Table 2.

Disorders to Consider in the Differential Diagnosis of Holt-Oram Syndrome (HOS)

Disorder/ConditionGene(s) /
Genetic
Mechanism		MOIClinical DescriptionComments
Duane-radial ray syndrome SALL4 AD
  • Uni- or bilateral Duane anomaly
  • Radial ray malformation (e.g, thenar hypoplasia, thumb hypoplasia, aplasia, duplication or triphalangeal thumb, radius hypoplasia or aplasia, shortening & radial deviation of forearms)
  • SALL4 pathogenic variants may rarely cause what appears to be clinically typical HOS (i.e., radial ray malformations & cardiac malformations).
  • Further clinical investigations frequently demonstrate features considered exclusionary of HOS (e.g., renal anomalies, Duane anomaly, sensorineural hearing loss).
Acro-renal-ocular syndrome AD
  • Radial ray malformations
  • Renal abnormalities
  • Ocular coloboma
  • Duane anomaly
Ulnar-mammary syndrome (OMIM 181450) TBX3 AD
  • Primarily involves ulnar ray (e.g., postaxial polydactyly)
  • Breast & nipple hypoplasia & delayed puberty
  • Congenital heart malformations (not commonly observed)
Townes-Brocks syndrome SALL1 AD
  • Triad of: imperforate anus; dysplastic ears (overfolded superior helices & preauricular tags) frequently associated w/sensorineural &/or conductive hearing impairment; & thumb malformations (duplication, hypoplasia, or triphalangeal thumbs)
  • Renal impairment incl ESRD w/or w/out structural abnormalities
  • Congenital heart disease
  • Foot malformations (flat feet, overlapping toes)
  • Genitourinary malformations
  • ID in ~10% of affected persons
Heart-hand syndrome II
(Tabatznik syndrome) 1		Not identifiedAD
  • Type D brachydactyly (shortening of distal phalanx of the thumb ± shortening of 4th & 5th metacarpals)
  • Sloping shoulders
  • Short upper limbs, bowing of distal radii, absence of styloid process of the ulna
  • Cardiac arrhythmias (e.g., supraventricular tachycardia)
  • Mild dysmorphic facial features
  • Mild ID
Heart-hand syndrome III (Spanish type) (OMIM 140450)Not identifiedAD
  • Type C brachydactyly (shortening of the middle phalanges) w/accessory wedge-shaped ossicle on proximal phalanx of index fingers
  • Feet typically more mildly affected
  • Intraventricular conduction defects (e.g., sick sinus syndrome)
Long thumb brachydactyly syndrome (OMIM 112430)Not identifiedAD
  • Symmetric elongation of thumb distal to proximal interphalangeal joint
  • Index finger brachydactyly
  • Clinodactyly
  • Narrow shoulders
  • Secondary short clavicles
  • Pectus excavatum
  • Cardiac abnormality is often a conduction defect.
Heart-hand syndrome, Slovenian type (OMIM 610140) LMNA AD
  • Familial progressive sinoatrial & atrioventricular conduction disease of adult onset w/sudden death
  • Dilated cardiomyopathy
  • Brachydactyly
  • Feet also involved
Fanconi anemia >20 genes 2AR
AD
XL
  • Short stature
  • Abnormal skin pigmentation
  • Malformations of thumbs, forearms, eyes, ears, oral cavity, genitourinary system, heart, gastrointestinal system, central nervous system
  • DD
  • Progressive bone marrow failure w/pancytopenia typically presenting in 1st decade, often initially w/thrombocytopenia or leukopenia
  • Increased risk for malignancy
Thrombocytopenia-absent radius syndrome (TAR)RBM8A 3AR
  • Bilateral absence of radii w/presence of both thumbs
  • Thrombocytopenia (<50 platelets/nL), generally transient
Other findings in TAR, (esp hematologic & neurologic) & frequent involvement of lower limbs differentiate TAR from HOS.
22q11.2 deletion syndrome (del22q11.2)Deletion of 22q11.2 DGCRAD
  • Congenital heart disease
  • ~6% of persons exhibit upper-extremity anomalies incl pre- & postaxial polydactyly, which may → misdiagnosis of HOS.
Other features in del22q11.2 incl palatal abnormalities (69%), learning difficulties (70%-90), & immune deficiency (77%), distinguish del22q11.2 from HOS.

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DGCR = DiGeorge chromosome region; ESRD = end-stage renal disease; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.
2.

Genes known to be associated with Fanconi anemia: BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2

3.

The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.

From: Holt-Oram Syndrome

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