal echocardiography findings were unremarkable. Follow-up ultrasonography performed at 29 weeks’ gestation by the same maternal-fetal medicine physician noted a thoracic circumference at the 25th percentile and new-onset polyhydramnios, with an amniotic fluid index of 31 cm. Follow-up ultrasonography at 35 weeks’ gestation noted an overall estimated fetal weight at the 13th percentile with a thoracic circumference lower than the 3rd percentile, a markedly bell-shaped chest, and an FL/AC ratio less than 0.16. The fetal head circumference and biparietal diameter measured greater than the 97th percentile and all long bones measured less than the 5th percentile. The patient was counseled on the poor prognosis and significant risk of pulmonary hypoplasia, and she desired a second opinion at our multidisciplinary fetal center.Fetal ultrasound evaluation at 36 weeks 5 days’ gestation at our institution (Fig 1) was notable for the following findings: These findings were highly suggestive of a lethal skeletal dysplasia.Skeletal dysplasia or osteochondrodysplasias include over 450 different conditions that affect bone and/or cartilage development. The approach to suspected skeletal dysplasia in the prenatal setting is multidisciplinary and should include those with experience in these disorders. With the advancement in genomic testing, an underlying molecular diagnosis can be identified in over half of these conditions. (1) Maternal-fetal medicine and fetal imaging specialists must obtain detailed imaging to properly distinguish nonlethal from lethal skeletal dysplasias. Genetic counselors aid in collecting a detailed family history, developing a genetic testing plan, and counseling/educating patients about the results and implications of recurrence. Delivery and postnatal planning for fetuses with skeletal dysplasias should include multidisciplinary discussion with pediatrics, neonatology, and often other pediatric subspecialties such as endocrinology and orthopedics. When imaging findings are suspicious for lethality, pediatric palliative care consultation is imperative.Suspicion for a skeletal dysplasia may be raised at the time of nuchal translucency ultrasonography at 11 to 13 weeks’ gestation. (2)(3) More commonly, the first indication of a skeletal dysplasia is noted at the time of the anatomic survey at 19 to 21 weeks’ gestation. On that ultrasound scan, standard views include an evaluation of the length of the femur and humerus. When suspicion is raised for a skeletal dysplasia, with findings such as shortened femur or humerus, fractures, or abnormal ossification, subsequent evaluation must include measurement of all long bones of the fetus and evaluation of the skull, facial profile, clavicles, scapula, hands, feet, and vertebrae. Sonographic findings of severe shortening in the long bones early in gestation (<24 weeks) suggest a more severe diagnosis.When the suspicion for skeletal dysplasia is high, the next task is to identify fetuses in which this condition is lethal. Clinical teams often rely on both ultrasonographic findings and molecular diagnosis to define lethality. Ultrasonographic findings that suggest lethality include (4)(5): In general, the chest to AC ratio does not differ as gestational age changes, and the mean value is 0.89. (6) The cardiac to chest circumference increases with gestational age, but in general should be less than 0.5; values greater than 0.5 suggest a small thoracic circumference (in cases of skeletal dysplasia) or cardiomegaly and should be investigated further. Finally, the FL to AC ratio is generally only obtained when assessing skeletal dysplasias; this ratio is not used in the routine assessment of fetal growth, and there are no published normalized values across gestational ages. The cutoff value of less than 0.16 for the FL to AC ratio was established in case series when determining lethality in cases of skeletal dysplasia. (7)Our institutional fetal center has experience with lethal skeletal dysplasia and can coordinate postnatal examination, imaging, and molecular testing. We counsel affected families that at the time of birth, the infant’s oxygen exchange is likely to be ineffective because of the high risk of severe pulmonary hypoplasia. For families interested in pursuing resuscitation, we review the initial resuscitation efforts that may be needed including intubation, chest compressions, umbilical line placement, and vasopressor medications and if the infant survives, they may need prolonged hospitalization, tracheostomy, surgical feeding tube, and long-term medical care after discharge. We also discuss that medical interventions may provide days to months of life for fetuses with this lethal disorder. (8)All individuals referred to our fetal center have an opportunity to meet with our board-certified prenatal genetic counselor. This is an invaluable resource; it affords families education in cytogenetic and molecular testing offered for specific prenatal diagnosis and helps coordinate testing specific to each family’s clinical scenario. When a patient is referred at less than 24 weeks’ gestation, an amniocentesis or chorionic villous procedure is recommended. At present, our general