Table 3.

Disorders to Consider in the Differential Diagnosis of Phelan-McDermid Syndrome

Differential DisorderGene / Genetic MechanismMOIClinical Features of the Differential Disorder
Overlapping w/Phelan-McDermid syndromeDistinguishing from Phelan-McDermid syndrome
Prader-Willi syndrome See footnote 1.
  • Neonatal hypotonia
  • Feeding difficulty
  • Intellectual deficit
  • Strabismus
  • ↑ appetite w/significant weight gain
  • Dolichocephaly, narrow bitemporal diameter
  • Almond-shaped eyes, strabismus
  • Small-appearing mouth w/thin upper lip & down-turned corners
  • Small hands & feet
  • Hypernasal speech, weak or squeaky cry in infancy
  • Hypogonadism

Angelman syndrome

See footnote 2.
  • Infantile hypotonia
  • DD
  • Absent speech
  • Unsteady gait
  • Minor dysmorphic features
  • Microcephaly w/flat occiput
  • Ataxia
  • Paroxysmal laughter, easily excitable
Velocardiofacial syndrome (See 22q11.2 Deletion Syndrome.)22q11.2 deletionAD
  • Hypotonia
  • Epicanthal folds
  • Narrow palpebral fissures
  • Broad nasal root
  • Speech delay
  • Renal abnormalities
  • DD
  • Cardiac defects
  • Palatal defects
  • Immune deficiency
  • Hypocalcemia
  • Milder neurologic signs
Williams syndrome 7q11.23 deletion 3AD
  • Hypotonia
  • DD
  • Puffy eyelids
  • Cardiovascular anomalies 4
  • Endocrine abnormalities 5
Trichorhinophalangeal syndrome TRPS1
8q23.3q24.11 deletion 6		AD
  • Hypotonia
  • Intellectual deficit
  • Bulbous nose
  • Large or prominent ears
  • Deep-set eyes
  • Thin hypoplastic toenails
  • Multiple cartilagineous exostoses
  • Redundant skin
  • Prominent philtrum, thin upper lip, sparse hair, small jaw
  • Growth restriction
Smith-Magenis syndrome RAI1
17p11.2 deletion 7		AD 8
  • Hypotonia
  • Speech delay
  • Psychomotor retardation
  • Flat midface
  • ↓ sensitivity to pain
  • Inattention & hyperactivity
  • Distinctive facial features
  • Behavioral abnormalities 9
Fragile X syndrome (See FMR1-Related Disorders.) FMR1 XL
  • Hypotonia
  • Speech delay
  • Autistic-like behavior
  • DD
  • Large head, long face, prominent forehead & chin, protruding ears
  • Connective tissue findings (joint laxity)
  • Large testes (post-pubertally)
FG syndrome (See MED12-Related Disorders.) MED12 XL
  • Hypotonia
  • ID
  • Delayed speech
  • Autistic-like behavior
  • Gastroesophageal reflux
  • Intestinal/anal atresia
  • Chronic constipation
  • Short stature
  • Vertebral malformations
  • Simple low-set ears
  • Characteristic personality traits incl outgoing, talkative, & impulsive behavior
Sotos syndrome NSD1 AD
  • Neonatal hypotonia & difficulty feeding
  • Mild ID
  • Delays in motor development
  • Dysmorphic features incl dolicocephaly, pointed chin, large hands
  • Autistic-like behavior
  • Receptive language skills more advanced than expressive language skills
  • Attention deficit disorder &/or aggressiveness
Affected children become more similar to their peers w/age.
Clark-Baraitser syndrome (OMIM 300602)UnknownXL 10
  • ID
  • Thick hands & feet
  • Absence of hypotonia
  • Obesity
  • Macroorchidism

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

PWS is caused by an absence of expression of imprinted genes in the paternally derived PWS / Angelman syndrome (AS) region (i.e., 15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy (UPD) 15, and, rarely, an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region. The risk to sibs is typically less than 1% if the affected child has a deletion or UPD, up to 50% if the affected child has an imprinting defect, and up to 25% if a parental chromosome translocation is present.

2.

Angelman syndrome is caused by disruption of maternally imprinted UBE3A located within the 15q11.2-q13 Angelman syndrome / Prader-Willi syndrome (AS/PWS) region. The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or UPD, and as high as 50% for probands with an ID or a pathogenic variant of UBE3A3.

3.

Williams syndrome is caused by a recurrent 7q11.23 contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (ELN).

4.

Cardiovascular anomalies in Williams syndrome: elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, and hypertension.

5.

Endocrine abnormalities in Williams syndrome: hypercalcemia, hypercalciuria, hypothyroidism, and early puberty

6.

TRPS I is associated with a heterozygous pathogenic variant in TRPS1; TRPS II is associated with a contiguous 8q23.3q24.11 deletion that spans the TRPS1-EXT1 interval.

7.

SMS is caused by an interstitial deletion of 17p11.2 or pathogenic variants in RAI1.

8.

Virtually all occurrences are de novo.

9.

Behavioral abnormalities in SMS: significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors.

10.

X-linked inheritance is presumed.

From: Phelan-McDermid Syndrome

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