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.