Common Monogenetic Conditions in Newborns

Pathophysiology

The PKHD1 gene encodes the protein fibrocystin, which is localized to the bile ducts, kidney, and pancreas. Fibrocystin is thought to play a role in primary cilia, which are important in kidney tubule and biliary cell function, and disease is due to loss of fibrocystin function.

Clinical Features

In ARPKD, ultrasounds can identify increased echogenicity and renal size. Prenatal ultrasounds can also detect oligohydramnios, which leads to pulmonary hypoplasia. The oligohydramnios can lead to abnormal facial features, which include low-set ears; flattened facial features, especially the nose; epicanthal folds; and micrognathia. Given the renal and pulmonary abnormalities, systemic hypertension and chronic lung disease are common. ARPKD is characterized by congenital hepatic fibrosis, but its clinical manifestations, including hepatosplenomegaly and portal hypertension, take time to develop. These manifestations sometimes develop as early as infancy but are more commonly seen in childhood.

Evaluation

To establish the ARPKD diagnosis, pathogenic mutations in both copies of the PKHD1 or DXIPIL gene should be present, with renal cystic enlargement and congenital hepatic fibrosis. Although liver biopsies can diagnose ARPKD, noninvasive imaging is preferred. There are numerous mutations in the PKHD1 gene, and to date there is no genotype-phenotype correlation that can help prognosticate the severity of the condition. Mutations in DZIPIL , which encodes a protein involved in ciliogenesis, can be considered if molecular testing for PKHD1 is normal.

Given the risk of pulmonary hypoplasia, monitoring the neonate’s respiratory status is critical. Regular lab work to access renal function and to ensure there are no serious electrolyte abnormalities is also important. Calcium, magnesium, sodium, chloride, potassium, liver function tests (albumin, prothrombin time [PT], and partial thromboplastin time [PTT]), vitamin E, 35-OH vitamin D, and fat-soluble vitamins need to be monitored to evaluate renal and hepatic function.

Management

Treatment is based on clinical presentation. Given the extent of renal and hepatobiliary disease, nephrotoxic agents like aminoglycosides and nonsteroidal antiinflammatory drugs should be avoided. Respiratory distress from pulmonary hypoplasia may require mechanical ventilation. If the neonate has anuria or oliguria, dialysis is likely necessary. Fluid balance is important because dehydration is common. Angiotensin II receptor inhibitors and/or angiotensin-converting enzyme inhibitors are usually first-line treatments for hypertension, and alpha- and beta-adrenoreceptor agonists should be avoided. If the renal disease is severe, erythropoietin-stimulating agents or iron supplements may be needed for anemia. Since the liver can be affected, it is important to monitor the neonate’s nutrition. Bile acid supplementation may be required if biliary dysfunction is significant with low serum levels of fat-soluble vitamins or if magnetic resonance cholangiopancreatography shows significant intrahepatic ductal dilation. Recurrent bacteremia can be a sign of bacterial cholangitis and should be treated aggressively with antibiotics. If portal hypertension is present, sclerotherapy can be used for esophageal varices. If the infant has feeding difficulties, feeding tubes or gastrostomy should be considered. Poor growth can result from chronic kidney disease, and growth hormone may be helpful, but this has not been rigorously demonstrated. Ursodeoxycholic acid can be used to decrease gallstone formation. If the portal hypertension is severe, it is important to immunize against meningococcus, Haemophilus influenzae type B, strep pneumococcus, and other encapsulated bacteria. For chronic lung disease, palivizumab can be beneficial.

A phase 1 clinical trail was completed to assess the effect of the multikinase inhibitor tesevatinib on the progression of renal and hepatobiliary disease in ARPKD. Although the trial is for children 5 to 12 years old, the data may help with the care of neonates in the future. More recently, phase 3 trails are recruiting neonates and children with ARPKD to look at the safety of the vasopressin V2 receptors competitive antagonist Tolvaptan and possible delays in dialysis.

Long-Term Outcomes

Advancements in neonatal resuscitation and management have led to improved survival for neonates with ARPKD. However, mortality is still high, with approximately 30% of individuals dying in the first year from pulmonary complications. If the infant survives the first year, 10-year survival is approximately 82%. However, there is significant morbidity from progressive renal failure and hepatic fibrosis. If the disease is extensive, a renal or renal-hepatic transplantation can be performed.

Pathophysiology

The fibroblast growth factor receptor type 3 ( FGFR3 ) gene produces a protein abundant in chondrocytes, the precursors of cartilaginous bone. FGFR3 is a cell-surface receptor that plays a role in cell proliferation. Achondroplasia is caused by a single mutation (glycine to arginine at amino acid 380) in the FGFR3 gene, which results in the continuous activation of the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase pathway in chondrocytes, which in turn inhibits endochondral ossification.

