Considering and making a genetic diagnosis early can help direct evaluation and management in the newborn, leading to better patient care.
Significant renal disease and subsequent pulmonary disease are common in autosomal recessive kidney disease, requiring supportive care.
Newborns with achondroplasia should have specific imaging and studies to decrease the risk of neurocervical junction compromise.
RASopathies should be considered in newborns with cardiac abnormalities (pulmonary valve stenosis, hypertrophic cardiomyopathy) and certain facial characteristics; gene panel testing is recommended given the phenotypic overlap of many of the conditions.
Tuberous sclerosis complex can be diagnosed prenatally and in the newborn, requiring monitoring and management of seizures to decrease morbidity and mortality.
Spinal muscular atrophy is now on newborn screening panels in many states and has approved medications and gene therapy that will change the natural history of this condition.
Many newborns with congenital myotonic dystrophy type 1 require respiratory and nutritional support in the first year of life.
Genetic conditions involving aneuploidy (trisomy 21, trisomy 18, trisomy 13) are commonly considered in an infant with multiple congenital anomalies or dysmorphic features. Genetic syndromes caused by pathogenic changes in a specific gene or set of genes may have more subtle findings in the newborn period and could be overlooked. Although the conditions are easier to recognize as the patient gets older, considering them in the differential diagnosis during the neonatal period is essential to directing appropriate management. Establishing a genetic diagnosis can lead to more efficient use of resources and proper care for the neonate.
Autosomal Recessive Polycystic Kidney Disease
Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common causes of neonatal cystic kidneys, with an incidence of 1 in 20,000 live births. There is wide variability in disease severity in the newborn period.
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.
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.
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.
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.
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.
Achondroplasia is the most common skeletal dysplasia, with an incidence of 1 in 25,000 to 30,000 live births. This autosomal-dominant disorder has 100% penetrance.
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.
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.
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 ).
|Features of Achondroplasia and Hypochondroplasia|
|Macrocephaly||Present in both but generally more severe in achondroplasia|
|Rhizomelic limb shortening|
|Redundant skin folds in the arms and legs|
|Craniocervical junction problems||More common||Less common|
|Intelligence||Normal intellect||Some have cognitive problems|
|Seizures||Less common||More common |
p.Asn540Lys > p.Lys650Asn
|Temporal lobe dysgenesis||Less common||More common |
p.Asn540Lys > p.Lys650Asn
|FGFR3 mutation in chromosome 4p16.3||Substitution of glycine to arginine (p.Gly380Arg) |
> 80% of cases are de novo mutations
|Substitution of asparagine to lysine |
Substitution of lysine to asparagine (p.Lys650Asn)—less common
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.
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.
RASopathies describe a group of genetic conditions that affect the RAS/MAPK pathway. Combined, the RASopathies affect 1 in 1000 individuals.
The Ras/MAPK pathway is a signal transduction pathway. Mutations in genes in the Ras/MAPK pathway directly or indirectly lead to genetic disorders that are grouped as RASopathies ( Fig. 79.2 ). A particular RASopathy can be caused by mutations in one of several genes. Similarly, different mutations in a single gene can lead to different RASopathies ( Table 79.2 ).
The PTPN11 gene produces a protein tyrosine phosphatase known as SHP2. Mutations in specific domains of the protein can cause SHP2 to constitutively activate signaling of the Ras/MAPK pathway. The SOS1 gene helps keep Ras inactive. Mutations in the SOS1 gene disrupt this inhibition, which in turn increases active Ras. The RAF1 gene encodes the protein CRAF, which has a binding, phosphorylation, and kinase domain; a mutation affecting the kinase domain increases Ras signaling. Mutations in the PTPN11 and SOS1 genes account for the majority of Noonan syndrome cases. Mutations in the PTPN11 and RAF1 genes account for most cases of Noonan syndrome with multiple lentigines. Specific mutations in the HRAS gene in exon 2 cause the protein GTPase HRas to remain active and increase Ras/MAPK signaling, causing Costello syndrome. The BRAF , MAP2K1 , and MAP2K2 genes make up proteins involved in the MAPK signaling pathway, and most mutations in these genes cause cardio-facio-cutaneous (CFC) syndrome by increasing kinase activity, which leads to increased MAPK pathway activation.