approach is to offer chromosome microarray and simultaneously proceed with single gene panel testing, sometimes referred to as a “skeletal dysplasia panel.” In some cases, whole-exome sequencing is performed. For patients who decline invasive testing, we offer the option of postnatal genetic testing with cord blood collected at the time of delivery. In these cases, the postnatal examination and skeletal survey may dictate more specific single gene testing if there is high suspicion for a specific diagnosis. Coordinating this testing and providing results to families offers them a better understanding of the specific diagnosis and risk of recurrence.At our institution, palliative care consultation is an integral part of any severe, life-limiting diagnosis, including those families who choose complete medical intervention/resuscitation after birth. This specialty serves as a bridge of care and provides consistency as families navigate from various medical subspecialties or locations (maternal-fetal medicine, neonatal intensive care, pediatric intensive care, cardiology, surgery, etc). By meeting families early in the prenatal period, palliative care specialists gain insight into the family dynamics, background (socioeconomic status, education, personal experiences), and religious/spiritual beliefs, among other factors. This temporal relationship helps families navigate the complex medical decisions and crossroads that neonates may face in the pre- and postnatal period.When a family has chosen palliative birth, we counsel patients regarding what the delivery room experience will be like. Before induction, our palliative care team offers families a stuffed bear with a digital recording of the fetal heart rate; this can serve as a memento for families in the future. We discuss with patients that we typically consider a cesarean delivery for maternal indications only. After birth, neonates are provided medications as needed (ie, buccal morphine) for comfort and, if the family is interested, assessment from nursing or physician staff. Families are provided bereavement materials; chaplain or spiritual support is offered to those who desire this. Families with young children are often provided age-appropriate reading books to help explain the loss of an expected sibling. Finally, patients are provided with mementos and photographs. Each family’s experience is somewhat unique and predicated on the family dynamic, background, and personal wishes around this difficult process.This patient had been properly counseled at approximately 25 weeks’ gestation regarding the prognosis for this severe skeletal dysplasia. When she presented to our clinic, she was somewhat hopeful that an evaluation by a new team might provide a better prognosis. She met with maternal-fetal medicine, neonatology, and pediatric palliative care specialists. Unfortunately, we confirmed the suspicion of a lethal skeletal dysplasia. We offered counseling regarding full resuscitative efforts, a palliative birth with comfort care, or termination followed by induction of labor, and coordinated genetic testing with postnatal evaluation to provide a specific diagnosis. She opted for an unmonitored, palliative induction following our institutional protocols for term induction of labor. The palliative care team educated the family on what comfort care measures we could provide after a palliative birth. Given the significantly small thoracic circumference and high suspicion for pulmonary hypoplasia, this family was counseled that neonatal survival was expected to be for a few hours after birth with this comfort care approach. The patient had an uncomplicated vaginal delivery at 37 weeks 0 days’ gestation. The neonate survived approximately 2 hours after birth with death attributed to pulmonary hypoplasia.Postmortem skeletal survey radiographs (Fig 2) revealed the following: Fetal cord blood was collected at the time of delivery and sent for microarray and skeletal dysplasia panel. This panel confirmed a diagnosis of type II collagenopathy, with a pathogenic variant identified in the COL2A1 gene. Based on the severe phenotype and dominant-negative glycine substitution, the final diagnosis was achondrogenesis type II. The family was counseled that most cases of achondrogenesis type II are the result of de novo mutations and have some association with advanced paternal age. Parental testing was offered to evaluate for somatic mosaicism. The couple was counseled that even with negative results on parental testing, the recurrence risk could be as high as 5% due to the inability to evaluate for gonadal mosaicism. The family declined further parental testing.Approximately 1 year later, the same patient presented to our fetal therapy center at 16 weeks’ gestation for establishment of care given her prior obstetrical history. This pregnancy was accurately dated with ultrasonography at 6 weeks and 1 day. Ultrasound evaluation revealed an overall growth 8 days less than expected, but long bone measurements were 2 weeks behind. The thoracic circumference measured lower than the 1st percentile (Fig 3). Given the history of a prior pregnancy affected with COL2A1-related achondrogenesis, this was concerning