Table 3.

Genes and Disorders of Interest in the Differential Diagnosis of Smith-Lemli-Opitz Syndrome

Gene(s)Differential Diagnosis DisorderMOIClinical Features of Differential Diagnosis Disorder
Overlapping w/SLOSDistinguishing from SLOS
B9D1
B9D2
CC2D2A
CEP290
KIF14
MKS1
NPHP3
RPGRIP1L
TCTN2
TMEM107
TMEM216
TMEM231
TMEM67
Meckel syndrome (OMIM PS249000)ARPolydactyly
  • Cystic renal disease
  • Encephalocele
BRAF
KRAS
LZTR1
MAP2K1
NRAS
PTPN11
RAF1
RIT1
SOS1
Noonan syndrome AD
AR 1
  • Broad posterior neck
  • Growth restriction
  • Hypospadias
  • Downslanting palpebral fissures
  • Pulmonic stenosis
DHCR24 Desmosterolosis (OMIM 602398)AR
  • Sterol metabolic disorder
  • Ambiguous genitalia
  • Cleft palate
  • Microcephaly
  • Total anomalous pulmonary venous drainage
  • Generalized osteosclerosis
  • Gingival nodules
  • Hypoplastic nasal bridge
  • Macrocephaly 2
  • Short limbs
  • Thick alveolar ridges
EBP MEND syndrome (OMIM 300960) or chondrodysplasia punctata-2 (CDPX2)XL
  • Sterol metabolic disorder
  • Midface hypoplasia
  • Narrow forehead
  • Ptosis
  • 2-3 toe syndactyly
  • Postaxial polydactyly
  • 4-5 finger syndactyly
  • Camptodactyly
  • Scoliosis
  • Hypopigmentation of the skin
FDFT1 Squalene synthase deficiency 3AR
  • 2-3 toe syndactyly
  • DD & ID
  • Facial dysmorphism
  • Genital abnormalities
  • Structural brain malformations
  • Congenital heart defects
  • Autism
  • Normal 7-DHC
  • ↑ plasma farnesol
  • Urine organic acids profile w/↑s in: methylsuccinate; mevalonate lactone; saturated & unsaturated branched-chain dicarboxylic acids
GLI3 Pallister-Hall syndrome ADPolydactylyHypothalamic hamartoblastoma
SC5D Lathosterolosis (OMIM 607330)AR
  • Sterol metabolic disorder
  • Cleft palate
  • 2-3 toe syndactyly
  • Hepatic steatosis
  • Microcephaly
  • Narrow forehead
Hematologic anomalies

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GC-MS = gas chromatograph-mass spectroscopy; ID = intellectual disability; MOI = mode of inheritance; SLOS = Smith-Lemli-Opitz syndrome; XL = X-linked

1.

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.

2.

Desmosterolosis may be associated with macrocephaly or microcephaly.

3.

Squalene synthase deficiency is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to Smith-Lemli-Optiz syndrome.

From: Smith-Lemli-Opitz Syndrome

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