Table 3.

Disorders to Consider in the Differential Diagnosis of Au-Kline Syndrome

Gene(s)DisorderMOIClinical Features of Disorder
Overlapping w/AKSDistinguishing from AKS
KDM6A
KMT2D 		Kabuki syndrome AD
XL 1
  • Postnatal growth deficiency
  • Congenital heart defects
  • Genitourinary anomalies
  • Elongated palpebral fissures, large, prominent ears, cleft palate, & dental anomalies
  • ID (mild to moderate)
  • Skeletal anomalies
  • Arched & broad eyebrows; short columella w/depressed nasal tip 2
  • Cleft lip or lip pits
  • Immunodeficiency
  • Craniosynostosis is rare.
BRAF
KRAS
LZTR1
MAP2K1
MRAS
NRAS
PTPN11
RAF1
RASA2
RIT1
RRAS2
SOS1
SOS2 		Noonan syndrome AD
AR 3
  • Short stature
  • Genitourinary anomalies; cryptorchidism in males
  • Coarse facial features
  • Ptosis
  • Prenatal cystic hygroma or ↑ nuchal translucency
  • Absence of typical AKS facial gestalt 4
  • DD of variable degree 5
  • Hypertrophic cardiomyopathy
  • Coagulation abnormalities
  • Myelodysplasia
GPC3
GPC4 		Simpson-Golabi-Behmel syndrome type 1 XL
  • Coarse facial features & macroglossia
  • ID (mild to severe)
  • Postaxial polydactyly
  • Supernumerary nipples
  • Vertebral anomalies
  • Absence of typical AKS facial gestalt 4
  • Typically affects males
  • Pre- & postnatal overgrowth
  • Polyhydramnios
  • Macrostomia
SKI Shprintzen-Goldberg syndrome AD
  • Aortic dilatation
  • Sagittal craniosynostosis, shallow orbits, palate abnormalities, &/or bifid uvula
  • ID (mild to moderate)
  • Skeletal anomalies
  • Absence of typical AKS facial gestalt 4
  • Marfanoid body habitus
  • Arachnodactyly & camptodactyly

AD = autosomal dominant; AKS = Au-Kline syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

KMT2D-related Kabuki syndrome is inherited in an autosomal dominant manner; KDM6A-related Kabuki syndrome is inherited in an X-linked manner.

2.

Shallow orbits, coarse features, broad nasal ridge, open, downturned mouth with macroglossia, and a deeply grooved tongue would be more suggestive of AKS.

3.

Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.

4.

See Clinical Description, Craniofacial.

5.

Individuals with AKS caused by loss-of-function HNRNPK variants typically have moderate-to-severe intellectual disability.

From: Au-Kline Syndrome

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