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NeoQuest October 2022: A Term Infant with Hypotonia

October 12, 2022

A one-month-old term male infant presents to the emergency department with bilateral upper extremity weakness. He is awake and alert and has a temperature of 100.6oF (38.1oC).  His exam is concerning for significant head lag with bilateral upper extremity and truncal hypotonia. He has absent bicep, brachioradialis, and tricep reflexes, as well as an absent Moro reflex. He has spontaneous movements of the lower extremities with mild hypotonia and diminished patellar reflexes. Spinal magnetic resonance imaging (MRI) reveals abnormal signal intensities in the thoracic and cervical regions of the spinal cord. Cerebrospinal fluid analysis demonstrates a WBC count of 16/μl with normal glucose and protein levels. A skeletal survey reveals abnormal findings in the long bones (Figure 1).

Figure 1. Diffuse abnormal bone mineralization (yellow arrows) of the (A) right radius, ulna, and humerus; (B) left radius, ulna, and humerus; (C) right tibia, fibula, and femur; and (D) left tibia, fibula, and femur. Image from: Schwemberger R and Priscilla J. Upper extremity hypotonia in a 5-week-old infant. Neoreviews. 23(10): e692–e6951

Which of the following diagnostic evaluations is most likely to confirm the underlying diagnosis:

  1. Electromyography and muscle biopsy
  2. FGFR3 mutation analysis
  3. Methylation-specific polymerase chain reaction testing
  4. Serum parathyroid hormone level
  5. Treponema pallidum particle agglutination assay

Answer: E. Treponema pallidum particle agglutination assay


This infant has signs of myelitis on spinal MRI; long bone periostitis, metaphysitis, and osteitis on skeletal survey (Figure 1); and mild cerebrospinal fluid (CSF) pleocytosis. This constellation of findings should prompt concern for congenital syphilis (CS) and an initial screen with a rapid plasma reagin titer, followed by confirmatory testing with a Treponema pallidum particle agglutination assay (TTPA) (Option E).

CS remains a major public health concern in the United States, and the increasing number of cases of primary and secondary syphilis among women of childbearing age corresponds with increasing CS cases and infant mortality due to CS.2,3 Although two-thirds of neonates with CS are asymptomatic at birth, early CS in children under 2 years of age is characterized by hepatosplenomegaly, lymphadenopathy, mucocutaneous rash, thrombocytopenia, rhinitis (“snuffles”), and bony abnormalities.1,3,4 Radiographic bony abnormalities, such as osteochondritis, periostitis, and metaphysitis are among the most commonly reported manifestations of early CS, occurring in up to 80% of symptomatic infants (Figure 2).4 Pathognomonic radiographic signs include Wimberger sign, defined by the focal destruction of the medial aspect of the proximal tibial metaphyses, and Wegner’s sign, which represents serrations or a “sawtooth” appearance of the metaphysis.4 The infant in this vignette presented with bilateral upper extremity hypotonia, consistent with pseudoparalysis of Parrot, a musculoskeletal manifestation first described by Jules Marie Parrot in 1871 that represents the decreased movement of extremities secondary to painful syphilitic periostitis.1,4

Figure 2. Radiographs of bilateral lower extremities demonstrating metaphyseal lucencies (blue arrows) and periosteal reaction (red arrow) in the long bones of the right lower extremity. Image from: Kwak J, Grady N, and Derrick M. An infant with skeletal abnormalities and facial dysmorphisms. Neoreviews. 2017;18(3):e180-e1834

As hypotonia and weakness in infants may be a manifestation of systemic illness, central nervous system dysfunction, or a disorder of the motor unit, the localization of hypotonia to central or peripheral etiologies can further delineate the cause of hypotonia (Table). This is essential for establishing the differential diagnosis and determining the infant’s prognosis, associated morbidities, and recurrence risk.