Because the RASopathies affect the same pathway, these genetic conditions have overlapping dysmorphic features and clinical manifestations ( Table 79.3 ). Prenatally, cystic hygroma or increased nuchal translucency is commonly seen. Polyhydramnios is another typical prenatal ultrasound finding. Postnatally, individuals with RASopathies have unifying craniofacial characteristics. Eyes can be hyperteloric (widely spaced) with downward slanting palpebral fissures, epicanthal folds, and ptosis. Ears can be low set and posteriorly rotated, whereas the neck is often short with redundant skin and a lower posterior hairline. Facial features can be milder or coarser, depending on the specific RASopathy. Congenital heart conditions, specifically pulmonary valve stenosis, hypertrophic cardiomyopathy, and ventricular septal defects, are common. Pectus abnormalities, wide-spaced nipples, cryptorchidism, hypotonia, and feeding difficulties can be observed. There is a spectrum of developmental delay, learning disabilities, and intellectual disability in these conditions. Approximately 50% of patients with CFC develop seizures, often starting in infancy. Although most cases develop after infancy, dermatologic manifestations can help distinguish between the various RASopathies. An exception is seen in Costello syndrome, with deep palmar creases and ulnar deviation of the fingers notable at birth.
|Prenatal||Cystic hygroma; nuchal translucency; polyhydramnios|
|Wrist ulnar deviation|
|Craniofacial||Hypertelorism, downward slanting palpebral fissures, ptosis |
Low-set, posteriorly rotated ears
|Cardiac||Pulmonary valve stenosis; hypertrophic cardiomyopathy; arrythmia|
|Chest||Widely spaced nipples; pectus abnormality|
|GI||Feeding issues (resolve with time)||Feeding issues|
|Renal||Mild structural change|
|Developmental delay |
|Mild intellectual disability||Developmental delay |
|ENT/audiology||SNHL||Recurrent otitis media|
|Orthopedics||Short stature||Fingers: ulnar deviation|
|Dermatologic||Follicular keratosis||Lentigines |
Café au lait
Deep crease on palms and soles
|Sparse hair |
A multigene panel analyzing genes associated with the Ras/MAPK pathway is the preferred method for diagnosing a RASopathy. Once a specific diagnosis is made, an echocardiogram and renal ultrasound should be performed to evaluate for structural abnormalities. Abnormalities in the neurologic exam may warrant a brain MRI to rule out structural abnormalities. If hypotonia leads to feeding difficulties, an endocrinology evaluation should be initiated to assess for growth hormone deficiency as an etiology for failure to thrive. Individuals with Noonan syndrome need to be screened for coagulopathy with a CBC, PT, and PTT.
Management guidelines have been established for many of the RASopathies. There are specific growth charts for Noonan syndrome and Noonan syndrome with multiple lentigines. Decreased growth velocity warrants an endocrinology evaluation for growth hormone deficiency. A feeding evaluation is advised if there is poor weight gain in the first 2 years. Most infants with Costello syndrome have severe feeding issues that require a nasogastric tube or a gastrostomy tube. If hypotonia is present, evaluations for developmental services are important. Developmental services are especially important with Costello syndrome because developmental delay and intellectual disability are nearly always present. Given that 50% of CFC individuals develop seizures, an electroencephalogram would be performed to assess for seizures.
With Noonan syndrome, if untreated, final height will be less than the third percentile. With growth hormone, final height is increased. Individuals with Costello syndrome have an increased risk of tumors (15%) including rhabdomyosarcoma and neuroblastoma. Although transitional cell bladder carcinoma is normally seen in adults, it can be seen in preteens and adolescents.
Tuberous Sclerosis Complex
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder with variable expressivity that affects multiple organ systems. The incidence is 1 in 6000 live births.
