NeoQuest May 2024: Limb Abnormality in a Newborn

An infant born by cesarean delivery has anomalies in his hands and feet (Figure 1). He also has a cone-shaped head with a wide anterior fontanelle, proptosis, hypertelorism, and retrognathia. The infant is found to have a genetic defect.

Figure 1: A. Infant’s left hand. B. (1 and 2) Bilateral feet following delivery. Image from: Das R, Poudel A, Pollack R. Syndactyly in a Newborn. Neoreviews. (2024);25(5):e282–e285.¹

Which of the following diagnoses is caused by a mutation in the same gene affecting this patient?

1. Achondroplasia
2. Crouzon syndrome
3. Fanconi anemia
4. Thanatophoric dysplasia type 1
5. Thanatophoric dysplasia type 2

Answer: B. Crouzon syndrome

Explanation:

The infant described in the vignette presents with bilateral syndactyly of the hands and feet, and  findings suggestive of craniosynostosis (wide anterior fontanelle in the setting of acrocephaly and a prominent forehead). This constellation of findings is pathognomonic for Apert syndrome. Apert syndrome, also referred to as acrocephalosyndactyly, is caused by a mutation of the fibroblast growth factor receptor 2 (FGFR2) gene.^1,2 Of the answer choices listed, Crouzon syndrome (or craniofacial dysostosis) (Option B) is also caused by a mutation of the FGFR2 gene.^1,2

Apert and Crouzon syndromes are characterized by the presence of autosomal dominant FGFR2-related syndromic craniosynostosis commonly involving the coronal sutures and/or multiple cranial sutures, maxillary hypoplasia, and upper airway anomalies including choanal atresia or stenosis (Figure 2).^3,4 In comparison to Crouzon syndrome and other FGFR2-related syndromes, Apert syndrome is uniquely characterized by syndactyly involving complex fusion of at least three digits on each hand and foot resulting in a ‘spade’ or ‘mitten’ deformity (Figure 1A).³ Additionally, patients with Apert syndrome are likely to have moderate-to-severe neurocognitive impairment, while patients with Crouzon syndrome typically have normal cognitive development.³ Table 1 shows a detailed summary of common syndromic craniosynostoses and their hallmark genetic and clinical features.⁵

Table 1: Common syndromic craniosynostoses and associated genetic and clinical features. Table from: Bautista G. Craniosynostosis: neonatal perspectives. Neoreviews. 2021;22(4):e250-e257.⁵ 

Figure 2: A. An infant with Apert syndrome with coronal craniosynostosis, a cone-shaped calvarium (acrocephaly), and hypertelorism. B. Axial paranasal computed tomography demonstrating bone concha hypertrophy and severe obstruction (yellow arrow). Image from: Bozkurt HB, Ermis B, Hafızoğlu T, et al. Hand, foot, cranium and face abnormalities in a newborn. Neoreviews. 2014;15(1):e45–e48.²

Almost all cases of achondroplasia (Option A) are caused by mutations in the transmembrane domain of the FGFR3 gene.⁶ Achondroplasia is inherited in an autosomal dominant pattern; however, 80% of cases are due to a de novo mutation.⁶ Achondroplasia is characterized as a short-limb skeletal dysplasia. Infants with achondroplasia have short stature, macrocephaly, rhizomelic shortening of the upper and lower extremities (Figure 3), and short fingers with the appearance of a trident (all fingers approximately equal in length with a space abutting both sides of the middle finger).^6,7

Figure 3: An infant with rhizomelic shortening of the left femur (blue arrow). Image from: Langston SJ, Krakow D, Chu A. Revisiting skeletal dysplasias in the newborn. Neoreviews. 2021;22(4):e216-e229.⁷

Fanconi anemia (or constitutional aplastic anemia) (Option C) is most commonly caused by a mutation in the FANCA gene; however, more than 20 additional genes are associated with Fanconi anemia.⁸ Fanconi anemia is characterized and diagnosed by increased chromosomal breakage and DNA damage when exposed to DNA cross-linking agents.⁸ Physical findings in Fanconi anemia are variable and can include intrauterine growth restriction, malformations of the radius and thumb (Figure 4), and scoliosis.^8,9 One-third of patients with Fanconi anemia do not present with any physical examination findings.⁸ Laboratory findings include pancytopenia, reticulocytopenia, and hypocellular bone marrow.⁸

Figure 4: An adult patient with Fanconi anemia with bilateral thumb anomalies. Image from: Bishara N, Clericuzio CL. Common dysmorphic syndromes in the NICU. Neoreviews. 2008;9 (1): e29–e38.⁹

Thanatophoric dysplasia (TD) type 1 (Option D) and type 2 (Option E) are short-limb skeletal dysplasias caused by mutations in the extracellular domain of the FGFR3 gene.^7,10 There are two types of TD; both are often lethal in the perinatal period due to narrowing of the thorax causing lung hypoplasia and respiratory failure.^10,11 TD type 1 is characterized by micromelia, bowed femurs, flat vertebral bodies, and macrocephaly with frontal bossing, while TD type 2 is characterized by micromelia, straight femurs, tall vertebral bodies, and moderate-to-severe craniosynostosis with cloverleaf skull deformity.¹¹

Did you know?
Patients with sagittal synostosis, the most common form of craniosynostosis, may require surgical correction as early as 6-12 weeks of age to avoid the need for more complex and extensive calvarial vault remodeling.⁴ Thus, early identification and referral to subspecialty care must be emphasized in the care and management of craniosynostosis. 

What are common secondary causes of craniosynostosis?
To find the answer, please refer to the following article: Bautista G. Craniosynostosis: neonatal perspectives. Neoreviews. 2021;22(4):e250-e257.⁵

NeoQuest May 2024 Authors:

Angelina June MD, FAAP, Fairfax Neonatal Associates, Fairfax, Virginia
Neena Jube-Desai, MD, MBA, FAAP, University of Maryland, Baltimore, Maryland

References

1. Das R, Poudel A, Pollack R. Syndactyly in a Newborn. Neoreviews. (2024);25(5):e282–e285
2. Bozkurt HB, Ermis B, Hafızoğlu T, et al. Hand, foot, cranium and face abnormalities in a newborn. Neoreviews. 2014;15(1):e45–e48
3. Evans KN, Hing AV, Cunningham ML. Craniofacial malformations. In: Avery's Diseases of the Newborn. Philadelphia, PA: Elsevier; 2018
4. Dias MS, Samson T, Rizk EB, et al. Identifying the misshapen head: craniosynostosis and related disorders. Pediatrics. 2020;146(3):e2020015511
5. Bautista G. Craniosynostosis: neonatal perspectives. Neoreviews. 2021;22(4):e250–e257
6. Pereira E. Achondroplasia. Pediatr Rev. 2019;40(6):316–318
7. Langston SJ, Krakow D, Chu A. Revisiting skeletal dysplasias in the newborn. Neoreviews. 2021;22(4):e216-e229
8. Joshi R, Myers E, Kokhanov A. Congenital disorders of red blood cells. Neoreviews. 2022;23(12):e813–e828
9. Bishara N, Clericuzio CL. Common dysmorphic syndromes in the NICU. Neoreviews. 2008;9 (1): e29–e38
10. Del Piccolo N, Placone J, Hristova K. Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization. Biophys J. 2015;108(2):272–278
11. French T, Savarirayan R. Thanatophoric Dysplasia. 2004 May 21 [Updated 2023 May 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024