for possible gonadal or somatic mosaicism. The patient declined invasive, diagnostic testing. She opted for expectant management, hoping that follow-up ultrasonography would reveal improved long bone growth. Unfortunately, follow-up imaging at 19 weeks’ gestation showed persistent delay in all long bone growth consistent with a severe skeletal dysplasia. She opted at that point for pregnancy termination. She underwent amniocentesis and feticidal potassium chloride injection at 23 weeks 6 days’ gestation followed by dilation and evacuation. Targeted testing revealed the same pathogenic variant in COL2A1. The patient and her partner both underwent parental testing. This revealed a maternal somatic mosaicism with 20% of lymphocytes carrying this same pathogenic variant.Type II collagen disorders derive from pathogenic variants in the COL2A1 gene. This heterogeneous group of disorders has various phenotypes with a wide spectrum of severity ranging from life-limiting to mild disease or isolated ocular involvement. Type II collagen has 3 identical α1 chains and is the major component of cartilage. These α1 chains form a triple-helical procollagen, which in turn forms a cross-linked extracellular network that adds strength to the connective tissue. (9) Single allele changes caused by point mutations can have a dominant-negative effect, resulting in a loss in the wild-type protein function.With the advent of molecular testing, phenotype-genotype matching in cases of skeletal dysplasia has become more difficult. The classic type II collagenopathies include many phenotypic descriptions that have overlapping features and varying prognosis. The most severe forms of type II collagen diseases include achondrogenesis type II, hypochrondrogenesis, and platyspondylic dysplasia (generally considered lethal in the prenatal or early postnatal period). Other moderately severe phenotypes in the neonatal period include Kniest dysplasia and spondyloepiphyseal dysplasia. Some may present in the childhood or adolescent period (Stickler syndrome type 1). (10) Differentiation between these disorders has traditionally been made with clinical and radiographic examination. However, skeletal dysplasia gene panel testing can offer a specific underlying molecular diagnosis and may avoid clinical examination bias or overlap. Despite this advantage, gene panels cannot include all known genetic variants and thus, may not identify an underlying cause. Panels also have the potential to add cost or a delay in diagnosis. Limitations aside, microarray and simultaneous gene panel testing in the prenatal period is a reasonable approach, given the lack of available phenotype/clinical examination in this period.At this patient’s initial presentation, no genetic testing was conducted, and the diagnosis of a lethal skeletal dysplasia was made based on sonographic features. Based on these findings, specific dysplasias on the differential included thanatophoric dysplasia, achondrogenesis type II, or hypophosphatasia, and less likely, osteogenesis imperfecta (perinatal lethal), campomelic dysplasia, or chondrodysplasia punctata (given the lack of specific sonographic features seen in these diagnoses). When considering these lethal disorders, the correlation between a prenatal sonographic diagnosis and postnatal/molecular diagnosis is excellent, (11)(12) and the accuracy of sonographic findings that predict lethality approaches 97%. However, in our experience, pairing molecular diagnostic testing with detailed prenatal ultrasonography provides a specific diagnosis and targeted reliable information about potential outcomes and expected clinical course.Molecular diagnosis also offers patients information on risk recurrence. Type II collagen disorders are inherited in an autosomal dominant fashion. Most individuals with a severe form (ie, achondrogenesis type II) have a de novo variant as the expected lifespan is perinatal lethal. Regardless, there is wide heterogeneity in this group of disorders and the overall incidence of both somatic and germline mosaicism is not known, with only case reports in the available literature. (13) In this case, identification of the patient as a somatic carrier would have confirmed her recurrence risk as being much higher than less than 1%. Likewise, she would have been counseled on preimplantation genetic testing of the known pathogenic variant to reduce this risk of recurrence.In summary, the ultrasonographic diagnostic accuracy of lethality in a fetus with skeletal dysplasia is highly accurate, which was found to be the case in this patient, and the patient was able to undergo a palliative delivery. She received a molecular diagnosis that was consistent with what was suspected on prenatal imaging. The patient was appropriately counseled on the expected outcome and the need for parental testing, even in cases of de novo gene change after her first affected pregnancy. Parental somatic mosaicism is extremely rare; this case demonstrates the difficult challenges in patients with suspected fetal skeletal dysplasia and highlights the importance of a multidisciplinary approach to imaging, antepartum/postpartum management, and genetic counseling and testing.