Patient 1
Full Term male transferred to Nicklaus Children’s Hospital’s neonatal
intensive care unit (NICU) at one week of age for concerns of an
underlying genetic etiology given dysmorphic features, respiratory
insufficiency and feeding difficulties. He was born via C-section from a
pregnancy complicated by intrauterine growth restriction (IUGR) and
clubfeet identified on second trimester ultrasound. At birth, he was
noted to be small for gestational age (SGA) (birth weight near
2nd percentile) and to have a wide posterior
fontanelle, down slanting palpebral fissures, micrognathia with limited
mouth opening; bilateral cryptorchidism; arthrogryposis multiplex
congenita (flexion deformity of wrists and proximal metacarpophalangeal
joints and bilateral talipes equinovarus); bilateral club feet;
Mongolian spot on the right buttock; hypertonia of upper and lower
extremities; weak suck and gag reflexes and; absent rooting and Moro
reflexes. Perinatal course was complicated by feeding difficulties with
nasogastric tube (NG tube) dependence, respiratory distress requiring
invasive respiratory support, apneic episodes and hypoglycemia requiring
treatment with dioxide.
Chest and abdominal x-rays, abdominal ultrasound, and echocardiogram
were reported as normal. Bone survey demonstrated findings consistent
with arthrogryposis, bilateral clubfeet, and eleven ribs. CT scan of the
face revealed a hypoplastic mandible, flattening of the condylar heads,
and bilaterally shallow temporomandibular joint glenoid fossa.
Botox injection was performed to help manage oral secretions at 1 month
of age. Subperiosteal release of the mouth floor was performed at 1
month of age to help with oral feeding and respiration. The patient
failed extubation after the release of the mouth floor. Due to high risk
for aspiration and continued respiratory issues, gastrostomy tube
(G-tube) with fundoplication and tracheostomy were performed at 6 weeks
of life.
In addition to the feeding and respiratory issues, there was suspicion
of partial diabetes insipidus due to persistent hypernatremia and low
urine osmolarityand specific gravity. Brain MRI showed suspicion of
ectopic neurohypophysis but was otherwise normal. The patient also had
episodes of hypoglycemia requiring continuous feeds and treatment with
diazoxide. Insulin, growth hormone, free fatty acids, cortisol, and
β-hydroxybutyrate random levels were unremarkable, although a critical
sample was unable to be collected during hypoglycemic events.
Initial genetic work-up included normal chromosome analysis, chromosome
microarray, spinal muscular atrophy analysis, and Fragile X testing. The
patient and both of his parents were then enrolled in the protocol for
rapid whole genome sequencing (rWGS).