Clinical Manifestations

Although achondroplasia can be suspected prenatally when shortened long bones are noted on third-trimester ultrasounds, many babies are not diagnosed until after birth. Skeletal findings include rhizomelic (proximal limb) shortening accompanied by redundant skin folds of the extremities and brachydactyly (shortened fingers) that may have a bifurcating appearance of the third and fourth fingers, giving a trident sign. Macrocephaly with frontal bossing and midface hypoplasia are common. A small and abnormally shaped foramen magnum is a notable finding in infants. As part of the skeletal dysplasia, the positioning and length of the Eustachian tube is altered, leading to an increased risk of otitis media. Because of the small chest size, some infants can develop restrictive pulmonary complications. Both central and obstructive sleep apnea can be seen in infants. Thoracolumbar kyphosis is seen in up to 95% of infants with achondroplasia. Lower-extremity bowing secondary to knee instability, internal tibial torsion, and lateral bowing is seen in some individuals. The proportionately large head size leads to delays in gross motor milestones.

Evaluation

Concerns for achondroplasia are normally raised after a thorough infant physical exam or from prenatal ultrasounds. FGFR3 gene mutation testing should be performed to confirm the diagnosis. Normally, a skeletal survey is done to identify characteristic findings such as disproportionate shortening of the long bones, squaring off of the iliac bones, a round-shaped pelvis, flattening of the acetabulum and vertebrae, and sacrosciatic notch narrowing. ^{, ,} It is important to note that if FGFR3 mutation testing for achondroplasia is negative, sequencing the gene may be warranted to rule out milder forms of FGFR3 -­related skeletal dysplasia such as hypochondroplasia ( Table 79.1 ).

Management

Once the diagnosis has been established, neuroimaging should be performed as early as possible to assess the craniocervical junction. Narrowing of this area causes increased mortality in infancy because vertebral arterial and spinal cord compression at the level of the foramen magnum can cause central sleep apnea, high cervical myelopathy, and even sudden death. Although brain computed tomography has standard measurements for the foramen magnum in infants with achondroplasia, brain magnetic resonance imaging (MRI) will give better images of the cervical spinal cord and brainstem. A polysomnography is also recommended to assess for central sleep apnea and hypopnea. Because infants with achondroplasia have small chests and the ribs can have a paradoxical movement with inspiration, the infant can appear to have retractions and respiratory distress during normal respiration. Extraaxial fluid and ventriculomegaly are common in children with achondroplasia. It is also more common for these infants to sweat more that the general population. Therefore these findings alone should not prompt further evaluation. However, rapid increase in head circumference, hyperreflexia, reflex asymmetry, clonus, severe hypotonia, and desaturations to <85% should raise suspicions for increased intracranial pressure or craniocervical compression and should prompt immediate consultation with a pediatric neurosurgeon.

For ongoing management, age- and sex-specific achondroplasia growth charts ensure the infant is growing at the appropriate velocity and not gaining excessive weight, which would exacerbate neurologic and orthopedic complications. ^, Additionally, infants can demonstrate unusual movements called preorthograde movements, which may raise concern in parents but are actually normal in achondroplasia. Given the common thoracolumbar kyphosis, activities that aggravate this, such as unsupported sitting or strollers with poor back support, should be avoided. Infants should be positioned prone during part of the waking day to increase muscle tone. If kyphosis worsens or does not spontaneously resolve when the child starts to walk, referral to a pediatric orthopedic surgeon is warranted to prevent neurologic complications. Because developmental delay is common, specific achondroplasia developmental norms were developed ( Fig. 79.1 ). Given that children with achondroplasia have expressive language delay, treatment of recurrent otitis media is recommended to reduce the possibility of conductive hearing loss. For this reason, audiology exams should be repeated at 1 year old and if any concerns are raised about the child’s hearing.

Because of the short stature, adaptive measures and occupational therapy are encouraged. Limb-lengthening is a surgical procedure to increase height in patients with achondroplasia but is controversial given the burden and complications. Growth hormone has been approved for achondrophasia. It results in increased growth velocity during the first 2 years of treatment, with an additional 3.5 cm in final height in males and 2.8 cm in final height in females, based on a long-term follow-up study.

In 2021, the FDA approved vosoritide, a C-type natriuretic peptide (CNP) analog. Normally CNP inhibits the MAPK signaling pathway, which in turn leads to endochondrial ossification and bone growth promotion. This medication can given as a daily injection in children at least 5 years old until the growth plates close. Studies showed an increased height of 1.57 cm a year.

Long-Term Outcomes

With the management described above, early mortality in infants with achondroplasia has decreased. If there are no neurologic complications, intelligence is normal. ^, Those with achondroplasia have near normal to normal life expectancy. Without intervention, the average height is approximately 131 cm in males and 124 cm in females.