The TSC1 and TSC2 genes produce the proteins hamartin and tuberin, respectively, which form a heterodimer. This heterodimer complex inhibits the mTOR pathway, which is known to regulate cell growth, proliferation, metabolism, survival, aging, memory, and immunity. Therefore pathogenic mutations in either the TSC1 or TSC2 gene disrupt the heterodimer and lead to increased mTOR pathway activity, which then causes abnormal cell proliferation and overgrowth.
Many features of TSC can be seen prenatally or within the neonatal period. Cardiac rhabdomyomas are the common initial manifestation and can be detected prenatally as early as 20 weeks’ gestational age. These rhabdomyomas can grow throughout gestation and typically regress after birth. Hypomelanotic macules, also known as “ash leaf spots,” are another common finding in infants. The combination of cardiac rhabdomyomas and hypomelanotic macules are observed in 85% of infants with TSC. Cortical dysplasias (tubers and white-matter abnormalities in the brain) and subependymal nodules (benign tumors that arise from the ependymal cells lining the lateral and third ventricles) are reported in 94% and 90% of TSC1 and TCS2, respectively. Given the structural brain abnormalities, seizures are commonly seen in TSC, including infantile seizures and focal epilepsy. Renal cysts and angiomyolipomas are benign but can increase in number and size over the individual’s life span and can lead to increased morbidity and mortality (see long-term outcomes). Retinal hamartomas (plaque-like lesions) are normally asymptomatic.
Over time, more skin findings develop ( Table 79.4 ) in almost every patient with TSC. Small 1- to 3-mm hypopigmented macules called “confetti” lesions are common on the extremities. Facial angiofibromas are usually symmetric over the face, appearing before 5 years old. Shagreen patches are raised yellow-brown hamartomas normally found on the torso, commonly in the lumbosacral area, and develop during the childhood or preteenage years. Periungual and subungual fibromas develop in the preteenage years along the proximal nail folds and can often disrupt nail growth.
|Genetic diagnostic criteria|
|Clinical diagnostic criteria|
|Diagnostic Criteria||Age of Onset||Diagnostic Modalities|
|Cortical dysplasias||Appear prenatally or at birth||Standard: Brain MRI with and without gadolinium|
|Subependymal giant cell astrocytoma||Appear prenatally or at birth||Alternatives: Head CT or head US (suboptimal results compared with MRI)|
|Also commonly seen during childhood or adolescent period|
|Cardiac rhabdomyoma||Appear prenatally or at birth||Echocardiogram (Echo)|
|≥3 Hypomelanotic macules at least 5 mm in diameter||At birth or during infancy||Physical exam|
|≥3 Angiofibromas or fibrous cephalic plaque||Appear starting 2–5 years old; increase in size and number during adolescence|
|Multiple retinal hamartomas||May appear in young children||Ophthalmologic evaluation|
|Shagreen patch||Appear in the first decade of life||Physical exam|
|≥2 Ungual fibromas||Usually appear during adolescence/adulthood|
|Lymphangioleiomyomatosis||Usually found in adults||Baseline pulmonary function test, 6-minute walk test, high-resolution CT scan, serum vascular endothelial growth factor type D (VEGF-D) level for patients ≥18 years of age|
|≥2 Angiomyolipomas||Standard: Abdomen MRI|
|Alternatives: Abdomen CT or abdomen US (suboptimal results compared with MRI)|
|“Confetti” skin lesions||Usually found in adults||Physical exam|
|>3 Dental enamel pits||Usually found in adults|
|≥2 Intraoral fibromas||Fibromas in the gingiva, oral mucosa, and tongue|
|Usually found in adults|
|Retinal achromic patch||Rare, with incidence of 1/20,000 of the general population||Ophthalmologic evaluation|
|Multiple renal cysts||May be seen in patients with TSC1 or TSC2 mutations, or in patients with contiguous deletion of the TSC2 and PKD1 genes||Standard: Abdomen MRI|
|Alternatives: Abdomen CT or abdomen US (suboptimal results compared with MRI)|