Table. Differentiation of central and peripheral hypotonia in the neonate.9

While electromyography/nerve conduction studies and muscle biopsy (Option A) are useful for localizing central and peripheral causes and can differentiate myopathic (eg, dystrophies, myopathies) versus neurogenic (eg, spinal muscular atrophy) processes, the constellation of findings in the infant in this vignette suggests a systemic illness that requires more targeted diagnostic testing.5

The presence of morphologic skeletal abnormalities and hypotonia may elicit concern for skeletal dysplasias or other related musculoskeletal disorders. Skeletal dysplasias can be evaluated by analyzing mutations in FGFR, which negatively affect long bone development by endochondral ossification.6 A gain-of-function mutation in FGFR3 can inhibit chondrogenesis and negatively affect bone mass, as seen in achondroplasia and thanatophoric dysplasia (Option B).6 However, the abnormal signal intensities on spinal MRI and CSF pleocytosis seen in the infant in this vignette are atypical in skeletal dysplasias.

Infants with severe tone abnormalities should also be evaluated for chromosomal disorders, such as Prader-Willi syndrome (PWS), diagnosed by methylation analysis of the chromosome region of 15q11-q13 (Option C). The hallmarks of PWS in the neonatal period are marked hypotonia and feeding difficulties, with other features such as almond-shaped eyes, small hands and feet, and cryptorchidism.7,8 Hypotonia in patients with PWS is often characterized by a central origin, in contrast to the infant in this vignette who had signs of peripheral hypotonia (Table).7,9

Hypotonia may also be seen in infants with bone mineralization defects, such as neonatal hyperparathyroidism (NHPT) (Option D). Infants with NHPT may be asymptomatic at birth but present within days to weeks with failure to thrive, poor feeding, and hypotonia. Severe hypercalcemia occurs, resulting in a progression of skeletal demineralization followed by multiple fractures and thoracic deformities. However, NHPT is unlikely to be associated with abnormalities in the CSF.

Did you know?

  • The World Health Organization estimated that in 2016, 1 million pregnant women had active syphilis infections.3 There are 200,000 fetal and neonatal deaths each year attributable to CS, making CS the second leading cause of preventable stillbirths globally, surpassed only by malaria.3

What are the physical exam maneuvers that assess postural (central) and peripheral tone in a newborn? To learn more about the four standard maneuvers to assess tone in the neonate, refer to: Yozawitz et al. Neonatal hypotonia. Neoreviews. 2018;19(8):e445–e4555

What are common genetic causes of newborns with hypotonia? To learn more about the breadth of molecular and cytogenetic techniques to evaluate hypotonic infants with or without dysmorphisms, refer to: Zand DJ, Zackai EH. Cytogenetic and molecular diagnoses of hypotonia in the newborn. Neoreviews. 2004;5(7):e296–e3008

NeoQuest October Authors
Lila S. Nolan, MD, Washington University School of Medicine
Elizabeth V. Schulz, MD, Uniformed Services University


  1. Schwemberger R, Joe P. Upper extremity hypotonia in a 5-week-old infant. Neoreviews. 2022;23(10): e692–e695
  2. Ghanem KG, Ram S, Rice PA. The modern epidemic of syphilis. N Engl J Med. 2020;382(9):845–854
  3. Easterlin MC, Ramanathan R, De Beritto T. Maternal-to-fetal transmission of syphilis and congenital syphilis. Neoreviews. 2021;22(9):e585–e599
  4. Kwak J, Grady N, Derrick M. Case 1: an infant with skeletal abnormalities and facial dysmorphisms. Neoreviews. 2017;18(3):e180–e183
  5. Yozawitz E, Delfiner L, Moshé SL. Neonatal hypotonia. Neoreviews. 2018;19(8):e445–e455
  6. Langston SJ, Krakow D, Chu A. Revisiting skeletal dysplasias in the newborn. Neoreviews. 2021;22(4):e216–e229
  7. Chandrasekaran P. Case 1: a hypotonic newborn. Neoreviews. 2016;17(6):e334–e335
  8. Zand DJ, Zackai EH. Cytogenetic and molecular diagnoses of hypotonia in the newborn. Neoreviews. 2004;5(7):e296–e300
  9. Sparks SE. Neonatal hypotonia. Clin Perinatol. 2015;42(2):363–371
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