CASE PRESENTATION
A female infant was born to a 28-year-old, gravida 4 now para 2 Pashtun mother at an estimated 39 weeks’ gestation. The pregnancy was notable for parental consanguinity but was otherwise uncomplicated. There was consistent prenatal care throughout with normal ultrasound scans and physical examinations. Medical records and detailed history from the mother’s prior pregnancies were unavailable. However, a previous live-born full term sibling of the patient was reportedly “swollen at birth” and died of a “fluid issue” shortly thereafter. The patient has one living older female full sibling with normal growth, health, and development to date (Figure 1A).
The infant was delivered through thick meconium-stained fluids and was hydropic and hypotonic. Diuretic-refractory edema worsened, with severe pitting edema and pleural effusions. After initiation of enteral formula and breast milk feeds on day 4 after birth, pleural effusions progressed, leading to further respiratory compromise necessitating high frequency ventilation by day 8 after birth. Enteral feeds were therefore discontinued; a thoracentesis was performed, and fluid analysis confirmed congenital chylothorax. Following the initial resuscitation, the patient experienced persistent hypotension, requiring maximal vasopressor support and stress-dose steroids to maintain hemodynamic stability. At 18 days after birth, the infant underwent aeromedical evacuation to a center with a higher level of neonatal critical care services.
Following transfer, and for the remainder of her inpatient hospital admission, the infant experienced a complex clinical course primarily affected by severe peripheral and airway edema, chylothoraces, and bone disease. A Tc-99m sulfur colloid lymphoscintigraphy study confirmed severe, diffuse, lymphatic dysplasia (Figure 2). An echocardiogram demonstrated normal cardiac function. The patient was found to have profound lymphopenia and non-hemolytic anemia. Lymphopenia was suspected to be complicated by chylothoraces and resolved following treatment of the chylothoraces with medium chain triglyceride formula followed by prolonged NPO status, octreotide infusion, and thoracostomy tube evacuation. Continued respiratory support was provided with high frequency ventilation to mitigate bilateral pleural effusions and pneumothoraces. Hypoalbuminemia resulted from persistent chylothoraces and was regularly treated with albumin infusions. At approximately six weeks of age, an extubation attempt proved unsuccessful due to persistent facial and airway edema. Tracheostomy was ultimately necessary, and the patient remained on intermittent mechanical ventilation.
Later in the hospital course, atraumatic femur and humerus fractures were incidentally found on plain radiographs, as well as diffuse abnormal bone mineralization. Laboratory evaluation showed normal calcium, phosphorous, 25-hydroxy vitamin D, alkaline phosphatase, urine calcium, urine phosphate, and parathyroid hormone levels. There were no other known genetic causes of bone fragility. A bone biopsy was performed to evaluate for tumoral calcinosis, infectious processes, or other explanations for pathologic fractures (Figure 3). The biopsy revealed abnormal endochondral ossification, failure of trabecular maturation, and absence of zonal maturation of cartilage to bone.
Extensive genetic testing was performed, to include a karyotype and CGH microarray. The karyotype demonstrated a normal female chromosome complement (46, XX). CGH microarray was normal, with no reported loss of heterozygosity, as would be expected when parents are consanguineous. Mitochondrial DNA testing and whole exome sequencing were performed through Medical Neurogenetics. Mitochondrial genome sequencing and deletion analysis as well as depletion studies were normal. Whole exome sequencing detected a homozygous variant of uncertain significance inPIEZO1 , c.2991+7C>T, near the donor splice site of exon 21. Follow up RNA studies revealed altered splicing consistent with a novel splice junction caused by the c.2991+7C>T variant, extending the transcript 5 bases beyond the canonical splice site, predicted to result in frameshift and premature termination of PIEZO1 with loss of more than 1500 amino acids (Figure 1B). The PIEZO1 , c.2991+7C>T variant was subsequently upgraded to likely pathogenic, and we concluded that this variant is responsible for our patient’s phenotype.
Exome sequencing also identified a homozygous variant of uncertain significance in LRP5 , c. 4049T>G, p.Leu1350Arg. The patient’s parents and 2-year-old sibling, with no history of bone fragility, were heterozygous for this variant. Single pathogenic variants in LRP5 are associated with autosomal dominant osteopetrosis, osteosclerosis, and osteoporosis, while biallelic pathogenic variants are associated with autosomal recessive osteoporosis-pseudoglioma syndrome and exudative vitreoretinopathy. The observed variant frequency in South Asian control individuals in the gnomAD database is approximately 22-fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP5 , strongly suggesting the variant is a benign polymorphism found primarily in populations of South Asian origin. We do not think this variant plays any role in our patient’s phenotype.